bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted therapy in pulmonary veno-occlusive disease: time for a rethink?
Authors: Luo Qin , Jin Qi , Zhao Zhihui , Zhao Qing , Yu Xue , Yan Lu , Zhang Yi , Xiong Changming , Liu Zhihong
Published: December 2019

Background

Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome.

Methods

PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted.

Results

Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years.

Conclusions

Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.
A patient with extensive cerebral calcification due to pseudohypoparathyroidism: a case report
Authors: De Silva S. W. , De Silva S. D. N. , De Silva C. E.
Published: December 2019

Background

Pseudohypoparathyroidism(PHP) is a heterogeneous group of disorders due to impaired activation of c AMP dependant pathways following binding of parathyroid hormone (PTH) to its receptor. In PHP end organ resistance to PTH results in hypocalcaemia, hyperphosphataemia and high PTH levels.

Case presentation

A 59 year old male presented with a history of progressive impairment of speech and unsteadiness of gait for 1 week and acute onset altered behavior for 1 day and one episode of generalized seizure. His muscle power was grade four according to MRC (medical research council) scale in all limbs and Chovstek’s and Trousseau’s signs were positive. Urgent non contrast computed tomography scan of the brain revealed extensive bilateral cerebral and cerebellar calcifications. A markedly low ionized calcium level of 0.5 mmol/l, an elevated phosphate level of 9.5 mg/dl (reference range: 2.7–4.5 mg/dl) and an elevated intact PTH of 76.3 pg/l were noted. His renal functions were normal. His hypocalcemia was accentuated by the presence of hypomagnesaemia. His 25 hydroxy vitamin D level was only marginally low which could not account for severe hypocalcaemia. A diagnosis of pseudohypoparathyroidism without phenotypic defects, was made due to hypocalcaemia and increased parathyroid hormone levels with cerebral calcifications. The patient was treated initially with parenteral calcium which was later converted to oral calcium supplements. His coexisting Vitamin D deficiency was corrected with 1αcholecalciferol escalating doses. His hypomagnesaemia was corrected with magnesium sulphate parenteral infusions initially and later with oral preparations. With treatment there was a significant clinical and biochemical response.

Conclusion

Pseudohypoparathyroidism can present for the first time in elderly resulting in extensive cerebral calcifications. Identification and early correction of the deficit will result in both symptomatic and biochemical response.
Oral health in children and adolescents with juvenile idiopathic arthritis – a systematic review and meta-analysis
Authors: Skeie Marit S. , Gil Elisabeth G. , Cetrelli Lena , Rosén Annika , Fischer Johannes , Åstrøm Anne Nordrehaug , Luukko Keijo , Shi Xieqi , Feuerherm Astrid J. , Sen Abhijit , Frid Paula , Rygg Marite , Bletsa Athanasia
Published: December 2019

Background

Observational studies examining the association between oral health and juvenile idiopathic arthritis (JIA) among children and adolescents have reported inconsistent findings. The aims of this systematic review and meta-analysis were to ascertain a potential difference in oral health and oral health-related quality of life (OHRQoL) among children and adolescents with JIA and healthy peers, and to assess the association of prevalence of oral diseases/conditions, temporomandibular disorders (TMD), including temporomandibular joint (TMJ) diseases, in relation to activity and severity of JIA.

Method

Medline Ovid, Embase, CINAHL, SweMed+ and Cochrane Library were searched up to 25 November 2018. All articles published in English, German and Scandinavian languages focusing on children and adolescents with JIA and without JIA in relation to oral health measures, were considered. Two authors independently evaluated observational studies for inclusion. The study quality was assessed using modified Newcastle Ottawa Scale. Meta-analysis was performed for studies focusing on dental caries as an outcome.

Results

Nineteen articles met the inclusion criteria, covering a range of oral diseases/conditions and OHRQoL. Eighteen studies had cross-sectional design. No mean difference of dmft/DMFT indices (decayed/missed/filled teeth) was observed between the JIA - and healthy group. None of the oral health measures including dental erosive wear, enamel defects, dental maturation and OHRQoL, indicated better oral health among children and adolescents with JIA compared to healthy group. However, periodontal conditions and TMD were more predominant among children and adolescents with JIA compared to healthy peers.

