bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid emergence from dexmedetomidine sedation in Sprague Dawley rats by repurposing an α2-adrenergic receptor competitive antagonist in combination with caffeine
Authors: Xie Zheng , Fox Aaron P.
Published: February 2023

Background

The α2 adrenergic receptor agonist dexmedetomidine is an important intravenous sedative with analgesic properties. Currently available dexmedetomidine reversal agents, like the α2-receptor antagonist atipamezole, cause serious adverse effects at the large dosages required for effective reversal; they are not used clinically. Without reversal agents, emergence times from dexmedetomidine sedation are slow. In this study we tested the ability of low-dose atipamezole, in combination with caffeine, to reverse dexmedetomidine sedation. The low dose of atipamezole employed should not be associated with unwanted effects.

Methods

Two different sedation protocols were employed. In the first protocol, a bolus of dexmedetomidine was rapidly applied and the drug was allowed to equilibrate for 10 min before rats received either saline (as control) or low-dose atipamezole with caffeine. Following this procedure, rats were placed on their backs. Emergence from sedation was the time for rats to recover their righting reflex and stand with 4 paws on the floor. A second sedation protocol simulated a pediatric magnetic resonance imaging (MRI) scan. Adult rats were sedated with dexmedetomidine for one hour followed by 30 min with both dexmedetomidine and propofol. At the end of 90 min, rats received either saline (control) or a combination of low-dose atipamezole, and caffeine. Recovery of the righting reflex was used as a proxy for emergence from sedation.

Results

Emergence from sedation, the time for rats to recover their righting reflex, decreased by ~ 90% when using an atipamezole dose ~ 20 fold lower than manufacturer’s recommendation, supplemented with caffeine. Using an atipamezole dose ~ tenfold lower than recommended, with caffeine, emergence times decreased by ~ 97%. A different stimulant, forskolin, when tested, was as effective as caffeine. For the MRI simulation, emergence times were decreased by ~ 93% by low-dose atipamezole with caffeine.

Conclusions

Low dose atipamezole with caffeine was effective at reversing dexmedetomidine sedation. Emergence was rapid and the rats regained not only their righting reflex but also their balance and their ability to carry out complex behaviors. These findings suggest that the combination of low dose atipamezole with caffeine may permit rapid clinical reversal of dexmedetomidine without unwanted effects.
Parenting and parenting resources among Chinese parents with children under three years of age: rural and urban differences
Authors: Han Jing , Hao Yinjun , Cui Naixue , Wang Zhenhui , Lyu Pingping , Yue Lei
Published: February 2023

Background

Parenting is essential for children’s development and preventing child abuse and neglect. Providing parenting services within the primary health care settings demonstrated effectiveness in improving parenting quality. However, little is known about the status of parenting and parenting resources in rural areas and whether they differ between rural and urban areas in Mainland China.

Objective

This study aimed to examine the rural–urban differences in parenting and availability of, utilization of, and need for parenting resources among Chinese parents with children under three years of age.

Participants and setting

A total of 425 parents of children under three years of age participated in an online survey between March and May 2020.

Methods

The Parenting and Family Adjustment Scale and Child Adjustment and Parenting Efficacy Scale were used to assess parenting, family adjustment, and parenting efficacy. The availability of, utilization of, and need for parenting resources were measured using self-developed questions based on literature. Chi-square tests, t tests, and Wilcoxon rank-sum test were used to examine the differences in responses between parents in rural and urban areas.

Results

Compared with their urban counterparts, rural parents reported a higher level of negative parenting and more limited parenting resources. Both rural and urban parents reported low availability and utilization of parenting resources as well as a great need for parenting support services.

Conclusions

Rural parents faced more parenting challenges and limited parenting resources compared with urban parents. Both rural and urban parents with children under three years of age reported great needs for parenting resources. These findings highlight the potential of delivering accessible, sustainable, and cost-effective parenting programs via the primary health care system for public welfare in both urban and rural areas, with more attention paid to rural parents to help them improve their parenting.
Revisiting fertility regulation and family ties in Tunisia
Authors: Frini Olfa , Muller Christophe
Published: February 2023

Background

We revisit fertility regulation in Tunisia by examining the role of the extended family. As marriage is the exclusive acknowledged childbearing context, we examine fertility analysis in Tunisia through the sequence: woman’s marriage age, post-marriage delay in the first use of contraception, and past and current contraceptive use. We trace the family socio-economic influences that operate through these decisions.

Methods

Using data from the 2001 PAP-FAM Tunisian survey, we estimate the duration and probability models of these birth control decisions.

Results

In Tunisia, family ties and socio-cultural environment appear to hamper fertility regulation that operates through the above decisions. This is notably the case for couples whose marriages are arranged by the extended family or who benefit from financial support from both parental families.

