bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative proteomics analysis of differentially expressed proteins induced by astragaloside IV in cervical cancer cell invasion
Authors: Xia Chenglai , He Zhihong , Cai Yantao
Published: March 2020

Background

Cervical cancer remains the second leading cause of mortality in women in developing countries. While surgery, chemotherapy, radiotherapy, and vaccine therapy are being applied for its treatment, individually or in combination, the survival rate in advanced cervical cancer patients is still very low. Traditional Chinese medicine has been found to be effective in the treatment of cervical cancer. Astragaloside IV (AS-IV), a compound belonging to Astragalus polysaccharides, shows anticancer activity through several cell signaling pathways. However, the detailed molecular mechanism governing the anticancer activity of AS-IV remains unknown.

Material and methods

In our study, we performed tumor xenograft analysis, transwell cell migration and invasion assay, Western blot analysis, and iTRAQ combination by parallel reaction monitoring (PRM) analysis to study the molecular mechanism of AS-IV in the suppression of cervical cancer cell invasion.

Results

Our results showed that AS-IV suppressed cervical cancer cell invasion and induced autophagy in them, with the tumor growth curve increasing slowly. We also identified 32 proteins that were differentially expressed in the SiHa cells when treated with AS-IV, with 16 of them involved in the upregulation and 16 in the downregulation of these cells. These differentially expressed proteins, which were predominantly actin–myosin complexes, controlled cell proliferation and cell development by steroid binding and altering the composition of the cell cytoskeleton. DCP1A and TMSB4X, the two proteins regulating autophagy, increased in cervical cancer cells when treated with AS-IV.

Conclusions

We conclude that AS-IV could inhibit cervical cancer invasion by inducing autophagy in cervical cancer cells. Since iTRAQ combination by PRM has been observed to be useful in identifying macromolecular target compounds, it may be considered as a novel strategy in the screening of anticancer compounds used in the treatment of cervical cancer.
Mixture toxicity in the Erft River: assessment of ecological risks and toxicity drivers
Authors: Markert Nele , Rhiem Stefan , Trimborn Michael , Guhl Barbara
Published: March 2020

Background

A vast number of chemical substances are released into the aquatic environment, leading to complex chemical mixtures in surface waters. Current water quality assessments, however, are based on the risk assessment of single substances. To consider potential mixture effects in water quality assessments, the North Rhine Westphalian State Agency for Nature, Environment and Consumer Protection (LANUV), Germany started a project assessing mixture toxicity in surface waters. This article summarises the mixture evaluation of chemical data collected by the Erftverband during a water sampling campaign in the Erft River in 2016/2017. Altogether, 153 substances were included in the analysis, of which 98 were detected. Two different approaches based on the concept of concentration addition were used to analyse the data. The results were compared to findings based on datasets from LANUV surveillance monitoring according to the EU Water Framework Directive.

Results

Acute and chronic mixture risk calculations indicated risks for 32% and up to 90% of the samples, respectively. The greatest acute toxic pressure was identified for the aquatic flora due to continuous exposure to varying pesticides, whereas the greatest chronic mixture risk was identified for fish as result of a ubiquitous presence of the pharmaceuticals diclofenac and ibuprofen. Overall, only a limited number of substances significantly contributed to the calculated mixture risks. However, these substances varied seasonally and regionally. When mixture risks were calculated based on different datasets, the monitoring design markedly affected the outcome of the mixture risk assessment. Data gaps of both ecotoxicological and exposure data lead to high uncertainties in the mixture risk assessment.

Conclusions

Ecotoxicological effects on aquatic organisms caused by chemical mixtures can be expected along the Erft River throughout the year. Both mixture risk assessment approaches can be used for a conservative assessment of mixture risks and characterise the aquatic pollution in the river more realistically than single substance assessments. For the integration of mixture risk evaluations into the assessment and management of the chemical water quality, a two-staged assessment combining both approaches is suggested. To improve future risk assessments, the accessibility and exchange of high-quality ecotoxicological data should be enhanced.
Effect of coronary artery bypass grafting on blood pressure response to head-up tilting
Authors: Hori Shinnosuke , Kamijo Yoshi-ichiro , Yuzaki Mitsuru , Kawabe Tetsuya , Minami Kohei , Umemoto Yasunori , Yokoyama Mao , Uenishi Hiroyasu , Nishimura Yoshiharu , Kouda Ken , Mikami Yukio , Tajima Fumihiro
Published: March 2020

