bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line antibiotic susceptibility pattern of toxigenic Corynebacterium diphtheriae in Indonesia
Authors: Husada Dominicus , Soegianto Sugi Deny Pranoto , Kurniawati Indra Suwarin , Hendrata Adi Pramono , Irawan Eveline , Kartina Leny , Puspitasari Dwiyanti , Basuki Parwati Setiono , Ismoedijanto
Published: December 2019

Background

Diphtheria has been reported as an outbreak in some regions in Indonesia, most especially in East Java Province. Resistance to penicillin, erythromycin, and other antibiotics, single or multiple, has been reported in several studies. This study aims to evaluate the first-line antibiotic susceptibility pattern of toxigenic Corynebacterium diphtheriae isolates.

Methods

This descriptive observational study was performed from August to November 2018. C. diphtheriae isolates were collected from diphtheria patients and carriers in East Java from 2012 to 2017 and kept at the Balai Besar Laboratorium Kesehatan Daerah Surabaya or the Public Health Laboratory of Surabaya. Sample selection was done by random cluster sampling. The sensitivity test by E-test®of the five antibiotics (penicillin, oxacillin, erythromycin, azithromycin, and clarithromycin) was done to determine the minimum inhibitory concentration (MIC). The Clinical and Laboratory Standards Institute M45A (2015) Corynebacterium spp. for penicillin and erythromycin was used as standard.

Results

From 114 targeted isolates, 108 were viable and toxigenic. The E-test was performed on the viable isolates. The majority of the hosts were male (58.3%), with median (range) age of 6.5 (1–14) years. Half of the samples were from the 1 to 5-year-old age group. The isolates were acquired much more from patients (78.7%) than carriers (21.3%) and from pharyngeal swab (74.1%). Most of these isolates were from Madura Island (47.2%) and the northern and eastern parts of the province (horseshoe area). Mitis isolates were the major variant (76.9%). The susceptibility pattern of C. diphtheriae to erythromycin was better than that to penicillin. The E-test result for penicillin was 68.52% susceptible, 31.48% intermediate, and 0% resistant (MIC range, < 0.016 to 2 μg/L) and for erythromycin (MIC range, < 0.016 to > 256 μg/L) was 85.2% susceptible, 12% intermediate, and 2.8% resistant The MIC range for oxacillin was 1 to 96 μg/L, while for both azithromycin and clarithromycin were <  0.016 to > 256 μg/L.

Conclusion

The susceptibility rate of C. diphtheriae to erythromycin is higher than that to penicillin. The regular update of antibiotic selection to the national guidelines is recommended. The MIC reference standard to azithromycin and clarithromycin is also needed.
Induction of labor compared to expectant management in term nulliparas with a latent phase of labor of more than 8 hours: a randomized trial
Authors: Sargunam Patrick Naveen , Bak Lindy Li Mei , Tan Peng Chiong , Vallikkannu Narayanan , Noor Azmi Mat Adenan , Zaidi Syeda Nureena , Win Sandar Tin , Omar Siti Zawiah
Published: December 2019

Background

Prolonged latent phase of labor is associated with adverse maternal and neonatal outcomes. Preliminary data indicate that labor induction for prolonged latent phase may reduce cesarean delivery. We performed a study powered to Cesarean delivery to evaluate labor induction compared to expectant management in full term nulliparas hospitalized for persistent contractions but non-progressive to established labor after an overnight stay.

Methods

From 2015 and 2017, nulliparas, ≥ 39 weeks’ gestation with prolonged latent phase of labor (persistent contractions after overnight hospitalization > 8 h), cervical dilation ≤3 cm, intact membranes and reassuring cardiotocogram were recruited. Participants were randomized to immediate induction of labor (with vaginal dinoprostone or amniotomy or oxytocin as appropriate) or expectant management (await labor for at least 24 h unless indicated intervention as directed by care provider). Primary outcome measure was Cesarean delivery.

Results

Three hundred eighteen women were randomized (159 to each arm). Data from 308 participants were analyzed. Cesarean delivery rate was 24.2% (36/149) vs. 23.3%, (37/159) RR 1.0 95% CI 0.7–1.6; P = 0.96 in induction of labor vs. expectant arms. Interval from intervention to delivery was 17.1 ± 9.9 vs. 40.1 ± 19.8 h; P < 0.001, intervention to active labor 9.6 ± 10.2 vs. 29.6 ± 18.5 h; P < 0.001, active labor to delivery 7.6 ± 3.6 vs. 10.5 ± 7.2 h; P < 0.001, intervention to hospital discharge 2.4 ± 1.2 vs. 2.9 ± 1.4 days; P < 0.001 and dinoprostone use was 19.5% (29/149) vs. 8.2% (13/159) RR 2.4 95% CI 1.3–4.4; P = 0.01 in IOL compared with expectant arms respectively. Intrapartum oxytocin use, epidural analgesia and uterine hyperstimulation syndrome, postpartum hemorrhage, patient satisfaction on allocated intervention, during labor and delivery and baby outcome were not significantly different across trial arms.

Conclusions

Induction of labor did not reduce Cesarean delivery rates but intervention to delivery and to hospital discharge durations are shorter. Patient satisfaction scores were similar. Induction of labor for prolonged latent phase of labor can be performed without apparent detriment to expedite delivery.