Conclusions

Based on the cross-sectional studies, periodontal diseases and TMD were found to be more frequent in children and adolescents with JIA compared to healthy peers. Furthermore, more high-quality studies with large sample size are needed before we infer any concrete conclusion regarding the association between the prevalence of oral and TMJ diseases or oral conditions in relation to activity and severity of JIA.
Choices and services related to contraception in the Gaza strip, Palestine: perceptions of service users and providers
Authors: Böttcher Bettina , Abu-El-Noor Mysoon , Abu-El-Noor Nasser
Published: December 2019

Background

Reliable contraception enables women and men to plan their family sizes and avoid unintended pregnancies, which can cause distress and anxiety, but also increase maternal mortality. This study explored potential barriers to contraceptive use for women in the Gaza Strip, Palestine from user and provider perspectives.

Methods

A convenient sample was used to recruit women, who were current contraception users, from three healthcare clinics that provide family planning care, two governmental and one non-governmental. A 16-item questionnaire was completed by 204 women, including socio-demographic data, contraceptive use and eight questions exploring user experience. Additionally, 51 women attended focus groups for a deeper insight into their contraceptive use experience and potential barriers. Furthermore, 14 healthcare providers were interviewed about their experience with service provision. Quantitative data are presented as means and frequencies and qualitative data were analysed item by item and are presented in themes jointly with the quantitative data.

Results

Women reported usage of only three main modern methods of contraception with 35.2% using intrauterine devices, 25.8% combined oral contraception and 16.4% condoms, while only 3.1% used the hormonal implant. Expectations from family planning services were low with most women attending the clinic having already decided their contraceptive method with decisions being made by husbands (41.2%) or women jointly with their partner (33.3%), only 13.7% took advice from service providers. Healthcare providers experienced high prevalence of beliefs that modern contraceptives cause infertility and cancer. Main barriers to effective family planning services were misconceptions of potential harm, poor availability and limited choice of contraceptive methods.

Conclusion

Women’s contraceptive choices in Gaza are limited by prevalent misconceptions and fears as well as recurring shortages, negatively impacting fertility control. Men are a major factor in choosing a contraceptive method, however, they have limited access to information and therefore, potentially more misconceptions. Therefore, male community members need to be included in the delivery of information on contraceptives to increase women’s choice. Furthermore, greater access to long-acting reversible contraceptives, such as the hormonal implant, and improved availability might be key factors in improving contraceptive uptake in Gaza and, thus, reducing unintended pregnancies.
Ethical concerns with the use of intelligent assistive technology: findings from a qualitative study with professional stakeholders
Authors: Wangmo Tenzin , Lipps Mirjam , Kressig Reto W. , Ienca Marcello
Published: December 2019

Background

Advances in artificial intelligence (AI), robotics and wearable computing are creating novel technological opportunities for mitigating the global burden of population ageing and improving the quality of care for older adults with dementia and/or age-related disability. Intelligent assistive technology (IAT) is the umbrella term defining this ever-evolving spectrum of intelligent applications for the older and disabled population. However, the implementation of IATs has been observed to be sub-optimal due to a number of barriers in the translation of novel applications from the designing labs to the bedside. Furthermore, since these technologies are designed to be used by vulnerable individuals with age- and multi-morbidity-related frailty and cognitive disability, they are perceived to raise important ethical challenges, especially when they involve machine intelligence, collect sensitive data or operate in close proximity to the human body. Thus, the goal of this paper is to explore and assess the ethical issues that professional stakeholders perceive in the development and use of IATs in elderly and dementia care.

Methods

We conducted a multi-site study involving semi-structured qualitative interviews with researchers and health professionals. We analyzed the interview data using a descriptive thematic analysis to inductively explore relevant ethical challenges.

Results

Our findings indicate that professional stakeholders find issues of patient autonomy and informed consent, quality of data management, distributive justice and human contact as ethical priorities. Divergences emerged in relation to how these ethical issues are interpreted, how conflicts between different ethical principles are resolved and what solutions should be implemented to overcome current challenges.

Conclusions

Our findings indicate a general agreement among professional stakeholders on the ethical promises and challenges raised by the use of IATs among older and disabled users. Yet, notable divergences persist regarding how these ethical challenges can be overcome and what strategies should be implemented for the safe and effective implementation of IATs. These findings provide technology developers with useful information about unmet ethical needs. Study results may guide policy makers with firsthand information from relevant stakeholders about possible solutions for ethically-aligned technology governance.
Fast read alignment with incorporation of known genomic variants
Authors: Guo Hongzhe , Liu Bo , Guan Dengfeng , Fu Yilei , Wang Yadong
Published: December 2019

Background

Many genetic variants have been reported from sequencing projects due to decreasing experimental costs. Compared to the current typical paradigm, read mapping incorporating existing variants can improve the performance of subsequent analysis. This method is supposed to map sequencing reads efficiently to a graphical index with a reference genome and known variation to increase alignment quality and variant calling accuracy. However, storing and indexing various types of variation require costly RAM space.

