bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world efficacy and safety of two doses of cabazitaxel (20 or 25 mg/m2) in patients with castration-resistant prostate cancer: results of a Japanese post-marketing surveillance study
Authors: Matsuyama Hideyasu , Matsubara Nobuaki , Kazama Hirotaka , Seto Takeshi , Tsukube Shoko , Suzuki Kazuhiro
Published: July 2020

Background

The recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice.

Methods

We compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching.

Results

The C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher’s p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230–not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50–1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57–0.99).

Conclusions

Clinicians should consider the patient’s risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2.

Trial registration

Not applicable.
Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment
Authors: Dey Shatovisha , Liu Sheng , Factora Tricia D. , Taleb Solaema , Riverahernandez Primavera , Udari Lata , Zhong Xiaoling , Wan Jun , Kota Janaiah
Published: July 2020

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression.

Methods

In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control.

Results

RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis.

Conclusions

Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.
Global incidence of Necrotizing Enterocolitis: a systematic review and Meta-analysis
Authors: Alsaied Amer , Islam Nazmul , Thalib Lukman
Published: July 2020

Background

Necrotizing Enterocolitis (NEC) is a major cause of morbidity and mortality in the Neonatal Intensive Care Unit (NICU), yet the global incidence of NEC has not been systematically evaluated. We conducted a systematic review and meta-analysis of cohort studies reporting the incidence of NEC in infants with Very Low Birth Weight (VLBW).

Methods

The databases searched included PubMed, MEDLINE, the Cochrane Library, EMBASE and grey literature. Eligible studies were cohort or population-based studies of newborns including registry data reporting incidence of NEC. Incidence were pooled using Random Effect Models (REM), in the presence of substantial heterogeneity. Additional, bias adjusted Quality Effect Models (QEM) were used to get sensitivity estimates. Subgroup analysis and meta-regression were used to explore the sources of heterogeneity. Funnel plots as appropriate for ratio measures were used to assess publication bias.

Results

A systematic and comprehensive search of databases identified 27 cohort studies reporting the incidence of NEC. The number of neonate included in these studies was 574,692. Of this 39,965 developed NEC. There were substantial heterogeneity between studies (I2 = 100%). The pooled estimate of NEC based on REM was 7.0% (95% CI: 6.0–8.0%). QEM based estimate (6.0%; 95% CI: 4.0–9.0%) were also similar. Funnel plots showed no evidence of publication bias. Although, NEC estimates are similar across various regions, some variation between high and low income countries were noted. Meta regression findings showed a statistically significant increase of NEC over time, quantified by the publication year.

Conclusion

Seven out of 100 of all VLBW infants in NICU are likely to develop NEC. However, there were considerable heterogeneity between studies. High quality studies assessing incidence of NEC along with associated risk factors are warranted.
Parental health literacy and health knowledge, behaviours and outcomes in children: a cross-sectional survey
Authors: de Buhr Elke , Tannen Antje
Published: July 2020

Background

Health literacy (HL) is closely associated with leading health indicators such as engaging in healthy behaviours and experiencing a healthy social environment. Parents represent a critical subgroup among the adult population since they are not only responsible for their own health but also for the health of their children. Previous research suggests that parents with low HL are less likely to meet the preventive and health care needs of their children but there are gaps in the available information and there is not any data available yet for the German context.

Methods

In preparation of an implementation study, a cross-sectional survey was conducted in 28 elementary and secondary schools in Germany. The parent questionnaire was completed by 4217 parents and included the short form of the European Health Literacy Survey Questionnaire (HLS-EU-Q16). The child questionnaire examined children’s health knowledge, behaviours and outcomes. For children between 6 and 10 years, a parent reported on behalf of their children (N = 1518). Students 11 years and older completed a self-administered questionnaire (N = 2776). Bivariate and multivariate analyses were carried out. Spearman’s Rho correlations assess the relationships between household characteristics, parental HL and the health behaviour and outcomes in children.

Results

Among the participating parents, 45.8% showed problematic or inadequate HL. The major determinants of high parental HL were high socio-economic status (SES) (r = .088***, 95% CI [.052, .124]), living in West Germany (r = .064***, 95% CI [.032, .096]) and older parental age (r = .057**, 95% CI [.024, .090]). In the multivariate model, only SES remained significant. High parental HL was associated with positive health behaviours in children including healthier nutrition, regular tooth brushing and more physical activity. The relationships between parental HL and smoking, alcohol, sexual activity among children and children’s weight were not significant.

