bluuebunny/crossref_metadata_2025 huggingface dataset:
KODY, an all-of-family response to co-occurring substance use and domestic violence: protocol for a quasi-experimental intervention trial
Authors: Kertesz Margaret , Humphreys Cathy , Fogden Larissa , Scott Katreena , Laslett Anne-Marie , Tsantefski Menka
Published: February 2022

Background

The co-occurrence of domestic violence with alcohol and other drugs significantly increases the severity of abuse and violence experienced by family members. Longitudinal studies indicate that substance use is one of few predictors of men’s continued use of, or desistance from, violence. Recent developments in men’s behaviour change programs have focused on men’s attitudes and behaviour towards their children, and the exploration of interventions that address the needs of all family members. However, the research evidence is limited on the most effective elements of men’s behaviour change programs in promoting the safety and wellbeing of child and women victim survivors.

This study aims to build on the existing evidence by trialling the KODY program which addresses harmful substance use by men who also perpetrate domestic violence; the safety and wellbeing of women and children; the needs of children in their own right, as well as in relationship with their mothers; and the development of an ‘all-of-family’ service response. The evaluation of these innovations, and the ramifications for policy development to support less fragmented service system responses, provide the rationale for the study.

Methods/Design

A quasi-experimental design will be used to assess the primary outcomes of improving the safety and wellbeing of mothers and children whose (ex)partners and fathers respectively participate in KODY (the trial program), when compared with ‘Caring Dadsstandard’ (the comparison group). Psychometric tests will be administered to fathers and mothers at baseline, post-program and at 3-month follow up. Data collection will occur over three years.

Discussion

By building the evidence base about responses to co-occurring domestic violence and substance use, this study aims to develop knowledge about improving safety outcomes for women and children, and to better understand appropriate support for children in families living at the intersection of domestic violence and substance use. It is anticipated that study findings will point to the ramifications for policy development to support less fragmented service system responses.

Trial registration

An application for registration with the Australian and New Zealand Clinical Trials Registry (https://www.anzctr.org.au/) was lodged on 20 December 2021 (Request number: 383206)—prospectively registered.
The impact of COVID-19 and associated measures on health, police, and non-government organisation service utilisation related to violence against women and children
Authors: Butler Nadia , Quigg Zara , Pearson Isabelle , Yelgezekova Zhamin , Nihlén Aasa , Bellis Mark A. , Yon Yongjie , Passmore Jonathon , Aguirre Isabel Yordi , Stöckl Heidi
Published: February 2022

Background

Globally, concerns have been raised that the priority implementation of public health measures in response to COVID-19 may have unintended negative impacts on a variety of other health and wellbeing factors, including violence. This study examined the impact of COVID-19 response measures on changes in violence against women and children (VAWC) service utilisation across European countries.

Methods

A rapid assessment design was used to compile data including a survey distributed across WHO Europe Healthy Cities Networks and Violence Injury Prevention Focal Points in WHO European Region member states, and a scoping review of media reports, journal articles, and reports. Searches were conducted in English and Russian and covered the period between 1 January 2020 and 17 September 2020. Data extracted included: country; violence type; service sector; and change in service utilisation during COVID-19. All data pertained to the period during which COVID-19 related public health measures were implemented compared to a period before restrictions were in place.

Results

Overall, findings suggested that there was a median reported increase in VAWC service utilisation of approximately 20% during the COVID-19 pandemic. Crucially, however, change in service utilisation differed across sectors. After categorising each estimate as reflecting an increase or decrease in VAWC service utilisation, there was a significant association between sector and change in service utilisation; the majority of NGO estimates (95.1%) showed an increase in utilisation, compared to 58.2% of law enforcement estimates and 42.9% of health and social care estimates.

Conclusions

The variation across sectors in changes in VAWC service utilisation has important implications for policymakers in the event of ongoing and future restrictions related to COVID-19, and more generally during other times of prolonged presence in the home. The increased global attention on VAWC during the pandemic should be used to drive forward the agenda on prevention, increase access to services, and implement better data collection mechanisms to ensure the momentum and increased focus on VAWC during the pandemic is not wasted.
Using health economic modelling to inform the design and development of an intervention: estimating the justifiable cost of weight loss maintenance in the UK
Authors: Bates Sarah E. , Thomas Chloe , Islam Nazrul , Ahern Amy L. , Breeze Penny , Griffin Simon , Brennan Alan
Published: February 2022

Background

There is a need to develop cost-effective weight loss maintenance interventions to prolong the positive impact of weight loss on health outcomes. Conducting pre-trial health economic modelling is recommended to inform the design and development of behavioural interventions. We aimed to use health economic modelling to estimate the maximum cost per-person (justifiable cost) of a cost-effective behavioural weight loss maintenance intervention, given an estimated intervention effect for individuals with: i) a Body Mass Index (BMI) of 28 kg/m2 or above without diabetes and ii) a diagnosis of type 2 diabetes prescribed a single non-insulin diabetes medication.

Methods

The School for Public Health Research Diabetes prevention model was used to estimate the lifetime Quality-adjusted life year (QALY) gains, healthcare costs, and maximum justifiable cost associated with a weight loss maintenance intervention. Based on a meta-analysis, the estimated effect of a weight loss maintenance intervention following a 9 kg weight loss, was a regain of 1.33 kg and 4.38 kg in years one and two respectively compared to greater regain of 2.84 kg and 5.6 kg in the control group. Sensitivity analysis was conducted around the rate of regain, duration of effect and initial weight loss.

