bluuebunny/crossref_metadata_2025 huggingface dataset:
AGAP2-AS1 as a prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease
Authors: Nakken Sigrid , Eikrem Øystein , Marti Hans-Peter , Beisland Christian , Bostad Leif , Scherer Andreas , Flatberg Arnar , Beisvag Vidar , Skandalou Eleni , Furriol Jessica , Strauss Philipp
Published: December 2021

Background

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and one of the most common cancers. While survival for localized ccRCC is good, the survival of metastatic disease is not, and thirty percent of patients with ccRCC develop metastases during follow-up. Although current scoring methods accurately identify patients at low progression risk, a small subgroup of those patients still experience metastasis. We therefore aimed to identify ccRCC progression biomarkers in “low-risk” patients who were potentially eligible for adjuvant treatments or more intensive follow-up.

Methods

We assembled a cohort of ccRCC patients (n  = 443) and identified all “low-risk” patients who later developed progressing tumors (n  = 8). Subsequently, we performed genome-wide expression profiling from formalin-fixed samples obtained at initial surgery from these “low-risk” patients and 16 matched patients not progressing to recurrence with metastasis. The patients were matched for Leibovich sore, creatinine, age, sex, tumor size and tumor stage. Key results were confirmed with qPCR and external data from The Cancer Genome Atlas.

Results

Principal component analysis indicated that systematic transcriptomic differences were already detectable at the time of initial surgery. One thousand one hundred sixty-seven genes, mainly associated with cancer and immune-related pathways, were differentially expressed between progressors and nonprogressors. A search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long noncoding RNA, correctly classified 23 of 24 samples, years (4.5 years average) in advance of the discovery of metastasis and without requiring larger gene panels. Subsequently, we confirmed AGAP2-AS1 gene overexpression by qPCR in the same samples (p  < 0.05). Additionally, in external data from The Cancer Genome Atlas, overexpression of AGAP2-AS1 is correlated with overall unfavorable survival outcome in ccRCC, irrespective of other prognostic predictors (p  = 2.44E−7).

Conclusion

AGAP2-AS1 may represent a novel biomarker identifying high-risk ccRCC patients currently classified as “low risk” at the time of surgery.
Putative pleiotropic effects of the knockdown resistance (L1014F) allele on the life-history traits of Anopheles gambiae
Authors: Medjigbodo Adandé A. , Djogbénou Luc S. , Djihinto Oswald Y. , Akoton Romaric B. , Abbey Emmanuella , Kakossou Rosaria M. , Sonounameto Eric G. , Salavi Esther B. J. , Djossou Laurette , Badolo Athanase
Published: December 2021

Background

Existing mechanisms of insecticide resistance are known to help the survival of mosquitoes following contact with chemical compounds, even though they could negatively affect the life-history traits of resistant malaria vectors. In West Africa, the knockdown resistance mechanism kdrR (L1014F) is the most common. However, little knowledge is available on its effects on mosquito life-history traits. The fitness effects associated with this knockdown resistance allele in Anopheles gambiae sensu stricto (s.s.) were investigated in an insecticide-free laboratory environment.

Methods

The life-history traits of Kisumu (susceptible) and KisKdr (kdr resistant) strains of An. gambiae s.s. were compared. Larval survivorship and pupation rate were assessed as well as fecundity and fertility of adult females. Female mosquitoes of both strains were directly blood fed through artificial membrane assays and then the blood-feeding success, blood volume and adult survivorship post-blood meal were assessed.

Results

The An. gambiae mosquitoes carrying the kdrR allele (KisKdr) laid a reduced number of eggs. The mean number of larvae in the susceptible strain Kisumu was three-fold overall higher than that seen in the KisKdr strain with a significant difference in hatching rates (81.89% in Kisumu vs 72.89% in KisKdr). The KisKdr larvae had a significant higher survivorship than that of Kisumu. The blood-feeding success was significantly higher in the resistant mosquitoes (84%) compared to the susceptible ones (34.75%). However, the mean blood volume was 1.36 µL/mg, 1.45 µL/mg and 1.68 µL/mg in Kisumu, homozygote and heterozygote KisKdr mosquitoes, respectively. After blood-feeding, the heterozygote KisKdr mosquitoes displayed highest survivorship when compared to that of Kisumu.

Conclusions

The presence of the knockdown resistance allele appears to impact the life-history traits, such as fecundity, fertility, larval survivorship, and blood-feeding behaviour in An. gambiae. These data could help to guide the implementation of more reliable strategies for the control of malaria vectors.
Impact of COVID-19 on routine malaria indicators in rural Uganda: an interrupted time series analysis
Authors: Namuganga Jane F. , Briggs Jessica , Roh Michelle E. , Okiring Jaffer , Kisambira Yasin , Sserwanga Asadu , Kapisi James A. , Arinaitwe Emmanuel , Ebong Chris , Ssewanyana Isaac , Maiteki-Ssebuguzi Catherine , Kamya Moses R. , Staedke Sarah G. , Dorsey Grant , Nankabirwa Joaniter I.
Published: December 2021

Background

In March 2020, the government of Uganda implemented a strict lockdown policy in response to the COVID-19 pandemic. Interrupted time series analysis (ITSA) was performed to assess whether major changes in outpatient attendance, malaria burden, and case management occurred after the onset of the COVID-19 epidemic in rural Uganda.

