bluuebunny/crossref_metadata_2025 huggingface dataset:
Application of the PDCA cycle for standardized nursing management in sepsis bundles
Authors: Liu Chunxia , Liu Yun , Tian Yiqing , Zhang Kun , Hao Guizhen , Shen Limin , Du Quansheng
Published: February 2022

Background

To explore the application effect of plan, do, check and action circulation management mode in improving the compliance of sepsis bundle treatment.

Methods

113 patients with sepsis admitted from January 1 to December 31, 2018 were selected as the control group, and the bundle treatment measures of sepsis were routinely implemented. The above treatment measures were completed within 6 h. 113 patients with sepsis admitted from January 1 to December 31, 2019 were selected as the study group. All clinical staff took the same measures as the control group, supplemented by PDCA cycle management. Objective to compare the changes of compliance of clinical staff to sepsis bundle treatment before and after the implementation of PDCA cycle management.

Results

Compared with the control group, the study group achieved the completion rate of sepsis bundle treatment in 1 h from 66.4 to 81.4%, the completion rate in 3 h from 77.0 to 89.4%, and the completion rate in 6 h from 82.3 to 95.6%. The difference was statistically significant (P < 0.05 for all).

Conclusions

The implementation of PDCA cycle management mode can effectively improve the compliance of clinical staff to the bundle treatment of sepsis, improve the treatment efficiency of sepsis, and improve the quality of medical care.
Indicators of suboptimal response to anti-tumor necrosis factor therapy in patients from China with inflammatory bowel disease: results from the EXPLORE study
Authors: Li Ji , Liu Zhanju , Hu Pinjin , Wen Zhonghui , Cao Qian , Zou Xiaoping , Chen Yan , Wang Yingde , Zhong Jie , Shen Xizhong , Demuth Dirk , Fadeeva Olga , Xie Li , Chen Jun , Qian Jiaming
Published: February 2022

Background

Prevalence of inflammatory bowel disease (IBD) is increasing in China. The EXPLORE study evaluated the incidence and indicators of suboptimal responses to first-line anti-tumor necrosis factor (TNF) in patients with ulcerative colitis (UC) or Crohn’s disease (CD). We present results for the mainland China subgroup.

Methods

A retrospective chart review was performed in adults with IBD at 10 centers in mainland China who initiated anti-TNF therapy between 01 March 2010 and 01 March 2015. The cumulative incidence of suboptimal response to first-line anti-TNF therapy was assessed over 24 months using the Kaplan–Meier method. Indicators of suboptimal response were: dose escalation, discontinuation, augmentation with non-biologic therapy, or IBD-related surgery/hospitalization. At site initiation, a survey was conducted with participating physicians to identify barriers to anti-TNF use.

Results

Of 287 patients (72% male) examined, 16/35 (45.7%) with UC and 123/252 (48.8%) with CD experienced a suboptimal response to first-line anti-TNF therapy at any point during the observation period (median 27.6 and 40.0 months, respectively). At 1 and 2 years post anti-TNF initiation, the cumulative incidence of suboptimal response was 51.4% and 75.7% for UC and 45.4% and 57.0% for CD, respectively. Median time to first suboptimal response was 7.2 months for UC and 14.3 months for CD. The most frequent indicator of suboptimal response was discontinuation of anti-TNF therapy (9/16, 56.3%) for UC and IBD-related hospitalization for CD (69/123, 56.1%) followed by augmentation with non-biologic therapy for both cohorts (5/16, 31.3% for UC and 28/123, 22.8% for CD). Dose escalation was the least frequent indicator of suboptimal response to anti-TNF therapy (CD: 4/123, 3.3%; UC: not cited as an indicator). The cumulative incidence of suboptimal response within 4 months of first-line anti-TNF therapy (primary non-response) was over 30% in both cohorts. Financial reasons and reimbursement were identified by surveyed physicians as the most common barriers to prescribing an anti-TNF therapy.

Conclusions

Over one-half of patients with IBD are at risk of experiencing a suboptimal response to first-line anti-TNF therapy at 2 years post-initiation in China. This study highlights a substantial unmet need associated with anti-TNF therapies in China. (Clinicaltrials.gov identifier: NCT03090139).
Physical activity level and associated factors among adult HIV patients in Ethiopia
Authors: Tegene Yadessa , Mengesha Selamawit , van der Starre Caroline , Lako Stephanie , Toma Alemayehu , Spigt Mark
Published: February 2022

Background

People living with HIV, who take antiretroviral therapy (ART), often enjoy long and healthy lives, but this therapy has well known metabolic adverse effects. Physical activity is found to be an important factor in improving these physiological parameters. This study aimed to determine physical activity level and associated factors among HIV patients in Ethiopia.

Methods

An institutional based cross sectional study was conducted from May to June 2019. We selected a total of 422 adult HIV patients, attending antiretroviral therapy clinics in three selected hospitals in Southern Ethiopia. Data were collected at routine care consultations by nine trained nurses using a pre-tested structured questionnaire. The level of physical activity was measured by the international physical activity questionnaire (IPAQ).