Conclusion

This calls for family planning policies that address more the extended families.
Prevalence, severity, and associated factors of depression in newly diagnosed people living with HIV in Kilimanjaro, Tanzania: a cross-sectional study
Authors: Madundo Kim , Knettel Brandon A. , Knippler Elizabeth , Mbwambo Jessie
Published: February 2023

Background

Depression is particularly common among people living with Human Immunodeficiency Virus (HIV), with some studies showing a prevalence of depression three times higher among people living with HIV as compared to the general public. The stress associated with being diagnosed with HIV can be quite impactful, including concerns about one’s long-term health, stigma, and the burden of long-term treatment. Therefore, it is common for a new HIV diagnosis to contribute to the onset of depressive symptoms. The objective of this study was to determine the prevalence and severity of depression, and its associated factors in people diagnosed with HIV within the past 12 months.

Methods

We conducted a cross-sectional survey with patients newly diagnosed with HIV at three hospitals in the Kilimanjaro region of Tanzania utilizing a locally validated version of the Patient Health Questionnaire-9 (PHQ-9) as a screener for depression, the Demographic Health Survey (SES-DHS8) for socio-demographic characteristics, and the Duke-UNC Functional Social Support Questionnaire (FSSQ) to assess perceived social support. We enrolled 272 participants between September and December 2020, diagnosed with HIV within the past 12 months. Analysis of Co-variance (ANCOVA) and Bonferroni post-hoc analysis were used to determine associations of sociodemographic variables with the dependent variable of depression.

Results

Overall prevalence of depression in our sample was 41%, including 54 participants (20%) with moderate symptoms, 42 (15%) with moderately severe symptoms, and 16 (6%) with severe symptoms. Severity was highest in participants diagnosed with HIV less than 1 month ago. An ANCOVA model (overall F = 4.72, p < 0.001) assessing factors associated with greater depression severity revealed significant effects of study site (F = 7.6, p < 0.001), female gender (F = 5.11, p = 0.02), and less time since HIV diagnosis (F = 12.3, p < 0.001).

Conclusion

The study demonstrates very high prevalence of depression among people living with HIV in this setting, particularly among those newly diagnosed, female participants, and those seen at the larger regional referral hospital. Integration of mental health screening and interventions into CTC care is vital in the first visits following a positive test result and may be tailored to meet the needs of patients at highest risk for developing symptoms of depression.
Trends in respiratory diseases before and after the COVID-19 pandemic in China from 2010 to 2021
Authors: Zuo Zhongbao , Yang Chunli , Ye Fei , Wang Miaochan , Wu Jing , Tao Chengjiang , Xun Yunhao , Li Zhaoyi , Liu Shourong , Huang Jinsong , Xu Aifang
Published: February 2023

Background

The ongoing benefits of coronavirus disease 2019 (COVID-19) nonpharmaceutical interventions (NPIs) for respiratory infectious diseases in China are still unclear. We aimed to explore the changes in seven respiratory infectious diseases before, during, and after COVID-19 in China from 2010 to 2021.

Methods

The monthly case numbers of seven respiratory infectious diseases were extracted to construct autoregressive integrated moving average (ARIMA) models. Eight indicators of NPIs were chosen from the COVID-19 Government Response Tracker system. The monthly case numbers of the respiratory diseases and the eight indicators were used to establish the Multivariable generalized linear model (GLM) to calculate the incidence rate ratios (IRRs).

Results

Compared with the year 2019, the percentage changes in 2020 and 2021 were all below 100% ranging from 3.81 to 84.71%. Pertussis and Scarlet fever started to increase in 2021 compared with 2020, with a percentage change of 183.46 and 171.49%. The ARIMA model showed a good fit, and the predicted data fitted well with the actual data from 2010 to 2019, but the predicted data was bigger than the actual number in 2020 and 2021. All eight indicators could negatively affect the incidence of respiratory diseases. The seven respiratory diseases were significantly reduced during the COVID-19 pandemic in 2020 and 2021 compared with 2019, with significant estimated IRRs ranging from 0.06 to 0.85. In the GLM using data for the year 2020 and 2021, the IRRs were not significant after adjusting for the eight indicators in multivariate analysis.

Conclusion

Our study demonstrated the incidence of the seven respiratory diseases decreased rapidly during the COVID-19 pandemic in 2020 and 2021. At the end of 2021, we did see a rising trend for the seven respiratory diseases compared to the year 2020 when the NPIs relaxed in China, but the rising trend was not significant after adjusting for the NPIs indicators. Our study showed that NPIs have an effect on respiratory diseases, but Relaxation of NPIs might lead to the resurgence of respiratory diseases.
Investigating the effectiveness of three school based interventions for preventing psychotic experiences over a year period – a secondary data analysis study of a randomized control trial
Authors: Staines Lorna , Healy Colm , Corcoran Paul , Keeley Helen , Coughlan Helen , McMahon Elaine , Cotter Padraig , Cotter David , Kelleher Ian , Wasserman Camilla , Brunner Romuald , Kaess Michael , Sarchiapone Marco , Hoven Christina W. , Carli Vladimir , Wasserman Danuta , Cannon Mary
Published: February 2023

Introduction

Psychotic experiences (PEs) are associated with increased risk of later mental disorders and so could be valuable in prevention studies. However, to date few intervention studies have examined PEs. Given this lack of evidence, in the current study a secondary data analysis was conducted on a clustered-randomized control trial (RCT) of 3 school based interventions to reduce suicidal behaviour, to investigate if these may reduce rates of PEs, and prevent PE, at 3-month and 1-year follow-up.