Methods

Individual level data from all outpatient visits collected from April 2017 to March 2021 at 17 facilities were analysed. Outcomes included total outpatient visits, malaria cases, non-malarial visits, proportion of patients with suspected malaria, proportion of patients tested using rapid diagnostic tests (RDTs), and proportion of malaria cases prescribed artemether-lumefantrine (AL). Poisson regression with generalized estimating equations and fractional regression was used to model count and proportion outcomes, respectively. Pre-COVID trends (April 2017-March 2020) were used to predict the’expected’ trend in the absence of COVID-19 introduction. Effects of COVID-19 were estimated over two six-month COVID-19 time periods (April 2020-September 2020 and October 2020–March 2021) by dividing observed values by expected values, and expressed as ratios.

Results

A total of 1,442,737 outpatient visits were recorded. Malaria was suspected in 55.3% of visits and 98.8% of these had a malaria diagnostic test performed. ITSA showed no differences between observed and expected total outpatient visits, malaria cases, non-malarial visits, or proportion of visits with suspected malaria after COVID-19 onset. However, in the second six months of the COVID-19 time period, there was a smaller mean proportion of patients tested with RDTs compared to expected (relative prevalence ratio (RPR) = 0.87, CI (0.78–0.97)) and a smaller mean proportion of malaria cases prescribed AL (RPR = 0.94, CI (0.90–0.99)).

Conclusions

In the first year after the COVID-19 pandemic arrived in Uganda, there were no major effects on malaria disease burden and indicators of case management at these 17 rural health facilities, except for a modest decrease in the proportion of RDTs used for malaria diagnosis and the mean proportion of malaria cases prescribed AL in the second half of the COVID-19 pandemic year. Continued surveillance will be essential to monitor for changes in trends in malaria indicators so that Uganda can quickly and flexibly respond to challenges imposed by COVID-19.
Pathways to loneliness: a mediation analysis investigating the social gradient of loneliness in persons with disabilities in Switzerland
Authors: Tough Hannah , Gross-Hemmi Mirja , Eriks-Hoogland Inge , Fekete Christine
Published: December 2021

Background

The experience of loneliness can have drastic consequences for health and quality of life. Given that loneliness is highly prevalent in persons with physical disabilities and that loneliness more profoundly affects persons of low socioeconomic status, more evidence is required in order to understand the mechanisms determining loneliness in this population. The objective of this study is therefore to investigate the potential pathways through which socioeconomic status influences loneliness in persons with spinal cord injury.

Methods

Mediation analysis utilising structural equation models and bias corrected and accelerated confidence intervals were used in order to test the mediation effects of health status, functioning, participation, social support and self-efficacy on the association between socioeconomic status and loneliness in persons with spinal cord injury. A latent construct was created for socioeconomic status with the indicators education, household income, financial hardship, subjective social status and engagement in paid work.

Results

This study found evidence to support the mediating role of psychosocial resources and of secondary health conditions in the association between socioeconomic status and loneliness. The study demonstrated robust associations between socioeconomic status and all potential mediators, whereby higher socioeconomic status was associated with better health, participation and psychosocial resources, however, not all potential mediators were associated with loneliness. The serial mediation model explained the interplay between socioeconomic status, mediators on different levels, and loneliness. For example, emotional support and self-efficacy were both positively associated with fewer restrictions to participation (0.08 (CI: 0.05, 0.12); 0.29 (CI: 0.24, 0.36) respectively), and fewer restrictions to participation were found to be a result of improved functional independence and fewer secondary health conditions (0.23 (CI: 0.15, 0.39); − 0.29 (CI: − 0.36, − 0.20) respectively).

Conclusions

Our findings highlight the vulnerability of persons with low socioeconomic status to loneliness in persons with spinal cord injury and identified potential mediating factors, such as health, functioning, participation and psychosocial resources, in the association between socioeconomic status and loneliness. This population-based evidence suggests potential targets of interventions on the pathway to loneliness, through which socioeconomic status influences loneliness. The complexity of the model shows the need for comprehensive interprofessional rehabilitation to identify and support people with lower socioeconomic status and concomitant risk factors for loneliness.
Epigenetic modulation of antitumor immunity for improved cancer immunotherapy
Authors: Dai Enyong , Zhu Zhi , Wahed Shudipto , Qu Zhaoxia , Storkus Walter J. , Guo Zong Sheng
Published: December 2021

Epigenetic mechanisms play vital roles not only in cancer initiation and progression, but also in the activation, differentiation and effector function(s) of immune cells. In this review, we summarize current literature related to epigenomic dynamics in immune cells impacting immune cell fate and functionality, and the immunogenicity of cancer cells. Some important immune-associated genes, such as granzyme B, IFN-γ, IL-2, IL-12, FoxP3 and STING, are regulated via epigenetic mechanisms in immune or/and cancer cells, as are immune checkpoint molecules (PD-1, CTLA-4, TIM-3, LAG-3, TIGIT) expressed by immune cells and tumor-associated stromal cells. Thus, therapeutic strategies implementing epigenetic modulating drugs are expected to significantly impact the tumor microenvironment (TME) by promoting transcriptional and metabolic reprogramming in local immune cell populations, resulting in inhibition of immunosuppressive cells (MDSCs and Treg) and the activation of anti-tumor T effector cells, professional antigen presenting cells (APC), as well as cancer cells which can serve as non-professional APC. In the latter instance, epigenetic modulating agents may coordinately promote tumor immunogenicity by inducing de novo expression of transcriptionally repressed tumor-associated antigens, increasing expression of neoantigens and MHC processing/presentation machinery, and activating tumor immunogenic cell death (ICD). ICD provides a rich source of immunogens for anti-tumor T cell cross-priming and sensitizing cancer cells to interventional immunotherapy. In this way, epigenetic modulators may be envisioned as effective components in combination immunotherapy approaches capable of mediating superior therapeutic efficacy.
3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway
Authors: Wang Ning , Li Xiajing , Zhong Zhiyong , Qiu Yaqi , Liu Shoupei , Wu Haibin , Tang Xianglian , Chen Chuxin , Fu Yingjie , Chen Qicong , Guo Tingting , Li Jinsong , Zhang Shuai , Zern Mark A. , Ma Keqiang , Wang Bailin , Ou Yimeng , Gu Weili , Cao Jie , Chen Honglin , Duan Yuyou
Published: December 2021