Results

The justifiable cost for a weight loss maintenance intervention at an ICER of £20,000 per QALY was £104.64 for an individual with a BMI of 28 or over and £88.14 for an individual with type 2 diabetes. Within sensitivity analysis, this varied from £36.42 to £203.77 for the former, and between £29.98 and £173.05 for the latter.

Conclusions

Researchers developing a weight loss maintenance intervention should consider these maximum justifiable cost estimates and the potential impact of the duration of effect and initial weight loss when designing intervention content and deciding target populations. Future research should consider using the methods demonstrated in this study to use health economic modelling to inform the design and budgetary decisions in the development of a behavioural interventions.
The relation between serum uric acid levels and diabetic peripheral neuropathy in type 2 diabetes in Guilan, north of Iran
Authors: Fayazi Haniye Sadat , Yaseri Maryam , Mortazavi Seyyede Sahere , Sharifhassan Zahra , Assadinia Ali-Sina
Published: February 2022

Background

Diabetic peripheral neuropathy (DPN) is one of the most common chronic microvascular complications in type 2 diabetes mellitus (T2DM). Hence, the present study aimed to investigate the association between Serum Uric Acid (SUA) levels and diabetic peripheral polyneuropathy in patients with type 2 diabetes.

Methods

We performed this case–control study during 2019–2020 on individuals with diabetes referring to the Razi clinic of Rasht, in the north of Iran. Polyneuropathy in patients was assessed based on the Neuropathy Disability Score (NDS), Diabetic neuropathy symptom score (DNS) scoring system, and electromyography (EMG)/nerve conduction velocity (NCV). The inclusion criterion for the control group was normal EMG/NCV. Then, the patients were assessed for SUA level and also laboratory results.

Results

In total, 230 patients with type 2 diabetes were examined. The mean SUA level in the DPN group was significantly higher compared to the control group (6.72 ± 1.75 vs. 4.57 ± 1.49 mg/dL). With increasing the SUA, the odds of developing neuropathy increased by 2.2 times (OR = 2.2). The risk factors for diabetic polyneuropathy included gender (male) (OR = 0.347), SBP (OR = 1.1), retinopathy (OR = 3.29), and microalbuminuria (OR = 4.44). The chance of developing polyneuropathy in patients with retinopathy was 3.3 times higher than in the control group, it was 4.4 times in microalbuminuria patients.

Conclusion

Elevated SUA level increased the chance of developing peripheral polyneuropathy in a person with type 2 diabetes. SUA levels higher than 5.25 mg / dL expose a person with type 2 diabetes to developing peripheral polyneuropathy.
Complementary medicine use in stroke survivors: a US nationally representative survey
Authors: Kohl-Heckl Wiebke K. , Koch Anna K. , Cramer Holger
Published: February 2022

Background

Stroke is the second most common cause of death worldwide. Even after surviving, long-term rehabilitation often becomes necessary and does not always lead to complete recovery. Guidelines focus on prevention of risk factors and present concepts for rehabilitation after a stroke. Additional to these recommendations, complementary medicine (CM) utilization is common among patients with neurological conditions. CM also offers a wide range of therapies for both prevention and rehabilitation in stroke. There is limited information available on CM utilization among stroke survivors and differences to patients without former stroke diagnosis.

Methods and results

This analysis was based on data of the 2017 National Health Interview survey (NHIS,n = 26,742; response rate 80,7%). We analyzed the prevalence of consultations among stroke patients with CM practitioners within the last 12 months and reasons for utilization. 3.1% of participants reported a stroke, individuals without a prior stroke diagnosis were more likely to have used CM in the past 12 months (31.3% without versus 28.9% with stroke). Consultations with a chiropractor and of using mind-body-medicine was higher in individuals without stroke diagnosis, while more stroke survivors had consulted a naturopath. Equal proportions had consulted a homeopath. Most common therapy approaches among stroke survivors were spiritual meditation (13.7%), progressive relaxation (5.4%), yoga (5.2%), mindfulness meditation (4.3%), mantra meditation (3.1%), guided imagery (2.6%) and tai chi (1.7%). CM use in stroke survivors was associated with female sex (adjusted odds ratio [AOR] = 2.12, 95% confidence interval [CI] = 1.56–2.88) and higher education (AOR = 1.94, CI = 1.42–2.65).

Conclusion

Stroke patients were less likely to take advantage of complementary medicine than the general population. Since there are many safe and beneficial options, stroke survivors might profit from better information about the existing possibilities regarding prevention and rehabilitation.
What is it like to organize a large-scale educational event for fellow students? A qualitative exploration of student participation in curriculum design
Authors: Olthuis Gert , Eggermont Florieke , Schouwenberg Bas , Oerlemans Anke , Tanck Esther
Published: February 2022

Background

Although students are increasingly involved in curriculum design, empirical research on practices of actual student participation is sparse. The purpose of this study is to explore the experiences of students who collaborated in the organizing committee of a large-scale educational event, the Radboud Student Conference (RSC), for fellow students.

Methods

We conducted three focus group interviews, in which 17 (bio) medical students of three different organizing teams shared their experiences regarding the organization of the large-scale teaching event. The analysis was conducted using thematic content analysis, in which the codes and codebook were constructed on the basis of the data.