Methods

The Irish site of the Saving and Empowering Young Lives in Europe study, trial registration (DRKS00000214), a cluster-RCT designed to examine the effect of school-based interventions on suicidal thoughts and behaviour. Seventeen schools (n = 1096) were randomly assigned to one of three intervention arms or a control arm. The interventions included a teacher training (gate-keeper) intervention, an interactive educational (universal-education) intervention, and a screening and integrated referral (selective-indicative) intervention. The primary outcome of this secondary data-analysis was reduction in point-prevalence of PEs at 12 months. A second analysis excluding those with PEs at baseline was conducted to examine prevention of PEs. Additional analysis was conducted of change in depression and anxiety scores (comparing those with/without PEs) in each arm of the intervention. Statistical analyses were conducted using mixed-effects modelling.

Results

At 12-months, the screening and referral intervention was associated with a significant reduction in PEs (OR:0.12,95%CI[0.02–0.62]) compared to the control arm. The teacher training and education intervention did not show this effect. Prevention was also observed only in the screening and referral arm (OR:0.30,95%CI[0.09–0.97]). Participants with PEs showed higher levels of depression and anxiety symptoms, compared to those without, and different responses to the screening and referral intervention & universal-education intervention.

Conclusions

This study provides the first evidence for a school based intervention that reduce & prevent PEs in adolescence. This intervention is a combination of a school-based screening for psychopathology and subsequent referral intervention significantly reduced PEs in adolescents. Although further research is needed, our findings point to the effectiveness of school-based programmes for prevention of future mental health problems.
The association of diabetes status and bone mineral density among US adults: evidence from NHANES 2005–2018
Authors: Liu Bo , Liu Jingshuang , Pan Junpeng , Zhao Chengliang , Wang Zhijie , Zhang Qiang
Published: February 2023

Backgrounds

We aimed to explore the relationship between diabetes status and bone mineral density (BMD) among adults with pre-diabetes and diabetes.

Methods

We collected and analyzed five cycles (2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018) data from NHANES. We removed the individuals containing missing values. The linear regression models were used to explore the relationship between diabetes status and bone mineral density. Finally, we performed subgroup analyzes by age, sex and race to find special populations.

Result

Finally, 9661 participants with complete data were involved in the study. 944 were diagnosed with pre-diabetes, and 2043 were with diabetes. We found that bone mineral density in the hip, femoral neck, and lumbar spine showed an upward trend in both prediabetic and diabetic patients in the three linear regression models. Further, after subgroup analysis, we found that this trend was more prominent in whites race, women, and those over 50 years old.

Conclusion

Using NHANES data from 2005 to 2018, we found that patients with abnormal glucose metabolism had increased bone mineral density.
Influence of gender and oral health knowledge on DMFT index: a cross sectional study among school children in Kaski District, Nepal
Authors: Chapain Kamal Prasad , Rampal Krishna Gopal , Gaulee Pokhrel Kalpana , Adhikari Chiranjivi , Hamal Deependra , Pokhrel Khem Narayan
Published: February 2023

Background

Oral health problems are highly prevalent among school children in Nepal. Poor oral health condition may be influenced by various factors. However, little is known about the sociodemographic and awareness related factors on oral health problems among school children in Nepal. Therefore, this study aimed to assess the association of gender and knowledge on DMFT index among school children.

Methods

A cross-sectional study was conducted among school children of Grade Seven in 12 schools of Kaski district in Nepal. Schools were randomly selected from the urban and semi-urban areas in the district. Data were collected covering oral health knowledge, socio-demographic characteristics, oral health condition and practices. The factors of poor oral health condition and practices were examined using t-test, one-way ANOVA, and multiple linear regression.

Results

Of the total participants (n = 669), 54.9% were females and their mean DMFT score was 1.82 (SD = 1.07). Total decayed score was higher among those who did not have knowledge that fluoride prevents decay compared to those who had knowledge about it (Being aware of fluoride prevents decay: Mean = 1.21 (SD = 1.54) versus not being aware of that: mean = 2.13 (SD = 2.13); p = 0.029). Females were more likely to have higher DMFT scores compared to males (β-coefficient = 0.43, 95% CI 0.13, 0.73, p = 0.005). In addition, higher knowledge score was negatively associated with higher DMFT score (β-coefficient = − 0.09, 95% CI − 0.20, -0.01, p = 0.047).