Methods

Aligning reads to a graph model-based index including the whole set of variants is ultimately an NP-hard problem in theory. Here, we propose a variation-aware read alignment algorithm (VARA), which generates the alignment between read and multiple genomic sequences simultaneously utilizing the schema of the Landau-Vishkin algorithm. VARA dynamically extracts regional variants to construct a pseudo tree-based structure on-the-fly for seed extension without loading the whole genome variation into memory space.

Results

We developed the novel high-throughput sequencing read aligner deBGA-VARA by integrating VARA into deBGA. The deBGA-VARA is benchmarked both on simulated reads and the NA12878 sequencing dataset. The experimental results demonstrate that read alignment incorporating genetic variation knowledge can achieve high sensitivity and accuracy.

Conclusions

Due to its efficiency, VARA provides a promising solution for further improvement of variant calling while maintaining small memory footprints. The deBGA-VARA is available at: https://github.com/hitbc/deBGA-VARA.
THRIVE study protocol: a randomized controlled trial evaluating a web-based app and tailored messages to improve adherence to adjuvant endocrine therapy among women with breast cancer
Authors: Paladino Andrew J. , Anderson Janeane N. , Krukowski Rebecca A. , Waters Teresa , Kocak Mehmet , Graff Carolyn , Blue Ryan , Jones Tameka N. , Buzaglo Joanne , Vidal Gregory , Schwartzberg Lee , Graetz Ilana
Published: December 2019

Background

Long-term use of adjuvant endocrine therapy (AET) among women with early-stage, hormone receptor-positive breast cancer significantly reduces the risk of hospitalizations, cancer recurrence, and mortality. AET is associated with adverse symptoms that often result in poor adherence. A web-enabled app offers a novel way to communicate and manage symptoms for women on AET. In a region with significant racial disparities in breast cancer outcomes, our study tests the impact of a web-enabled app that collects and transmits patient-reported symptoms to healthcare teams to facilitate timely and responsive symptom management on medication adherence.

Methods

In this randomized controlled trial, we randomize 300 patients initiating AET to one of three arms: 1) an “App” group (n = 100) that receives weekly reminders to use the THRIVE study app; 2) an “App+Feedback” group (n = 100) that receives weekly reminders and tailored feedback based on their use of the app; or 3) a “Usual Care” group (n = 100) that receives usual care only. Participants are stratified by race: 50% White and 50% Black. The duration of the intervention is six months following enrollment, and outcomes are assessed at 12-months. The primary outcome is adherence, which is captured using an electronic monitoring pillbox. Secondary outcomes include symptom burden, quality of life, self-efficacy for managing symptoms, and healthcare costs. We also evaluate the impact of the intervention on racial disparities in adherence. Data are derived from three sources: electronic health record data to capture treatment changes, healthcare utilization, and health outcomes; self-report survey data related to adherence, symptom burden, and quality of life; and an electronic medication monitoring device that captures adherence.

Discussion

A successful web-enabled intervention could be disseminated across systems, conditions, and populations. By evaluating the impact of this intervention on a comprehensive set of measures, including AET adherence, patient outcomes, and costs, our study will provide valuable and actionable results for providers, policy makers, and insurers who strive to achieve the “Triple Aim” – reduce costs while improving health outcomes and the patient care experience.

Trial registration

NCT03592771. Prospectively registered on July 19, 2018.
Multiple chronic conditions and associated health care expenses in US adults with cancer: a 2010–2015 Medical Expenditure Panel Survey study
Authors: Davis-Ajami Mary Lynn , Lu Zhiqiang K. , Wu Jun
Published: December 2019

Background

Cancer increases the risk of developing one or more chronic conditions, yet little research describes the associations between health care costs, utilization patterns, and chronic conditions in adults with cancer. The objective of this study was to examine the treated prevalence of chronic conditions and the association between chronic conditions and health care expenses in US adults with cancer.

Methods

This retrospective observational study used US Medical Expenditure Panel Survey (MEPS) Household Component (2010–2015) data sampling adults diagnosed with cancer and one or more of 18 select chronic conditions. The measures used were treated prevalence of chronic conditions, and total and chronic condition-specific health expenses (per-person, per-year). Generalized linear models assessed chronic condition-specific expenses in adults with cancer vs. without cancer and the association of chronic conditions on total health expenses in adults with cancer, respectively, by controlling for demographic and health characteristics. Accounting for the complex survey design in MEPS, all data analyses and statistical procedures applied longitudinal weights for national estimates.