Result

The mean age of participants was 38.7 ± 9.13 years. Of the participants, 68% were physically inactive, with a higher proportion of inactive women (74%) than men (61%) [(AOR = 1.64, 95% CI (1.07, 2.53)]. In addition, urban vs. rural residents [(AOR = 2.57, 95% CI (1.16, 5.72)] and patients who were on ART for ≥ 24 months [(AOR = 1.88, 95% CI (1.15, 3.08)] had higher odds of having a low physical activity level.

Conclusion

Most people living with HIV and receiving ART have low physical activity levels. Especially female and urban living patients and those with longer treatment duration have low levels of physical activity. More insight is needed on the reasons for physical inactivity among HIV patients and physical activity programs for HIV patients in low-income countries need to be developed.
Color-coded summation images for the evaluation of blood flow in endovascular aortic dissection fenestration
Authors: Augustin Anne Marie , Wolfschmidt Franziska , Elsässer Thilo , Sauer Alexander , Dierks Alexander , Bley Thorsten Alexander , Kickuth Ralph
Published: February 2022

Background

To analyze the benefit of color-coded summation images in the assessment of target lumen perfusion in patients with aortic dissection and malperfusion syndrome before and after fluoroscopy-guided aortic fenestration.

Methods

Between December 2011 and April 2020 25 patients with Stanford type A (n = 13) or type B dissection (n = 12) and malperfusion syndromes were treated with fluoroscopy-guided fenestration of the dissection flap using a re-entry catheter. The procedure was technically successful in 100% of the cases and included additional iliofemoral stent implantation in four patients. Intraprocedural systolic blood pressure measurements for gradient evaluation were performed in 19 cases. Post-processed color-coded DSA images were obtained from all DSA series before and following fenestration. Differences in time to peak (dTTP) values in the compromised aortic lumen and transluminal systolic blood pressure gradients were analyzed retrospectively. Correlation analysis between dTTP and changes in blood pressure gradients was performed.

Results

Mean TTP prior to dissection flap fenestration was 6.85 ± 1.35 s. After fenestration, mean TTP decreased significantly to 4.96 ± 0.94 s (p < 0.001). Available systolic blood pressure gradients between the true and the false lumen were reduced by a median of 4.0 mmHg following fenestration (p = 0.031), with significant reductions in Stanford type B dissections (p = 0.013) and minor reductions in type A dissections (p = 0.530). A moderate correlation with no statistical significance was found between dTTP and the difference in systolic blood pressure (r = 0.226; p = 0.351).

Conclusions

Hemodynamic parameters obtained from color-coded DSA confirmed a significant reduction of TTP values in the aortic target lumen in terms of an improved perfusion in the compromised aortic region. Color-coded DSA might thus be a suitable complementary tool in the assessment of complex vascular patterns prevailing in aortic dissections, especially when blood pressure measurements are not conclusive or feasible.
A score of non-contrast transthoracic echocardiography to screen patent foramen ovale in patients with embolic stroke of undetermined source
Authors: Zhang Hui , Tang Haiyan , Wu Fei , Yu Chun , Dong Qiang , Cao Wenjie
Published: February 2022

Background

The aim of this study was to develop a screening score system of non-contrast transthoracic echocardiography (TTE) for patent foramen ovale (PFO) in patients with embolic stroke of undetermined source (ESUS).

Methods

We performed a retrospective analysis of 218 consecutive patients with a recent ESUS from 2015 to 2018, who received TTE and transcranial Doppler (TCD) as routine examinations. PFO was diagnosed by the bubble test of TCD. Significant differences of the non-contrast TTE findings and patient characteristics between PFO group and non-PFO group were selected into a score.

Results

PFO was diagnosed in 35.8% (78/218) of the patients. Compared with non-PFO group, a larger median aortic root diameter (ARd) (34 mm vs. 32 mm, p = 0.005), a lower median peak E wave velocity (Em) (61.5 cm/s vs. 68 cm/s, p = 0.005) and a lower incidence rate of mitral regurgitation (34.6% vs. 50.7%, p = 0.022) were seen in PFO group. ARd>33 mm and Em < 72 cm/s were the best thresholds to predict PFO in ROC analysis. A four-point score system (MEAD) including TTE criteria (including ARd>33 mm, Em < 72 cm/s and without mitral regurgitation) and no history of diabetes predicted PFO with an area under curve of 0.67 (95%CI 0.57–0.72, p < 0.001). MEAD score ≥ 3 was the best threshold to predict PFO with an accuracy of 0.64 (95% CI 0.57–0.7), a sensitivity of 0.65 (95% CI 0.53–0.75) and a specificity of 0.63 (95% CI 0.55–0.71).

Conclusion

The MEAD score measured with non-contrast TTE can be used to select patients for bubble test of TCD to increase the diagnostic yield of PFO after ESUS.
Healthcare professionals’ experiences and perceptions regarding health care of indigenous pregnant women in Ecuador
Authors: Carpio-Arias Tannia Valeria , Verdezoto Nervo , Guijarro-Garvi Marta , Abril-Ulloa Victoria , Mackintosh Nicola , Eslambolchilar Parisa , Ruíz-Cantero María Teresa
Published: February 2022

Background

Pregnancy is an important life experience that requires uniquely tailored approach to health care. The socio-cultural care practices of indigenous pregnant women (IPW) are passed along the maternal line with respect to identity, worldview and nature. The cultural differences between non-indigenous healthcare professionals (HPs) and IPW could present a great challenge in women’s health care. This article presents an analysis from a human rights and gender perspective of this potential cultural divide that could affect the health of the IPW in an Andean region of Ecuador with the objective of describing the health challenges of IPWs as rights holders through the experiences and perceptions of HP as guarantors of rights.