Trial registration

Registered in Malaysia National Medical Research Register (NMRR-15-16-23,886) on 6 January 2015 and the International Standard Randomised Controlled Trials Number registry, registration number ISRCTN14099170 on 5 Nov 2015.
How to improve the quality of care for women with postpartum haemorrhage at Onandjokwe Hospital, Namibia: quality improvement study
Authors: Nsangamay Tshimanga , Mash Robert
Published: December 2019

Background

Postpartum haemorrhage (PPH) is the leading direct cause of maternal morbidity and mortality worldwide. The sustainable development goals aim to reduce the maternal mortality ratio to 70 per 100,000 live births. In Namibia, the ratio was reported as 265 per 100,000 live births in 2015 and yet little is published on emergency obstetric care. The majority of deliveries in Namibia are facility-based. The aim of this study was to assess and improve the quality of care for women with PPH at Onandjokwe Hospital, Namibia.

Methods

A criterion-based audit cycle in all 82 women with PPH from 2015 using target standards for structure, process and outcomes of care. The audit team then planned and implemented interventions to improve the quality of care over a 10-month period. The audit team repeated the audit on all 70 women with PPH from the same 10-month period. The researchers compared audit results in terms of the number of target standards achieved and any significant change in the proportion of patients’ care meeting the predetermined criteria.

Results

In the baseline audit 12/19 structural, 0/9 process and 0/3 outcome target standards were achieved. On follow up 19/19 structural, 6/9 process and 2/3 outcome target standards were met. There was one maternal death in the baseline group and none in the follow up group. Overall 6/9 process and 2/3 outcome criteria significantly improved (p <  0.05) from baseline to follow up. Key interventions included training of nursing and medical staff in obstetric emergencies, ensuring that guidelines and standard operating protocols were easily available, reorganising care to ensure adequate monitoring of women postpartum and ensuring that essential equipment was available and functioning.

Conclusion

The study demonstrates that the quality of care for emergency obstetrics can be improved by audit cycles that focus on the structure and process of care. Other hospitals in Namibia and the region could adopt the process of continuous quality improvement and similar strategies.
Prevalence of unwanted pregnancy among Iranian women: an updated meta-analysis
Authors: Sayehmiri Kourosh , Ebtekar Fariba , Zarei Mozhdeh , Gheshlagh Reza Ghanei
Published: December 2019

Background

Unwanted pregnancy is a global issue with adverse outcomes for the mother, child, family, and society. Previous studies in Iran have reported different prevalence rates for unwanted pregnancy. This meta-analysis was aimed at estimating the overall prevalence of unwanted pregnancy among Iranian women.

Methods

A total of 20 articles in English or Persian, published between 2012 and December 2018, were collected. The search was conducted in national and international databases, including Scientific Information Database (SID), MagIran, PubMed, Scopus, and Web of Science, using the following keywords: ‘Unplanned pregnancy’, ‘Unintended pregnancy’, ‘Unwanted pregnancy’, and ‘Mistimed pregnancy’. The data were analyzed using the meta-analysis method and the random effects model. Heterogeneity among studies was assessed using the I2 statistic. All analyses were performed using Stata, version 12.

Results

Analysis of 20 studies with a total sample size of 16,298 showed that the prevalence of unwanted pregnancy among Iranian women was 26% (95% Confidence Interval [CI]: 23–28). This prevalence was higher in the regions 5 and 2 of Iran (27%) than the other regions, and had no significant decrease between 2012 and 2018 (p = 0. 937).

Conclusion

More than one-fourth of pregnancies among Iranian women are unwanted. Providing training programs for couples who do not plan to have children along with the support policies aimed at stimulating population growth, can be an important step in overcoming the issue of unwanted pregnancy and reducing the illegal abortions related to it.
RETRACTED ARTICLE: Swainsonine represses glioma cell proliferation, migration and invasion by reduction of miR-92a expression
Authors: Sun Libo , Jin Xingyi , Xie Lijuan , Xu Guangjun , Cui Yunxia , Chen Zhuo
Published: December 2019

Background

Swainsonine is a natural indolizidine alkaloid, its anti-tumor activity has been widely reported in varied cancers. This study aimed to investigate whether Swainsonine exerted anti-tumor impact on glioma cells, likewise uncovered the relative molecular mechanisms.

Methods

After administration with diverse concentrations of Swainsonine, cell growth, migration and invasion in U251 and LN444 cells were appraised by the common-used CCK-8, BrdU, flow cytometry and Transwell assays. MiR-92a mimic, inhibitor and the correlative NC were transfected into U251 and LN444 cells, and assessment of miR-92a expression was by utilizing qRT-PCR. Functions of miR-92a in above-mentioned cell biological processes were analyzed again in Swainsonine-treated cells. The momentous proteins of cell cycle, apoptosis and PI3K/AKT/mTOR pathway were ultimately examined by western blot.

Results

Swainsonine significantly hindered cell proliferation through decreasing cell viability, declining the percentage of BrdU cells, down-regulating CyclinD1 and up-regulating p16 expression. Enhancement of percentage of apoptotic cells was presented in Swainsonine-treated cells via activating cleaved-Caspase-3 and cleaved-Caspase-9. Additionally, Swainsonine impeded the abilities of migration and invasion by decreasing MMP-2, MMP-9, Vimentin and E-cadherin. Repression of miR-92a was observed in Swainsonine-treated cells, and miR-92a overexpression overturned the anti-tumor activity of Swainsonine in glioma cells. Finally, western blot assay displayed that Swainsonine hindered PI3K/AKT/mTOR pathway via regulating miR-92a.