Conclusion

Being female students and those having lower level of knowledge on oral health attributed to higher DMFT index. Periodic dental check-up coupled with oral health education on regular brushing, use of fluoridated paste, tongue cleaning and care of gum diseases are recommended in schools.
Antioxidant and antiproliferative potentials of phenolic-rich extracts from biotransformed grape pomace in colorectal Cancer
Authors: Mišković Špoljarić Katarina , Šelo Gordana , Pešut Ena , Martinović Josipa , Planinić Mirela , Tišma Marina , Bucić-Kojić Ana
Published: February 2023

Background

Colorectal carcinoma is one of the most commonly diagnosed malignancies worldwide. Consumption of dietary supplements and nutraceuticals such as phenolic compounds may help combat colorectal carcinoma. The effect of two phenolic-rich extracts prepared from biotransformed grape pomace on the antioxidant properties and antiproliferative activity against two colorectal cancer cell lines (Caco-2 and SW620) were investigated.

Methods

A 15-day solid-state fermentation with the white-rot fungi Phanerochaete chrysosporium and Trametes gibbosa was used to biotransform grape pomace. Solid-liquid extraction was then performed to extract bioactive compounds. The extract was analyzed for the determination of phenolic compounds by ultra-high performance liquid chromatography and in vitro assays of biological activities (antioxidant activity, antiproliferative activity, cell cycle analysis).

Results

The 4 days of solid-state fermentation proved to be the optimal period to obtain the maximum yield of phenolic compounds. The tested extracts showed significant antioxidant and antiproliferative activities. Grape pomace treated with P. chrysosporium and T. gibbosa reduced cancer cell growth by more than 60% at concentrations (solid/liquid ratio) of 1.75 mg/mL and of 2.5 mg/mL, respectively. The cell cycle perturbations induced by the grape pomace extracts resulted in a significant increase in the number of cells in the S (9.8%) and G2/M (6.8%) phases of SW620 exposed to T. gibbosa after 48 hours, while P. chrysosporium increased the percentage of cells in the G1 phase by 7.7%. The effect of grape pomace extracts on Caco-2 was less pronounced.

Conclusions

The obtained results suggest the presence of bioactive compounds in biotransformed grape pomace as a residue from winemaking, which could be used to prevent colon cancer.
Japan should initiate the discussion on voluntary assisted dying legislation now
Authors: Asai Atsushi , Okita Taketoshi , Shimakura Yoko , Tanaka Masashi , Fukuyama Miki
Published: February 2023

Background

No laws or official guidelines govern voluntary assisted dying (VAD) in Japan. A legislative bill on the termination of life-sustaining measures has yet to be sent to deliberations for legislation, due to strong opposition that has prevented it from being submitted to the Diet. However, Japan has recently witnessed several cases involving VAD.

Main text

Against this backdrop, we argue that Japan should begin discussion on VAD legislation, referring to the Voluntary Assisted Dying Act 2017 (VADA2017), which was established in 2017 in Victoria, Australia. VADA2017 puts in place a wide range of stringent safeguards and is considered worldwide to be the safest and most conservative policy on a physician offering assisted dying based on the patient’s premeditated request. We consider what opposing opinions from society would arise in response to the VADA2017. Among these will include arguments against VAD itself, those against the validation of this act, and opinions that oppose even the initiation of the dialogue on VAD.

Conclusions

We conclude that to protect the right to life among those placed in vulnerable positions and, at the same time, to respect decision-making of those who wish for immediate death due to unbearable suffering, the dialogue must immediately begin with that on introducing a policy more conservative than that of the VADA2017, which solidly considers arguments against VAD.
Opening the “black box” of organizational coaching for implementation
Authors: Fleddermann Kathryn , Jacobson Nora , Horst Julie , Madden Lynn M , Haram Eric , Molfenter Todd
Published: February 2023

Background

Organizational coaching to promote the implementation of evidence-informed interventions is becoming more popular in healthcare organizations. In order to open the “black box” of coaching for implementation, we first developed, then tested the rigor and utility of a model of coaching for implementation.

Methods

Interviews with nine experienced coaches were conducted and inductively coded to develop a model of coaching for implementation. Later, forty coaching calls with behavioral health organizations in Ohio, Wisconsin, and Florida were analyzed with directed content analysis using a priori codes based on this model.

Results

The coaching work that occurred during these calls aligned closely with the model of coaching for implementation developed by our team. Most coaching work was devoted to building capacity; almost as much work focused on building relationships. Very little coaching work was dedicated to building sustainability. Use of tools for organizational change and implementation remained relatively consistent across all coaching periods.

Conclusion

Understanding what occurs during a successful coaching intervention will improve the effectiveness of coaching as an implementation strategy. Future research should focus on which processes and patterns make coaching more likely to promote specific implementation outcomes.
Postabortion and safe abortion care coverage, capacity, and caseloads during the global gag rule policy period in Ethiopia and Uganda
Authors: Stillman Melissa , Kibira Simon P. S. , Shiferaw Solomon , Makumbi Fredrick , Seme Assefa , Sully Elizabeth A. , Ha Lilian , Giorgio Margaret
Published: February 2023

Background

Abortion-related complications contribute to preventable maternal mortality, accounting for 9.8% of maternal deaths globally, and 15.6% in sub-Saharan Africa. High-quality postabortion care (PAC) can mitigate the negative health outcomes associated with unsafe abortion. While the expanded Global Gag Rule policy did not prohibit the provision of PAC, other research has suggested that over-implementation of the policy has resulted in impacts on these services. The purpose of this study was to assess health facilities’ capacity to provide PAC services in Uganda and PAC and safe abortion care (SAC) in Ethiopia during the time in which the policy was in effect.