Methods

We conducted 15 in-depth interviews with HPs who care for IPW in Chimborazo, Pichincha provinces of Ecuador. We utilized a semi-structured interview guide including questions about the experiences and perceptions of HPs in delivering health care to IPW. The interviews were recorded, transcribed and subjected to thematic analysis in Spanish and translated for reporting.

Results

We found disagreements and discrepancies in the Ecuadorian health service that led to the ignorance of indigenous cultural values. Common characteristics among the indigenous population such as illiteracy, low income and the age of pregnancy are important challenges for the health system. The gender approach highlights the enormous challenges: machismo, gender stereotypes and communication problems that IPWs face in accessing quality healthcare.

Conclusions

Understanding the diverse perspectives of IPW, acknowledging their human rights particularly those related to gender, has the potential to lead to more comprehensive and respectful health care delivery in Ecuador. Further, recognizing there is a gender and power differential between the provider and the IPW can lead to improvements in the quality of health care delivery and reproductive, maternal and child health outcomes.
FCER1G positively relates to macrophage infiltration in clear cell renal cell carcinoma and contributes to unfavorable prognosis by regulating tumor immunity
Authors: Dong Keqin , Chen Wenjin , Pan Xiuwu , Wang Hongru , Sun Ye , Qian Cheng , Chen Weijie , Wang Chao , Yang Fu , Cui Xingang
Published: February 2022

Background

Tumor-associated macrophages (TAMs) are closely related to unfavorable prognosis of patients with clear cell renal cell carcinoma (ccRCC). However, the important molecules in the interaction between ccRCC and TAMs are unclear.

Methods

TCGA-KIRC gene expression data of tumor tissues and normal tissues adjacent to tumor were compared to identify differentially expressed genes in ccRCC. TAMs related genes were discovered by analyzing the correlation between these differentially expressed genes and common macrophage biomarkers. Gene set enrichment analysis was performed to predict functions of TAMs related gene. The findings were further validated using RNA sequencing data obtained from the CheckMate 025 study and immunohistochemical analysis of samples from 350 patients with ccRCC. Kaplan–Meier survival curve, Cox regression analysis and Harrell’s concordance index analysis were used to determine the prognostic significance.

Results

In this study, we applied bioinformatic analysis to explore TAMs related differentially expressed genes in ccRCC and identified 5 genes strongly correlated with all selected macrophage biomarkers:STAC3,LGALS9,TREM2,FCER1G, andPILRA. Among them,FCER1Gwas abundantly expressed in tumor tissues and showed prognostic importance in patients with ccRCC who received treatment with Nivolumab; however, it did not exhibit prognostic value in those treated with Everolimus. We also discovered that high expression levels ofFCER1Gare related to T cell suppression. Moreover, combination ofFCER1Gand macrophage biomarkerCD68can improve the prognostic stratification of patients with ccRCC from TCGA-KIRC. Based on the immunohistochemical analysis of samples from patients with ccRCC, we further validated that FCER1G and CD68 are both highly expressed in tumor tissue and correlate with each other. Higher expression of CD68 or FCER1G in ccRCC tissue indicates shorter overall survival and progression-free survival; patients with high expression of both CD68 and FCER1G have the worst outcome. Combining CD68 and FCER1G facilitates the screening of patients with a worse prognosis from the same TNM stage group.

Conclusions

High expression ofFCER1Gin ccRCC is closely related to TAMs infiltration and suppression of T cell activation and proliferation. Combining the expression levels of FCER1G and macrophage biomarker CD68 may be a promising postoperative prognostic index for patients with ccRCC.
Comparison of Botulinum toxin type A with surgery for the treatment of intermittent exotropia in children
Authors: Su Han , Fu Jing , Wu Xiao , Sun Ali , Zhao Bowen , Hong Jie
Published: February 2022

Background

The aim of this study was to observe the effectiveness of botulinum toxin type A (BTA) in the treatment of intermittent exotropia (IXT) in children compared with strabismus surgery.

Methods

One hundred forty-four children with a clear diagnosis of IXT and an indication for surgery were eligible for inclusion. Subjects were divided into two groups based on parental decision: the BTA injection group (injection group) or the conventional surgery group (surgery group). All cases were followed up for 6 months. The primary outcome was a comparison of the success rate (deviation between − 10 and + 10 PD) between the two groups at 6 months after the initial treatment. Secondary outcomes included change in deviation, visual function, and post-surgical complications.

Results

Seventy-two patients were enrolled in each group. At 6-month follow-up, there was no significant difference in the success rate between the injection and surgery groups (52.8% vs 66.7%, P = 0.13; postoperative deviation − 12.22 ± 10.80 PD vs − 9.17 ± 10.30 PD, P = 0.09). The binocular Visual function, except for near stereoacuity, improved after treatment in both groups, while the fusion recovery rate was higher in the surgical group (68.1% vs 95.8%, P < 0.001). Transient complications in the injection group included diplopia, ptosis, and subconjunctival hemorrhage, whereas subconjunctival hemorrhage, conjunctival edema, foreign body sensation, pain, and diplopia were seen in the surgical group. The complications of BTA were relatively mild.