Background

Exosomes secreted from stem cells exerted salutary effects on the fibrotic liver. Herein, the roles of exosomes derived from human embryonic stem cell (hESC) in anti-fibrosis were extensively investigated. Compared with two-dimensional (2D) culture, the clinical and biological relevance of three-dimensional (3D) cell spheroids were greater because of their higher regeneration potential since they behave more like cells in vivo. In our study, exosomes derived from 3D human embryonic stem cells (hESC) spheroids and the monolayer (2D) hESCs were collected and compared the therapeutic potential for fibrotic liver in vitro and in vivo.

Results

In vitro, PKH26 labeled-hESC-Exosomes were shown to be internalized and integrated into TGFβ-activated-LX2 cells, and reduced the expression of profibrogenic markers, thereby regulating cellular phenotypes. TPEF imaging indicated that PKH26-labeled-3D-hESC-Exsomes possessed an enhanced capacity to accumulate in the livers and exhibited more dramatic therapeutic potential in the injured livers of fibrosis mouse model. 3D-hESC-Exosomes decreased profibrogenic markers and liver injury markers, and improved the level of liver functioning proteins, eventually restoring liver function of fibrosis mice. miRNA array revealed a significant enrichment of miR-6766-3p in 3D-hESC-Exosomes, moreover, bioinformatics and dual luciferase reporter assay identified and confirmed the TGFβRII gene as the target of miR-6766-3p. Furthermore, the delivery of miR-6766-3p into activated-LX2 cells decreased cell proliferation, chemotaxis and profibrotic effects, and further investigation demonstrated that the expression of target gene TGFβRII and its downstream SMADs proteins, especially phosphorylated protein p-SMAD2/3 was also notably down-regulated by miR-6766-3p. These findings unveiled that miR-6766-3p in 3D-hESC-Exosomes inactivated SMADs signaling by inhibiting TGFβRII expression, consequently attenuating stellate cell activation and suppressing liver fibrosis.

Conclusions

Our results showed that miR-6766-3p in the 3D-hESC-Exosomes inactivates smads signaling by restraining TGFβRII expression, attenuated LX2 cell activation and suppressed liver fibrosis, suggesting that 3D-hESC-Exosome enriched-miR-6766-3p is a novel anti-fibrotic therapeutics for treating chronic liver disease. These results also proposed a significant strategy that 3D-Exo could be used as natural nanoparticles to rescue liver injury via delivering antifibrotic miR-6766-3p.

Graphical Abstract
Recent advances of nanotechnology-based tumor vessel-targeting strategies
Authors: Zhu Dongjie , Li Yang , Zhang Zhengjia , Xue Zeyu , Hua Zhenglai , Luo Xinyi , Zhao Ting , Lu Cheng , Liu Yuanyan
Published: December 2021

Tumor vessels can provide oxygen and nutrition for solid tumor tissue, create abnormal tumor microenvironment (TME), and play a vital role in the development, immune escape, metastasis and drug resistance of tumor. Tumor vessel-targeting therapy has become an important and promising direction in anti-tumor therapy, with the development of five anti-tumor therapeutic strategies, including vascular disruption, anti-angiogenesis, vascular blockade, vascular normalization and breaking immunosuppressive TME. However, the insufficient drug accumulation and severe side effects of vessel-targeting drugs limit their development in clinical application. Nanotechnology offers an excellent platform with flexible modified surface that can precisely deliver diverse cargoes, optimize efficacy, reduce side effects, and realize the combined therapy. Various nanomedicines (NMs) have been developed to target abnormal tumor vessels and specific TME to achieve more efficient vessel-targeting therapy. The article reviews tumor vascular abnormalities and the resulting abnormal microenvironment, the application of NMs in the tumor vessel-targeting strategies, and how NMs can improve these strategies and achieve multi-strategies combination to maximize anti-tumor effects.

Graphical Abstract
A multifunctional AIE gold cluster-based theranostic system: tumor-targeted imaging and Fenton reaction-assisted enhanced radiotherapy
Authors: Hua Yue , Wang Yuan , Kang Xue , Xu Fan , Han Zhen , Zhang Chong , Wang Zhao-Yang , Liu Jun-Qi , Zhao Xueli , Chen Xiaoyuan , Zang Shuang-Quan
Published: December 2021

Background

As cancer is one of the main leading causes of mortality, a series of monotherapies such as chemotherapy, gene therapy and radiotherapy have been developed to overcome this thorny problem. However, a single treatment approach could not achieve satisfactory effect in many experimental explorations.