Results

The following four themes were derived from the data. 1) Collaboration, which concentrated on fellow students, teachers who were involved as supervisors, and persons outside the organizing team such as caterers, educational support office members, lecturers, physicians and researchers. 2) Planning and division of labor, with students experiencing a mutual dependence and noticing a gradual improvement of their skills. 3) Freedom implies responsibility, which indicted that students experienced a significant freedom to develop the RSC week, but at the same time felt the responsibility to deliver a successful final week of the academic year. 4) Personal development, where students mentioned the opportunity to practice skills that differed from standard (bio) medical electives.

Conclusions

We conclude that (bio) medical students are capable of bearing the responsibility to organize a large-scale educational event. Organizing the RSC was an educational experience in the form of cooperative and experiential learning which contributed to students’ personal development. Organizing the event gave students both a sense of freedom and the responsibility to succeed. Supervision of faculty members seemed a prerequisite, and tended to be supportive rather than guiding.
Towards digital health equity - a qualitative study of the challenges experienced by vulnerable groups in using digital health services in the COVID-19 era
Authors: Kaihlanen Anu-Marja , Virtanen Lotta , Buchert Ulla , Safarov Nuriiar , Valkonen Paula , Hietapakka Laura , Hörhammer Iiris , Kujala Sari , Kouvonen Anne , Heponiemi Tarja
Published: February 2022

Background

The COVID-19 pandemic has given an unprecedented boost to already increased digital health services, which can place many vulnerable groups at risk of digital exclusion. To improve the likelihood of achieving digital health equity, it is necessary to identify and address the elements that may prevent vulnerable groups from benefiting from digital health services. This study examined the challenges experienced by vulnerable groups in using digital health services during the COVID-19 pandemic.

Methods

Qualitative descriptive design was utilized. Semi-structured interviews were conducted between October 2020 and May 2021. The participants (N = 74) were older adults, migrants, mental health service users, high users of health services, and the unemployed. Qualitative content analysis with both inductive and deductive approach was used to analyze the data. Challenges related to the use of digital health services were interpreted through digital determinants of health from the Digital Health Equity Framework.

Results

For most of the participants the access to digital health services was hampered by insufficient digital, and / or local language skills. The lack of support and training, poor health, as well as the lack of strong e-identification or suitable devices also prevented the access. Digital services were not perceived to be applicable for all situations or capable of replacing face-to-face services due to the poor communication in the digital environment. Fears and the lack of trust regarding digital platforms were expressed as well as concerns related to the security of the services. Contact with a health care professional was also considered less personal and more prone to misunderstandings in the digital environment than in face-to-face services. Finally, digital alternatives were not always available as desired by participants, or participants were unaware of existing digital services and their value.

Conclusion

Several development needs in the implementation of digital health services were identified that could improve equal access to and benefits gained from digital services in the future. While digital health services are increasing, traditional face-to-face services will still need to be offered alongside the digital ones to ensure equal access to services.
Evaluating caregivers’ service quality perceptions: impact-range performance and asymmetry analyses
Authors: Wang Wen-Fu , Chen Chun-Min , Jhang Kai-Ming , Su Yung-Yu
Published: February 2022

Background

This study aimed to analyze family caregivers’ (FCs) dementia care service perceptions to identify the various attributes impacting FCs satisfaction and dissatisfaction.

Methods

This is a cross-sectional survey study using convenience sampling methods. A self-completion questionnaire was developed from the Service Quality scale and distributed using a convenience sampling method to family caregivers in community-based dementia care centers to determine their perceptions of service quality in dementia care. Both exploratory factor analysis and reliability analysis were conducted to confirm the validity and factor structure of the scale. This study employed Impact Range Performance Analysis (IRPA) and Impact Asymmetry Analysis (IAA) to analyze the data obtained from FCs across five attribute dimensions (Tangibles, Reliability, Responsiveness, Assurance, and Empathy). Priorities for service improvement were derived using a three-step analytical framework.

Results

This study reported that the overall perceived performance of service provided is high. The results indicated that practitioners should focus on attributes such as demand coordination, appropriate services, timely service, barrier-free environment, care-giving process, fire and safety compliance, professional knowledge, and reliable services, which have a higher range of impact on customer service and low impact-asymmetry and attribute performance scores.

Conclusion

This study used expectation and perceived performance to suggest that the priorities for improvement and resource allocation in dementia care centers vary across different attributes. Thus, attentiveness toward satisfying user demand could improve patient care and caregiver satisfaction. The dimensions and attributes identified by our study can serve as basic data for future research on the long-term care system.
Severe phenotypes of B3GAT3-related disorder caused by two heterozygous variants: a case report and literature review
Authors: Li Ying , Zhang Chuangwen , Zhang Hongyu , Feng Weiqi , Wang Qiuji , Fan Ruixin
Published: February 2022

Background

Linkeropathies refers to a series of extremely rare hereditary connective tissue diseases affected by various glycosyltransferases in the biosynthesis of proteoglycans. We report for the first time two heterozygous variants of B3GAT3 in a Chinese infant, in whom Marfan syndrome was suspected at birth.