Blood pressure response to head-up tilt (HUT) in 7 healthy subjects and 9 patients before and after coronary artery bypass grafting (CABG) was measured during supine and 15-min 60° HUT. Stroke volume (SV) and ejection fraction (EF) were assessed by echocardiography. Baseline mean arterial pressure (MAP) and heart rate (HR) in patients before CABG were similar to healthy subjects. MAP in patients decreased by 6 (4–9) mmHg [median (1st–3rd quartiles)] during 7–12 mmHg of HUT with decreased cardiac output (CO = SV × HR) while HR remained unchanged. MAP in healthy subjects remained unchanged during HUT with increased HR. Body weight decreased by 3.5 (2.5–3.7) kg and MAP decreased by 6 (2–13) mmHg during the last 3-min HUT while HR increased after CABG. Decreases in SV and CO during HUT disappeared after CABG. Blood pressure decreased during HUT in patients before and after CABG regardless of HR response.
Robust high-throughput assays to assess discrete steps in ubiquitination and related cascades
Authors: Fenteany Gabriel , Gaur Paras , Sharma Gaurav , Pintér Lajos , Kiss Ernő , Haracska Lajos
Published: March 2020

Background

Ubiquitination and ubiquitin-like protein post-translational modifications play an enormous number of roles in cellular processes. These modifications are constituted of multistep reaction cascades. Readily implementable and robust methods to evaluate each step of the overall process, while presently limited, are critical to the understanding and modulation of the reaction sequence at any desired level, both in terms of basic research and potential therapeutic drug discovery and development.

Results

We developed multiple robust and reliable high-throughput assays to interrogate each of the sequential discrete steps in the reaction cascade leading to protein ubiquitination. As models for the E1 ubiquitin-activating enzyme, the E2 ubiquitin-conjugating enzyme, the E3 ubiquitin ligase, and their ultimate substrate of ubiquitination in a cascade, we examined Uba1, Rad6, Rad18, and proliferating cell nuclear antigen (PCNA), respectively, in reconstituted systems. Identification of inhibitors of this pathway holds promise in cancer therapy since PCNA ubiquitination plays a central role in DNA damage tolerance and resulting mutagenesis. The luminescence-based assays we developed allow for the quantitative determination of the degree of formation of ubiquitin thioester conjugate intermediates with both E1 and E2 proteins, autoubiquitination of the E3 protein involved, and ubiquitination of the final substrate. Thus, all covalent adducts along the cascade can be individually probed. We tested previously identified inhibitors of this ubiquitination cascade, finding generally good correspondence between compound potency trends determined by more traditional low-throughput methods and the present high-throughput ones.

Conclusions

These approaches are readily adaptable to other E1, E2, and E3 systems, and their substrates in both ubiquitination and ubiquitin-like post-translational modification cascades.
Exogenous supply of Hsp47 triggers fibrillar collagen deposition in skin cell cultures in vitro
Authors: Khan Essak S. , Sankaran Shrikrishnan , Llontop Lorena , del Campo Aránzazu
Published: March 2020

Background

Collagen is a structural protein that provides mechanical stability and defined architectures to skin. In collagen-based skin disorders this stability is lost, either due to mutations in collagens or in the chaperones involved in collagen assembly. This leads to chronic wounds, skin fragility, and blistering. Existing approaches to treat such conditions rely on administration of small molecules to simulate collagen production, like 4-phenylbutyrate (4-PBA) or growth factors like TGF-β. However, these molecules are not specific for collagen synthesis, and result in unsolicited side effects. Hsp47 is a collagen-specific chaperone with a major role in collagen biosynthesis. Expression levels of Hsp47 correlate with collagen deposition. This article explores the stimulation of collagen deposition by exogenously supplied Hsp47 (collagen specific chaperone) to skin cells, including specific collagen subtypes quantification.

Results

Here we quantify the collagen deposition level and the types of deposited collagens after Hsp47 stimulation in different in vitro cultures of cells from human skin tissue (fibroblasts NHDF, keratinocytes HaCat and endothelial cells HDMEC) and mouse fibroblasts (L929 and MEF). We find upregulated deposition of fibrillar collagen subtypes I, III and V after Hsp47 delivery. Network collagen IV deposition was enhanced in HaCat and HDMECs, while fibril-associated collagen XII was not affected by the increased intracellular Hsp47 levels. The deposition levels of fibrillar collagen were cell-dependent i.e. Hsp47-stimulated fibroblasts deposited significantly higher amount of fibrillar collagen than Hsp47-stimulated HaCat and HDMECs.

Conclusions

A 3-fold enhancement of collagen deposition was observed in fibroblasts upon repeated dosage of Hsp47 within the first 6 days of culture. Our results provide fundamental understanding towards the idea of using Hsp47 as therapeutic protein to treat collagen disorders.
Whole genome resequencing reveals an association of ABCC4 variants with preaxial polydactyly in pigs
Authors: Ma Cheng , Khederzadeh Saber , Adeola Adeniyi C. , Han Xu-Man , Xie Hai-Bing , Zhang Ya-Ping
Published: March 2020

Background

Polydactyly is one of the most common congenital limb dysplasia in many animal species. Although preaxial polydactyly (PPD) has been comprehensively studied in humans as a common abnormality, the genetic variations in other animal species have not been fully understood. Herein, we focused on the pig, as an even-toed ungulate mammal model with its unique advantages in medical and genetic researches, two PPD families consisting of four affected and 20 normal individuals were sequenced.