Results

In this study, we report the fabrication of cyclic RGD peptide (cRGD) modified Au4-iron oxide nanoparticle (Au4-IO NP-cRGD) based on aggregation-induced emission (AIE) as a multifunctional theranostic system. Besides Au4 cluster-based fluorescence imaging and enhanced radiotherapy, iron oxide (IO) nanocluster could realize magnetic resonance (MR) imaging and Fenton reaction-based chemotherapy. Abundant toxic reactive oxygen species generated from X-ray irradiation and in situ tumor-specific Fenton reaction under acidic microenvironment leads to the apoptotic and necrotic death of cancer cells. In vivo studies demonstrated good biocompatibility of Au4-IO NP-cRGD and a high tumor suppression rate of 81.1% in the synergistic therapy group.

Conclusions

The successful dual-modal imaging and combined tumor therapy demonstrated AIE as a promising strategy for constructing multifunctional cancer theranostic platform.

Graphical Abstract
Serum folate concentration and health-related quality of life among the elderly in South Korea
Authors: Lee Eunmi , Park Sangshin
Published: December 2021

Background

The purpose of this study was to investigate the association between serum folate concentration and health-related quality of life (HRQOL) among the elderly in South Korea.

Materials and methods

The data used in this study were drawn from 1,021 participants over 65 years old in the Korea National Health and Nutrition Examination Survey from 2016–2018. HRQOL was measured by the EQ-5D questionnaire. Participants were divided into tertiles of folate concentration (ranges 1.7–5.6, 5.7–9.4, and 9.5–31.9 ng/mL). We performed multivariable linear regression to examine the relationship between folate and HRQOL, and multivariable logistic regression to examine the relationship between folate and the dimensional problem of HRQOL.

Results

Higher folate concentrations were significantly associated with higher HRQOL in the elderly. The average HRQOL score of the elderly in the highest tertile of the folate level was 0.0289 higher than that of the lowest tertile (coefficient: 0.0289; 95% CI 0.0016, 0.0563). The HRQOL score increased by 0.0174 points when the folate concentration increased by 100%. When analyzing specific dimensions, a significant association with folate concentration was found only for the self-care dimension of HRQOL (odds ratio for self-care problems: 0.63; 95% CI 0.41, 0.99).

Conclusions

The elderly with higher serum folate concentration tended to have higher HRQOL. Among HRQOL dimensions, self-care was only significantly associated with folate concentration.
Evaluation of health-related quality of life of Covid-19 patients: a hospital-based study in South Central Ethiopia
Authors: Kaso Abdene Weya , Agero Gebi , Hurisa Zewdu , Kaso Taha , Ewune Helen Ali , Hailu Alemayehu
Published: December 2021

Background

Covid-19 causes a wide range of symptoms in patients, ranging from mild manifestations to severe disease and death. This study assessed the health-related quality of life (HRQOL) and associated factors of Covid-19 patients using primary data from confirmed cases in South Central Ethiopia.

Methods

We employed a facility-based, cross-sectional study design and conducted the study at the Bokoji Hospital Covid-19 treatment centre. A structured questionnaire and the EQ-5D-3L scale were used to collect the data for analysis. The HRQOL results measured by the EQ-5D-3L tool were converted to a health state utility (HSU) using the Zimbabwe tariff. The average health utility index and HSU–visual analogue scale across diverse sociodemographic and clinical characteristics were compared using the Mann–Whitney U test or Kruskal–Wallis test. We employed a multiple linear regression to examine factors associated with HSU values simultaneously. The data were analysed using STATA version 15.

Results

The overall mean HSU score from the EQ-5D was 0.688 (SD: 0.285), and the median was 0.787 (IQR 0.596, 0.833). The mean HSU from the visual analogue scale score was 0.69 (SD: 0.129), with a median of 0.70 (IQR 0.60, 0.80). Those who received dexamethasone and intranasal oxygen supplement, those with comorbidity, those older than 55 years and those with a hospital stay of more than 15 days had significantly lower HSU scores than their counterparts (p < .001).

Conclusion

Covid-19 substantially impaired the HRQOL of patients in Ethiopia, especially among elderly patients and those with comorbidity. Therefore, clinical follow-up and psychological treatment should be encouraged for these groups. Moreover, the health utility values from this study can be used to evaluate quality adjusted life years for future cost-effectiveness analyses of prevention and treatment interventions against Covid-19.
Emotional dysregulation and health related quality of life in young adults with ADHD: a cross sectional study
Authors: Ben-Dor Cohen Maayan , Eldar Eran , Maeir Adina , Nahum Mor
Published: December 2021

Objective

Attention Deficit Hyperactivity Disorder (ADHD) is associated with emotional dysregulation (ED) and impaired health related quality of life (HRQoL). However, the role of ED in explaining the relationship between ADHD and HRQoL is unclear. The purpose of the present study was to do so in a sample of non-referred young adults with and without ADHD.

Method

The study design was cross-sectional. A non-clinical sample of 63 young adults with ADHD (mean age = 24.86 years, SD = 3.25, 78% university students) and 69 gender-matched controls (mean age = 23.84 years, SD = 2.59, 89% university students) were recruited. The Adult ADHD Quality-of-Life scale was used to measure HRQoL; The Self-Report Wender–Reimherr Adult Attention Deficit Disorder Scale and the Difficulties in Emotion Regulation Scale were used to measure ED. Group differences on all measures were tested using univariate and multivariate analyses of covariance, while controlling for age. Finally, a moderation analysis was used in order to examine the impact of ED on HRQoL beyond that accounted for by ADHD symptoms.