Case presentation

A 2-month-old boy from a non-consanguineous Chinese family without a family history presented severe phenotypes of joint dislocation, obvious flexion contractures of the elbow, arachnodactyly with slightly adducted thumbs, cranial dysplasia, foot abnormalities and aortic root dilation; Marfan syndrome was suspected at birth. Our patient was the youngest, at the age of 2 months, to experience aortic root dilation. Two B3GAT3 variants, NM_012200.2, c.752T>C, p.V251A and c.47C>A, p.S16*, with heterozygosity were identified in the patient by whole-exome sequencing; the variants were inherited from his parents. During close follow-up, significant changes in the cranial profile and obvious external hydrocephalus were present at the age of 7 months, which differs from previously reported cases.

Conclusion

We diagnosed a patient with congenital heart defects at an early age with a B3GAT3-related disorder instead of Marfan syndrome and expanded the spectrum of B3GAT3-related disorders. We also provide a literature review of reported B3GAT3 cases; for at least one of the variants, this is the first report of genotype–phenotype correlations in individuals with cardiovascular defects being related to the acceptor substrate-binding subdomain of B3GAT3.
Clinical and economic burden of comorbid coronary artery disease in patients with acute exacerbation of chronic obstructive pulmonary disease: sex differences in a nationwide cohort study
Authors: Cui Yanan , Zhan Zijie , Ma Yiming , Huang Ke , Liang Chen , Mao Xihua , Zhang Yaowen , Ren Xiaoxia , Lei Jieping , Chen Yan , Yang Ting , Wang Chen
Published: February 2022

Background

Coronary artery disease (CAD) is a common comorbidity of chronic obstructive pulmonary disease (COPD). However, data related to the impact of CAD on outcomes of acute exacerbation of COPD (AECOPD) are limited and whether the relationship depends on sex remains unknown. Our aim was to determine the impact of comorbid CAD on clinical outcomes among men and women with AECOPD.

Methods

We used data from the acute exacerbation of chronic obstructive pulmonary disease inpatient registry (ACURE) study, which is a nationwide observational real-world study conducted between September 2017 and February 2020 at 163 centers in patients admitted with AECOPD as their primary diagnosis. Patients were stratified according to the presence or absence of CAD in men and women. The primary outcomes were the length of hospital stay and economic burden during hospitalization.

Results

Among 3906 patients included in our study, the prevalence of CAD was 17.0%, and it was higher in women than in men (19.5% vs. 16.3%; P = 0.034). Age and other cardiovascular diseases were common factors associated with comorbid CAD in men and women, while body-mass index, cerebrovascular disease, and diabetes were determinants in men and pre-admission use of long-acting beta-adrenoceptor agonist and home oxygen therapy were protective factors in women. Only in men, patients with CAD had a longer length of hospital stay (median 10.0 vs. 9.0 days, P < 0.001), higher total cost during hospitalization (median $1502.2 vs. $1373.4, P < 0.001), and more severe COPD symptoms at day 30 compared to those without CAD. No significant difference was found in women. Comorbid CAD showed no relationship with 30-day readmission or death regardless of sex. In our real-world study, mortality/readmission risk within 30 days increased in patients with previous frequent hospitalizations and poorer pulmonary function.

Conclusions

In hospitalized AECOPD patients, comorbid CAD was significantly associated with poorer short-term outcomes in men. Clinicians should have heightened attention for men with comorbid CAD to achieve an optimal management of AECOPD patients.
ZHX2 inhibits thyroid cancer metastasis through transcriptional inhibition of S100A14
Authors: Zhang Yankun , Sun Min , Gao Lifen , Liang Xiaohong , Ma Chunhong , Lu Jinghui , Yue Xuetian
Published: February 2022

Background

Thyroid cancer is the most common malignant endocrine tumour, and metastasis has become the main reason for treatment failure. However, the underlying molecular mechanism of thyroid cancer metastasis remains poorly understood. We investigated the role of the tumour suppressor zinc fingers and homeoboxes 2 (ZHX2) in the metastasis of thyroid cancer.

Methods

To study the role of ZHX2 in thyroid cancer metastasis, we evaluated the EMT process using cell migration, wound healing and lung metastatic tumour formation in vitro and in vivo models.

Results

ZHX2 expression was significantly decreased in thyroid cancer tissues, which correlated with poor prognosis of thyroid cancer patients. ZHX2 knockdown significantly promoted the migration of thyroid cancer cells. Mechanistically, ZHX2 associated with the S100 calcium binding protein A14 (S100A14) promoter to decrease the transcription of S100A14. Moreover, S100A14 was highly expressed in human thyroid cancer samples, and its expression negatively correlated with ZHX2 expression.

Conclusions

Inhibition of S100A14 attenuated the ZHX2 knockdown-induced enhanced metastasis of thyroid cancer cells both in vitro and in vivo. The evidence presented here suggests that ZHX2 inhibits the progression of thyroid cancer by blocking S100A14-mediated metastasis.
Identification of key serum biomarkers for the diagnosis and metastatic prediction of osteosarcoma by analysis of immune cell infiltration
Authors: Chen Zhihao , Li Liubing , Li Ziyuan , Wang Xi , Han Mingxiao , Gao Zongshuai , Wang Min , Hu Gangfeng , Xie Xiaolu , Du Hong , Xie Zonggang , Zhang Haifang
Published: February 2022

Background

The role of circular RNAs (circRNAs) and microRNAs (miRNAs) in osteosarcoma (OS) development has not been fully elucidated. Further, the contribution of the immune response to OS progression is not well defined. However, it is known that circRNAs and miRNAs can serve as biomarkers for the diagnosis, prognosis, and therapy of many cancers. Thus, the aim of this study was to identify novel key serum biomarkers for the diagnosis and metastatic prediction of OS by analysis of immune cell infiltration and associated RNA molecules.