Conclusions

BTA is as effective as surgery in the treatment of IXT in children, but the recovery of the fusion is lower than surgery.

Trial registration

The study has completed the clinical registration on (ChiCTR-INR-17013777).
Prevalence and factors associated with lipid-lowering medications use for primary and secondary prevention of cardiovascular diseases among Malaysians: the REDISCOVER study
Authors: Baharudin Noorhida , Mohamed-Yassin Mohamed-Syarif , Daher Aqil Mohammad , Ramli Anis Safura , Khan Nor-Ashikin Mohamed Noor , Abdul-Razak Suraya
Published: February 2022

Background

Lipid-lowering medications (LLM) are commonly used for secondary prevention, as well as for primary prevention among patients with high global cardiovascular risk and with diabetes. This study aimed to determine the prevalence of LLM use among high-risk individuals [participants with diabetes, high Framingham general cardiovascular (FRS-CVD) score, existing cardiovascular disease (CVD)] and the factors associated with it.

Methods

This is a cross-sectional analysis from the baseline recruitment (years 2007 to 2011) of an ongoing prospective study involving 11,288 participants from 40 rural and urban communities in Malaysia. Multiple logistic regression was used to identify characteristics associated with LLM use.

Results

Majority (74.2%) of participants with CVD were not on LLM. Only 10.5% of participants with high FRS-CVD score, and 17.1% with diabetes were on LLM. Participants who were obese (OR = 1.80, 95% CI: 1.15–2.83), have diabetes (OR = 2.38, 95% CI: 1.78–3.19), have hypertension (OR = 2.87, 95% CI: 2.09–3.95), and attained tertiary education (OR = 2.25, 95% CI: 1.06–4.78) were more likely to be on LLM. Rural residents had lower odds of being on LLM (OR = 0.58, 95% CI: 0.41–0.82). In the primary prevention group, participants with high FRS-CVD score (OR = 3.81, 95% CI: 2.78–5.23) and high-income earners (OR = 1.54, 95% CI: 1.06–2.24) had higher odds of being on LLM.

Conclusions

LLM use among high CVD-risk individuals in the primary prevention group, and also among individuals with existing CVD was low. While CVD risk factors and global cardiovascular risk score were positively associated with LLM use, sociodemographic disparities were observed among the less-educated, rural residents and low-income earners. Measures are needed to ensure optimal and equitable use of LLM.
Cognitive reserve over life course and 7-year trajectories of cognitive decline: results from China health and retirement longitudinal study
Authors: Chen Xuanji , Xue Baowen , Hu Yaoyue
Published: February 2022

Background

Cognitive reserve (CR) could partly explain the individual heterogeneity in cognitive decline. No study measured CR from a life course perspective and investigated the association between CR and trajectories of cognitive decline in older Chinese adults.

Methods

Data of 6795 Chinese adults aged 60+ from China Health and Retirement Longitudinal Study were used. Global cognition score (0–32) was assessed in all four waves. A life-course CR score was constructed using markers of childhood circumstance, education, highest occupational class, and leisure activities in later life. Latent growth curve modelling (LGCM) was applied to assess the association between CR and trajectories of cognitive decline.

Results

For the life-course CR, factor loadings of markers in adulthood and later life were larger than that of markers in childhood. The life-course CR score (ranged between − 2.727 and 6.537, SD: 1.74) was higher in urban Chinese adults (0.75, SD: 1.90) than in rural Chinese adults (− 0.50, SD: 1.43). The unconditional LGCM results showed that urban older Chinese adults had better global cognition at baseline (intercept: 15.010, 95% CI: 14.783, 15.237) and a slower rate of cognitive decline per year (linear slope: -0.394, 95% CI: − 0.508, − 0.281) than their rural counterparts (intercept: 12.144, 95% CI: 11.960, 12.329; linear slope: -0.498, 95% CI: − 0.588, − 0.408). After controlling for all covariates, one-unit higher CR score was associated with 1.615 (95% CI: 1.521, 1.709) and 1.768 (95% CI: 1.659, 1.876) unit higher global cognition at baseline for urban and rural older Chinese adults, respectively. The slower rate of cognitive decline associated with higher CR was more evident in rural residents (slope: 0.083, 95% CI: 0.057, 0.108) than in their urban counterparts (0.054, 95% CI: 0.031, 0.077).

Conclusions

CR was associated with better baseline cognition and slower cognitive decline in Chinese older adults. Although rural residents were disadvantaged in both CR and cognition, the protective effect of CR against cognitive decline was stronger for them than in those who live in urban area.
Reasons for low utilization of intrauterine device utilisation amongst short term contraceptive users in Hossana town, Southern Ethiopia: a qualitative study
Authors: Woldeyohannes Demelash , Arega Abinet , Mwanri Lillian
Published: February 2022

Background

Intrauterine devices (IUDs) are one of the long-acting, safe and effective methods of contraception in women across the world. However, this method is underutilised in many countries, including Ethiopia. Several quantitative studies have been used to address this problem and generated a list of factors associated with this problem. However, this list lacks detailed and local contexts that are necessary to inform local solutions. The current study uses a qualitative method to explore determinants of IUDs underutilization among short term modern contraceptive users from the maternal health services in the study setting. The use of a qualitative study design is necessary to obtain and rich contextual details that can inform the development of locally appropriate strategies to increase the IUDs uptake in the study area and improve women’s reproductive health outcomes.