Results

Both HRQoL and ED were significantly worse for the ADHD group compared to the control group. The medication status of the ADHD group participants had no significant effect on the level of ADHD symptoms, ED or HRQoL. ED moderated the effect of ADHD symptoms on HRQoL for the ADHD group.

Conclusion

The findings support the centrality of ED in ADHD and its crucial influence on HRQoL. Young adults with ADHD and high levels of ED are at risk for aversive impact on their well-being regardless of their ADHD symptoms level.
Long-term oncologic safety of immediate reconstructive surgery in patients with invasive breast cancer: a retrospective matched-cohort study
Authors: Song Yanni , Sun Shanshan , Li Dalin , Han Jiguang , Niu Ming , Luo Sai , Xu Haiqian , Huang Rui , Zhang Sihang , Wu Yang , Wu Qiqi , Xiong Jing , Hao Lijun
Published: December 2021

Objective

Immediate reconstruction (IR) is a safe and effective surgical treatment for patients with breast cancer. We aimed to assess the prognosis, aesthetic outcomes, and patient satisfaction of IR compared with breast conservation surgery (BCS) and total mastectomy (TM).

Methods

This retrospective matched-cohort study was conducted between May 2005 and December 2014. We established two cohorts according to the tumor (T) size of breast cancer. In the T≤3cm group, cases (IR) and controls (BCS or TM) were matched for age, pathological tumor size, and pathologic nodal status in a 1:1:1 ratio. In the T>3cm group, cases (IR) and controls (TM) were matched with the same factors and ratio. The primary outcome was the 5-year disease-free survival (DFS). The secondary outcome was patient satisfaction and quality of life.

Results

A total of 12,678 breast cancer patients were assessed for eligibility, of which 587 were included (T≤3 cm group: 155 IR vs 155 BCS vs 155 TM; T>3cm group: 61 IR vs 61 TM). In the T≤3 cm cohort, patients who underwent IR had no difference compared with those who underwent BCS or TM regarding the 5-year DFS (P=0.539); however, an improved aesthetic satisfaction, psychosocial, and sexual well-being were achieved in the IR group (P<0.001). In the T>3 cm cohort, the IR group had a worse median 5-year DFS (P=0.044), especially for Her2+ or triple-negative breast carcinoma (TNBC) subtypes compared with the TM group.

Conclusions

IR improves aesthetic satisfaction, psychosocial, and sexual well-being for breast cancer patients with T≤3 cm. For patients with T > 3 cm invasive breast cancer, TM is superior to IR as it predicts a better 5-year DFS.
Framework for assessing the performance of the Ghanaian health system: study protocol
Authors: Kumah Emmanuel , Ankomah Samuel E. , Fusheini Adam , Agyei-Baffour Peter , Ayanore Martin A. , Asravor Richard K. , Kesse Felix O. , Mwini Emmanuel , Otchere Godfred
Published: December 2021

Background

Assessing the performance of health systems through quantitative and qualitative methods is recognized as an effective approach to strengthening national health systems. However, while many high-income countries have institutionalized health system performance assessment (HSPA) as an integral component of their respective health systems, few studies on HSPA have been documented in low- and middle-income countries, including Ghana. This study aims at providing a comprehensive framework for periodic assessment of the performance of the entire health system in Ghana.

Methods

The study will have four work packages. First, a structured review will be conducted to identify both international and national HSPA frameworks that could be applied to the Ghanaian context. Second, based on the structured review, an assessment framework tailored to the Ghanaian health system context will be developed. Third, the draft framework will be presented and discussed with experts and stakeholders for its appropriateness, feasibility and acceptability. Finally, the framework will be piloted to assess its effectiveness and suitability for full-scale implementation.

Discussion

Currently, Ghana does not have a full-fledged HSPA tool that provides a holistic health sector-wide approach to assessing health system performance. Thus, developing this HSPA framework for the country will provide a tool for periodic and comprehensive assessment of the performance of the health system, which can be compared with that of other countries. Such a comparison will offer the opportunity for mutual learning and for exploring new options for formulating more effective national health policies. As this is expected to be the first attempt to develop a comprehensive HSPA framework in Ghana, this study will provide a basis for future discussions on how to further develop and implement HSPA programmes in the country.
Detecting prognostic biomarkers of breast cancer by regularized Cox proportional hazards models
Authors: Li Lingyu , Liu Zhi-Ping
Published: December 2021

Background

The successful identification of breast cancer (BRCA) prognostic biomarkers is essential for the strategic interference of BRCA patients. Recently, various methods have been proposed for exploring a small prognostic gene set that can distinguish the high-risk group from the low-risk group.

Methods

Regularized Cox proportional hazards (RCPH) models were proposed to discover prognostic biomarkers of BRCA from gene expression data. Firstly, the maximum connected network with 1142 genes by mapping 956 differentially expressed genes (DEGs) and 677 previously BRCA-related genes into the gene regulatory network (GRN) was constructed. Then, the 72 union genes of the four feature gene sets identified by Lasso-RCPH, Enet-RCPH,$$L_{0}$$L0-RCPH and SCAD-RCPH models were recognized as the robust prognostic biomarkers. These biomarkers were validated by literature checks, BRCA-specific GRN and functional enrichment analysis. Finally, an index of prognostic risk score (PRS) for BRCA was established based on univariate and multivariate Cox regression analysis. Survival analysis was performed to investigate the PRS on 1080 BRCA patients from the internal validation. Particularly, the nomogram was constructed to express the relationship between PRS and other clinical information on the discovery dataset. The PRS was also verified on 1848 BRCA patients of ten external validation datasets or collected cohorts.