Methods

Human OS differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified by analysis of microarray data downloaded from Gene Expression Omnibus (GEO) datasets. Further, characteristic patterns of OS-infiltrating immune cells were analyzed. On this basis, we identified statistically significant transcription factors. Moreover we performed pathway enrichment analysis, constructed protein–protein interaction networks, and devised competitive endogenous RNA (ceRNA) networks. Biological targets of the ceRNA networks were evaluated and potential OS biomarkers confirmed by RT-qPCR analysis of the patients’ serum.

Results

Seven differentially expressed circRNAs, 166 differentially expressed miRNAs, and 175 differentially expressed mRNAs were identified. An evaluation of cellular OS infiltration identified the highest level of infiltration by M0 macrophages, M2 macrophages, and CD8+ T cells, with M0 macrophages and CD8+ T cells as the most prominent. Significant patterns of tumor-infiltrating immune cells were identified by principal component analysis. Moreover, 185 statistically significant transcription factors were associated with OS. Further, in association with immune cell infiltration, hsa-circ-0010220, hsa-miR-326, hsa-miR-338-3p, and FAM98A were identified as potential novel biomarkers for OS diagnosis. Of these, FAM98A had the most promise as a diagnostic marker for OS and OS metastasis. Most importantly, a novel diagnostic model consisting of these four biomarkers (hsa-circ-0010220, hsa-miR-326, hsa-miR-338-3p, and FAM98A) was established with a 0.928 AUC value.

Conclusions

In summary, potential serum biomarkers for OS diagnosis and metastatic prediction were identified based on an analysis of immune cell infiltration. A novel diagnostic model consisting of these four promising serum biomarkers was established. Taken together, the results of this study provide a new perspective by which to understand immunotherapy of OS.
Apoptotic changes and aquaporin-1 expression in the choroid plexus of cerebral malaria patients
Authors: Srisook Charit , Glaharn Supattra , Punsawad Chuchard , Viriyavejakul Parnpen
Published: February 2022

Background

Cerebral malaria (CM) is associated with sequestration of parasitized red blood cells (PRBCs) in the capillaries. Often, the association of CM with cerebral oedema is related with high mortality rate. Morphological changes of the choroid plexus (CP) and caspase-3 expression in CM have not been reported. In addition, limited knowledge is known regarding the role of aquaporin (AQP)-1 in CM. The present study evaluated changes in the CP, explored apoptotic changes and AQP-1 expression in CP epithelial cells (CPECs) in fatal CM patients.

Methods

CP from fatal Plasmodium falciparum malaria patients (5 non-CM [NCM], 16 CM) were retrieved and prepared for histopathological evaluation. Caspase-3 and AQP-1 expressions in CPECs were investigated by immunohistochemistry.

Results

Histologically, apoptotic changes in CPECs were significantly observed in the CM group compared with the NCM and normal control (NC) groups (p < 0.05). These changes included cytoplasmic and nuclear condensation/shrinkage of CPECs and detachment of CPECs from the basement membrane. The apoptotic changes were positively correlated with caspase-3 expression in the nuclei of CPECs. In addition, AQP-1 expression in CPECs was significantly decreased in the CM group compared with the NCM and NC groups (all p < 0.001). A negative correlation (rs =  − 0.450, p = 0.024) was documented between caspase-3 expression in the nuclei of CPECs and AQP-1.

Conclusions

Apoptotic changes and altered AQP-1 expression may contribute to CPEC dysfunction and subsequently reduce cerebrospinal fluid production, affecting the water homeostasis in the brains of patients with CM.
UHMK1-dependent phosphorylation of Cajal body protein coilin alters 5-FU sensitivity in colon cancer cells
Authors: Niu Huan , Zhao Meng , Huang Jing , Wang Jing , Si Yang , Cheng Shan , Ding Wei
Published: February 2022

Resistance to 5-fluorouracil (5-FU) in chemotherapy and recurrence of colorectal tumors is a serious concern that impedes improvements to clinical outcomes. In the present study, we found that conditioned medium (CM) derived from 5-FU-resistant HCT-8/FU cells reduced 5-FU chemosensitivity in HCT-8 colon cancer cells, with corresponding changes to number and morphology of Cajal bodies (CBs) as observable nuclear structures. We found that U2AF homology motif kinase 1 (UHMK1) altered CB disassembly and reassembly and regulated the phosphorylation of coilin, a major component of CBs. This subsequently resulted in a large number of variations in RNA alternative splicing that affected cell survival following 5-FU treatment, induced changes in intracellular phenotype, and transmitted preadaptive signals to adjacent cells in the tumor microenvironment (TME). Our findings suggest that CBs may be useful for indicating drug sensitivity or resistance in tumor cells in response to stress signals. The results also suggest that UHMK1 may be an important factor for maintaining CB structure and morphology by regulating splicing events, especially following cellular exposure to cytotoxic drugs.