Results

Our results showed that the PPD in the sampled pigs were not related to previously reported variants. A strong association was identified atABCC4and it encodes a transmembrane protein involved in ciliogenesis. We found that the affected and normal individuals were highly differentiated atABCC4, and all the PPD individuals shared long haplotype stretches as compared with the unaffected individuals. A highly differentiated missense mutation (I85T) inABCC4was observed at a residue from a transmembrane domain highly conserved among a variety of organisms.

Conclusions

This study reportsABCC4as a new candidate gene and identifies a missense mutation for PPD in pigs. Our results illustrate a putative role of ciliogenesis process in PPD, coinciding with an earlier observation of ciliogenesis abnormality resulting in pseudo-thumb development in pandas. These results expand our knowledge on the genetic variations underlying PPD in animals.
Effect of thrombus aspiration on microcirculatory resistance and ventricular function in patients with high thrombus burden
Authors: Firman Doni , Alkatiri Amir Aziz , Taslim Imammurahman , Wangi Surya Buana , Pranata Raymond
Published: March 2020

Background

Studies have not demonstrated consistent outcomes following thrombus aspiration in Primary Percutaneous Coronary Intervention (PPCI). We investigated the relationship between thrombus aspiration and microvascular obstruction as measured using Index of Microcirculatory Resistance (IMR) immediately following PPCI and Left Ventricle Function Improvement measured using Global Longitudinal Strain (GLS) six months following PPCI. Our aim is to determine microvascular obstruction and left ventricle function improvement six months following thrombus aspiration during PPCI.

Methods

This was a single-center, observational, prospective non-randomized study involving 45 patients with thrombus score 4–5 (defined as high thrombus burden) and Thrombolysis in Myocardial Infarction (TIMI) flow of 0–2 who subsequently underwent PPCI. Thrombus aspiration was conducted based on physician discretion. The IMR was measured immediately following the procedure. All patients underwent echocardiography to measure GLS at 24 h, 3 months and 6 months following PPCI.

Results

Thirty-three (73%) patients underwent thrombus aspiration during PPCI and twelve (27%) patients underwent the conventional PPCI. No significant difference in IMR was found between the group that underwent thrombus aspiration and the group that underwent conventional PCI (51.9 ± 41.5 vs 47.1 ± 35.6 p = 0.723). TIMI flow after PPCI was worse in thrombus aspiration group (OR 5.2 [1.2–23.2], p = 0.041). There was no difference in GLS between two groups at 6-month follow-up (− 13.0 ± 3.4 vs − 12.8 ± 4.6, p = 0.912).

Conclusion

This study indicates no benefit of thrombus aspiration during PPCI in reducing either microvascular obstruction or left ventricular function at 6-month follow-up for patients with high thrombus burden. Nevertheless, further studies are required before definite conclusions can be made.
Role of miR-92a-3p, oxidative stress, and p38MAPK/NF-κB pathway in rats with central venous catheter related thrombosis
Authors: Gan Xiao , Zhao Huihan , Wei Yan , Jiang Qingjuan , Wen Cui , Ying Yanping
Published: March 2020

Background

miR-92a-3p and oxidative stress are reportedly associated with venous thrombosis. However, the role of miR-92a-3p and oxidative stress in catheter-related thrombosis (CRT) remains ambiguous. Herein, we studied the roles of miR-92a-3p, oxidative stress, and p38-mitogen-activated protein kinase/nuclear factor kappa-B (MAPK/NF-κB) pathway in CRT.

Methods

Forty-five male rats were randomly and equally divided into control, sham operation, and CRT groups. The rats were sacrificed after 10 days. Reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) levels in the serum were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of miR-92a-3p, heme oxygenase-1 (HO-1), NF-κB p65, and p38 MAPK in the venous tissues were detected with quantitative polymerase chain reaction (qPCR) and Western blot.

Results

Thrombosis was observed only in the CRT group. Compared with the levels in the control and sham operation groups, ROS and MDA significantly increased in the CRT group, but SOD significantly decreased. qPCR and Western blot results showed that miR-92a-3p, HO-1, p38 MAPK, and NF-κB p65 expression was significantly upregulated in the venous tissues of the CRT group. Moreover, miR-92a-3p was positively correlated with HO-1, which was positively correlated with p38 MAPK and NF-κB p65.

Conclusion

miR-92a-3p was correlated with oxidative stress in CRT. miR-92a-3p and oxidative stress contributed to endothelial dysfunction and simultaneously was associated with CRT.
Multiple imputation by predictive mean matching in cluster-randomized trials
Authors: Bailey Brittney E. , Andridge Rebecca , Shoben Abigail B.
Published: March 2020

Background

Random effects regression imputation has been recommended for multiple imputation (MI) in cluster randomized trials (CRTs) because it is congenial to analyses that use random effects regression. This method relies heavily on model assumptions and may not be robust to misspecification of the imputation model. MI by predictive mean matching (PMM) is a semiparametric alternative, but current software for multilevel data relies on imputation models that ignore clustering or use fixed effects for clusters. When used directly for imputation, these two models result in underestimation (ignoring clustering) or overestimation (fixed effects for clusters) of variance estimates.