Methods

We collected abortion care data between 2018 and 2020 from public health facilities in Ethiopia (N = 282) and Uganda (N = 223). We adapted a signal functions approach to create composite indicators of health facilities’ capacity to provide basic and comprehensive PAC and SAC and present descriptive statistics documenting the state of service provision both before and after the GGR went into effect. We also investigate trends in caseloads over the time-period.

Results

In both countries, service coverage was high and improved over time, but facilities’ capacity to provide basic PAC services was low in Uganda (17.8% in 2019) and Ethiopia (15.0% in 2020). The number of PAC cases increased by 15.5% over time in Uganda and decreased by 7% in Ethiopia. Basic SAC capacity increased substantially in Ethiopia from 66.7 to 82.8% overall, due in part to an increase in the provision of medication abortion, and the number of safe abortions increased in Ethiopia by 9.7%.

Conclusions

The findings from this analysis suggest that public health systems in both Ethiopia and Uganda were able to maintain essential PAC/SAC services during the GGR period. In Ethiopia, there were improvements in the availability of safe abortion services and an overall improvement in the safety of abortion during this time-period. Despite loss of partnerships and potential disruptions in referral chains, lower-level facilities were able to expand their capacity to provide PAC services. However, PAC caseloads increased in Uganda which could indicate that, as hypothesized, abortion became more stigmatized, less accessible and less safe.
Integrative single-cell RNA-seq and ATAC-seq analysis of myogenic differentiation in pig
Authors: Cai Shufang , Hu Bin , Wang Xiaoyu , Liu Tongni , Lin Zhuhu , Tong Xian , Xu Rong , Chen Meilin , Duo Tianqi , Zhu Qi , Liang Ziyun , Li Enru , Chen Yaosheng , Li Jianhao , Liu Xiaohong , Mo Delin
Published: February 2023

Background

Skeletal muscle development is a multistep process whose understanding is central in a broad range of fields and applications, from the potential medical value to human society, to its economic value associated with improvement of agricultural animals. Skeletal muscle initiates in the somites, with muscle precursor cells generated in the dermomyotome and dermomyotome-derived myotome before muscle differentiation ensues, a developmentally regulated process that is well characterized in model organisms. However, the regulation of skeletal muscle ontogeny during embryonic development remains poorly defined in farm animals, for instance in pig. Here, we profiled gene expression and chromatin accessibility in developing pig somites and myotomes at single-cell resolution.

Results

We identified myogenic cells and other cell types and constructed a differentiation trajectory of pig skeletal muscle ontogeny. Along this trajectory, the dynamic changes in gene expression and chromatin accessibility coincided with the activities of distinct cell type-specific transcription factors. Some novel genes upregulated along the differentiation trajectory showed higher expression levels in muscular dystrophy mice than that in healthy mice, suggesting their involvement in myogenesis. Integrative analysis of chromatin accessibility, gene expression data, and in vitro experiments identified EGR1 and RHOB as critical regulators of pig embryonic myogenesis.

Conclusions

Collectively, our results enhance our understanding of the molecular and cellular dynamics in pig embryonic myogenesis and offer a high-quality resource for the further study of pig skeletal muscle development and human muscle disease.
Immunotherapies in rare cancers
Authors: Vivekanandhan Sneha , Bahr Deborah , Kothari Ashish , Ashary Mohammed Ali , Baksh Mizba , Gabriel Emmanuel
Published: February 2023

Cancer remains a leading cause of death worldwide, placing a significant burden on healthcare systems as well as the global economy. Rare cancers comprise a group of about 200 cancers that individually occur at extremely low frequencies. In the United States (US), their frequency is approximately 15 cases per 100,000 people, and it is even lower in Europe with approximately 6 cases per 100,000 people. However, combined their frequency of occurrence is much higher than any singular cancer. Cancer treatment and management has tremendously improved in the last decade, particularly with the administration of immune-based therapies. The four most prevalent immune-based therapies are (1) the use of immune-checkpoint inhibitors, (2) macrophage therapy, (3) Chimeric Antigen Receptor (CAR) T cell therapy, and (4) neoantigen-based therapies. In our review, we discuss these various aproaches and their implementation in the treatment of a variety of rare cancers. Furthermore, we discuss their limitations and potential strategies to overcome them to enhance the therapeutic efficacy of these approaches. Finally, our article presents the future directions and other additional immune therapies that may be incorporated into the treatment of rare cancers.
Retraction Note: Tumour-originated exosomal miR-155 triggers cancer-associated cachexia to promote tumour progression
Authors: Wu Qi , Sun Si , Li Zhiyu , Yang Qian , Li Bei , Zhu Shan , Wang Lijun , Wu Juan , Yuan Jingping , Yang Changhua , Li Juanjuan , Sun Shengrong
Published: February 2023

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-018-0899-5.
Impact of total cerebral small vessel disease score on ophthalmic artery morphologies and hemodynamics
Authors: Wang Jia-lin , Cheng Xue-ru , Meng Zhao-yang , Wang Yan-ling
Published: February 2023

Background

Cerebral small vessel disease (CSVD) is a systemic disease, affecting not only the brain, but also eyes and other organs. The total CSVD score is a tool for comprehensive evaluation of brain lesions in patients with CSVD. The ophthalmic artery (OA) is a direct response to ocular blood flow. However, little is known about the correlation between CSVD and characteristics of OA. We investigated the OA morphologies and hemodynamics in patients with CSVD and the correlation between these changes and the total CSVD score.