Results

Among 3657 eligible adults with cancer, 83.9% (n = 3040; representing 16 million US individuals per-year) had at least one chronic condition, and 29.7% reported four or more conditions. Among those with cancer, hypertension (59.7%), hyperlipidemia (53.6%), arthritis (25.6%), diabetes (22.2%), and coronary artery disease (18.2%) were the five most prevalent chronic conditions. Chronic conditions accounted for 30% of total health expenses. Total health expenses were $6388 higher for those with chronic conditions vs. those without (p < 0.001). Health expenses associated with chronic conditions increased by 34% in adults with cancer vs. those without cancer after adjustment.

Conclusions

In US adults with cancer, the treated prevalence of common chronic conditions was high and health expenses associated with chronic conditions were higher than those without cancer. A holistic treatment plan is needed to improve cost outcomes.
Identifying relevant concepts and factors for the sustainability of evidence-based practices within acute care contexts: a systematic review and theory analysis of selected sustainability frameworks
Authors: Nadalin Penno Letitia , Davies Barbara , Graham Ian D. , Backman Chantal , MacDonald Ibo , Bain Julie , Johnson Alekhya Mascarenhas , Moore Julia , Squires Janet
Published: December 2019

Background

There is growing recognition among healthcare professionals that the sustainability of evidence-based practices (EBPs) within different settings is variable and suboptimal. Understanding why a particular EBP might be sustained in one setting and not another remains unclear. Recent reviews illustrate the need to identify and analyze existing frameworks/models/theories (F/M/Ts) that focus solely on the sustainability of EBPs in specific healthcare settings, such as acute care, to illuminate key determinants and facilitate appropriate selection to guide practice and research.

Methods

We conducted a systematic review to extract sustainability frameworks. This involved using two available syntheses of the literature and a systematic search of four databases from January 2015 to July 2018: CINHAL, MEDLINE, Embase, and ProQuest. We included studies published in English, and if they included sustainability F/M/Ts recommended for use in acute care or an unspecified healthcare organization/setting. F/M/Ts explicitly recommended for use in public health and or community settings were excluded. We then conducted a comparative analysis of F/M/Ts using a modified theory analysis approach, to understand the theoretical underpinnings of each F/M/T, their determinants and concepts hypothesized to influence the sustained use of EBPs within an acute care context.

Results

Of 2967 identified citations from the 2 available syntheses and the systematic review, 8 F/M/Ts met the inclusion criteria. We identified 37 core factors, of which 16 were recorded as common factors (occurring within 4 or more of the 8 included F/M/Ts). All factors grouped into 7 main themes: innovation, adopters, leadership and management, inner context, inner processes, outer context, and outcomes.

Conclusions

This systematic review is the first to include a comprehensive analysis of healthcare sustainability F/M/Ts for the sustained use of EBPs in acute care settings. Findings reveal insights into sustainability as a “process or ongoing stage of use” following initial implementation, suggesting this construct should be added to the definition of sustainability. Results provide a resource of available F/M/Ts and hypothesized factors to consider for acute care team members who are planning or currently implementing EBPs with the goal of improving patient outcomes. It also provides a basis for future research on sustainability in acute care.
The accuracy of species-specific allometric equations for estimating aboveground biomass in tropical moist montane forests: case study of Albizia grandibracteata and Trichilia dregeana
Authors: Daba Damena Edae , Soromessa Teshome
Published: December 2019

Background

Application of allometric equations for quantifying forests aboveground biomass is a crucial step related to efforts of climate change mitigation. Generalized allometric equations have been applied for estimating biomass and carbon storage of forests. However, adopting a generalized allometric equation to estimate the biomass of different forests generates uncertainty due to environmental variation. Therefore, formulating species-specific allometric equations is important to accurately quantify the biomass. Montane moist forest ecosystem comprises high forest type which is mainly found in the southwestern part of Ethiopia. Yayu Coffee Forest Biosphere Reserve is categorized into Afromontane Rainforest vegetation types in this ecosystem. This study was aimed to formulate species-specific allometric equations for Albizia grandibracteata Tuab. and Trichilia dregeana Sond. using the semi-destructive method.

Results

Allometric equations in form of power models were developed for each tree species by evaluating the statistical relationships of total aboveground biomass (TAGB) and dendrometric variables. TAGB was regressed against diameter at breast height (D), total height (H), and wood density (ρ) individually and in a combination. The allometric equations were selected based on model performance statistics. Equations with the higher coefficient of determination (adj.R2), lower residual standard error (RSE), and low Akaike information criterion (AIC) values were found best fitted. Relationships between TAGB and predictive variables were found statistically significant (p ≤ 0.001) for all selected equations. Higher bias was reported related to the application of pan-tropical or generalized allometric equations.