Graphical Abstract
Early-phase administration of human amnion-derived stem cells ameliorates neurobehavioral deficits of intracerebral hemorrhage by suppressing local inflammation and apoptosis
Authors: Kuramoto Yoji , Fujita Mitsugu , Takagi Toshinori , Takeda Yuki , Doe Nobutaka , Yamahara Kenichi , Yoshimura Shinichi
Published: February 2022

Background

Intracerebral hemorrhage (ICH) is a significant cause of death and disabilities. Recently, cell therapies using mesenchymal stem cells have been shown to improve ICH-induced neurobehavioral deficits. Based on these findings, we designed this study to evaluate the therapeutic efficacy and underlying mechanisms by which human amnion-derived stem cells (hAMSCs) would ameliorate neurobehavioral deficits of ICH-bearing hosts.

Methods

hAMSCs were induced from amnia obtained by cesarean section and administered intravenously to ICH-bearing mice during the acute phase. The mice were then subject to multitask neurobehavioral tests at the subacute phase. We attempted to optimize the dosage and timing of the hAMSC administrations. In parallel with the hAMSCs, a tenfold higher dose of human adipose-derived stem cells (ADSCs) were used as an experimental control. Specimens were obtained from the ICH lesions to conduct immunostaining, flow cytometry, and Western blotting to elucidate the underlying mechanisms of the hAMSC treatment.

Results

The intravenous administration of hAMSCs to the ICH-bearing mice effectively improved their neurobehavioral deficits, particularly when the treatment was initiated at Day 1 after the ICH induction. Of note, the hAMSCs promoted clinical efficacy equivalent to or better than that of hADSCs at 1/10 the cell number. The systemically administered hAMSCs were found in the ICH lesions along with the local accumulation of macrophages/microglia. In detail, the hAMSC treatment decreased the number of CD11b+CD45+ and Ly6G+ cells in the ICH lesions, while splenocytes were not affected. Moreover, the hAMSC treatment decreased the number of apoptotic cells in the ICH lesions. These results were associated with suppression of the protein expression levels of macrophage-related factors iNOS and TNFα.

Conclusions

Intravenous hAMSC administration during the acute phase would improve ICH-induced neurobehavioral disorders. The underlying mechanism was suggested to be the suppression of subacute inflammation and apoptosis by suppressing macrophage/microglia cell numbers and macrophage functions (such as TNFα and iNOS). From a clinical point of view, hAMSC-based treatment may be a novel strategy for the treatment of ICH.
The impact of economic freedom on COVID-19 pandemic control: the moderating role of equality
Authors: Huang Guanglv , Yu Xiaoli , Long Qinyi , Huang Liqin , Luo Siyang
Published: February 2022

Background

The absence of pharmaceutical interventions made it particularly difficult to mitigate the first outbreak of coronavirus disease 2019 (COVID-19). The current study investigated how economic freedom and equality influenced the pandemic control process.

Methods

In Study 1, we assessed the effect of economic freedom and equality on COVID-19 pandemic control from nations worldwide. We collected the cumulative number of confirmed cases over time to perform logistic curve fitting and obtain the speed at which the first wave of the pandemic was controlled, and partial correlation analysis and representational similarity analysis (RSA) were performed to assess the similarity between economic freedom and the speed of pandemic control. In Study 2, an evolutionary game model in which economic freedom affects the speed of pandemic control through optimization of the allocation of available resources was developed. In Study 3, we used experimental manipulation to elucidate the psychological mechanism relating economic freedom and resource allocation.

Results

The economic freedom of nation could be used to positively predict the speed of pandemic control and the related similarity pattern. Equality was found to moderate the correlation and representational similarity between economic freedom and the speed of pandemic control. The evolutionary game model revealed a mechanism whereby economic freedom influences the speed of pandemic control through high resource availability. Furthermore, cooperation was found to be a possible psychological mechanism explaining how economic freedom increases resource availability.

Conclusions

Economic freedom has a positive effect on the control of the COVID-19 pandemic only among highly egalitarian nations. New interventions are needed to help countries heighten economic freedom and equality as they continue to battle COVID-19 and other collective threats.
Intake of flavonoids from Astragalus membranaceus ameliorated brain impairment in diabetic mice via modulating brain-gut axis
Authors: Li Xuling , Zhao Tingting , Gu Junling , Wang Zhe , Lin Jing , Wang Rushang , Duan Tingting , Li Zhenghai , Dong Ruixue , Wang Weiming , Hong Kin-Fong , Liu Zhilong , Huang Wenbo , Gui Dingkun , Zhou Hua , Xu Youhua
Published: February 2022

Background

Brain impairment is one of a major complication of diabetes. Dietary flavonoids have been recommended to prevent brain damage. Astragalus membranaceus is a herbal medicine commonly used to relieve the complications of diabetes. Flavonoids is one of the major ingredients of Astragalus membranaceus, but its function and mechanism on diabetic encepholopathy is still unknown.

Methods

Type 2 diabetes mellitus (T2DM) model was induced by high fat diet and STZ in C57BL/6J mice, and BEnd.3 and HT22 cell lines were applied in the in vitro study. Quality of flavonoids was evaluated by LC–MS/MS. Differential expressed proteins in the hippocampus were evaluated by proteomics; influence of the flavonoids on composition of gut microbiota was analyzed by metagenomics. Mechanism of the flavonoids on diabetic encepholopathy was analyzed by Q-PCR, Western Blot, and multi-immunological methods et al.