Conclusions

These discoveries corroborated that Swainsonine exerted anti-tumor impacts on glioma cells via repression of miR-92a, and inactivation of PI3K/AKT/mTOR signaling pathway.
Human papillomavirus type 18 oncoproteins exert their oncogenicity in esophageal and tongue squamous cell carcinoma cell lines distinctly
Authors: Boon Siaw Shi , Chen Zigui , Li Jintao , Lee Karen Y. C. , Cai Liuyang , Zhong Rugang , Chan Paul K. S.
Published: December 2019

Background

Increasing evidence indicates an etiological role of human papillomavirus (HPV) in head and neck cancers, particularly oropharyngeal squamous cell carcinoma (OPSCC). However, the association between HPV and other cancers, including esophageal and tongue remains unclear. This study delineated the molecular characteristics of HPV18 E6 and E7 in esophageal (EC109 and EC9706) and tongue (Tca83) cancer cell lines with reference to cervical cancer (HeLa).

Methods

We analysed the HPV transcription profiles of esophageal and tongue cancer cells through Next-generation RNA sequencing, and the role of HPV18 E6 and E7 in these cells was assessed via siRNA approach, Western blotting and immunofluorescence assays.

Results

Overall, the HPV transcription profiles of esophageal and tongue cancer cells mimicked that of cervical cancer cells, with notable disruption of E2, and expression of E6, spliced E6 (E6*), E7, E1 and L1 transcripts. As with cervical cancer cells, p53 and its downstream transactivation target, p21, were found to be the major targets of E6 in esophageal and tongue cancer cell lines. Intriguingly, E7 preferentially targeted p130 in the two esophageal cancer cell lines, instead of pRb as in cervical cancer. Tca83 exhibited an E7 to E6 transcript ratio comparable to HeLa (cervix), targeted the ERK1/2 and MMP2 pathways, and was dependent on E6 and E7 to survive and proliferate. In contrast, both the esophageal cancer cell lines were distinct from HeLa in these aspects.

Conclusions

This is the first study that delineates transcript expression and protein interaction of HPV18 E6 and E7 in esophageal and tongue cancer cell lines, suggesting that HPV plays a role in inducing these cancers, albeit via distinct pathways than those observed in cervical cancer.
Application value of three-dimensional arterial spin labeling perfusion imaging in investigating cerebral blood flow dynamics in normal full-term neonates
Authors: Wang Jia-Ning , Li Jia , Liu Huai-Jun , Yin Xiao-Ping , Zhou Huan , Zheng Ya-Ting , An Na , Liang Si , Geng Zuo-Jun
Published: December 2019

Background

This study aims to investigate the application value of three-dimensional arterial spin labeling (3DASL) in investigating cerebral blood flow dynamics in full-term neonates.

Methods

A total of 60 full-term neonates without known intracranial pathology were recruited for 3DASL examination. These neonates were divided into three groups: 1–3 day group, 4–7 day group, and 8–15 day group. On the cerebral blood flow (CBF) images, regions of interest (ROI) were selected from the frontal white matter, parietal white matter, basal ganglia, corona radiata, thalamus and brainstem, and the CBF values of each ROI were recorded. The CBF values of ROIs at bilaterally symmetric locations, the values of each ROI between males and females, and the values of each ROI among these three different age groups were compared.

Results

The difference in CBF values of the frontal white matter, parietal white matter, basal ganglia, corona radiata and thalamus at the bilateral symmetric positions were not statistically significant. There was no statistical difference in the CBF values of each brain region between the male and female groups. The CBF values at the basal ganglia region, corona radiata and parietal white matter were higher in the 8–15 day group, when compared to the 1–3 day and 4–7 day groups (P < 0.05). The CBF value at the basal ganglia region was higher in the 4–7 day group, when compared to the 1–3 day group (P < 0.05). The CBF value at the frontal white matter was lower in the 4–7 day group, when compared to the 1–3 day and 8–15 day group (P < 0.05). The CBF value at the brainstem was higher in the 4–7 day group, when compared to the 1–3 day and 8–15 day groups (P < 0.05).

Conclusion

The 3DASL can quantitatively measure CBF, and be used to evaluate cerebral hemodynamics in neonates. The basal ganglia region and corona radiata CBF increases with the increase in neonatal diurnal age.
Longitudinal trajectories of comorbid PTSD and depression symptoms among U.S. service members and veterans
Authors:   for the Millennium Cohort Study Team, Armenta Richard F. , Walter Kristen H. , Geronimo-Hara Toni Rose , Porter Ben , Stander Valerie A. , LeardMann Cynthia A.
Published: December 2019

Background

Posttraumatic stress disorder (PTSD) often co-occurs with other psychiatric disorders, particularly major depressive disorder (MDD). The current study examined longitudinal trajectories of PTSD and MDD symptoms among service members and veterans with comorbid PTSD/MDD.

Methods

Eligible participants (n = 1704) for the Millennium Cohort Study included those who screened positive at baseline for both PTSD (PTSD Checklist–Civilian Version) and MDD (Patient Health Questionnaire). Between 2001 and 2016, participants completed a baseline assessment and up to 4 follow-up assessments approximately every 3 years. Mixture modeling simultaneously determined trajectories of comorbid PTSD and MDD symptoms. Multinomial regression determined factors associated with latent class membership.