Conclusions

The results confirm a relationship between low parental HL, SES and some child health behaviours likely to negatively impact their health and wellbeing including less healthy nutrition and less exercise. Strengthening the health knowledge and competencies of parents may contribute to improved child outcomes particularly in the areas of nutrition, exercise and dental health.
Parenting as an inhibitor of gender disparities in alcohol use: the case of early adolescents in China
Authors: Bo Ai , Jaccard James
Published: July 2020

Background

Gender differences in alcohol use are more substantial among early adolescents in China than in the United States, presumably because of more permissive drinking norms for boys than girls in Chinese culture. This study tested a theory that gender differences in early experimentation with alcohol can be reduced through general parenting practices. Whereas traditional research has identified mediators of gender differences in alcohol use, the current research isolated moderators of gender differences and developed their implications for prevention programs.

Methods

The study analyzed the data from the China Global School-Based Student Health Survey (n = 8805 middle school students in four cities). Youth completed anonymous surveys in classroom settings. The study examined interaction effects between gender and parenting variables using multiple regression with robust standard errors.

Results

Early adolescent boys exhibited higher levels of drinking than girls for all drinking outcomes. The gender differences in drinking were negatively associated with the level of perceived parental monitoring, parental involvement in adolescent school performance, and parental empathy in a nonlinear way.

Conclusions

Results suggested that early adolescents’ perceptions of general parenting practice nonlinearly moderated gender disparities in alcohol use.
Use of technology for public health surveillance reporting: opportunities, challenges and lessons learnt from Kenya
Authors: Njeru Ian , Kareko David , Kisangau Ngina , Langat Daniel , Liku Nzisa , Owiso George , Dolan Samantha , Rabinowitz Peter , Macharia Daniel , Ekechi Chinyere , Widdowson Marc-Alain
Published: July 2020

Background

Effective public health surveillance systems are crucial for early detection and response to outbreaks. In 2016, Kenya transitioned its surveillance system from a standalone web-based surveillance system to the more sustainable and integrated District Health Information System 2 (DHIS2). As part of Global Health Security Agenda (GHSA) initiatives in Kenya, training on use of the new system was conducted among surveillance officers. We evaluated the surveillance indicators during the transition period in order to assess the impact of this training on surveillance metrics and identify challenges affecting reporting rates.

Methods

From February to May 2017, we analysed surveillance data for 13 intervention and 13 comparison counties. An intervention county was defined as one that had received refresher training on DHIS2 while a comparison county was one that had not received training. We evaluated the impact of the training by analysing completeness and timeliness of reporting 15 weeks before and 12 weeks after the training. A chi-square test of independence was used to compare the reporting rates between the two groups. A structured questionnaire was administered to the training participants to assess the challenges affecting surveillance reporting.

Results

The average completeness of reporting for the intervention counties increased from 45 to 62%, i.e. by 17 percentage points (95% CI 16.14–17.86) compared to an increase from 49 to 52% for the comparison group, i.e. by 3 percentage points (95% CI 2.23–3.77). The timeliness of reporting increased from 30 to 51%, i.e. by 21 percentage points (95% CI 20.16–21.84) for the intervention group, compared to an increase from 31 to 38% for the comparison group, i.e.by 7 percentage points (95% CI 6.27–7.73). Major challenges for the low reporting rates included lack of budget support from government, lack of airtime for reporting, health workers strike, health facilities not sending surveillance data, use of wrong denominator to calculate reporting rates and surveillance officers having other competing tasks.

Conclusions

Training plays an important role in improving public health surveillance reporting. However, to improve surveillance reporting rates to the desired national targets, other challenges affecting reporting must be identified and addressed accordingly.
Use and value of systematic reviews in English local authority public health: a qualitative study
Authors: South Emily , Lorenc Theo
Published: July 2020

Background

Responsibility for public health in England transferred from the National Health Service to local authorities in 2013, representing a different decision-making environment. Systematic reviews are considered the gold standard of evidence for clinical decision-making but little is known about their use in local government public health. This study aimed to explore the extent to which public health decision-makers in local authorities engage with systematic reviews and how they do so.

Methods

Semi-structured interviews were conducted with senior public health practitioners (n = 14) in Yorkshire and the Humber local authorities. Sampling was purposive and involved contacting Directors of Public Health directly and snowballing through key contacts. Face-to-face or telephone interviews were digitally recorded, transcribed verbatim and analysed using the Framework Method.