Methods

This cross-sectional observational study included 34 eyes from 22 patients with CSVD and 10 eyes from 5 healthy controls. The total CSVD score was rated according to the CSVD signs on magnetic resonance imaging. OA morphological characteristics were measured on the basis of 3D OA model reconstruction. OA hemodynamic information was calculated using computational fluid dynamics simulations.

Results

The total CSVD score negatively correlated with the OA diameter, blood flow velocity, and mass flow ratio (all P < 0.05). After adjusting for potential confounding factors, the total CSVD score was still independently correlated with the OA blood velocity (β = − 0.202, P = 0.005). The total CSVD score was not correlated with OA angle (P > 0.05). The presence of cerebral microbleeds and enlarged perivascular spaces was correlated with the OA diameter (both P < 0.01), while the lacunar infarcts and white matter hyperintensities were correlated with the OA blood velocity (both P < 0.001).

Conclusions

The decrease of the blood velocity in the OA was associated with the increase in the total CSVD score. The changes of the OA diameter and velocity were associated with the presence of various CSVD signs. The findings suggest that more studies are needed in the future to evaluate CSVD by observing the morphologies and hemodynamics of OA.
Role of mitochondrial metabolic disorder and immune infiltration in diabetic cardiomyopathy: new insights from bioinformatics analysis
Authors: Peng Cheng , Zhang Yanxiu , Lang Xueyan , Zhang Yao
Published: February 2023

Background

Diabetic cardiomyopathy (DCM) is one of the common cardiovascular complications of diabetes and a leading cause of death in diabetic patients. Mitochondrial metabolism and immune-inflammation are key for DCM pathogenesis, but their crosstalk in DCM remains an open issue. This study explored the separate roles of mitochondrial metabolism and immune microenvironment and their crosstalk in DCM with bioinformatics.

Methods

DCM chip data (GSE4745, GSE5606, and GSE6880) were obtained from NCBI GEO, while mitochondrial gene data were downloaded from MitoCarta3.0 database. Differentially expressed genes (DEGs) were screened by GEO2R and processed for GSEA, GO and KEGG pathway analyses. Mitochondria-related DEGs (MitoDEGs) were obtained. A PPI network was constructed, and the hub MitoDEGs closely linked to DCM or heart failure were identified with CytoHubba, MCODE and CTD scores. Transcription factors and target miRNAs of the hub MitoDEGs were predicted with Cytoscape and miRWalk database, respectively, and a regulatory network was established. The immune infiltration pattern in DCM was analyzed with ImmuCellAI, while the relationship between MitoDEGs and immune infiltration abundance was investigated using Spearman method. A rat model of DCM was established to validate the expression of hub MitoDEGs and their relationship with cardiac function.

Results

MitoDEGs in DCM were significantly enriched in pathways involved in mitochondrial metabolism, immunoregulation, and collagen synthesis. Nine hub MitoDEGs closely linked to DCM or heart failure were obtained. Immune analysis revealed significantly increased infiltration of B cells while decreased infiltration of DCs in immune microenvironment of DCM. Spearman analysis demonstrated that the hub MitoDEGs were positively associated with the infiltration of pro-inflammatory immune cells, but negatively associated with the infiltration of anti-inflammatory or regulatory immune cells. In the animal experiment, 4 hub MitoDEGs (Pdk4, Hmgcs2, Decr1, and Ivd) showed an expression trend consistent with bioinformatics analysis result. Additionally, the up-regulation of Pdk4, Hmgcs2, Decr1 and the down-regulation of Ivd were distinctly linked to reduced cardiac function.

Conclusions

This study unraveled the interaction between mitochondrial metabolism and immune microenvironment in DCM, providing new insights into the research on potential pathogenesis of DCM and the exploration of novel targets for medical interventions.
Sunitinib efficacy with minimal toxicity in patient-derived retinoblastoma organoids
Authors: Srimongkol Atthapol , Laosillapacharoen Natanan , Saengwimol Duangporn , Chaitankar Vijender , Rojanaporn Duangnate , Thanomchard Thanastha , Borwornpinyo Suparerk , Hongeng Suradej , Kaewkhaw Rossukon
Published: February 2023

Background

Recurrence of retinoblastoma (RB) following chemoreduction is common and is often managed with local (intra-arterial/intravitreal) chemotherapy. However, some tumors are resistant to even local administration of maximum feasible drug dosages, or effective tumor control and globe preservation may be achieved at the cost of vision loss due to drug-induced retinal toxicity. The aim of this study was to identify drugs with improved antitumor activity and more favorable retinal toxicity profiles via screening of potentially repurposable FDA-approved drugs in patient-derived tumor organoids.