Methods

We develop MI procedures based on PMM that leverage these opposing estimated biases in the variance estimates in one of three ways: weighting the distance metric (PMM-dist), weighting the average of the final imputed values from two PMM procedures (PMM-avg), or performing a weighted draw from the final imputed values from the two PMM procedures (PMM-draw). We use Monte-Carlo simulations to evaluate our newly proposed methods relative to established MI procedures, focusing on estimation of treatment group means and their variances after MI.

Results

The proposed PMM procedures reduce the bias in the MI variance estimator relative to established methods when the imputation model is correctly specified, and are generally more robust to model misspecification than even the random effects imputation methods.

Conclusions

The PMM-draw procedure in particular is a promising method for multiply imputing missing data from CRTs that can be readily implemented in existing statistical software.
Diagnosis of vascular invasion in pancreatic ductal adenocarcinoma using endoscopic ultrasound elastography
Authors: Yamada Kenta , Kawashima Hiroki , Ohno Eizaburo , Ishikawa Takuya , Tanaka Hiroyuki , Nakamura Masanao , Miyahara Ryoji , Ishigami Masatoshi , Hirooka Yoshiki , Fujishiro Mitsuhiro
Published: March 2020

Background

Vascular invasion is an important criterion for resectability and deciding the therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC), but imaging diagnosis is currently difficult. Endoscopic ultrasound (EUS) elastography (EG) images have band-like artifacts on the border between tumor and vessel due to different movement if the tumor is not connected to the vessel, i.e., no invasion. Based on this phenomenon, we assessed the usefulness of EUS-EG in the diagnosis of vascular invasion in PDAC.

Methods

The subjects were 44 out of 313 patients with PDAC who underwent EUS between January 2015 and November 2018, followed by surgery, no chemotherapy or radiotherapy, and pathological evaluation. Diagnostic accuracies of vascular invasion using dynamic computed tomography (CT), EUS B-mode and EUS-EG were compared with histopathological diagnosis.

Results

In 44 subjects (48 sites) who underwent both dynamic CT and EUS-B mode, the sensitivity, specificity and accuracy were 0.733, 0.697 and 0.708 on dynamic CT (48 sites); 0.733, 0.606 and 0.646 in EUS B-mode (48 sites); and 0.917, 0.900 and 0.906 in EUS-EG (32 sites). In 27 subjects (29 sites) with a tumor contacting a vessel with no vascular obstruction or stenosis on dynamic CT, the sensitivity, specificity and accuracy were 0.556, 0.750 and 0.690 on dynamic CT; 0.667, 0.700 and 0.690 in EUS B-mode; and 0.889, 0.850 and 0.862 in EUS-EG.

Conclusions

These results suggest that EUS combined with EG improves diagnostic performance of vascular invasion in PDAC, especially in cases of which vascular invasion cannot be clearly assessed by dynamic CT.
Medication beliefs and use of medication lists – is there a connection? Results from a before-and-after study in Germany
Authors: Straßner Cornelia , Mahler Cornelia , Strauß Beate , Wehrmann Ulrich , Krug Katja , Szecsenyi Joachim , Haefeli Walter Emil , Seidling Hanna Marita
Published: March 2020

Background

Despite increasing digitalisation the paper-based medication list remains one of the most important instruments for the documentation and exchange of medication-related information. However, even elderly patients with polypharmacy who are at high risk for medication errors and adverse drug events, frequently do not receive or use a complete and comprehensible medication list. Increasing the use of medication lists would be a great contribution to medication safety and facilitate the work of health care providers.

Methods

This study is related to the project MeinPlan (MyPlan) which comprised an information campaign on safe drug administration in the Rhine-Neckar region in South Germany. The campaign was evaluated in a before-and-after study based on a survey among two independent, representative samples of citizens over 65 years. In total, 5034 questionnaires were analysed. While the effects of the primary outcome (the percentage of citizens using a medication list) have been reported elsewhere, this analysis focusses on the effects of the campaign on citizens’ medication beliefs and assesses whether medication beliefs are associated with the use of medication lists, the use of over-the-counter drugs and the use of the tools offered by the campaign. Medication beliefs were assessed with the German version of the General Beliefs About Medicines Questionnaire (BMQ) which results in subscales for “General Overuse”, “General Usefulness” and “General Harm”. The use of medication lists and over-the-counter drugs was assessed with self-developed questionnaire items.

Results

No statistically significant change in citizens’ medication beliefs before and after the campaign could be detected. Likewise, no association between medication beliefs and the use of medication lists, the use of over-the-counter drugs or the use of the tools offered by the campaign could be shown.