Results

We found that flavonoids from Astragalus membranaceus (TFA) significantly ameliorated brain damage by modulating gut-microbiota-brain axis: TFA oral administration decreased fasting blood glucose and food intake, repaired blood brain barrier, protected hippocampus synaptic function; improved hippocampus mitochondrial biosynthesis and energy metabolism; and enriched the intestinal microbiome in high fat diet/STZ-induced diabetic mice. In the in vitro study, we found TFA increased viability of HT22 cells and preserved gut barrier integrity in CaCO2 monocellular layer, and PGC1α/AMPK pathway participated in this process.

Conclusion

Our findings demonstrated that flavonoids from Astragalus membranaceus ameliorated brain impairment, and its modulation on gut-brain axis plays a pivotal role. Our present study provided an alternative solution on preventing and treating diabetic cognition impairment.
Gene-Interaction-Sensitive enrichment analysis in congenital heart disease
Authors: Woodward Alexa A. , Taylor Deanne M. , Goldmuntz Elizabeth , Mitchell Laura E. , Agopian A.J. , Moore Jason H. , Urbanowicz Ryan J.
Published: February 2022

Background

Gene set enrichment analysis (GSEA) uses gene-level univariate associations to identify gene set-phenotype associations for hypothesis generation and interpretation. We propose that GSEA can be adapted to incorporate SNP and gene-level interactions. To this end, gene scores are derived by Relief-based feature importance algorithms that efficiently detect both univariate and interaction effects (MultiSURF) or exclusively interaction effects (MultiSURF*). We compare these interaction-sensitive GSEA approaches to traditionalχ2rankings in simulated genome-wide array data, and in a target and replication cohort of congenital heart disease patients with conotruncal defects (CTDs).

Results

In the simulation study and for both CTD datasets, both Relief-based approaches to GSEA captured more relevant and significant gene ontology terms compared to the univariate GSEA. Key terms and themes of interest include cell adhesion, migration, and signaling. A leading edge analysis highlighted semaphorins and their receptors, the Slit-Robo pathway, and other genes with roles in the secondary heart field and outflow tract development.

Conclusions

Our results indicate that interaction-sensitive approaches to enrichment analysis can improve upon traditional univariate GSEA. This approach replicated univariate findings and identified additional and more robust support for the role of the secondary heart field and cardiac neural crest cell migration in the development of CTDs.
Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer
Authors: Sun Lulu , Ding Huan , Jia Yiming , Shi Mengyao , Guo Daoxia , Yang Pinni , Wang Yu , Liu Fanghua , Zhang Yonghong , Zhu Zhengbao
Published: February 2022

Background

Preclinical and epidemiological studies indicate a potential chemopreventive role of low-density lipoprotein cholesterol (LDL-C) -lowering drugs in the risks of breast cancer and prostate cancer, but the causality remains unclear. We aimed to evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) with risks of breast cancer and prostate cancer using a two-sample Mendelian randomization (MR) method.

Methods

Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with LDL-C in a genome-wide association study (GWAS) meta-analysis from the Global Lipids Genetics Consortium (GLGC; up to 188,577 European individuals) were used to proxy inhibition of HMG-CoA reductase, NPC1L1, and PCSK9. Summary statistics with outcomes were obtained from a GWAS meta-analysis of the Breast Cancer Association Consortium (BCAC; 228,951 European females) and a Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL; 140,254 European males) consortium. SNPs were combined into multiallelic models and MR estimates representing lifelong inhibition of targets were generated using the inverse-variance weighted method.

Results

Genetically proxied inhibition of HMG-CoA reductase (OR: 0.84; 95% CI 0.74–0.95; P = 0.005) and NPC1L1 (OR: 0.72; 95% CI 0.58–0.90; P = 0.005) equivalent to a 1-mmol/L (38.7 mg/dL) reduction in LDL-C was associated with reduced breast cancer risk. There were no significant associations of genetically proxied inhibition of PCSK9 with breast cancer. In contrast, genetically proxied inhibition of PCSK9 (OR: 0.81; 95% CI 0.73–0.90; P < 0.001) but not HMG-CoA reductase and NPC1L1 was negatively associated with prostate cancer. In the secondary analysis, genetically proxied inhibition of HMG-CoA reductase (OR: 0.82; 95% CI 0.71–0.95; P = 0.008) and NPC1L1 (OR: 0.66; 95% CI 0.50–0.86; P = 0.002) was associated with estrogen receptor-positive breast cancer, whereas there was no association of HMG-CoA reductase and NPC1L1 with estrogen receptor-negative breast cancer.

Conclusions

Genetically proxied inhibition of HMG-CoA reductase and NPC1L1 was significantly associated with lower odds of breast cancer, while genetically proxied inhibition of PCSK9 was associated with reduced risk of prostate cancer. Further randomized controlled trials are needed to confirm the respective roles of these LDL-C-lowering drugs in breast cancer and prostate cancer.
Efficacy of active hexose correlated compound on survival of patients with resectable/borderline resectable pancreatic cancer: a study protocol for a double-blind randomized phase II study
Authors: Hashimoto Daisuke , Satoi Sohei , Ishikawa Hideki , Kodera Yasuhiro , Kamei Keiko , Hirano Satoshi , Fujii Tsutomu , Uemura Kenichiro , Tsuchida Akihiko , Yamada Suguru , Yamamoto Tomohisa , Hirota Kiichi , Sekimoto Mitsugu
Published: February 2022

Background

The prognosis of pancreatic ductal adenocarcinoma remains very poor. One possible reason for the short survival of patients with this disease is malnutrition, which can be present at the initial diagnosis, and continue after pancreatectomy. Then, it is important to improve nutritional status and to decrease adverse events during neoadjuvant and adjuvant chemotherapy. Active hexose correlated compound (AHCC) is a standardized extract of cultured Lentinula edodes mycelia, and is considered a potent biological response modifier in the treatment of cancer. To evaluate the survival impact of AHCC on the patients with pancreatic ductal adenocarcinoma, we plan to perform this trial.