Conclusions

Formulating species-specific allometric equations is found important for accurate tree biomass estimation and quantifying the carbon stock. The developed biomass regression models can be applied as a species-specific equation to the montane moist forest ecosystem of southwestern Ethiopia.
Generating microglia from human pluripotent stem cells: novel in vitro models for the study of neurodegeneration
Authors: Speicher Anna M. , Wiendl Heinz , Meuth Sven G. , Pawlowski Matthias
Published: December 2019

Microglia play an essential role for central nervous system (CNS) development and homeostasis and have been implicated in the onset, progression, and clearance of numerous diseases affecting the CNS. Previous in vitro research on human microglia was restricted to post-mortem brain tissue-derived microglia, with limited availability and lack of scalability. Recently, the first protocols for the generation of microglia from human pluripotent stem cells have become available, thus enabling the implementation of powerful platforms for disease modeling, drug testing, and studies on cell transplantation. Here we give a detailed and comprehensive overview of the protocols available for generating microglia from human pluripotent stem cells, highlighting the advantages, drawbacks, and operability and placing them into the context of current knowledge of human embryonic development. We review novel insights into microglia biology and the role of microglia in neurological diseases as drawn from the new methods and provide an outlook for future lines of research involving human pluripotent stem cell-derived microglia.
The variome concept: focus on CNVariome
Authors: Iourov Ivan Y. , Vorsanova Svetlana G. , Yurov Yuri B.
Published: December 2019

Background

Variome may be used for designating complex system of interplay between genomic variations specific for an individual or a disease. Despite the recognized complexity of genomic basis for phenotypic traits and diseases, studies of genetic causes of a disease are usually dedicated to the identification of single causative genomic changes (mutations). When such an artificially simplified model is employed, genomic basis of phenotypic outcomes remains elusive in the overwhelming majority of human diseases. Moreover, it is repeatedly demonstrated that multiple genomic changes within an individual genome are likely to underlie the phenome. Probably the best example of cumulative effect of variome on the phenotype is CNV (copy number variation) burden. Accordingly, we have proposed a variome concept based on CNV studies providing the evidence for the existence of a CNVariome (the set of CNV affecting an individual genome), a target for genomic analyses useful for unraveling genetic mechanisms of diseases and phenotypic traits.

Conclusion

Variome (CNVariome) concept suggests that a genomic milieu is determined by the whole set of genomic variations (CNV) within an individual genome. The genomic milieu is likely to result from interplay between these variations. Furthermore, such kind of variome may be either individual or disease-specific. Additionally, such variome may be pathway-specific. The latter is able to affect molecular/cellular pathways of genome stability maintenance leading to occurrence of genomic/chromosome instability and/or somatic mosaicism resulting in somatic variome. This variome type seems to be important for unraveling disease mechanisms, as well. Finally, it appears that bioinformatic analysis of both individual and somatic variomes in the context of diseases- and pathway-specific variomes is the most promising way to determine genomic basis of the phenome and to unravel disease mechanisms for the management and treatment of currently incurable diseases.
Two case reports of fetal alcohol syndrome: broadening into the spectrum of cardiac disease to personalize and to improve clinical assessment
Authors: Onesimo R. , De Rose C. , Delogu A. B. , Battista A. , Leoni C. , Veltri S. , De Rosa G. , Zampino G.
Published: December 2019

Background

Fetal alcohol spectrum disorder (FASD) refers to a broad spectrum of disabilities, in infants and children, resulting from moderate to excessive prenatal alcohol exposure.

Significant associations with alcohol exposure were already reported with congenital structural heart defects: i.e. ventricular septal defects, atrial septal defects, conotruncal defects.

Cases presentation

We describe two cases of children with FASD, both admitted to the Center for Rare Diseases and Birth Defects of Policlinico Universitario Agostino Gemelli, in whom asymptomatic cardiac rhythm alterations were detected in absence of structural cardiovascular system anomalies or cardiac channelopathies.

Conclusions

No other reports about cardiac rhythm anomalies in individuals affected by FASD are actually available from the literature.