Results

Four distinct classes (chronic, relapse, gradual recovery, and rapid recovery) described symptom trajectories of PTSD/MDD. Membership in the chronic class was associated with older age, service branch, deployment with combat, anxiety, physical assault, disabling injury/illness, bodily pain, high levels of somatic symptoms, and less social support.

Conclusions

Comorbid PTSD/MDD symptoms tend to move in tandem, and, although the largest class remitted symptoms, almost 25% of participants reported chronic comorbid symptoms across all time points. Results highlight the need to assess comorbid conditions in the context of PTSD. Future research should further evaluate the chronicity of comorbid symptoms over time.
Red flags for the early detection of spinal infection in back pain patients
Authors: Yusuf Mohamed , Finucane Laura , Selfe James
Published: December 2019

Background

Red flags are signs and symptoms that are possible indicators of serious spinal pathology. There is limited evidence or guidance on how red flags should be used in practice. Due to the lack of robust evidence for many red flags their use has been questioned. The aim was to conduct a systematic review specifically reporting on studies that evaluated the diagnostic accuracy of red flags for Spinal Infection in patients with low back pain.

Methods

Searches were carried out to identify the literature from inception to March 2019. The databases searched were Medline, CINHAL Plus, Web of Science, Embase, Cochrane, Pedro, OpenGrey and Grey Literature Report. Two reviewers screened article texts, one reviewer extracted data and details of each study, a second reviewer independently checked a random sample of the data extracted.

Results

Forty papers met the eligibility criteria. A total of 2224 cases of spinal infection were identified, of which 1385 (62%) were men and 773 (38%) were women mean age of 55 (± 8) years. In total there were 46 items, 23 determinants and 23 clinical features. Spinal pain (72%) and fever (55%) were the most common clinical features, Diabetes (18%) and IV drug use (9%) were the most occurring determinants. MRI was the most used radiological test and Staphylococcus aureus (27%), Mycobacterium tuberculosis (12%) were the most common microorganisms detected in cases.

Conclusion

The current evidence surrounding red flags for spinal infection remains small, it was not possible to assess the diagnostic accuracy of red flags for spinal infection, as such, a descriptive review reporting the characteristics of those presenting with spinal infection was carried out. In our review, spinal infection was common in those who had conditions associated with immunosuppression. Additionally, the most frequently reported clinical feature was the classic triad of spinal pain, fever and neurological dysfunction.
History of childhood abuse is associated with less positive treatment outcomes in socially stable women with alcohol use disorder
Authors: Schückher Fides , Sellin Tabita , Engström Ingemar , Berglund Kristina
Published: December 2019

Background

To examine the relationship between treatment outcome, as measured according to change in alcohol consumption, and a history of childhood abuse (emotional, physical, sexual) in socially stable women undergoing treatment for alcohol use disorder (AUD).

Methods

Participants were assessed using the Addiction Severity Index and the Mini International Neuropsychiatric Interview at the beginning of treatment (n = 75), end of treatment (n = 59) and 12 month follow-up after treatment (n = 57). Self-report data on alcohol consumption were obtained at all three time-points using the Alcohol Habits Inventory-Revised 2. Self-report data on childhood maltreatment were obtained at the beginning of treatment using the Childhood Trauma Questionnaire-short form. Study outcomes were changes in alcohol consumption (grams of pure alcohol per week), risk-drinking and reported abstinence.

Results

Of the 75 women enrolled, 38 (50.7%) reported a history of childhood abuse and the rest did not. Both groups showed a significant improvement in all three outcomes at the end of treatment and at 12-month follow-up. At the end of treatment, a significant inter-group difference was found for reported abstinence (non-abused group, 39.3% vs abused, 12.9%; p < 0.05). At 12-month follow-up, significant inter-group differences were observed for all treatment outcomes, with superior outcomes being found for the non-abused group, including a higher proportion of women with reported abstinence (55.6% vs 13.3%; p < 0.01).

Conclusion

The present findings suggest that an evaluation of a possible history of childhood abuse is warranted in all women seeking treatment for AUD, irrespective of social stability. In terms of clinical practice, the results suggest that additional interventions may be warranted in this population.
The pro-apoptotic effect of a Terpene-rich Annona cherimola leaf extract on leukemic cell lines
Authors: Ammoury Carl , Younes Maria , El Khoury Marianne , Hodroj Mohammad H. , Haykal Tony , Nasr Peter , Sily Marilyne , Taleb Robin I. , Sarkis Rita , Khalife Rana , Rizk Sandra
Published: December 2019

Background

The edible fruit Annona cherimola has previously shown many nutritional and medicinal properties. The current study evaluates the anti-cancer and anti-proliferative properties of Annona cherimola ethanolic leaf extract (AELE) on Acute Myeloid Leukemia (AML) cell lines cultured in vitro (Monomac-1 and KG-1).

Methods

The anti-proliferative effect of A. cherimola ethanolic leaf extract was evaluated via cell viability assay. Its pro-apoptotic effect was assessed through Cell Death ELISA and dual Annexin V/PI staining. To further investigate the molecular mechanism by which the extract promoted apoptosis and inhibited the proliferation of the AML cells used, apoptotic protein expression was determined through western blots. Extract composition was elucidated by Gas Chromatography-Mass Spectrometry (GC-MS).