Conclusions

A campaign focussing on the risks of drug administration did not change the medication beliefs of the targeted population. Moreover, citizens’ general medication beliefs do not seem to be crucial for their decision to use a medication list or over-the-counter drugs. Strategies to improve the use of medication lists by patients should focus on other influential factors, such as individual benefits and barriers and socio-psychological factors.
Couple-based collaborative management model of type 2 diabetes mellitus for community-dwelling older adults in China: protocol for a hybrid type 1 randomized controlled trial
Authors: Liao Jing , Wu Xueji , Wang Caixuan , Xiao Xiaochun , Cai Yiyuan , Wu Min , Liu Yuyang , Chen Xiongfei , Wu Shaolong , Yang Yung Jen , Xu Dong (Roman)
Published: March 2020

Background

China’s limited health care resources cannot meet the needs of chronic disease treatment and management of its rapid growing ageing population. The improvement and maintenance of patient’s self-management is essential to disease management. Given disease management mainly occurs in the context of family, this study proposes to validate a Couple-based Collaborative Management Model of chronic diseases that integrates health professionals and family supporters; such as to empower the couples with disease management knowledge and skills, and to improve the couples’ health and quality of life.

Methods

The proposed study will validate a couple-based collaborative management model of Type 2 Diabetes Mellitus (T2DM) in a community-based multicenter, two-arm, randomized controlled trial of block design in Guangzhou, China. Specifically, 194 T2DM patients aged ≥55 and their partners recruited from community health care centers will be randomized at the patient level for each center at a 1:1 ratio into the couple-based intervention arm and the individual-based control arm. For the intervention arm, both the patients and their spouses will receive four-weekly structured group education & training sessions and 2 months of weekly tailored behavior change boosters; while these interventions will be only provided to the patients in the control group. Behavior change incentives will be targeted at the couples or only at the patient respectively. Treatment effects on patients’ hemoglobin, spouses’ quality of life, alongside couples’ behavior outcomes will be compared between arms. Study implementation will be evaluated considering its Reach, Effectiveness, Adoption, Implementation and Maintenance following the RE-AIM framework.

Discussion

This study will generate a model of effective collaboration between community health professionals and patients’ family, which will shield light on chronic disease management strategy for the increasing ageing population.

Trial registration

Chinese Clinical Trial Registry, ChiCTR1900027137, Registered 1st Nov. 2019
How can gastro-intestinal tuberculosis diagnosis be improved? A prospective cohort study
Authors: Lowbridge Christopher , Fadhil Soraya A. M. , Krishnan Gayathri D. , Schimann Emma , Karuppan Raman Muthu , Sriram Nagaraj , Rajahram Giri Shan , Menon Jayaram , Patel Aatish , William Timothy , Paul Dawn Carmel , Ralph Anna P.
Published: March 2020

Background

Gastrointestinal tuberculosis (TB) is diagnostically challenging; therefore, many cases are treated presumptively. We aimed to describe features and outcomes of gastrointestinal TB, determine whether a clinical algorithm could distinguish TB from non-TB diagnoses, and calculate accuracy of diagnostic tests.

Methods

We conducted a prospective cohort study of hospitalized patients in Kota Kinabalu, Malaysia, with suspected gastrointestinal TB. We recorded clinical and laboratory characteristics and outcomes. Tissue samples were submitted for histology, microscopy, culture and GeneXpert MTB/RIF®. Patients were followed for up to 2 years.

Results

Among 88 patients with suspected gastrointestinal TB, 69 were included in analyses; 52 (75%) had a final diagnosis of gastrointestinal TB; 17 had a non-TB diagnosis. People with TB were younger (42.7 versus 61.5 years, p = 0.01) and more likely to have weight loss (91% versus 64%, p = 0.03). An algorithm using age < 44, weight loss, cough, fever, no vomiting, albumin > 26 g/L, platelets > 340 × 109/L and immunocompromise had good specificity (96.2%) in predicting TB, but very poor sensitivity (16.0%). GeneXpert® performed very well on gastrointestinal biopsies (sensitivity 95.7% versus 35.0% for culture against a gold standard composite case definition of confirmed TB). Most patients (79%) successfully completed treatment and no treatment failure occurred, however adverse events (21%) and mortality (13%) among TB cases were high. We found no evidence that 6 months of treatment was inferior to longer courses.

Conclusions

The prospective design provides important insights for clinicians managing gastrointestinal TB. We recommend wider implementation of high-performing diagnostic tests such as GeneXpert® on extra-pulmonary samples.
Tubular secretion of creatinine and kidney function: an observational study
Authors: Zhang Xuehan , Rule Andrew D. , McCulloch Charles E. , Lieske John C. , Ku Elaine , Hsu Chi-yuan
Published: March 2020

Background

Prior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.

Methods

To fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.

Results

Observed CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.