We would like to make an alert for clinician, given the possibility of finding anomalies of heart conduction and rhythm in children affected by FASD even without structural congenital heart disease.
Variable- versus constant-frequency deep-brain stimulation in patients with advanced Parkinson’s disease: study protocol for a randomized controlled trial
Authors: Jia Fumin , Zhang Jianguo , Wang Huimin , Liang Zhanhua , Liu Weiguo , Wang Xuelian , Liu Yiming , Guo Yi , Ling Zhipei , Cai Xiaodong , Wu Xi , Wu Jianjun , Lv Wen , Xu Xin , Zhang Wenbin , Li Luming
Published: December 2019

Background

Deep-brain stimulation targeting the subthalamic nucleus (STN) can be used to treat motor symptoms and dyskinesia in the advanced stages of Parkinson’s disease (PD). High-frequency stimulation (HFS) of the STN can lead to consistent, long-term improvement of PD symptoms. However, the effects of HFS on the axial symptoms of PD, specifically freezing of gait, can be limited or cause further impairment. While this can be alleviated via relatively low-frequency stimulation (LFS) in selected patients, LFS does not control all motor symptoms of PD. Recently, the National Engineering Laboratory for Neuromodulation reported preliminary findings regarding an efficient way to combine the advantages of HFS and LFS to form variable-frequency stimulation (VFS). However, this novel therapeutic strategy has not been formally tested in a randomized trial.

Methods/design

We propose a multicenter, double-blind clinical trial involving 11 study hospitals and an established deep-brain stimulation team. The participants will be divided into a VFS and a constant-frequency stimulation group. The primary outcome will be changes in stand–walk–sit task scores after 3 months of treatment in the “medication off” condition. Secondary outcome measures include specific item scores on the Freezing of Gait Questionnaire and quality of life. The aim of this trial is to investigate the efficacy and safety of VFS compared with constant-frequency stimulation.

Discussion

This is the first randomized controlled trial to comprehensively evaluate the effectiveness and safety of VFS of the STN in patients with advanced PD. VFS may represent a new option for clinical treatment of PD in the future.

Trial registration

ClinicalTrials.gov, NCT03053726. Registered on February 15, 2017.
Contribution of aroma compounds to the antioxidant properties of roasted white yam (Dioscorea rotundata)
Authors: Lasekan Ola , Teoh Li Shing
Published: December 2019

Background

The aroma chemistry and the contribution of the aroma compounds to the anti-oxidative properties of roasted yam have yet to be characterized. The growing popularity of roasted yam in regions where they are being consumed calls for a concerted effort to elucidate their aroma chemistry as well as their anti-oxidative properties.

Results

The aroma compounds in roasted white yam (Dioscorea rotundata) were isolated and identified using static headspace-gas chromatography-mass spectrometry (SH–GC–MS) and gas chromatography–olfactometry (GC–O). In addition, the anti-oxidative activities of the most abundant volatile heterocyclic compounds (2 pyrroles, 4 furans and 3 pyrazines) were evaluated on their inhibitory effect towards the oxidation of hexanal for a period of 30 days. Twenty-nine aroma-active compounds with a flavour dilution (FD) factor range of 2–256 and an array of odour notes were obtained. Among them, the highest odour activities (FD ≥ 128) factors were determined for 2-acetyl furan and 2-acetylpyrrole. Other compounds with significant FD factors ≥ 32 were; 2-methylpyrazine, ethyl furfural, and 5-hydroxy methyl furfural.

Conclusion

Results of the anti-oxidative activity showed that the pyrroles exhibited the greatest antioxidant activity among all the tested heterocyclic compounds. This was followed by the furans and the pyrazines which had the least antioxidant activity.
Efficacy and safety of evogliptin in the treatment of type 2 diabetes mellitus in a Brazilian population: a randomized bridging study
Authors: Cercato Cintia , Felício Joao Soares , Russo Luis Augusto Tavares , Borges Joao Lindolfo Cunha , Salles Joao , Muskat Patricia , Bonansea Teresa , Chacra Antonio Roberto , Eliaschewitz Freddy Goldberg , Forti Adriana Costa
Published: December 2019

Background

Evogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO’s clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg).

Methods

In this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12—baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < − 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned.

Results

HbA1c mean reductions were − 1.26% (90% CI − 1.7%, − 0.8%), − 1.12% (90% CI − 1.4%, − 0.8%), − 1.29% (90% CI − 1.6%, − 1.0%), and − 1.15% (90% CI − 1.5%, − 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of − 18.94 mg/dL, − 21.17 mg/dL, and − 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO’s “target” dose (5 mg) was confirmed. No safety concerns were identified.

Conclusions

These results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg).