Results

Public health practitioners described using systematic reviews directly in decision-making and engaging with them more widely in a range of ways, often through a personal commitment to professional development. They saw themselves as having a role to advocate for the use of rigorous evidence, including systematic reviews, in the wider local authority. Systematic reviews were highly valued in principle and public health practitioners had relevant skills to find and appraise them. However, the extent of use varied by individual and local authority and was limited by the complexity of decision-making and various barriers. Barriers included that there were a limited number of systematic reviews available on certain public health topics, such as the wider determinants of health, and that the narrow focus of reviews was not reflective of complex public health decisions facing local authorities. Reviews were used alongside a range of other evidence types, including grey literature. The source of evidence was often considered an indicator of quality, with specific organisations, such as Public Health England, NICE and Cochrane, particularly trusted.

Conclusions

Research use varies and should be considered within the specific decision-making and political context. There is a need for systematic reviews to be more reflective of the decisions facing local authority public health teams.
Effect of preoperative segmental range of motion on patient outcomes in cervical disc arthroplasty
Authors: Wu Ting-kui , Liu Hao , Ding Chen , Rong Xin , He Jun-bo , Huang Kang-kang , Hong Ying , Wang Bei-yu
Published: July 2020

Background

Cervical disc arthroplasty (CDA) has been demonstrated, in clinical trials, as an effective and safe treatment for patients diagnosed with radiculopathy and/or myelopathy. However, the current CDA indication criteria, based on the preoperative segmental range of motion (ROM), comprises a wide range of variability. Although the arthroplasty level preserved ROM averages 7°-9° after CDA, there are no clear guidelines on preoperatively limited or excessive ROM at the index level, which could be considered as suitable for CDA.

Methods

This was a retrospective study of patients who underwent CDA between January 2008 and October 2018 using Prestige-LP discs in our hospital. They were divided into the small-ROM (≤5.5°) and the large-ROM (> 12.5°) groups according to preoperatively index-level ROM. Clinical outcomes, including the Japanese Orthopedics Association (JOA), Neck Disability Index (NDI), and Visual Analogue Scale (VAS) scores, were evaluated. Radiological parameters, including cervical lordosis, disc angle (DA), global and segmental ROM, disc height (DH), and complications were measured.

Results

One hundred and twenty six patients, with a total of 132 arthroplasty segments were analyzed. There were 64 patients in the small-ROM and 62 in the large-ROM group. There were more patients diagnosed with cervical spondylosis in the small-ROM than in the large-ROM group (P = 0.046). Patients in both groups had significantly improved JOA, NDI, and VAS scores after surgery, but the intergroup difference was not significant. Patients in the small-ROM group had dramatic postoperative increase in cervical lordosis, global and segmental ROM (P < 0.001). However, there was a paradoxical postoperative decrease in global and segmental ROM in the large-ROM group postoperatively (P < 0.001). Patients in the small-ROM group had lower preoperative DH (P = 0.012), and a higher rate of postoperative heterotopic ossification (HO) (P = 0.037).

Conclusion

Patients with preoperatively limited segmental ROM had severe HO, and achieved similar postoperative clinical outcomes as patients with preoperatively excessive segmental ROM. Patients with preoperatively limited segmental ROM showed a postoperative increase in segmental mobility, which decreased in patients with preoperatively excessive segmental ROM.
Long non-coding RNA CCHE1 participates in postoperative distant recurrence but not local recurrence of osteosarcoma possibly by interacting with ROCK1
Authors: Zhang Zhi , Yu Tao , Geng Wei
Published: July 2020

Background

Clinical treatment of osteosarcoma suffers from high recurrence rate. Therefore, is of great clinical values to develop predictive markers for recurrent osteosarcoma. Cervical carcinoma high-expressed lncRNA 1 (lncRNA CCHE1) participates in several types of malignancies, while its functionality in osteosarcoma is unknown. This study was therefore carried out to explore the involvement of lncRNA CCHE1 in recurrent osteosarcoma.

Methods

A total of 87 osteosarcoma patients received surgical resection and 38 healthy volunteers were included in this study. The 87 osteosarcoma patients were followed up for 5 years to record the recurrence of osteosarcoma. Plasma levels of lncRNA CCHE1 and ROCK1 on the day of discharge and during follow-up were measured by real-time quantitative PCR and ELISA, respectively. The effects of CCHE1 siRNA silencing on ROCK1 expression were analyzed by real-time quantitative PCR and western blot. Transwell assay was performed to analyze the role of lncRNA CCHE1 and ROCK1 in regulating cell invasion and migration.