Methods

This is a prospective multicenter phase II trial in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma to investigate the efficacy of AHCC regarding survival. Patients will begin taking AHCC or placebo on the first day of neoadjuvant therapy. AHCC or placebo will be continued until 2 years after surgery. The primary endpoint will be 2-year disease-free survival. The secondary endpoints are the completion rate, dose intensity, and adverse event profile of preoperative chemotherapy; response rate to preoperative chemotherapy; rate of decrease in tumor marker (carbohydrate antigen 19-9, carcinoembryonic antigen) concentrations during preoperative chemotherapy; entry rate, completion rate, dose intensity, and adverse event profile of adjuvant chemotherapy; safety of the protocol therapy (adverse effect of AHCC); 2-year overall survival rate; and nutrition score before and after preoperative chemotherapy, and before and after adjuvant chemotherapy. We will enroll 230 patients, and the study involves eight leading Japanese institutions that are all high-volume centers in pancreatic surgery.

Discussion

AHCC is expected to function as a supportive food in patients with pancreatic ductal adenocarcinoma, to reduce the proportion of severe adverse events related to neoadjuvant chemotherapy, and to increase the completion proportion of multimodal treatments, resulting in improved survival.

Trial registration

The trial protocol has been registered in the protocol registration system at the Japan Registry of Clinical Trials (Trial ID: jRCTs051200029). At the time of the submission of this paper (October 2020), the protocol version is 2.0. The completion date is estimated to be November 2024.
Light sheet fluorescence microscopy for the investigation of blood-sucking arthropods dyed via artificial membrane feeding
Authors: ten Bosch Lars , Habedank Birgit , Candeo Alessia , Bassi Andrea , Valentini Gianluca , Gerhard Christoph
Published: February 2022

Physical methods to control pest arthropods are increasing in importance, but detailed knowledge of the effects of some of these methods on the target organisms is lacking. The aim of this study was to use light sheet fluorescence microscopy (LSFM) in anatomical studies of blood-sucking arthropods in vivo to assess the suitability of this method to investigate the morphological structures of arthropods and changes in these structures over time, using the human louse Pediculus humanus (Phthiraptera: Pediculidae) as sample organism. Plasma treatment was used as an example of a procedure employed to control arthropods. The lice were prepared using an artificial membrane feeding method involving the ingestion of human blood alone and human blood with an added fluorescent dye in vitro. It was shown that such staining leads to a notable enhancement of the imaging contrast with respect to unstained whole lice and internal organs that can normally not be viewed by transmission microscopy but which become visible by this approach. Some lice were subjected to plasma treatment to inflict damage to the organisms, which were then compared to untreated lice. Using LSFM, a change in morphology due to plasma treatment was observed.

These results demonstrate that fluorescence staining coupled with LSFM represents a powerful and straightforward method enabling the investigation of the morphology—including anatomy—of blood-sucking lice and other arthropods.

Graphical Abstract
Secular trends in cryoglobulinemia mortality in the USA in the era of direct-acting antivirals
Authors: Guo Qianyu , Gao Jinfang , Duan Jiaoniu , Hou Ruihong , Lu Tsung-Hsueh , Zhang Liyun
Published: February 2022

Background

Hepatitis C virus (HCV) is the main etiology of cryoglobulinemia with mortality around 25%. Little is known on the changes in cryoglobulinemia mortality after the introduction of direct-acting antivirals (DAA) for treatment of HCV in 2014 in the USA.

Methods

We used the multiple-cause mortality files compiled by the National Center for Health Statistics to calculate cryoglobulinemia mortality from 1999 to 2018. The proportionate mortality ratio (PMR) of cryoglobulinemia cases with HCV and those with autoimmune diseases was computed to assess the impact of introduction of DAA.

Results

We identified 1299 people aged ≥ 20 years who died with cryoglobulinemia between 1999 and 2018. The cryoglobulinemia mortality (deaths per million) declined from 1999 (0.4) to 2010 (0.22) and mildly increased to 2014 (0.26), and then decreased abruptly from 2014 to 2018 (0.19) with annual percent change of − 14.3%. The proportion of cryoglobulinemia patients with HCV was 39% (118/302) in 2009–2013 and 26% (81/310) in 2014–2018, with a PMR of 0.67 (95% CI 0.50–0.89). By contrast, the proportion of cryoglobulinemia patients with systemic autoimmune diseases was 2.6% (8/302) in 2009–2013 and 4.2% (13/310) in 2014–2018, with a PMR of 1.58 (95% CI 0.66–3.82).

Conclusion

The changes in cryoglobulinemia mortality during the past two decades are mainly related to the aging and dying of the “baby boomer” cohort who had a high HCV prevalence and to the introduction of a DAA in 2014.