Conclusions

These data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR.
Cytokine dysregulation persists in childhood post Neonatal Encephalopathy
Authors: Zareen Zunera , Strickland Tammy , Eneaney Victoria Mc , Kelly Lynne A. , McDonald Denise , Sweetman Deirdre , Molloy Eleanor J.
Published: March 2020

Background

Cytokines are possible mediators of neuroinflammation and associated with adverse outcome in neonatal encephalopathy (NE). Our aim was to explore cytokine response in children with Neonatal Encephalopathy (NE) at school age compared to age-matched controls.

Method

Follow up at school age, children who had NE and age-matched controls were assessed for their cytokine responses and neurodevelopment outcome. Pro- and anti-inflammatory cytokines in the serum, [Interleukin (IL)-1α, IL-1β, IL-2, IL-6, IL-8, IL-18, Tumor necrosis factor (TNF)-α, TNF β, Interferon (IFN)-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), IL-10 & IL-1RA] were measured at baseline and in response to in vitro stimulation with lipopolysaccharide (LPS: endotoxin).

Results

GM-CSF, TNF-β, IL-2 IL-6 and IL-8 were significantly elevated at school age following NE (n = 40) compared to controls (n = 37). A rise in GM-CSF, IL-8, TNF-α, IL-1β, & IL-6 were seen in NE group following LPS stimulation. Relative LPS hypo-responsiveness was also noted in children with severe NE with IL-10, VEGF, EPO and TNF-β. Elevated TNF-β was associated with low gross motor scores on assessment at school age.

Conclusion

School-age children post-NE had significantly altered cytokine responses to endotoxin compared to controls. TNF-β was associated with adverse developmental outcomes. This suggests the inflammatory process may persist into childhood and a longer therapeutic window may be available for neuroprotection therapies.
Luteal blood flow as a predictive factor for methotrexate treatment outcomes in women with unruptured tubal pregnancy
Authors: Wang Li , Pei Meili , Yang Ting , Zhao Juan , Yang Xiaofeng
Published: March 2020

Background

Blood flow in the corpus luteum is associated with luteal function. However, the impact of luteal blood flow on methotrexate (MTX) treatment in women with unruptured tubal pregnancy has not been reported. The aim of the present study was to observe the impact of luteal blood flow on the therapeutic effect of MTX in women with unruptured tubal pregnancy.

Methods

A prospective observational study recruited 129 women with unruptured tubal pregnancy in the First Affiliated Hospital of Xi’an Jiaotong University from September 2016 to June 2018. One hundred and fifteen women were treated successfully with MTX, and women were divided into 2 groups according to luteal blood flow: the poor luteal blood flow group and the abundant luteal blood flow group. The therapeutic effects were compared between the two groups.

Results

Women in the abundant luteal blood flow group had a significantly higher serum β-human chorionic gonadotropin (β-hCG) level 4 days, 1 week and 2 weeks after MTX treatment compared with women in the poor luteal blood flow group (P < 0.05). The average diameter of the ectopic mass 1 week, 2 weeks and 3 weeks after MTX treatment in women with abundant luteal blood flow was significantly larger (P < 0.05), and the time of serum β-hCG clearance and ectopic mass disappearance were significantly longer compared with those in women in the poor luteal blood flow group (P < 0.05).

Conclusions

Luteal blood flow might be a predictive factor for MTX treatment outcomes in women with unruptured tubal pregnancy, and those with abundant luteal blood flow need a longer recovery time.
Unintended pregnancy and maternal health complications: cross-sectional analysis of data from rural Uttar Pradesh, India
Authors: Dehingia Nabamallika , Dixit Anvita , Atmavilas Yamini , Chandurkar Dharmendra , Singh Kultar , Silverman Jay , Raj Anita
Published: March 2020

Background

This study aims to explore the potential association between unintended pregnancy and maternal health complications. Secondarily, we test whether antenatal care (ANC) and community health worker (CHW) visits moderate the observed association between unintended pregnancy and maternal health complications.

Methods

Cross sectional data were collected using a multistage sampling design to identify women who had a live birth in the last 12 months across 25 highest risk districts of Uttar Pradesh (N = 3659). Participants were surveyed on demographics, unintendedness of last pregnancy, receipt of ANC clinical visits and community outreach during pregnancy, and maternal complications. Regression models described the relations between unintended pregnancy and maternal complications. To determine if receipt of ANC and CHW visits in pregnancy moderated associations between unintended pregnancy and maternal complications, we used the Mantel-Haenzel risk estimation test and stratified logistic models testing interactions of unintended pregnancy and receipt of health services to predict maternal complications.

Results

Around one-fifth of the women (16.9%) reported that their previous pregnancy was unintended. Logistic regression analyses revealed that unintended pregnancy was significantly associated with maternal complications- pre-eclampsia (AOR:2.06; 95% CI:1.57–2.72), postpartum hemorrhage (AOR:1.46; 95% CI: 1.01–2.13) and postpartum pre-eclampsia (AOR:2.34; 95% CI:1.47–3.72). Results from the Mantel Haenszel test indicated that both ANC and CHW home visit in pregnancy significantly affect the association between unintended pregnancy and postpartum hemorrhage (p < 0.001).