Results

We observed that, on the day of discharge, plasma lncRNA CCHE1 was upregulated in osteosarcoma patients who developed distant recurrence (DR) during follow-up than in osteosarcoma patients who developed local recurrence (LR), patients with non-recurrence (NR) and healthy controls. On the day of discharge, plasma levels of ROCK1 were higher in DR, LR and NR groups in comparison to healthy controls. On the day of discharge, plasma levels of lncRNA CCHE1 were positively correlated with plasma levels of ROCK1 only in patients who developed DR during follow-up, but not in patients who developed LR, NR and control groups. During follow-up, plasma levels of lncRNA CCHE1 were further increased in DR group but slightly decreased in LR and NR groups. LncRNA CCHE1 siRNA silencing inhibited, while ROCK1 overexpression promoted osteosarcoma cell invasion and migration. ROCK1 overexpression attenuated the role of CCHE1. LncRNA CCHE1 siRNA silencing led to inhibited ROCK1 expression in cancer cells.

Conclusion

Therefore, lncRNA CCHE1 may participate in postoperative distant recurrence of osteosarcoma caner possibly by interacting with ROCK1 to promote cancer cell invasion and migration.
Survival analysis in gastric cancer: a multi-center study among Iranian patients
Authors: Talebi Atefeh , Mohammadnejad Afsaneh , Akbari Abolfazl , Pourhoseingholi Mohamad Amin , Doosti Hassan , Moghimi-Dehkordi Bijan , Agah Shahram , Bahardoust Mansour
Published: July 2020

Background

Gastric cancer (GC) has been considered as the 5th most common type of cancer and the third leading cause of cancer-associated death worldwide. The aim of this historical cohort study was to evaluate the survival predictors for all patients with GC using the Cox proportional hazards, extended Cox, and gamma-frailty models.

Methods

This historical cohort study was performed according to documents of 1695 individuals having GC referred to three medical centers in Iran from 2001 to 2018. First, most significant prognostic risk factors on survival were selected, Cox proportional hazards, extended Cox, gamma-frailty models were applied to evaluate the effects of the risk factors, and then these models were compared with the Akaike information criterion.

Results

The age of patients, body mass index (BMI), tumor size, type of treatment and grade of the tumor increased the hazard rate (HR) of GC patients in both the Cox and frailty models (P < 0.05). Also, the size of the tumor and BMI were considered as time-varying variables in the extended Cox model. Moreover, the frailty model showed that there is at least an unknown factor, genetic or environmental factors, in the model that is not measured (P < 0.05).

Conclusions

Some prognostic factors, including age, tumor size, the grade of the tumor, type of treatment and BMI, were regarded as indispensable predictors in patients of GC. Frailty model revealed that there are unknown or latent factors, genetic and environmental factors, resulting in the biased estimates of the regression coefficients.
A hospital-based study on complementary and alternative medicine use among diabetes patients in Rajshahi, Bangladesh
Authors: Rafi Md. Abdur , Azad Dewan Tasnia , Bhattacharjee Mridula , Rahman Nikita , Mubin Kazi Abdul , Rahman Md. Ajijur , Hossain Md. Golam
Published: July 2020

Background

The use of complementary and alternative medicine (CAM) among type 2 diabetes mellitus (T2DM) patients is increasing worldwide. It can affect optimum glycemic management. This study was to determine the rate and influencing factors of CAM use among diabetes patients as well as their effect on glycemic control.

Methods

This cross-sectional study was conducted among T2DM patients attending the outpatient department of Rajshahi Medical College Hospital. It is a tertiary hospital in the northern part of Bangladesh. A face-to-face interview with a pretested structured questionnaire was used for data collection. Chi-square (χ2) test and multivariate logistic regression model were used in this study for data analysis.

Results

Out of 244 T2DM patients, 86 (35.2%) used CAM. Multivariate logistic regression model showed that lower family income group (AOR = 8.7, 95% CI: 2.15–35.22, p-value 0.002), having no institutional education (AOR = 3.4, 95% CI: 1.17–9.87, p-value 0.025) and having diabetes for more than five years (AOR = 2.821, 95% CI: 1.34–5.94, p-value 0.006) were the most influential predictors of CAM use. The most commonly used CAMs were herbal products (67.4%) and homeopathic medicine (37.2%). Most of the CAM users (72%) were influenced by friends, neighbors, and family members. The most common reasons behind CAM use were reported to be the belief that CAM helped control diabetes better (44.2%) and easy availability and lower cost (27.9%). More than half of the users reported the efficacy of CAM as ‘nothing significant’, while others reported as somewhat good. 14% of CAM users experienced side-effects, especially gastrointestinal upset. It was observed that using CAM was associated with poor glycemic control (AOR = 2.25, 95% CI: 1.14–4.44, p-value 0.018).