Trial registration ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016).
64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study
Authors: Pérès Elodie A. , Toutain Jérôme , Paty Louis-Paul , Divoux Didier , Ibazizène Méziane , Guillouet Stéphane , Barré Louisa , Vidal Aurélien , Cherel Michel , Bourgeois Mickaël , Bernaudin Myriam , Valable Samuel
Published: December 2019

Background

Diacetyl-bis(N4-methylthiosemicarbazone), labeled with 64Cu (64Cu-ATSM) has been suggested as a promising tracer for imaging hypoxia. However, various controversial studies highlighted potential pitfalls that may disable its use as a selective hypoxic marker. They also highlighted that the results may be tumor location dependent. Here, we first analyzed uptake of Cu-ATSM and its less lipophilic counterpart Cu-Cl2 in the tumor over time in an orthotopic glioblastoma model. An in vitro study was also conducted to investigate the hypoxia-dependent copper uptake in tumor cells. We then further performed a comprehensive ex vivo study to compare 64Cu uptake to hypoxic markers, specific cellular reactions, and also transporter expression.

Methods

μPET was performed 14 days (18F-FMISO), 15 days (64Cu-ATSM and 64Cu-Cl2), and 16 days (64Cu-ATSM and 64Cu-Cl2) after C6 cell inoculation. Thereafter, the brains were withdrawn for further autoradiography and immunohistochemistry. C6 cells were also grown in hypoxic workstation to analyze cellular uptake of Cu complexes in different oxygen levels.

Results

In vivo results showed that Cu-ASTM and Cu-Cl2 accumulated in hypoxic areas of the tumors. Cu-ATSM also stained, to a lesser extent, non-hypoxic regions, such as regions of astrogliosis, with high expression of copper transporters and in particular DMT-1 and CTR1, and also characterized by the expression of elevated astrogliosis. In vitro results show that 64Cu-ATSM showed an increase in the uptake only in severe hypoxia at 0.5 and 0.2% of oxygen while for 64Cu-Cl2, the cell retention was significantly increased at 5% and 1% of oxygen with no significant rise at lower oxygen percentages.

Conclusion

In the present study, we show that Cu-complexes undoubtedly accumulate in hypoxic areas of the tumors. This uptake may be the reflection of a direct dependency to a redox metabolism and also a reflection of hypoxic-induced overexpression of transporters. We also show that Cu-ATSM also stained non-hypoxic regions such as astrogliosis.
Respiratory syncytial virus prophylaxis for prevention of recurrent childhood wheeze and asthma: a protocol for a systematic review
Authors: Quinn Lauren Alexandra , Shields Michael D. , Groves Helen E.
Published: December 2019

Background

Lower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) has been associated with greater risk of recurrent wheezing and subsequent asthma. However, it is still unclear whether this association is causal or not. RSV-specific monoclonal antibodies have been shown to reduce RSV-related hospitalisations in high-risk infants, i.e. those born pre-term, but the longer term follow-up has given conflicting evidence for the prevention of recurrent wheeze or asthma.

Objective

We aim to perform a systematic review and meta-analysis to determine whether or not prophylaxis with a monoclonal antibody for prevention of RSV-bronchiolitis reduces the risk of subsequent recurrent wheeze or asthma. If so, this would support the hypothesis that the association between RSV and recurrent wheeze and/or asthma is causative.

Methods

To identify relevant studies, we will search a number of databases including Medline, Embase, PubMed and Web of Science and will also manually look for unpublished data by contacting the manufacturers of monoclonal antibodies. The intervention being investigated is RSV-specific monoclonal antibody prophylaxis, and the outcome being measured is recurrent wheeze and/or asthma. Studies will be screened according to inclusion/exclusion criteria, to include primary studies of any study design type. Eligible studies will then be evaluated for quality and assessed for bias independently by three reviewers using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) approach. The results of the studies will be extracted into 2 × 2 outcome tables, and a meta-analysis will be carried out to produce forest plots based on relative risk. Heterogeneity will be assessed using the I2 statistic. The statistical software we will use is StatsDirect.

Discussion

This review will aid in determining if the relationship between RSV and asthma development is a causal one, by showing the effect (if any) of RSV prophylaxis on subsequent recurrent wheeze/asthma. If this study shows RSV prophylaxis to have no effect on the outcome of recurrent wheeze/asthma, the question of causality remains.
The bifurcation analysis and optimal feedback mechanism for an SIS epidemic model on networks
Authors: Chen Lijuan , Huang Shouying , Chen Fengde , Fu Mingjian
Published: December 2019