Method

A qualitative study was conducted in Hossana town public health facilities, Southern Ethiopia from November 1–30, 2019. A total of thirteen in-depth interviews were conducted including with: 11 short term contraceptive users, one health centre head and one health extension worker. The interview guide comprised semi-structured questions. Interviews were audio recorded, transcribed and collected data analysed thematically.

Result

The main key determinants of IUDs service underutilisation were identified from participants’ narratives, including: (1) poor knowledge about the benefits of IUDs, (2) insufficient counselling and ineffective delivery of health information to aid women in decision making, (3) the absence of trained health personals, and shortage of supplies.

Conclusion

Results indicate that the poor utilisation of IUDs services is determined by both the service provider and the consumer related factors. Poor knowledge of short term users of contraception is a critical factor because without knowledge, clients may not use the available services effectively. The shortage of necessary supplies, poor provider–client relationships, and poor counselling by service providers are also service factors that act as barriers to uptake of IUDs. Efforts should be made to increase IUDs utilization by focusing on educating women about the importance of IUDs, improving counselling of mothers and strengthening the health systems, including allocating more resources to increase access to IUDs among the service users.
Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development
Authors: Munblit Daniel , Nicholson Timothy R. , Needham Dale M. , Seylanova Nina , Parr Callum , Chen Jessica , Kokorina Alisa , Sigfrid Louise , Buonsenso Danilo , Bhatnagar Shinjini , Thiruvengadam Ramachandran , Parker Ann M. , Preller Jacobus , Avdeev Sergey , Klok Frederikus A. , Tong Allison , Diaz Janet V. , Groote Wouter De , Schiess Nicoline , Akrami Athena , Simpson Frances , Olliaro Piero , Apfelbacher Christian , Rosa Regis Goulart , Chevinsky Jennifer R. , Saydah Sharon , Schmitt Jochen , Guekht Alla , Gorst Sarah L. , Genuneit Jon , Reyes Luis Felipe , Asmanov Alan , O’Hara Margaret E. , Scott Janet T. , Michelen Melina , Stavropoulou Charitini , Warner John O. , Herridge Margaret , Williamson Paula R.
Published: February 2022

Background

A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden.

Main text

While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data.

Conclusions

A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.
Overexpression of wild type RRAS2, without oncogenic mutations, drives chronic lymphocytic leukemia
Authors: Hortal Alejandro M. , Oeste Clara L. , Cifuentes Claudia , Alcoceba Miguel , Fernández-Pisonero Isabel , Clavaín Laura , Tercero Rut , Mendoza Pilar , Domínguez Verónica , García-Flores Marta , Pintado Belén , Abia David , García-Macías Carmen , Navarro-Bailón Almudena , Bustelo Xosé R. , González Marcos , Alarcón Balbino
Published: February 2022

Background

Chronic lymphocytic leukemia (CLL) is the most frequent, and still incurable, form of leukemia in the Western World. It is widely accepted that cancer results from an evolutionary process shaped by the acquisition of driver mutations which confer selective growth advantage to cells that harbor them. Clear examples are missense mutations in classic RAS genes (KRAS, HRAS and NRAS) that underlie the development of approximately 13% of human cancers. Although autonomous B cell antigen receptor (BCR) signaling is involved and mutations in many tumor suppressor genes and oncogenes have been identified, an oncogenic driver gene has not still been identified for CLL.

Methods

Conditional knock-in mice were generated to overexpress wild type RRAS2 and prove its driver role. RT-qPCR analysis of a human CLL sample cohort was carried out to measure RRAS2 transcriptional expression. Sanger DNA sequencing was used to identify a SNP in the 3’UTR region of RRAS2 in human CLL samples. RNAseq of murine CLL was carried out to identify activated pathways, molecular mechanisms and to pinpoint somatic mutations accompanying RRAS2 overexpression. Flow cytometry was used for phenotypic characterization and shRNA techniques to knockdown RRAS2 expression in human CLL.

Results

RRAS2 mRNA is found overexpressed in its wild type form in 82% of the human CLL samples analyzed (n = 178, mean and median = 5-fold) as well as in the explored metadata. A single nucleotide polymorphism (rs8570) in the 3’UTR of the RRAS2 mRNA has been identified in CLL patients, linking higher expression of RRAS2 with more aggressive disease. Deliberate overexpression of wild type RRAS2 in mice, but not an oncogenic Q72L mutation in the coding sequence, provokes the development of CLL. Overexpression of wild type RRAS2 in mice is accompanied by a strong convergent selection of somatic mutations in genes that have been identified in human CLL. R-RAS2 protein is physically bound to the BCR and mediates BCR signals in CLL.