Conclusion

Our study demonstrated that some modifiable factors are associated with the use of CAM, and it cannot maintain good glycemic control. So, patients should be made aware of the ineffectiveness and bad effects of CAM by enhancing educational and poverty-alleviating programs.
Caregivers' role in using a personal electronic health record: a qualitative study of cancer patients and caregivers in Germany
Authors: Weis Aline , Pohlmann Sabrina , Poss-Doering Regina , Strauss Beate , Ullrich Charlotte , Hofmann Helene , Ose Dominik , Winkler Eva C. , Szecsenyi Joachim , Wensing Michel
Published: July 2020

Background

Particularly in the context of severe diseases like cancer, many patients wish to include caregivers in the planning of treatment and care. Many caregivers like to be involved but feel insufficiently enabled. This study aimed at providing insight into patients’ and caregivers’ perspectives on caregivers’ roles in managing the patient portal of an electronic personal health record (PHR).

Methods

A descriptive qualitative study was conducted comprising two study phases: (1) Usability tests and interviews with patients with cancer and caregivers (2) additional patient interviews after a 3-month-pilot-testing of the PHR. For both study parts, a convenience sample was selected, focusing on current state of health and therapy process and basic willingness to participate and ending up with a mixed sample as well as saturation of data. All interviews were audio-recorded, pseudonymized, transcribed verbatim and qualitatively analyzed.

Results

Two main categories emerged from qualitative data: ‘Caregivers’ role’ and ‘Graduation of access rights’ – consisting of four subcategories each. The interviewed patients (n = 22) and caregivers (n = 9) felt that the involvement of caregivers is central to foster the acceptance of a PHR for cancer patients. However, their role varied from providing technical support to representing patients, e.g. if the patient’s state of health made this necessary. Heterogeneous opinions emerged regarding the question whether caregivers should receive full or graduated access on a patient’s PHR.

Conclusions

In order to support the patient and to participate in the care process, caregivers need up-to-date information on the patient’s health and treatment. Nevertheless, some patients do not want to share all medical data with caregivers, which might strain the patient-caregiver relationship. This needs to be considered in development and implementation of personal health records. Generally, in the debate on patient portals of a personal health record, paying attention to the role of caregivers is essential. By appreciating the important relationship between patients and caregivers right from the beginning, implementation, of a PHR would be enhanced.

Trial registration

ISRCTN85224823. Date of registration: 23/12/2015 (retrospectively registered).
Drug switching in the Netherlands: a cohort study of 20 active substances
Authors: Glerum Pieter J. , Maliepaard Marc , de Valk Vincent , Burger David M. , Neef Kees
Published: July 2020

Background

For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches.

Methods

We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient’s prescribed drug with a similar drug from a different manufacturer.

Results

We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import.

Conclusions

Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.
Prognostic value of an autophagy-related gene expression signature for endometrial cancer patients
Authors: Wang Hui , Ma Xiaoling , Liu Jinhui , Wan Yicong , Jiang Yi , Xia Yankai , Cheng Wenjun
Published: July 2020

Background

Autophagy is associated with cancer development. Autophagy-related genes play significant roles in endometrial cancer (EC), a major gynecological malignancy worldwide, but little was known about their value as prognostic markers. Here we evaluated the value of a prognostic signature based on autophagy-related genes for EC.

Methods

First, various autophagy-related genes were obtained via the Human Autophagy Database and their expression profiles were downloaded from The Cancer Genome Atlas. Second, key prognostic autophagy-related genes were identified via univariate, LASSO and multivariate Cox regression analyses. Finally, a risk score to predict the prognosis of EC was calculated and validated by using the test and the entire data sets. Besides, the key genes mRNA expression were validated using quantitative real-time PCR in clinical tissue samples.

Results

A total of 40 differentially expressed autophagy-related genes in EC were screened and five of them were prognosis-related (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1). A prognostic signature was constructed based on these five genes using the train set, which stratified EC patients into high-risk and low-risk groups (p < 0.05). In terms of overall survival, the analyses of the test set and the entire set yielded consistent results (test set: p < 0.05; entire set: p < 0.05). Time-dependent ROC analysis suggested that the risk score predicted EC prognosis accurately and independently (0.674 at 1 year, 0.712 at 3 years and 0.659 at 5 years). A nomogram with clinical utility was built. Patients in the high-risk group displayed distinct mutation signatures compared with those in the low-risk group. For clinical sample validation, we found that EIF4EBP1and ERBB2 had higher level in EC than that in normal tissues while CDKN1B, DLC1 and GRID1 had lower level, which was consistent with the results predicted.