Conclusion

Unintended pregnancy is associated with increased risk for maternal health complications, but provision of ANC clinical visits and CHW home visits in pregnancy may be able to reduce potential effects of unintended pregnancy on maternal health.
Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma
Authors: Sriskandarajah Priya , De Haven Brandon Alexis , MacLeod Kenneth , Carragher Neil O. , Kirkin Vladimir , Kaiser Martin , Whittaker Steven R.
Published: March 2020

Background

Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM.

Methods

The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time.

Results

The Tra/Dex combination demonstrated synergistic cytotoxicity in KRASG12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth.

Conclusions

Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.
Bacterial etiology of ocular and periocular infections, antimicrobial susceptibility profile and associated factors among patients attending eye unit of Shashemene comprehensive specialized hospital, Shashemene, Ethiopia
Authors: Mohammed Ahmed Adem , Ali Musa Mohammed , Zenebe Mengistu Hailemariam
Published: March 2020

Background

Eye infection is a public health problem in developing countries including Ethiopia. Bacteria are major causative agents of eye infections that can lead to loss of vision. The objective of this study was to determine bacterial etiology of ocular and periocular infections, antimicrobial susceptibility profile and associated factors among patients who visited the eye unit of Shashamane Comprehensive Specialized Hospital (SCSH).

Method

A hospital-based cross-sectional study was conducted at SCSH from September 1, 2018, to March 30, 2019. Specimens from the ocular and periocular areas were collected from a total of 332 patients who visited the eye unit. Specimens were inoculated on blood agar, chocolate agar, MacConkey agar, and mannitol salt agar. Isolated bacteria were identified by a series of biochemical tests using the standard bacteriological method. Antimicrobial susceptibility test was performed according to the Clinical and Laboratory Standard Institute by disk diffusion method. Factors that could be associated with ocular and periocular infection were collected by using structured questionnaire. Data analysis was done using SPSS version 22.0 software package. A P value less than 0.05 was considered statistically significant.

Result

Out of the total 332 study participants with ocular and periocular infections, 198(60%) were culture positive. The proportion of Gram-positive and Gram-negative bacteria were 135(68.2%) and 63(31.8%) respectively. Among Gram-positive bacteria, Staphylococcus aureus were predominant. Among Gram-negative bacteria, Escherichia coli were predominant. Most S. aureus were resistant to penicillin.

Conclusion

Majority of ocular and periocular infections in this study were caused by bacteria; Gram-positive bacteria were responsible for most cases.
Suspected paracetamol overdose in Monrovia, Liberia: a matched case–control study
Authors: Haidar Mohamad K. , Vogt Florian , Takahashi Kensuke , Henaff Fanny , Umphrey Lisa , Morton Nikola , Bawo Luke , Kerkula Joseph , Ferner Robin , Porten Klaudia , Baud Frederic J.
Published: March 2020

Background

A cluster of cases of unexplained multi-organ failure was reported in children at Bardnesville Junction Hospital (BJH), Monrovia, Liberia. Prior to admission, children’s caregivers reported antibiotic, antimalarial, paracetamol, and traditional treatment consumption. Since we could not exclude a toxic aetiology, and paracetamol overdose in particular, we implemented prospective syndromic surveillance to better define the clinical characteristics of these children. To investigate risk factors, we performed a case–control study.

Methods

The investigation was conducted in BJH between July 2015 and January 2016. In-hospital syndromic surveillance identified children with at least two of the following symptoms: respiratory distress with normal pulse oximetry while breathing ambient air; altered consciousness; hypoglycaemia; jaundice; and hepatomegaly. After refining the case definition to better reflect potential risk factors for hepatic dysfunction, we selected cases identified from syndromic surveillance for a matched case–control study. Cases were matched with in-hospital and community-based controls by age, sex, month of illness/admission, severity (in-hospital), and proximity of residence (community).

Results

Between July and December 2015, 77 case-patients were captured by syndromic surveillance; 68 (88%) were under three years old and 35 (46%) died during hospitalisation. Of these 77, 30 children met our case definition and were matched with 53 hospital and 48 community controls. Paracetamol was the most frequently reported medication taken by the cases and both control groups. The odds of caregivers reporting supra-therapeutic paracetamol consumption prior to admission was higher in cases compared to controls (OR 6.6, 95% CI 2.1–21.3). Plasma paracetamol concentration on day of admission was available for 19 cases and exceeded 10 μg/mL in 10/13 samples collected on day one of admission, and 4/9 (44%) collected on day two.