Methods

Genomic profiling of five RB organoids and the corresponding parental tissues was performed. RB organoids were screened with 133 FDA-approved drugs, and candidate drugs were selected based on cytotoxicity and potency. RNA sequencing was conducted to generate a drug signature from RB organoids, and the effects of drugs on cell cycle progression and proliferative tumor cone restriction were examined. Drug toxicity was assessed with human embryonic stem cell-derived normal retinal organoids. The efficacy/toxicity profiles of candidate drugs were compared with those of drugs in clinical use.

Results

RB organoids maintained the genomic features of the parental tumors. Sunitinib was identified as highly cytotoxic against both classical RB1-deficient and novel MYCN-amplified RB organoids and inhibited proliferation while inducing differentiation in RB. Sunitinib was a more effective suppressor of proliferative tumor cones in RB organoids and had lower toxicity in normal retinal organoids than either melphalan or topotecan.

Conclusion

The efficacy and retinal toxicity profiles of sunitinib suggest that it could potentially be repurposed for local chemotherapy of RB.
HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway
Authors: Liu Yunzhi , Xu Qishan , Deng Fan , Zheng Zhuojun , Luo Jialiang , Wang Ping , Zhou Jia , Lu Xiao , Zhang Liyun , Chen Zhengliang , Zhang Qifan , Chen Qingyun , Zuo Daming
Published: February 2023

Background

Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis.

Methods

RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan–Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development.

Results

We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model.

Conclusion

Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.
A NEw MOdel of individualized and patient-centered follow-up for women with gynecological cancer (the NEMO study)—protocol and rationale of a randomized clinical trial
Authors: Bergholdt Stinne Holm , Hansen Dorte Gilsaa , Johnsen Anna Thit , Boman Bo Snedker , Jensen Pernille Tine
Published: February 2023

Background

Follow-up programs for gynecological cancer patients are currently under revision. There is limited evidence that traditional follow-up and clinical examinations improve survival in an early-stage gynecological setting. Further, traditional follow-up programs fail to accommodate the patient’s need for psychosocial and sexual supportive care and to actively involve patients and their relatives in the follow-up process. Individualized programs may replace traditional routine follow-up with fixed intervals and length. Focusing on alarm-symptoms and self-reporting may ensure detection of recurrence while allowing a continuous attention to the patient’s well-being and return to daily life.

In this study, a nurse-led, individualized, and need-based intervention with a specific focus on patient empowerment is tested against a standard physician-led model primarily focusing on the detection of recurrence.

Methods

The study is designed as a clinical, randomized trial conducted in one of four national onco-gynecological centers in Denmark. Patients with early-stage cervical or endometrial cancer are eligible for inclusion. The intervention group undergoes individualized, nurse-led follow-up supporting patient empowerment including repeated use of electronic patient-reported outcome measures (ePROMs) before each contact as a dialogue support tool. The follow-up contacts are mainly conducted by telephone. All project nurses attended a special training program before project start and are all well-educated and dedicated onco-gynecological nurses. The control group receives standard, physician-led, follow-up without use of ePROMs or specific focus on empowerment.

The effect of the intervention is evaluated by questionnaires completed by patients at baseline (3 months after surgery) and 12, 18, and 36 months after surgery. Outcomes include empowerment using the Skill and technique subscale of the HEI-Q questionnaire as the primary outcome while fear of cancer recurrence and health-related quality of life as well as the remaining subscales of the HEI-Q represent secondary outcomes. Data is collected by use of the REDCap technology, which also provides a customized visual support function for the dialogue tool.

Discussion

This study will provide new information about follow-up in early-stage gynecological cancer settings and thereby contribute to improvement of future follow-up programs. Importantly, the study will provide knowledge about the impact of specific focus on patient empowerment in follow-up programs and, further, how to facilitate empowerment among patients.

Trial registration

The study is registered at clinicaltrials.gov: ID no. NCT03838861. Registered on 6 February 2019.

Protocol version 2, issue date 21 November 2022.
Prophylactic effect of retromuscular mesh placement during loop ileostomy closure on incisional hernia incidence—a multicentre randomised patient- and observer-blind trial (P.E.L.I.O.N trial)
Authors: Müller Sven , Weyhe Dirk , Herrle Florian , Horvath Philipp , Bachmann Robert , von Ehrlich-Treuenstätt Viktor , Heger Patrick , Nasir Nadir , Klose Christina , Ritz Alexander , Sander Anja , Grohmann Erich , Dörr-Harim Colette , Mihaljevic André L.
Published: February 2023

Background

Incisional hernia is a frequent complication following loop ileostomy reversal. Incisional hernias are associated with morbidity, loss of health-related quality of life and costs and warrant the investigation of prophylactic measures. Prophylactic mesh implantation at the time of surgical stoma reversal has shown to be a promising and safe method to prevent incisional hernias in this setting. However, the efficacy of this method has not yet been investigated in a large multicentre randomised-controlled trial (RCT) with adequate external validity. The P.E.L.I.O.N. trial will evaluate the efficacy of prophylactic mesh reinforcement after loop ileostomy closure in decreasing the rate of incisional hernia versus standard closure alone.