Conclusions

Based on five autophagy-related genes (CDKN1B, DLC1, EIF4EBP1, ERBB2 and GRID1), our model can independently predict the OS of EC patients by combining molecular signature and clinical characteristics.
Correction to: Methods and indicators for measuring patterns of human exposure to malaria vectors
Authors: Monroe April , Moore Sarah , Okumu Fredros , Kiware Samson , Lobo Neil F. , Koenker Hannah , Sherrard-Smith Ellie , Gimnig John , Killeen Gerry F.
Published: July 2020

An amendment to this paper has been published and can be accessed via the original article.
Norepinephrine transporter-derived homing peptides enable rapid endocytosis of drug delivery nanovehicles into neuroblastoma cells
Authors: Haddad Yazan , Charousova Marketa , Zivotska Hana , Splichal Zbynek , Merlos Rodrigo Miguel Angel , Michalkova Hana , Krizkova Sona , Tesarova Barbora , Richtera Lukas , Vitek Petr , Stokowa-Soltys Kamila , Hynek David , Milosavljevic Vedran , Rex Simona , Heger Zbynek
Published: July 2020

Background

Currently, the diagnosis and treatment of neuroblastomas—the most frequent solid tumors in children—exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides.

Results

The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (< − 228 kJ/mol). The peptides were comprehensively characterized by computational and spectroscopic methods showing ~ 21% β-sheets/aggregation for GASNGINAYL and ~ 27% α-helix for SLWERLAYGI. After decorating 12-nm ferritin-based nanovehicles with cysteinated peptides, both peptides exhibited high potential for use in actively targeted neuroblastoma nanotherapy with exceptional in vitro biocompatibility and stability, showing minor yet distinct influences of the peptides on the global expression profiles. Upon binding to hNET with fast binding kinetics, GASNGINAYLC peptides enabled rapid endocytosis of ferritins into neuroblastoma cells, leading to apoptosis due to increased selective cytotoxicity of transported payload ellipticine. Peptide-coated nanovehicles significantly showed higher levels of early apoptosis after 6 h than non-coated nanovehicles (11% and 7.3%, respectively). Furthermore, targeting with the GASNGINAYLC peptide led to significantly higher degree of late apoptosis compared to the SLWERLAYGIC peptide (9.3% and 4.4%, respectively). These findings were supported by increased formation of reactive oxygen species, down-regulation of survivin and Bcl-2 and up-regulated p53.

Conclusion

This novel homing nanovehicle employing GASNGINAYLC peptide was shown to induce rapid endocytosis of ellipticine-loaded ferritins into neuroblastoma cells in selective fashion and with successful payload. Future homing peptide development via lead optimization and functional analysis can pave the way towards efficient peptide-based active delivery of nanomedicines to neuroblastoma cells.
Changes in peripheral mitochondrial DNA copy number in metformin-treated women with polycystic ovary syndrome: a longitudinal study
Authors: Yang Po-Kai , Chou Chia-Hong , Chang Chin-Hao , Chen Shee-Uan , Ho Hong-Nerng , Chen Mei-Jou
Published: July 2020

Background

Patients with polycystic ovarian syndrome (PCOS) are associated with known alterations in mitochondria DNA copy number (mtDNA-CN). The aim of this study is to study the change in mtDNA-CN in patients with PCOS who were treated with metformin.

Methods

This is a prospective cohort of patients with PCOS, who received metformin for one year. From 2009 to 2015, 88 women diagnosed with PCOS, based on the Rotterdam criteria, were enrolled. Serial measurements of mtDNA-CN, 8-hydroxydeoxyguanosine (8-OHdG), anthropometric, metabolic, endocrine, and inflammatory markers were obtained before and after 3, 6, and 12 months of treatment.

Results

A significant decrease in mtDNA-CN was seen over the course of one year. Other markers, including 8-OHdG, testosterone, free androgen index, blood pressure and liver enzymes, also decreased in the same interval. On regression analysis, there was a significant association between the change in mtDNA-CN and serum total testosterone, and no association between mtDNA-CN and metabolic factors.

Conclusions

Treatment with metformin is associated with a time-dependent decrease in mtDNA-CN in patients with PCOS who are treated over the course of one year. This may signify a reduction in mitochondria dysfunction. The change in mtDNA-CN corresponds to a similar change in serum total testosterone, and suggests a possible relationship between mtDNA-CN and testosterone.