Results

The nomogram highlighted that the importance of PRS in guiding significance for the prognosis of BRCA patients. In addition, the PRS of 301 normal samples and 306 tumor samples from five independent datasets showed that it is significantly higher in tumors than in normal tissues ($$P<0.05$$P<0.05). The protein expression profiles of the three genes, i.e.,ADRB1,SAV1andTSPAN14, involved in the PRS model demonstrated that the latter two genes are more strongly stained in tumor specimens. More importantly, external validation illustrated that the high-risk group has worse survival than the low-risk group ($$P<0.05$$P<0.05) in both internal and external validations.

Conclusions

The proposed pipelines of detecting and validating prognostic biomarker genes for BRCA are effective and efficient. Moreover, the proposed PRS is very promising as an important indicator for judging the prognosis of BRCA patients.
An artificial neural-network approach to identify motor hotspot for upper-limb based on electroencephalography: a proof-of-concept study
Authors: Choi Ga-Young , Han Chang-Hee , Lee Hyung-Tak , Paik Nam-Jong , Kim Won-Seok , Hwang Han-Jeong
Published: December 2021

Background

To apply transcranial electrical stimulation (tES) to the motor cortex, motor hotspots are generally identified using motor evoked potentials by transcranial magnetic stimulation (TMS). The objective of this study is to validate the feasibility of a novel electroencephalography (EEG)-based motor-hotspot-identification approach using a machine learning technique as a potential alternative to TMS.

Methods

EEG data were measured using 63 channels from thirty subjects as they performed a simple finger tapping task. Power spectral densities of the EEG data were extracted from six frequency bands (delta, theta, alpha, beta, gamma, and full) and were independently used to train and test an artificial neural network for motor hotspot identification. The 3D coordinate information of individual motor hotspots identified by TMS were quantitatively compared with those estimated by our EEG-based motor-hotspot-identification approach to assess its feasibility.

Results

The minimum mean error distance between the motor hotspot locations identified by TMS and our proposed motor-hotspot-identification approach was 0.22 ± 0.03 cm, demonstrating the proof-of-concept of our proposed EEG-based approach. A mean error distance of 1.32 ± 0.15 cm was measured when using only nine channels attached to the middle of the motor cortex, showing the possibility of practically using the proposed motor-hotspot-identification approach based on a relatively small number of EEG channels.

Conclusion

We demonstrated the feasibility of our novel EEG-based motor-hotspot-identification method. It is expected that our approach can be used as an alternative to TMS for motor hotspot identification. In particular, its usability would significantly increase when using a recently developed portable tES device integrated with an EEG device.
Classification of Parkinson’s disease with freezing of gait based on 360° turning analysis using 36 kinematic features
Authors: Park Hwayoung , Shin Sungtae , Youm Changhong , Cheon Sang-Myung , Lee Myeounggon , Noh Byungjoo
Published: December 2021

Background

Freezing of gait (FOG) is a sensitive problem, which is caused by motor control deficits and requires greater attention during postural transitions such as turning in people with Parkinson’s disease (PD). However, the turning characteristics have not yet been extensively investigated to distinguish between people with PD with and without FOG (freezers and non-freezers) based on full-body kinematic analysis during the turning task. The objectives of this study were to identify the machine learning model that best classifies people with PD and freezers and reveal the associations between clinical characteristics and turning features based on feature selection through stepwise regression.

Methods

The study recruited 77 people with PD (31 freezers and 46 non-freezers) and 34 age-matched older adults. The 360° turning task was performed at the preferred speed for the inner step of the more affected limb. All experiments on the people with PD were performed in the “Off” state of medication. The full-body kinematic features during the turning task were extracted using the three-dimensional motion capture system. These features were selected via stepwise regression.

Results

In feature selection through stepwise regression, five and six features were identified to distinguish between people with PD and controls and between freezers and non-freezers (PD and FOG classification problem), respectively. The machine learning model accuracies revealed that the random forest (RF) model had 98.1% accuracy when using all turning features and 98.0% accuracy when using the five features selected for PD classification. In addition, RF and logistic regression showed accuracies of 79.4% when using all turning features and 72.9% when using the six selected features for FOG classification.

Conclusion

We suggest that our study leads to understanding of the turning characteristics of people with PD and freezers during the 360° turning task for the inner step of the more affected limb and may help improve the objective classification and clinical assessment by disease progression using turning features.
Viral metagenomics reveals two novel anelloviruses in feces of experimental rats
Authors: Ning Song-Yi , Zhou Ming-Ming , Yang Jie , Zeng Jian , Wang Jia-Ping
Published: December 2021

Background

Rodents are widely distributed and are the natural reservoirs of a diverse group of zoonotic viruses. Thus, analyzing the viral diversity harbored by rodents could assist efforts to predict and reduce the risk of future emergence of zoonotic viral diseases. Rodents are commonly used in animal testing, particularly mice and rats. Experimental rats are important animal models, and a history of pathogenic infections in these animals will directly affect the animal trial results. The pathogenicity of Anellovirus (AV) remains poorly understood due to the lack of a suitable model cell line or animal to support the viral cycle. This study aimed to discover possible anelloviruses from the virome in feces of experimental rats by viral metagenomic technique.