Results

Our results showed that the treatment with A. cherimola ethanolic leaf extract exhibited an inhibitory effect on the proliferation of both cancer cell lines used in a dose- and time-dependent manner, with no toxic effects on normal mononuclear cells (MNCs) isolated from human bone marrow. This effect was mediated by DNA fragmentation and apoptosis, as revealed by Cell Death ELISA and dual Annexin V/PI staining. Western blot analysis revealed a Bax/Bcl2 dependent mechanism of apoptosis, as well as PARP cleavage, confirming the apoptotic results observed previously. These effects may be attributed to the presence of terpenes which constitute a large component of the leafy extract, as revealed via GC-MS.

Conclusion

All the data presented in our study show that the terpene-rich A. cherimola ethanolic leaf extract exhibits an anti-proliferative and pro-apoptotic effect on the AML cell lines used.
Helminthostachys zeylanica alleviates hepatic steatosis and insulin resistance in diet-induced obese mice
Authors: Chang Ting-Chen , Chiang Hao , Lai Yu-Heng , Huang Yu-Ling , Huang Hsiu-Chen , Liang Yu-Chih , Liu Hui-Kang , Huang Cheng
Published: December 2019

Background

Obesity and its associated health conditions, type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), are worldwide health problems. It has been shown that insulin resistance is associated with increased hepatic lipid and causes hepatic steatosis through a myriad of mechanisms, including inflammatory signaling.

Methods

Helminthostachys zeylanica (HZ) is used widely as a common herbal medicine to relieve fever symptoms and inflammatory diseases in Asia. In the present study, we evaluated whether HZ has therapeutic effects on obesity, NAFLD and insulin resistance. The protective effects of HZ extract were examined using free fatty acid-induced steatosis in human HuS-E/2 cells and a high-fat diet-induced NAFLD in mice.

Results

The major components of the HZ extract are ugonins J and K, confirmed by HPLC. Incubation of human hepatocytes, HuS-E/2 cells, with palmitate markedly increased lipid accumulation and treatment with the HZ extract significantly decreased lipid deposition and facilitated AMPK and ACC activation. After 12 weeks of a high-fat diet with HZ extract treatment, the HFD mice were protected from hyperlipidemia and hyperglycemia. HZ extract prevented body weight gain, adipose tissue expansion and adipocyte hypertrophy in the HFD mice. In addition, fat accumulation was reduced in mice livers. Moreover, the insulin sensitivity-associated index, which evaluates insulin function, was also significantly restored.

Conclusions

These results suggest that HZ has a promising pharmacological effect on high-fat diet-induced obesity, hepatic steatosis and insulin resistance, which may have the potential for clinical application.
Prediction of health care expenditure increase: how does pharmacotherapy contribute?
Authors: Jödicke Annika M. , Zellweger Urs , Tomka Ivan T. , Neuer Thomas , Curkovic Ivanka , Roos Malgorzata , Kullak-Ublick Gerd A. , Sargsyan Hayk , Egbring Marco
Published: December 2019

Background

Rising health care costs are a major public health issue. Thus, accurately predicting future costs and understanding which factors contribute to increases in health care expenditures are important. The objective of this project was to predict patients healthcare costs development in the subsequent year and to identify factors contributing to this prediction, with a particular focus on the role of pharmacotherapy.

Methods

We used 2014–2015 Swiss health insurance claims data on 373′264 adult patients to classify individuals’ changes in health care costs. We performed extensive feature generation and developed predictive models using logistic regression, boosted decision trees and neural networks. Based on the decision tree model, we performed a detailed feature importance analysis and subgroup analysis, with an emphasis on drug classes.

Results

The boosted decision tree model achieved an overall accuracy of 67.6% and an area under the curve-score of 0.74; the neural network and logistic regression models performed 0.4 and 1.9% worse, respectively. Feature engineering played a key role in capturing temporal patterns in the data. The number of features was reduced from 747 to 36 with only a 0.5% loss in the accuracy. In addition to hospitalisation and outpatient physician visits, 6 drug classes and the mode of drug administration were among the most important features. Patient subgroups with a high probability of increase (up to 88%) and decrease (up to 92%) were identified.

Conclusions

Pharmacotherapy provides important information for predicting cost increases in the total population. Moreover, its relative importance increases in combination with other features, including health care utilisation.
Targeted regulation of fibroblast state by CRISPR-mediated CEBPA expression
Authors: Liu Wei , Meridew Jeffrey A. , Aravamudhan Aja , Ligresti Giovanni , Tschumperlin Daniel J. , Tan Qi
Published: December 2019

Background

Fibroblasts regulate tissue homeostasis and the balance between tissue repair and fibrosis. CCAAT/enhancer-binding protein alpha (CEBPA) is a key transcription factor that regulates adipogenesis. CEBPA has been shown to be essential for lung maturation, and deficiency of CEBPA expression leads to abnormal lung architecture. However, its specific role in lung fibroblast regulation and fibrosis has not yet been elucidated.

Methods

Lung fibroblast CEBPA expression, pro-fibrotic and lipofibroblast gene expression were assessed by qRT-PCR. CEBPA gain and loss of function experiments were carried out to evaluate the role of CEBPA in human lung fibroblast activation with and without TGF-β1 treatment. Adipogenesis assay was used to measure the adiopogenic potential of lung fibroblasts. Finally, CRISPR activation system was used to enhance endogenous CEBPA expression.