Trial registration

ClinicalTrials.gov, NCT00172523. Registered September 15, 2005
Validity and reliability of an accelerometer-based assessgame to quantify upper limb selective voluntary motor control
Authors: Keller Jeffrey W. , Fahr Annina , Balzer Julia , Lieber Jan , van Hedel Hubertus J. A.
Published: July 2020

Introduction

Current clinical assessments measure selective voluntary motor control (SVMC) on an ordinal scale. We introduce a playful, interval-scaled method to assess SVMC in children with brain lesions and evaluate its validity and reliability.

Methods

Thirty-one neurologically intact children (median [1st-3rd quartile]: 11.6 years [8.5–13.9]) and 33 patients (12.2 years [8.8–14.9]) affected by upper motor neuron lesions with mild to moderate impairments participated. Using accelerometers, they played a movement tracking game (assessgame) with isolated joint movements (shoulder, elbow, lower arm [pro−/supination], wrist, and fingers), yielding an accuracy score. Involuntary movements were recorded simultaneously and resulted in an involuntary movement score. Both scores were normalized to the performance of 33 neurologically intact adults (32.5 years [27.9; 38.3]), which represented physiological movement patterns.

We correlated the assessgame outcomes with the Manual Ability Classification System, Selective Control of the Upper Extremity Scale, and a therapist rating of involuntary movements. Furthermore, a robust ANCOVA was performed with age as covariate, comparing patients to their healthy peers at the age levels of 7.5, 9, 10.5, 12, and 15 years.

Intraclass correlation coefficients and smallest real differences indicated relative and absolute reliability.

Results

Correlations (Kendall/Spearman) for the accuracy score were τ = 0.29 (p = 0.035; Manual Ability Classification System), ρ = − 0.37 (p = 0.035; Selective Control of the Upper Extremity Scale), and ρ = 0.64 (p < 0.001; therapist rating). Correlations for the involuntary movement metric were τ = 0.37 (p = 0.008), ρ = − 0.55 (p = 0.001), and ρ = 0.79 (p < 0.001), respectively. The robust ANCOVAs revealed that patients performed significantly poorer than their healthy peers in both outcomes and at all age levels except for the dominant/less affected arm, where the youngest age group did not differ significantly. Robust intraclass correlation coefficients and smallest real differences were 0.80 and 1.02 (46% of median patient score) for the accuracy and 0.92 and 2.55 (58%) for involuntary movements, respectively.

Conclusion

While this novel assessgame is valid, the reliability might need to be improved. Further studies are needed to determine whether the assessgame is sensitive enough to detect changes in SVMC after a surgical or therapeutic intervention.
Patterns and predictors of exclusive breastfeeding in Chinese Australian mothers: a cross sectional study
Authors: Kuswara Konsita , Campbell Karen J. , Hesketh Kylie D. , Zheng Miaobing , Laws Rachel
Published: July 2020

Background

While exclusive breastfeeding is recommended to 6 months of age, just 15% of mothers in Australia achieve this. The rate appears to be even lower among mothers born in China, where 90% have introduced infant formula by this time. This study aimed to examine infant feeding patterns in the first 12 months of life and the factors associated with exclusive breastfeeding at 4 months of age and infant formula introduction by 1 month of age among Chinese Australian mothers.

Methods

Chinese Australian women with a child aged 1 to 4 years born in Australia were recruited through social media and asked to complete an online survey. Chinese ethnicity was defined as the mother or her parents having been born in mainland China, Taiwan or Hong Kong. Infant feeding practices since birth and a range of psychosocial and cultural factors were assessed. A total of 289 Chinese Australian mothers completed the survey. The relationships between exposure variables and exclusive breastfeeding at 4 months or infant formula use by 1 month were examined using multivariable logistic regression.

Results

Almost all (93%) mothers initiated breastfeeding, however by 1 month of age exclusive breastfeeding rates reduced to 44%, with a further decline to 33 and 18% at 4 and 6 months respectively. Concurrently, 7% of parents reported infant formula feeding at birth increasing to 55 and 63% at 1 and 6 months of age respectively. The rates of any breastfeeding were 81% at 6 months and 50% at 12 months of age. Breastfeeding intention, self-efficacy and awareness of the infant feeding guidelines were key factors associated with sustained exclusive breastfeeding to 4 months.

Conclusions

While Chinese Australian mothers had comparable exclusive breastfeeding rates at 6 months to the general Australian population, twice as many had introduced infant formula by 1 month of age. There is an urgent need to support Chinese Australian mothers in the perinatal period to strengthen their knowledge, intention and confidence to delay early introduction of infant formula and promote exclusive breastfeeding in the early postpartum period.
Heart-lung transplantation for idiopathic pulmonary arterial hypertension and giant pulmonary artery aneurysm – case report
Authors: Eadington T. , Santhanakrishnan K. , Venkateswaran R.
Published: July 2020

Backgound

Idiopathic pulmonary arterial hypertension (IPAH) is a rare condition that requires lung transplantation in patients’ refractory to medical therapy. Pulmonary artery aneurysm (PAA) is a documented complication of IPAH however, optimal management and timing of intervention for this rare entity is not well understood.