It is well known that the feedback mechanism or the individual’s intuitive response to the epidemic can have a vital effect on the disease’s spreading. In this paper, we investigate the bifurcation behavior and the optimal feedback mechanism for an SIS epidemic model on heterogeneous networks. Firstly, we present the bifurcation analysis when the basic reproduction number is equal to unity. The direction of bifurcation is also determined. Secondly, different from the constant coefficient in the existing literature, we incorporate a time-varying feedback mechanism coefficient. This is more reasonable since the initiative response of people is constantly changing during different process of disease prevalence. We analyze the optimal feedback mechanism for the SIS epidemic network model by applying the optimal control theory. The existence and uniqueness of the optimal control strategy are obtained. Finally, a numerical example is presented to verify the efficiency of the obtained results. How the topology of the network affects the optimal feedback mechanism is also discussed.
A toolkit with nine district types to support municipalities in taking an integrated approach to prevention
Authors: Storm Ilse , Post Nikkie , Verweij Antonia , Leenaars Karlijn
Published: December 2019

Background

Not only do people differ in their health, so do districts within municipalities. For example, city centres have different characteristics and health issues than villages or post-war neighbourhoods. This is why the Dutch National Institute for Public Health and the Environment has developed a toolkit, ‘Prevention in the district’, based on nine different types of district.

Methods

The aim of the toolkit is to help municipalities implement an integrated approach to prevention by providing tailored, practical information. We therefore looked at the best way to improve the connection between the available knowledge and local needs. Based on data analysis, expert opinion and working sessions with professionals and local policymakers, we developed a toolkit with three related tools.

Results

The following tools were developed: 1) nine district types with their prominent characteristics and 14 themes for prevention (ranging from loneliness to overweight); 2) a data guide containing a set of indicators to assess the district health profile; 3) a prevention guide containing a mix of evidence-based interventions for the 14 themes. The tools are presented in a toolkit (a clickable PDF) to emphasise the fact that they form a coherent whole. The link between data and interventions is considered to be particularly innovative.

Conclusion

The three tools support the improvement of the health and well-being of residents in a district. The first indications are that the toolkit empowers municipalities and lets them work towards an integrated approach. An integrated approach in both district health profiles and district plans could also serve as an example for other countries.
Simultaneous exposure to vinylcyclohexene and methylmercury in Drosophila melanogaster: biochemical and molecular analyses
Authors: Piccoli Bruna Candia , Segatto Ana Lúcia Anversa , Oliveira Cláudia Sirlene , D’Avila da Silva Fernanda , Aschner Michael , da Rocha João Batista Teixeira
Published: December 2019

Background

Exposure to vinylcyclohexene (VCH) and methylmercury (MeHg+) can induce oxidative stress and gene modulation. Several studies have been evaluating the effects of VCH and MeHg+, but little is known about interactive effects between them. This work aimed to assess the exposure and co-exposure effects of MeHg+and VCH on oxidative stress and gene modulation inDrosophila melanogaster.

Methods

Reactive species production, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities were evaluated after exposure and co-exposure to VCH (1 mM) and MeHg+ (0.2 mM) for one or three days in the head and body (thorax and abdomen) of flies. The expression of genes related to redox state and inflammatory response was evaluated after exposure and co-exposure to VCH and MeHg+ for three days.

Results

Survival decreased only in flies co-exposed to VCH and MeHg+for three days. All treatments increased total reactive species production after one day of exposure. However, no significant changes were observed in the head after three days of exposure. One day of exposure to VCH caused an increase in the head GST activity, whereas MeHg+induced an increase after three days of exposure. Regarding the body, all treatments increased GST activity after one day of exposure, but only the flies exposed to MeHg+presented an increase in GST activity after three days of exposure. Treatments did not alter AChE activity in the head. As for gene expression, there was a significant increase in the Relish transcription factor gene in the flies’ body, but Nrf2, Keap1, Jafrac1, TrxR1, and NF-κβ were not altered.

Conclusion

The results suggest that exposure to VCH and MeHg+induce oxidative stress and activation of an inflammatory response in fruit flies.
Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans
Authors: Soares Fabiana Gomes Nascimento , Göethel Gabriela , Kagami Luciano Porto , das Neves Gustavo Machado , Sauer Elisa , Birriel Estefania , Varela Javier , Gonçalves Itamar Luís , Von Poser Gilsane , González Mercedes , Kawano Daniel Fábio , Paula Fávero Reisdorfer , de Melo Eduardo Borges , Garcia Solange Cristina , Cerecetto Hugo , Eifler-Lima Vera Lucia
Published: December 2019

Background

Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds.

Methods

Trypanocidal activity:

Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50).

Toxicity assays:

Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure.

Structure-activity relationship:

A classificatory model was built using 3D descriptors.

Results

Two of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds.

Conclusion

Two coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.