Results

We found that CEBPA gene expression is significantly decreased in IPF-derived fibroblasts compared to normal lung fibroblasts. CEBPA knockdown in normal human lung fibroblasts enhanced fibroblast pro-fibrotic activation and ECM production. CEBPA over-expression by transient transfection in IPF-derived fibroblasts significantly reduced pro-fibrotic gene expression, ECM deposition and αSMA expression and promoted the formation of lipid droplets measured by Oil Red O staining and increased lipofibroblast gene expression. Inhibition of the histone methyl transferase G9a enhanced CEBPA expression, and the anti-fibrotic effects of G9a inhibition were partially mediated by CEBPA expression. Finally, targeted CRISPR-mediated activation of CEBPA resulted in fibroblasts switching from fibrogenic to lipofibroblast states.

Conclusions

CEBPA expression is reduced in human IPF fibroblasts and its deficiency reduces adipogenic potential and promotes fibrogenic activation. CEBPA expression can be rescued via an inhibitor of epigenetic repression or by targeted CRISPR activation, leading to reduced fibrogenic activation.
Abiraterone acetate and docetaxel with androgen deprivation therapy in high-volume metastatic hormone-sensitive prostate cancer in China: an indirect treatment comparison and cost analysis
Authors: Hu Xin , Qu Shuli , Yao Xingxing , Li Chaoyun , Liu Yanjun , Wang Jianye
Published: December 2019

Background

To conduct an indirect treatment comparison of patients with high-volume mHSPC and a cost analysis between Abi-ADT and Doc-ADT therapies in China.

Methods

The Bucher technique for indirect treatment comparison was used. A cost analysis was conducted from both healthcare and patient perspectives.

Results

The indirect treatment comparison demonstrated no significant difference in PFS for Abi-ADT versus Doc-ADT (HR: 0.84, 95% CI 0.66–1.07). Doc-ADT therapy costs less than Abi-ADT, with potential savings of up to RMB 887,057 per patient from the healthcare perspective and RMB 226,210 per patient from the patient perspective.

Conclusions

No significant differences in PFS between Doc-ADT and Abi-ADT therapy for patients with high-volume mHSPC. Doc-ADT therapy is a cost-saving alternative to Abi-ADT in China.
Veterinary use of bacteriophage therapy in intensively-reared livestock
Authors: Gigante Adriano , Atterbury Robert J
Published: December 2019

Zoonoses are infectious diseases transmitted directly or indirectly between animals and humans. Several important zoonotic pathogens colonize farm animals asymptomatically, which may lead to contamination of the food chain and public health hazards. Moreover, routine sampling of carcasses at retail by government authorities over the past 20 years suggests the prevalence of antibiotic resistance in foodborne pathogens has increased. If this continues, antibiotics may be ineffective against such pathogens in the future and alternative approaches, such as phage therapy, may be necessary. Intensive livestock farming is the only realistic way of meeting the demand for meat from an increasing global population and growth in middle class consumers in developing countries, particularly in Asia. This review elaborates on the use of phages to control zoonotic pathogens in intensively-reared livestock (poultry and pigs).
Total cross-sectional area of the femoral neck nutrient foramina measured to assess arterial vascular beds in the femoral head
Authors: Mei Jiong , Quan Kun , Wang Hua , Dai Yahui , Zhang Fangfang , Ni Ming
Published: December 2019

Background

A detailed understanding of the blood supply to the femoral head is required to plan the surgery in the femoral neck and head area. However, information about the blood vessel networks in the femoral head is inadequate.

Methods

The surface of the femoral neck of 100 dry cadaveric adult femur specimens was scanned using a 3D scanner. The scanning distance was 200 mm, precision 0.01 mm, and measuring point 0.04 mm. The images were acquired at a resolution of 1,310,000 pixels. Digital imaging data were recorded from the femoral neck surface. The diameters of the nutrient foramina of the superior, inferior and anterior retinacular arteries, and the ligamentum teres arteries were determined and divided into five groups.

Results

The mean cumulative cross-sectional area of the nutrient foramina was as follows: canals of the superior, inferior, anterior, and ligamentum retinacular arteries were 15.59 mm2, 3.63 mm2, 4.32 mm2, and 1.58 mm2, respectively. Next, we analyzed the canals of the superior, inferior, anterior and ligamentum retinacular arteries, respectively, via 3D scanner. We found that the canals of the superior retinacular arteries appear to supply more blood to the femoral head than the canals of the other three types of arteries.

Conclusions

Our results demonstrated that surgeries of the femoral neck and femoral head will be improved with prior 3D scanning and lead to better outcomes in surgeries involving the hip area.
A prenatal diagnosis and genetics study of five pedigrees in the Chinese population with Xp22.31 microduplication
Authors: Zhuang Jianlong , Wang Yuanbai , Zeng Shuhong , Lv Chunling , Lin Yiming , Jiang Yuying
Published: December 2019

Background

Copy number variations (CNVs) can contribute to human phenotype, phenotypic diversity and disease susceptibility, while others may benign. In the current study, an attempt to investigate the pathogenicity of CNVs in chromosome Xp22.31 was explored.

Methods

G-banding and SNP-array techniques were used to analyze chromosome karyotypes and CNVs in fetuses. Parents associate with five different pedigrees possessing high risk factors in pregnancy were considered with such parameters as advanced age, high risk of serological screening and ultrasound abnormalities.