Case report

We report a case of a 51-year-old female who underwent heart-lung transplantation for IPAH and giant PAA. The extreme size of the PAA and underlying pathology encountered in this case precluded both lung transplantation and conventional aneurysm repair.

Conclusion

This case demonstrates that heart-lung transplantation is a good surgical option for IPAH complicated by giant sized PAA and right heart failure.
Evolution of Haemophilia Care in Europe: 10 years of the principles of care
Authors: Noone D. , O’Mahony B. , Peyvandi F. , Makris M. , Bok A.
Published: July 2020

Introduction

The European principles of care in haemophilia marked their first decade in 2018. These guiding principles were the beginning of the European Haemophilia Consortium (EHC) review of countries’ adherence to these principles in 2009, 2012, 2015 and 2018. The aim of this paper was to examine the implementation of the principles and how they have impacted the evolution of care in the last decade, as well as to identify remaining gaps and proposes future directions.

Methods

In 2018, the EHC distributed a survey to EHC national member organisations in English and Russian and encouraged them to discuss responses with local clinicians for accuracy. Data was also cross-referenced and validated for countries in earlier surveys using additional available resources.

Results

The 10-year-old European principles had a significant impact on the development of care for haemophilia and related bleeding disorders in Europe. They set objectives around which multi-stakeholder groups have established recommendations and specific steps for the progressive improvement of care for bleeding disorders. However, some have been promoted and implemented more than others.

Conclusion

Monitoring adherence to, and impact of, the European Principles of Care significantly assists in tracking developments and highlighting gaps. Countries’ inability to report consistent and coherent data remains a challenge and hinders both provision of treatment and care for patients as well as optimal national and European healthcare systems.
Neurological manifestations of COVID-19: a systematic review
Authors: Nepal Gaurav , Rehrig Jessica Holly , Shrestha Gentle Sunder , Shing Yow Ka , Yadav Jayant Kumar , Ojha Rajeev , Pokhrel Gaurab , Tu Zhi Lan , Huang Dong Ya
Published: July 2020

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global spread of coronavirus disease (COVID-19). Our understanding of the impact this virus has on the nervous system is limited. Our review aims to inform and improve decision-making among the physicians treating COVID-19 by presenting a systematic analysis of the neurological manifestations experienced within these patients.

Methods

Any study, released prior to May 20, 2020, that reported neurological manifestations in patients infected by SARS-CoV-2 was systematically reviewed using the PRISMA (Preferred Reporting Items for Systemic review and Meta-Analysis) statement.

Results

Our systematic review included data from 37 articles: twelve retrospective studies, two prospective studies, and the rest case reports/series. The most commonly reported neurological manifestations of COVID-19 were myalgia, headache, altered sensorium, hyposmia, and hypogeusia. Uncommonly, COVID-19 can also present with central nervous system manifestations such as ischemic stroke, intracerebral hemorrhage, encephalo-myelitis, and acute myelitis, peripheral nervous manifestations such as Guillain-Barré syndrome and Bell’s palsy, and skeletal muscle manifestations such as rhabdomyolysis.

Conclusion

While COVID-19 typically presents as a self-limiting respiratory disease, it has been reported in up to 20% of patients to progress to severe illness with multi-organ involvement. The neurological manifestations of COVID-19 are not uncommon, but our study found most resolve with treatment of the underlying infection. Although the timeliness of this review engages current challenges posed by the COVID-19 pandemic, readers must not ignore the limitations and biases intrinsic to an early investigation.
Cell type-specific genome scans of DNA methylation divergence indicate an important role for transposable elements
Authors: Kartal Önder , Schmid Marc W. , Grossniklaus Ueli
Published: July 2020

In population genomics, genetic diversity measures play an important role in genome scans for divergent sites. In population epigenomics, comparable tools are rare although the epigenome can vary at several levels of organization. We propose a model-free, information-theoretic approach, the Jensen-Shannon divergence (JSD), as a flexible diversity index for epigenomic diversity. Here, we demonstrate how JSD uncovers the relationship between genomic features and cell type-specific methylome diversity inArabidopsis thaliana. However, JSD is applicable to any epigenetic mark and any collection of individuals, tissues, or cells, for example to assess the heterogeneity in healthy organs and tumors.