Methods

Fecal samples were collected from 10 commercial SD rats and pooled into a sample pool and then subjected to libraries construction which was then sequenced on Illumina MiSeq platform. The sequenced reads were analyzed using viral metagenomic analysis pipeline and two novel anelloviruses (AVs) were identified from fecal sample of experimental rats. The prevalence of these two viruses was investigated by conventional PCR.

Results

The complete genomic sequence of these two AVs were determined and fully characterized, with strain name ratane153-zj1 and ratane153-zj2. The circular genomes of ratane153-zj1 and ratane153-zj2 are 2785 nt and 1930 nt in length, respectively, and both include three ORFs. Ratane153-zj1 closely clustered with members within the genus Wawtorquevirus and formed a separate branch based on the phylogenetic tree constructed over the amino acid sequence of ORF1 of the two AVs identified in this study and other related AVs. While the complete amino acid sequences of ORF1 of ratane153-zj2 (nt 335 to 1390) had the highest sequence identity with an unclassified AV (GenBank No. ATY37438) from Chinchilla lanigera, and they clustered with one AV (GenBank No. QYD02305) belonging to the genus Etatorquevirus from Lynx rufus. Conventional PCR with two sets of specific primers designed based on the two genomes, respectively, showed that they were detectable at a low frequency in cohorts of experimental rats.

Conclusion

Our study expanded the genome diversity of AVs and provided genetic background information of viruses existed in experimental rats.
Simulation study reveals factors that affect the predominance of SARS-CoV-2 novel variant
Authors: Furuse Yuki
Published: December 2021

The novel variants of the SARS-CoV-2 are a great global concern for the ongoing COVID-19 pandemic. However, how the novel variants predominate and replace existing strains remains elusive. In this study, I simulated the infection spread to investigate what kinds of viral, immunological, and epidemiological factors affect the predominance of SARS-CoV-2 novel variants. The results showed that the increase of the transmissibility of the novel variant substantially enhanced the predominance probability. In addition, the increasing trend of the infection spread, the large case number of the epidemic, and the ability of immune escape of the novel variant increased the predominance probability. A small number of cases and a decreasing trend of an entire epidemic, including not only the novel variant but also earlier strains, are especially important to reduce the chance of the predominance of the novel variant and delay the process. Good control of the COVID-19 epidemic could make the disease burden small and sequester the spread of the SARS-CoV-2 novel variants.
Histopathology of the broad class of carbon nanotubes and nanofibers used or produced in U.S. facilities in a murine model
Authors: Fraser Kelly , Hubbs Ann , Yanamala Naveena , Mercer Robert R. , Stueckle Todd A. , Jensen Jake , Eye Tracy , Battelli Lori , Clingerman Sidney , Fluharty Kara , Dodd Tiana , Casuccio Gary , Bunker Kristin , Lersch Traci L. , Kashon Michael L. , Orandle Marlene , Dahm Matthew , Schubauer-Berigan Mary K. , Kodali Vamsi , Erdely Aaron
Published: December 2021

Background

Multi-walled carbon nanotubes and nanofibers (CNT/F) have been previously investigated for their potential toxicities; however, comparative studies of the broad material class are lacking, especially those with a larger diameter. Additionally, computational modeling correlating physicochemical characteristics and toxicity outcomes have been infrequently employed, and it is unclear if all CNT/F confer similar toxicity, including histopathology changes such as pulmonary fibrosis. Male C57BL/6 mice were exposed to 40 µg of one of nine CNT/F (MW #1–7 and CNF #1–2) commonly found in exposure assessment studies of U.S. facilities with diameters ranging from 6 to 150 nm. Human fibroblasts (0–20 µg/ml) were used to assess the predictive value of in vitro to in vivo modeling systems.

Results

All materials induced histopathology changes, although the types and magnitude of the changes varied. In general, the larger diameter MWs (MW #5–7, including Mitsui-7) and CNF #1 induced greater histopathology changes compared to MW #1 and #3 while MW #4 and CNF #2 were intermediate in effect. Differences in individual alveolar or bronchiolar outcomes and severity correlated with physical dimensions and how the materials agglomerated. Human fibroblast monocultures were found to be insufficient to fully replicate in vivo fibrosis outcomes suggesting in vitro predictive potential depends upon more advanced cell culture in vitro models. Pleural penetrations were observed more consistently in CNT/F with larger lengths and diameters.

Conclusion

Physicochemical characteristics, notably nominal CNT/F dimension and agglomerate size, predicted histopathologic changes and enabled grouping of materials by their toxicity profiles. Particles of greater nominal tube length were generally associated with increased severity of histopathology outcomes. Larger particle lengths and agglomerates were associated with more severe bronchi/bronchiolar outcomes. Spherical agglomerated particles of smaller nominal tube dimension were linked to granulomatous inflammation while a mixture of smaller and larger dimensional CNT/F resulted in more severe alveolar injury.
Estimating the impact of neonatal abstinence system interventions on Medicaid: an incremental cost analysis
Authors: López-Soto Diana , Griffin Paul M.
Published: December 2021

Background

Neonatal abstinence syndrome (NAS) incidence has significantly increased in the US in recent years. It is therefore important to develop effective intervention protocols that mitigate the long-term consequences of this condition for the mother, her child, and the community.

Methods

We used Monte Carlo simulation to estimate the impact of four interventions for NAS and their combinations on pregnant women with opioid use disorder. The key outputs were changes in incremental costs from baseline from the Medicaid perspective and from a total systems perspective and effect size changes. Simulation parameters and costs were based on the literature and baseline model validation was performed using Medicaid claims for Indiana.