Results

The fetuses’ amniotic fluid karyotypes were 46, XX and those of their parents with the five pedigrees revealed no abnormalities. Here, we noticed a series of individuals with Xp22.31 duplications ranging from 534.6 kb to 1.6 Mb. It was detected through SNP array that the fetuses in Pedigree 1 and 2 had ~ 600 kb duplications in the Xp22.31 region of their X chromosomes which contained two OMIM genes, HDHD1 (OMIM: 306480) and part of STS (OMIM: 300747). The fetuses of Pedigrees 3, 4 and 5 had 1.6 Mb duplication in the same chromosome which contained four OMIM genes: HDHD1 (OMIM: 306480), STS (OMIM: 300747), PNPLA4 (OMIM: 300102) and VCX (OMIM: 300229). The duplications in the fetuses of Pedigrees 1 and 5 were inherited from the non-phenotypic parents. Pedigrees 3 and 4 refused to perform parental verification. Finally, four of the five pedigrees continue towards pregnancy with no abnormalities being observed during followed-ups.

Conclusion

Our study first showed duplications of Xp22.31 in Chinese population. Clinical and genetic investigation on five different pedigrees, we consider the duplication of these fragments as likely benign copy number variants (CNVs). We suggest that the duplications of Xp22.31 with recurrent duplication as a benign CNVs .
Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming
Authors: Wang Zhe , Sun Hanxue , Provaznik Jan , Hackert Thilo , Zöller Margot
Published: December 2019

Background

Cancer-initiating cell (CIC) exosomes (CIC-TEX) are suggested reprogramming Non-CIC. Mode of message transfer and engagement of CIC-markers being disputed, we elaborated the impact of CD44v6 and Tspan8 on the response of Non-CIC.

Methods

Non-metastasizing CD44v6- and Tspan8-knockdown (kd) pancreatic cancer cells served as Non-CIC. CIC-TEX coculture-induced changes were evaluated by deep-sequencing and functional assays. Tumor progression was surveyed during in vivo CIC-TEX treatment.

Results

Deep-sequencing of CIC-TEX-cocultured CD44v6kd-Non-CIC revealed pronounced mRNA changes in signaling, transport, transcription and translation; altered miRNA affected metabolism, signaling and transcription. CIC-TEX coculture-induced changes in Tspan8kd-Non-CIC mostly relied on CIC-TEX-Tspan8 being required for targeting. CIC-TEX transfer supported apoptosis resistance and significantly promoted epithelial mesenchymal transition, migration, invasion and (lymph)angiogenesis of the kd Non-CIC in vitro and in vivo, deep-sequencing allowing individual mRNA and miRNA assignment to altered functions. Importantly, CIC-TEX act as a hub, initiated by CD44v6-dependent RTK, GPCR and integrin activation and involving CD44v6-assisted transcription and RNA processing. Accordingly, a kinase inhibitor hampered CIC-TEX-fostered tumor progression, which was backed by an anti-Tspan8 blockade of CIC-TEX binding.

Conclusions

This in depth report on the in vitro and in vivo impact of CIC-TEX on CD44v6kd and Tspan8kd Non-CIC unravels hub CIC-TEX activity, highlighting a prominent contribution of the CIC-markers CD44v6 to signaling cascade activation, transcription, translation and miRNA processing in Non-CIC and of Tspan8 to CIC-TEX targeting. Blocking CIC-TEX binding/uptake and uptake-initiated target cell activation significantly mitigated the deleterious CIC-TEX impact on CD44v6kd and Tspan8kd Non-CIC.
Correction to: iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy
Authors:   on behalf of the iHIVARNA consortium, de Jong Wesley , Aerts Joeri , Allard Sabine , Brander Christian , Buyze Jozefien , Florence Eric , van Gorp Eric , Vanham Guido , Leal Lorna , Mothe Beatriz , Thielemans Kris , Plana Montse , Garcia Félipe , Gruters Rob
Published: December 2019

Following publication of the original article [1], we have been notified that end note would need to be adjusted.
Drug screening approach combines epigenetic sensitization with immunochemotherapy in cancer
Authors: Facciotto Chiara , Casado Julia , Turunen Laura , Leivonen Suvi-Katri , Tumiati Manuela , Rantanen Ville , Kauppi Liisa , Lehtonen Rainer , Leppä Sirpa , Wennerberg Krister , Hautaniemi Sampsa
Published: December 2019

Background

The epigenome plays a key role in cancer heterogeneity and drug resistance. Hence, a number of epigenetic inhibitors have been developed and tested in cancers. The major focus of most studies so far has been on the cytotoxic effect of these compounds, and only few have investigated the ability to revert the resistant phenotype in cancer cells. Hence, there is a need for a systematic methodology to unravel the mechanisms behind epigenetic sensitization.

Results

We have developed a high-throughput protocol to screen non-simultaneous drug combinations, and used it to investigate the reprogramming potential of epigenetic inhibitors. We demonstrated the effectiveness of our protocol by screening 60 epigenetic compounds on diffuse large B-cell lymphoma (DLBCL) cells. We identified several histone deacetylase (HDAC) and histone methyltransferase (HMT) inhibitors that acted synergistically with doxorubicin and rituximab. These two classes of epigenetic inhibitors achieved sensitization by disrupting DNA repair, cell cycle, and apoptotic signaling. The data used to perform these analyses are easily browsable through our Results Explorer. Additionally, we showed that these inhibitors achieve sensitization at lower doses than those required to induce cytotoxicity.