Conclusions

The results indicate that overexpression of wild type RRAS2 is behind the development of CLL.
GnRH antagonist weakens endometrial stromal cells growth ability by decreasing c-kit receptor expression
Authors: Xu Ding-Fei , Liu Pei-Pei , Fan Lu , Xie Qi , Zhang Zhi-Qin , Wang Li-Qun , Wu Qiong-Fang , Tan Jun
Published: February 2022

Background

Several surveys have reported that patients treated with gonadotropin-releasing hormone antagonist (GnRH-ant) protocol showed a significantly lower rate of implantation and clinical pregnancy compared to GnRH agonist (GnRH-a) protocol during in vitro fertilization-fresh embryo transfer. Subsequent studies imputed this poor outcome to the negative effects of GnRH-ant on endometrial receptive. However, the mechanisms were not fully understood.

Methods

The clinical data of 2815 patients undergoing fresh embryo transfer in our center were analyzed. Human endometrial stromal cells (ESCs) from healthy women undergoing elective pregnancy termination of a normal pregnancy at 8–10 weeks gestation were treated with GnRH-analogs or imatinib (c-kit receptor inhibitor). CCK8 and Flow cytometry were used to investigated the growth ability of ESCs. Immunofluorescence staining and western blot was used to detected the target proteins.

Results

The clinical data showed that the endometrial thickness on HCG Day were significantly lower in GnRH-ant group. Although no difference of embryo quality in these two groups, GnRH-ant group showed remarkably decreased rate of HCG positive, embryo implantation and pregnancy. Moreover, GnRH-ant significantly reduced the proliferation and induced the apoptosis of ESCs. Furthermore, the expression and activation of c-kit receptor, which played pivotal roles during embryo implantation, were observably decreased by GnRH-ant. Inhibiting the activation of c-kit by imatinib remarkably suppressed the proliferation and promoted the apoptosis of ESCs. Additionally, the phosphorylation of AKT and expression of Cyclin D1, which were closely related with cellular growth, were distinctly lessened after treating with imatinib.

Conclusions

In summary, our study showed that GnRH-ant weakened the activization of c-kit receptor by decreasing its expression, causing the impaired growth ability of ESCs. Our findings provided a new insight into the effects of GnRH-ant on endometrium.
Building global capacity for COVID-19 vaccination through interactive virtual learning
Authors: Goldin Shoshanna , Hood Nancy , Pascutto Alexandre , Bennett Celine , Barbosa de Lima Ana Carolina , Devereaux Nicole , Caric Aleksandra , Rai Karan , Desai Shalini , Lindstrand Ann , Struminger Bruce
Published: February 2022

Background

To support the introduction of the COVID-19 vaccine, the World Health Organization and its partners developed an interactive virtual learning initiative through which vaccination stakeholders could receive the latest guidance, ask questions, and share their experiences. This initiative, implemented between 9 February 2021 and 15 June 2021, included virtual engagement between technical experts and participants during a 15-session interactive webinar series as well as web and text-messaging discussions in English and French.

Methods

This article uses a mixed-methods approach to analyze survey data collected following each webinar and a post-series survey conducted after the series had concluded. Participant data were tracked for each session, and feedback surveys were conducted after each session to gauge experience quality and content usability. Chi-square tests were used to compare results across professions (health workers, public health practitioners, and others).

Results

The COVID-19 Vaccination: Building Global Capacity webinar series reached participants in 179 countries or 93% of the WHO Member States; 75% of participants were from low- and middle-income countries. More than 60% of participants reported using the resources provided during the sessions, and 47% reported sharing these resources with colleagues. More than 79% of participants stated that this initiative significantly improved their confidence in preparing for and rolling out COVID-19 vaccinations; an additional 20% stated that the initiative “somewhat” improved their confidence. In the post-series survey, 70% of participants reported that they will “definitely use” the knowledge derived from this learning series in their work; an additional 20% will “probably use” and 9% would “possibly use” this knowledge in their work.

Conclusion

The COVID-19 Vaccination: Building Global Capacity learning initiative used a digital model of dynamic, interactive learning at scale. The initiative enhanced WHO’s ability to disseminate knowledge, provide normative guidance, and share best practices to COVID-19 vaccination stakeholders in real time. This approach allowed WHO to hear the information needs of stakeholders and respond by developing guidance, tools, and training to support COVID-19 vaccine introduction. WHO and its partners can learn from this capacity-building experience and apply best practices for digital interactive learning to other health programs moving forward.
The effect of Ebola virus disease on maternal health service utilisation and perinatal outcomes in West Africa: a systematic review
Authors: Kassa Zemenu Yohannes , Scarf Vanessa , Fox Deborah
Published: February 2022

Background

Ebola outbreaks pose a major threat to global public health, especially in Sub-Saharan Africa. These outbreaks disrupt the already fragile maternal health services in West Africa. The aims of this study is to assess the effect of Ebola virus disease (EVD) on maternal health service utilisation and perinatal outcomes.

Methods

This systematic review was conducted in West Africa, and the databases used were Medline, PubMed, CINAHL, Scopus, EMBASE and African journals online. Studies that reported the effect of the Ebola outbreak on maternal health services in West Africa were eligible for this systematic review. The search was limited to articles written in the English language only and published between 2013 and 2020. Three authors independently appraised the articles, and the data were extracted using a standardised data extraction format. The findings were synthesised using a narrative summary, tables, and figures.