Results

Compared to baseline, the resulting simulation estimates showed that three interventions significantly decreased Medicaid incremental costs by 8% (mandatory opioid testing (MOT)), 4% (patient navigators), and 3% (peer recovery coaches). The combination of the three interventions reduced Medicaid direct costs by 26%. Reductions were similar for total system incremental costs (ranging from 2 to 24%), though MOT was found to increase costs of overdose death based on productivity loss. NAS case reductions ranged from 1% (capacity change) to 13% (MOT).

Conclusions

Using systems-based modeling, we showed that costs associated with NAS can be significantly reduced. However, effective implementation would require the involvement and coordination of several stakeholders. In addition, careful protocols for MOT should be considered to ensure pregnant women don’t forgo prenatal care for fear of punitive consequences.
Proton therapy with a fixed beamline for skull-base chordomas and chondrosarcomas: outcomes and toxicity
Authors: Gordon Konstantin , Gulidov Igor , Koryakin Sergey , Smyk Daniil , Makeenkova Tatyana , Gogolin Danil , Lepilina Olga , Golovanova Olga , Semenov Alexey , Dujenko Sergey , Medvedeva Kira , Mardynsky Yuri
Published: December 2021

Aim

This study presents an analysis (efficacy and toxicity) of outcomes in patients with skull-base chordomas or chondrosarcomas treated with a fixed horizontal pencil proton beam.

Background

Chordomas (CAs) and chondrosarcomas (CSAs) are rare tumours that are usually located near the base of the skull and very close to the brain's most critical structures. Proton therapy (PT) is often considered the best radiation treatment for these diseases, but it is still a limited resource. Active scanning PT delivered via a fixed pencil beamline might be a promising option.

Methods

This is a single-centre experience describing the results of proton therapy for 31 patients with CA (n = 23) or CSA (n = 8) located near the base of the skull. Proton therapy was utilized by a fixed pencil beamline with a chair to position the patient between May 2016 and November 2020. Ten patients underwent resection (32.2%), 15 patients (48.4%) underwent R2 resection, and 6 patients had unresectable tumours (19.4%). In 4 cases, the tumours had been previously irradiated. The median PT dose was 70 GyRBE (relative biological efficacy, 1.1) [range, 60 to 74] with 2.0 GyRBE per fraction. The mean GTV volume was 25.6 cm3 [range, 4.2–115.6]. Patient demographics, pathology, treatment parameters, and toxicity were collected and analysed. Radiation-induced reactions were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) v 4.0.

Results

The median follow-up time was 21 months [range, 4 to 52]. The median overall survival (OS) was 40 months. The 1- and 2-year OS was 100%, and the 3-year OS was 66.3%. Four patients died due to non-cancer-related reasons, 1 patient died due to tumour progression, and 1 patient died due to treatment-related injuries. The 1-year local control (LC) rate was 100%, the 2-year LC rate was 93.7%, and the 3-year LC rate was 85.3%. Two patients with CSA exhibited progression in the neck lymph nodes and lungs. All patients tolerated PT well without any treatment interruptions. We observed 2 cases of ≥ grade 3 toxicity, with 1 case of grade 3 myelitis and 1 case of grade 5 brainstem injury.

Conclusion

Treatment with a fixed proton beam shows promising disease control and an acceptable toxicity rate, even the difficult-to-treat subpopulation of patients with skull-base chordomas or chondrosarcomas requiring dose escalation.
Severity and location of lumbar spine stenosis affects the outcome of total knee arthroplasty
Authors: Sheppard William L. , McKay Kevin M. , Upfill-Brown Alexander , Blumstein Gideon , Park Howard Y. , Shah Akash , Sassoon Adam A. , Park Don Y.
Published: December 2021

Background

Recent studies have noted that patients with pre-existing lumbar spinal stenosis (LSS) have lower functional outcomes after total knee arthroplasty (TKA). Given that LSS manifests heterogeneously in location and severity, its influence on knee replacement merits a radiographically targeted analysis. We hypothesize that patients with more severe LSS will have diminished knee mobility before and after TKA.

Methods

This retrospective case series assessed all TKAs performed at our institution for primary osteoarthritis from 2017–2020. Preoperative lumbar magnetic resonance image (MRI) with no prior lumbar spine surgery was necessary for inclusion. Stenosis severity was demonstrated by (1) anterior–posterior (AP) diameter of the thecal sac and (2) morphological grade. TKA outcomes in 103 cases (94 patients) were assessed by measuring preoperative and postoperative arc of motion (AOM), postoperative flexion contracture, and need for manipulation under anesthesia.

Results

Patients with mild stenosis did significantly better in terms of postoperative knee AOM. As AP diameter decreased at levels L1–2, L2–3, L3–4, and L4–5, there was a significant reduction in preoperative-AOM (p < 0.001 for each), with a 16 degree decrease when using patients’ most stenotic level (p < 0.001). The same was noted with respect to increased morphological grade (p < 0.001), with a 5 degree decrease for patients’ most stenotic level (p < 0.001).

Conclusion

Severe LSS, which is readily demonstrated by a reduction in the AP diameter of the thecal sac or increased morphological grade on MRI, correlated with a significant reduction in preoperative AOM that was not improved after TKA. Persistent postoperative reductions in AOM may contribute to reduced patient satisfaction and recovery.

Level of evidence: Level 4