Methods

P.E.L.I.O.N. is a multicentre, patient- and observer-blind RCT. Patients undergoing loop ileostomy closure will undergo intraoperative 1:1 randomisation into either abdominal wall closure with a continuous slowly absorbable suture in small-stitch technique without mesh reinforcement (control group) or abdominal wall closure with an additional reinforcement with a retromuscular non-absorbable, macro-pore (pore size ≥ 1000 μm or effective porosity >0%) light-weight monofilament or mixed structure mesh. A total of 304 patients (152 per group) will need to be randomised in the study. Based on inclusion and exclusion criteria, 1,014 patients are expected to be screened for eligibility in order to recruit the necessary number of patients. The primary endpoint will be the frequency of incision hernias within 24 months according to the European Hernia Society definition. Secondary endpoints will be the frequency of surgical site occurrences (including surgical site infections, wound seromas and hematomas, and enterocutaneous fistulas), postoperative pain, the number of revision surgeries and health-related quality of life. Safety will be assessed by measuring postoperative complications ≥ grade 3 according to the Dindo-Clavien classification.

Discussion

Depending on the results of the P.E.L.I.O.N. trial, prophylactic mesh implantation could become the new standard for loop ileostomy reversal.

Trial registration

DRKS00027921, U1111-1273-4657
Phytochemical analysis, antioxidant capacities, and in vitro biological activities of the extract of seed coat as by-products of pea
Authors: Gazwi Hanaa S. S. , Omar Maha O. A. , Mahmoud Magda E.
Published: February 2023

Converting seed coat peas (hulls) (SCP) into beneficial products provides a solution for waste treatment. This study aimed to investigate the phytoconstituents and biological activities of SCP extract. Phytochemical screening, total bioactive compounds, and GC–MS analysis were evaluated. Then, the antioxidant, antibacterial, anticancer, and antiviral activities of SCP extract were determined. The results demonstrate that SCP extract has bioactive compounds such as carbohydrates (29.53 ± 4.23 mg/mL), protein (0.24 ± 0.02 mg/mL), phenolics (27.04 ± 0.94 mg GAE/g extract), and flavonoids (17.19 ± 0.48 mg QE/g extract). The existence of more than 16 substances was determined using GC–MS analysis. The extract showed potential antioxidant activities, with the maximum activity seen for extract (IC50 µg/mL) = 79.16 ± 1.77 for DPPH, 67.40 ± 5.20 for ORAC, and 61.22 ± 4.81 for ABTS assays. The SCP extract showed potent antimicrobial activity against four gram-positive bacteria (Bacillus cereus, Streptomyces sp., Staphylococcus aureus, and Salmonella sp.) and two gram-negative bacteria (Escherichia coli and Pseudomonas sp.). SCP extract exhibited potential anticancer activity against lymphoma U937 and leukemic cells (THP1). The extract exhibited potential antiviral activity, with a selectivity index (SI) equal to 11.30 and 18.40 against herpes simplex-II (HSV-2) and adenovirus (Ad7), respectively. The results demonstrate more accurate information about peas by-products' chemical and antioxidant activities in various applications. The chemical components of peas by-products were found to have an in vitro antioxidant, antibacterial, and antiviral activity against leukemia and lymphoma.
Documenting cannabis use in primary care: a descriptive cross-sectional study using electronic medical record data in Alberta, Canada
Authors: Soos Boglarka , Garies Stephanie , Cornect-Benoit Ashley , Montgomery Lori , Sharpe Heather , Rittenbach Katherine , Manca Donna , Duerksen Kimberley , Forst Brian , Drummond Neil
Published: February 2023

Objective

Documenting cannabis use is important for patient care, but no formal requirements for consistent reporting exist in primary care. The objective of this study was to understand how cannabis use is documented in primary care electronic medical record (EMR) data.

Results

This was a cross-sectional study using de-identified EMR data from over 398,000 patients and 333 primary care providers in Alberta, Canada. An automated pattern-matching algorithm was developed to identify text and ICD-9 diagnostic codes indicating cannabis use in the EMR. There was a total of 11,724 records indicating cannabis use from 4652 patients, representing approximately 1.2% of the patient sample. Commonly used terms and ICD-9 codes included cannabis, marijuana/marihuana, THC, 304.3 and 305.2. Nabilone was the most frequently prescribed cannabinoid medication. Slightly more males and those with a chronic condition had cannabis use recorded more often. Overall, very few patients have cannabis use recorded in primary care EMR data and this is not captured in a systematic way. We propose several strategies to improve the documentation of cannabis use to facilitate more effective clinical care, research, and surveillance.