Results

Twelve studies met the inclusion criteria and were used for this systematic review synthesis. The results showed that antenatal care significantly decreased during Ebola virus disease and strove to recover post-Ebola virus disease. Women were less likely to have institutional childbirth during Ebola virus disease and struggled to recover post-Ebola virus disease. In addition, this review revealed a substantially higher rate of maternal mortality post EVD than those observed before or during the outbreak.

Conclusion

Based on our findings, antenatal care, institutional childbirth, and postnatal care are attempting to recover post-Ebola virus disease. We recommended that responsible bodies and stakeholders need to prepare locally tailored interventions to increase the number of women attending ANC, institutional childbirth, and PNC services post-EVD and future outbreaks including COVID-19. In order to build trust, creating community networks between health care providers and trusted community leaders may increase the number of women attending antenatal care (ANC), institutional childbirth and postnatal care (PNC) post-EVD and during future outbreaks. Further studies are needed to examine health centre and hospital availability and accessibility, and capacity to deliver maternal health services post-Ebola virus disease and future outbreaks.
How can we consider variable RBE and LETd prediction during clinical practice? A pediatric case report at the Normandy Proton Therapy Centre using an independent dose engine
Authors: Mein Stewart , Kopp Benedikt , Vela Anthony , Dutheil Pauline , Lesueur Paul , Stefan Dinu , Debus Jürgen , Haberer Thomas , Abdollahi Amir , Mairani Andrea , Tessonnier Thomas
Published: February 2022

Background

To develop an auxiliary GPU-accelerated proton therapy (PT) dose and LETd engine for the IBA Proteus®ONE PT system. A pediatric low-grade glioma case study is reported using FRoG during clinical practice, highlighting potential treatment planning insights using variable RBE dose (DvRBE) and LETd as indicators for clinical decision making in PT.

Methods

The physics engine for FRoG has been modified for compatibility with Proteus®ONE PT centers. Subsequently, FRoG was installed and commissioned at NPTC. Dosimetric validation was performed against measurements and the clinical TPS, RayStation (RS-MC). A head patient cohort previously treated at NPTC was collected and FRoG forward calculations were compared against RS-MC for evaluation of 3D-Γ analysis and dose volume histogram (DVH) results. Currently, treatment design at NPTC is supported with fast variable RBE and LETd calculation and is reported in a representative case for pediatric low-grade glioma.

Results

Simple dosimetric tests against measurements of iso-energy layers and spread-out Bragg Peaks in water verified accuracy of FRoG and RS-MC. Among the patient cohort, average 3D-Γ applying 2%/2 mm, 3%/1.5 mm and 5%/1 mm were > 97%. DVH metrics for targets and OARs between FRoG and RayStation were in good agreement, with ∆D50,CTV and ∆D2,OAR both ⪅1%. The pediatric case report demonstrated implications of different beam arrangements on DvRBE and LETd distributions. From initial planning in RayStation sharing identical optimization constraints, FRoG analysis led to plan selection of the most conservative approach, i.e., minimized DvRBE,max and LETd,max in OARs, to avoid optical system toxicity effects (i.e., vision loss).

Conclusion

An auxiliary dose calculation system was successfully integrated into the clinical workflow at a Proteus®ONE IBA facility, in excellent agreement with measurements and RS-MC. FRoG may lead to further insight on DvRBE and LETd implications to help clinical decision making, better understand unexpected toxicities and establish novel clinical procedures with metrics currently absent from the standard clinical TPS.
Similarities and differences between rat and mouse chondrocyte gene expression induced by IL-1β
Authors: Ding Dao-Fang , Xue Yan , Zhang Jun-Peng , Zhang Zeng-Qiao , Li Wen-Yao , Cao Yue-Long , Xu Jian-Guang
Published: February 2022

Background

Osteoarthritis (OA) is the most prevalent degenerative joint disease. In vitro experiments are an intuitive method used to investigate its early pathogenesis. Chondrocyte inflammation models in rats and mice are often used as in vitro models of OA. However, similarities and differences between them in the early stages of inflammation have not been reported.

Objective

This paper seeks to compare the chondrocyte phenotype of rats and mice in the early inflammatory state and identify chondrocytes suitable for the study of early OA.

Methods

Under similar conditions, chondrocytes from rats and mice were stimulated using the same IL-1β concentration for a short period of time. The phenotypic changes of chondrocytes were observed under a microscope. The treated chondrocytes were subjected to RNA-seq to identify similarities and differences in gene expression. Chondrocytes were labelled with EdU for proliferation analysis. Cell proliferation-associated proteins, including minichromosome maintenance 2 (MCM2), minichromosome maintenance 5 (MCM5), Lamin B1, proliferating cell nuclear antigen (PCNA), and Cyclin D1, were analysed by immunocytochemical staining, cell immunofluorescence, and Western blots to verify the RNA-seq results.

Results

RNA-seq revealed that the expression patterns of cytokines, chemokines, matrix metalloproteinases, and collagen were similar between the rat and mouse chondrocyte inflammation models. Nonetheless, the expression of proliferation-related genes showed the opposite pattern. The RNA-seq results were further verified by subsequent experiments. The expression levels of MCM2, MCM5, Lamin B1, PCNA, and Cyclin D1 were significantly upregulated in rat chondrocytes (P < 0.05) and mouse chondrocytes (P < 0.05).