Conclusions

Our drug screening approach provides a systematic framework to test non-simultaneous drug combinations. This methodology identified HDAC and HMT inhibitors as successful sensitizing compounds in treatment-resistant DLBCL. Further investigation into the mechanisms behind successful epigenetic sensitization highlighted DNA repair, cell cycle, and apoptosis as the most dysregulated pathways. Altogether, our method adds supporting evidence in the use of epigenetic inhibitors as sensitizing agents in clinical settings.
DNA methylation data by sequencing: experimental approaches and recommendations for tools and pipelines for data analysis
Authors: Rauluseviciute Ieva , Drabløs Finn , Rye Morten Beck
Published: December 2019

Sequencing technologies have changed not only our approaches to classical genetics, but also the field of epigenetics. Specific methods allow scientists to identify novel genome-wide epigenetic patterns of DNA methylation down to single-nucleotide resolution. DNA methylation is the most researched epigenetic mark involved in various processes in the human cell, including gene regulation and development of diseases, such as cancer. Increasing numbers of DNA methylation sequencing datasets from human genome are produced using various platforms—from methylated DNA precipitation to the whole genome bisulfite sequencing. Many of those datasets are fully accessible for repeated analyses. Sequencing experiments have become routine in laboratories around the world, while analysis of outcoming data is still a challenge among the majority of scientists, since in many cases it requires advanced computational skills. Even though various tools are being created and published, guidelines for their selection are often not clear, especially to non-bioinformaticians with limited experience in computational analyses. Separate tools are often used for individual steps in the analysis, and these can be challenging to manage and integrate. However, in some instances, tools are combined into pipelines that are capable to complete all the essential steps to achieve the result. In the case of DNA methylation sequencing analysis, the goal of such pipeline is to map sequencing reads, calculate methylation levels, and distinguish differentially methylated positions and/or regions. The objective of this review is to describe basic principles and steps in the analysis of DNA methylation sequencing data that in particular have been used for mammalian genomes, and more importantly to present and discuss the most pronounced computational pipelines that can be used to analyze such data. We aim to provide a good starting point for scientists with limited experience in computational analyses of DNA methylation and hydroxymethylation data, and recommend a few tools that are powerful, but still easy enough to use for their own data analysis.
Deviation from normative brain development is associated with symptom severity in autism spectrum disorder
Authors: Tunç Birkan , Yankowitz Lisa D. , Parker Drew , Alappatt Jacob A. , Pandey Juhi , Schultz Robert T. , Verma Ragini
Published: December 2019

Background

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition. The degree to which the brain development in ASD deviates from typical brain development, and how this deviation relates to observed behavioral outcomes at the individual level are not well-studied. We hypothesize that the degree of deviation from typical brain development of an individual with ASD would relate to observed symptom severity.

Methods

The developmental changes in anatomical (cortical thickness, surface area, and volume) and diffusion metrics (fractional anisotropy and apparent diffusion coefficient) were compared between a sample of ASD (n = 247) and typically developing children (TDC) (n = 220) aged 6–25. Machine learning was used to predict age (brain age) from these metrics in the TDC sample, to define a normative model of brain development. This model was then used to compute brain age in the ASD sample. The difference between chronological age and brain age was considered a developmental deviation index (DDI), which was then correlated with ASD symptom severity.

Results

Machine learning model trained on all five metrics accurately predicted age in the TDC (r = 0.88) and the ASD (r = 0.85) samples, with dominant contributions to the model from the diffusion metrics. Within the ASD group, the DDI derived from fractional anisotropy was correlated with ASD symptom severity (r = − 0.2), such that individuals with the most advanced brain age showing the lowest severity, and individuals with the most delayed brain age showing the highest severity.

Limitations

This work investigated only linear relationships between five specific brain metrics and only one measure of ASD symptom severity in a limited age range. Reported effect sizes are moderate. Further work is needed to investigate developmental differences in other age ranges, other aspects of behavior, other neurobiological measures, and in an independent sample before results can be clinically applicable.

Conclusions

Findings demonstrate that the degree of deviation from typical brain development relates to ASD symptom severity, partially accounting for the observed heterogeneity in ASD. Our approach enables characterization of each individual with reference to normative brain development and identification of distinct developmental subtypes, facilitating a better understanding of developmental heterogeneity in ASD.
ChemScanner: extraction and re-use(ability) of chemical information from common scientific documents containing ChemDraw files
Authors: Nguyen An , Huang Yu-Chieh , Tremouilhac Pierre , Jung Nicole , Bräse Stefan
Published: December 2019

We developed ChemScanner, a software that can be used for the extraction of chemical information from ChemDraw binary (CDX) or ChemDraw XML-based (CDXML) files and to retrieve the ChemDraw scheme from DOC, DOCX or XML documents. This can facilitate the reuse of chemical information embedded into diverse documents used as standard storage and communication instrument in chemical sciences (e.g. for student’s theses, PhD theses, or publications). The extracted information is processed to reactions, molecules, as well as additional text and values and can be accessed via the ChemScanner UI. ChemScanner supports the export to Excel and CML, the direct import of the extracted data to the Open Source ELN Chemotion or the use via “copy and paste” of selected information. The software was designed with a focus on the processing of documents with embedded molecular structure information as CDX or CDXML as these are the most common file formats for chemical drawings. The project aims to support the chemists in their efforts to re-use chemistry research data by providing them missing tools for an automated assembly of reaction data.