Conclusions

In a context with limited diagnostic capacity, this study highlights the possibility of supratherapeutic doses of paracetamol as a factor in multi-organ failure in a cohort of children admitted to BJH. In this setting, a careful history of pre-admission paracetamol consumption may alert clinicians to the possibility of overdose, even when confirmatory laboratory analysis is unavailable. Further studies may help define additional toxicological characteristics in such contexts to improve diagnoses.
Impact of personality on adherence to and beliefs about ADHD medication, and perceptions of ADHD in adolescents
Authors: Emilsson Maria , Gustafsson Per , Öhnström Gisela , Marteinsdottir Ina
Published: March 2020

Background

Adherence to attention deficit hyperactivity disorder (ADHD) medication can prevent serious consequences, possibly with lifelong effects. Numerous factors have been observed that influence adherent behaviour, but the impact of personality traits has been inadequately explored. The purpose of this study was to explore the associations between personality traits and adherence to ADHD medication, beliefs about the medication, and perceptions of ADHD.

Method

Adolescents (n = 99) on ADHD medication were administered: Health-Relevant Personality Traits Five-Factor Inventory, Medication Adherence Report Scale, Beliefs about Medicines Specific and Brief Illness Perceptions Questionnaires.

Results

The personality trait Antagonism correlated with adherence behaviour (r = − 0.198,p = 0.005) and perceived personal control of ADHD (r = − 0.269,p = 0.007). Negative Affectivity correlated with beliefs regarding necessity (r = 0.319,p = 0.001), concerns (r = 0.344,p = 0.001), and experienced side effects of medication (r = 0.495,p = 0.001), alongside perceptions regarding duration (r = 0.272,p = 0.007), identity (r = 0.388,p < 0.001), being emotionally affected (r = 0.374,p < 0.01), personal control (r = − 0.287,p = 0.004) and concerns about ADHD (r = 0.465,p < 0.001). Impulsivity correlated with perceived consequences (r = − 0.226,p = 0.0255) and personal control of ADHD (r = − 0.379,p < 0.001). Hedonic Capacity correlated with concerns about medication (r = − 0.218,p = 0.0316) and perceived identification with ADHD (r = − 0.203,p = 0.045).

Conclusion

Personality traits are related to adherence, beliefs about ADHD medicines and perceptions of ADHD. Antagonism is associated with adherence, especially intentional non-adherence, while Negative Affectivity correlates with numerous perceptions of ADHD and beliefs about medications. Personality assessments could be useful in the care and treatment of adolescents with ADHD.
A pilot randomised trial comparing a mindfulness-based stress reduction course, a locally-developed stress reduction intervention and a waiting list control group in a real-life municipal health care setting
Authors: Juul Lise , Pallesen Karen Johanne , Bjerggaard Mette , Nielsen Corina , Fjorback Lone Overby
Published: March 2020

Background

The purpose of the present study was to conduct a pilot randomised controlled trial (RCT) to lend support to a larger effectiveness RCT comparing Mindfulness-Based Stress Reduction (MBSR), a locally-developed stress reduction intervention (LSR) and a waiting list control group in a Danish municipal health care center setting.

Methods

A three-armed parallel pilot RCT was conducted among 71 adults who contacted a Danish municipal health care center due to stress-related problems. Recruitment was made between January and April 2018 and followed usual procedures. Exclusion criteria: 1) acute treatment-demanding clinical depression or diagnosis of psychosis or schizophrenia, 2) abuse of alcohol, drugs, medicine, 3) pregnancy. Randomisation was performed by an independent data manager using the REDCap electronic data capture tool. The primary outcome was a description of RCT feasibility (recruitment and retention rates regarding intervention participation and 12-week follow-up). Secondary outcomes were completion rates regarding questionnaire data and proposed effect-estimates of outcome measures considered to be used in the following real RCT. Type of intervention and outcome assessment were not blinded.

Results

We recruited 71 of 129 eligible individuals from the target population (55, 95%CI: 46–64). Forty-two (59%) were females. Median age: 44 years (1-quartile:34, 3-quartile:50). Twenty-nine (41%) had < 16 years of education. Forty-eight (68%) were employed; 30 of these 48 (63%) were on sick leave. Mean scores for perceived stress (PSS): 25.4 ± 5.3; symptoms of anxiety and depression (SCL-5): 2.9 ± 0.6, and well-being (WHO-5): 31.7 ± 8.5 indicated a need for intervention. 16/24 (67, 95%CI: 45 to 84) who were allocated to MBSR and 17/23 (74, 95%CI: 52 to 90) who were allocated to LSR participated in ≥5 sessions. The loss to follow-up at 12 weeks: MBSR: 5 (21% (95% CI: 7 to 42), LSR: 5 (22% (95% CI: 7 to 44) and waiting list: 4 (17% (95% CI: 5 to 37). This was acceptable and evenly distributed. The results indicated MBSR to be superior.

Conclusions

An RCT assessing the effectiveness of stress reduction interventions in a real-life municipal health care setting is feasible among adults with a clear need for stress reduction interventions based on scores on mental health.

Trial registration

ClinicalTrials.gov. Identifier:NCT03663244. Registered September 10, 2018.