Conclusions

Based on the findings, the rat chondrocyte inflammation model may help in the study of the early pathological mechanism of OA.
Caregivers’ experience of sleep management in Smith–Magenis syndrome: a mixed-methods study
Authors: Agar Georgie , Bissell Stacey , Wilde Lucy , Over Nigel , Williams Caitlin , Richards Caroline , Oliver Chris
Published: February 2022

Background

Smith–Magenis syndrome (SMS) is a rare genetic syndrome associated with a unique profile of early morning waking and daytime sleepiness. Children with SMS evidence high rates of self-injury and aggression and have a preference for adult over peer attention, with strong motivation to interact with a particular caregiver. In addition, people with SMS have lower adaptive functioning skills relative to cognitive abilities and demonstrate high levels of impulsivity. Taken together, these factors may result in individuals being awake overnight requiring vigilant caregiver supervision. Despite these complexities, no study has described the strategies caregivers take to keep their children with SMS safe overnight or considered the impact of these experiences on caregivers or the wider family.

Methods

The current study used a mixed-methods approach to consider sleep management strategies and challenges for caregivers of people with SMS at different ages. Caregivers completed an international online survey about sleep management and related difficulties, use of interventions and access to services and support. Semi-structured interviews were conducted with 14 caregivers in the UK to increase understanding of caregiver experiences and priorities for change in the UK context. Interviews were transcribed verbatim and coded using thematic analysis.

Results

Evidence from the online survey (n = 40) revealed wide-ranging impacts of poor sleep on the person with SMS and the wider family. Only 5% of caregivers reported that the sleep problems had no impact on their child, and 76% reported a moderately or extremely significant impact on themselves. For some individual caregivers, sleep management difficulties improved over time whereas for others no change was reported. Weekly respite emerged as the ideal provision for 49% of caregivers, although only 14% had access to this. The majority of caregivers (54%) received no respite. Thematic analysis of qualitative interviews revealed interactions between aspects of the behavioural phenotype of SMS which may contribute to complex and unusual presentations in relation to sleep management and safety.

Conclusions

Caregivers’ priorities for sleep management and support were delineated, with key implications for services in terms of the use of SMS-sensitive strategies and respite provision.
CXCR4-targeted nanotoxins induce GSDME-dependent pyroptosis in head and neck squamous cell carcinoma
Authors: Rioja-Blanco Elisa , Arroyo-Solera Irene , Álamo Patricia , Casanova Isolda , Gallardo Alberto , Unzueta Ugutz , Serna Naroa , Sánchez-García Laura , Quer Miquel , Villaverde Antonio , Vázquez Esther , León Xavier , Alba-Castellón Lorena , Mangues Ramon
Published: February 2022

Background

Therapy resistance, which leads to the development of loco-regional relapses and distant metastases after treatment, constitutes one of the major problems that head and neck squamous cell carcinoma (HNSCC) patients currently face. Thus, novel therapeutic strategies are urgently needed. Targeted drug delivery to the chemokine receptor 4 (CXCR4) represents a promising approach for HNSCC management. In this context, we have developed the self-assembling protein nanotoxins T22-PE24-H6 and T22-DITOX-H6, which incorporate the de-immunized catalytic domain ofPseudomonas aeruginosa(PE24) exotoxin A and the diphtheria exotoxin (DITOX) domain, respectively. Both nanotoxins contain the T22 peptide ligand to specifically target CXCR4-overexpressing HNSCC cells. In this study, we evaluate the potential use of T22-PE24-H6 and T22-DITOX-H6 nanotoxins for the treatment of HNSCC.

Methods

T22-PE24-H6 and T22-DITOX-H6 CXCR4-dependent cytotoxic effect was evaluated in vitro in two different HNSCC cell lines. Both nanotoxins cell death mechanisms were assessed in HNSCC cell lines by phase-contrast microscopy, AnnexinV/ propidium iodide (PI) staining, lactate dehydrogenase (LDH) release assays, and western blotting. Nanotoxins antitumor effect in vivo was studied in a CXCR4+HNSCC subcutaneous mouse model. Immunohistochemistry, histopathology, and toxicity analyses were used to evaluate both nanotoxins antitumor effect and possible treatment toxicity. GSMDE and CXCR4 expression in HNSCC patient tumor samples was also assessed by immunohistochemical staining.

Results

First, we found that both nanotoxins exhibit a potent CXCR4-dependent cytotoxic effect in vitro. Importantly, nanotoxin treatment triggered caspase-3/Gasdermin E (GSDME)-mediated pyroptosis. The activation of this alternative cell death pathway that differs from traditional apoptosis, becomes a promising strategy to bypass therapy resistance. In addition, T22-PE24-H6 and T22-DITOX-H6 displayed a potent antitumor effect in the absence of systemic toxicity in a CXCR4+subcutaneous HNSCC mouse model. Lastly, GSDME was found to be overexpressed in tumor tissue from HNSCC patients, highlighting the relevance of this strategy.

Conclusions

Altogether, our results show that T22-PE24-H6 and T22-DITOX-H6 represent a promising therapy for HNSCC patients. Remarkably, this is the first study showing that both nanotoxins are capable of activating caspase-3/GSDME-dependent pyroptosis, opening a novel avenue for HNSCC treatment.