bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards definitive management of allergic rhinitis: best use of new and established therapies
Authors: Hossenbaccus Lubnaa , Linton Sophia , Garvey Sarah , Ellis Anne K.
Published: May 2020

Background

Allergic rhinitis (AR) is an inflammatory disease of the nasal mucosa impacting up to 25% of Canadians. The standard of care for AR includes a treatment plan that takes into account patient preferences, the severity of the disease, and most essentially involves a shared decision-making process between patient and provider.

Body

Since their introduction in the 1940s, antihistamines (AHs) have been the most utilized class of medications for the treatment of AR. First-generation AHs are associated with adverse central nervous system (CNS) and anticholinergic side effects. On the market in the 1980s, newer generation AHs have improved safety and efficacy. Compared to antihistamines, intranasal corticosteroids (INCS) have significantly greater efficacy but longer onset of action. Intranasal AH and INCS combinations offer a single medication option that offers broader disease coverage and faster symptom control. However, cost and twice-per-day dosing remain a major limitation. Allergen immunotherapy (AIT) is the only disease-modifying option and can be provided through subcutaneous (SCIT) or sublingual (SLIT) routes. While SCIT has been the definitive management option for many years, SLIT tablets (SLIT-T) have also been proven to be safe and efficacious.

Conclusion

There is a range of available treatment options for AR that reflect the varying disease length and severity. For mild to moderate AR, newer generation AHs should be the first-line treatment, while INCS are mainstay treatments for moderate to severe AR. In patients who do not respond to INCS, a combination of intranasal AH/INCS (AZE/FP) should be considered, assuming that cost is not a limiting factor. While SCIT remains the option with the most available allergens that can be targeted, it has the potential for severe systemic adverse effects and requires weekly visits for administration during the first 4 to 6 months. SLIT-T is a newer approach that provides the ease of being self-administered and presents a reduced risk for systemic reactions. In any case, standard care for AR includes a treatment plan that takes into account disease severity and patient preferences.
Elevated de novo protein synthesis in FMRP-deficient human neurons and its correction by metformin treatment
Authors: Utami Kagistia Hana , Yusof Nur Amirah Binte Mohammad , Kwa Jing Eugene , Peteri Ulla-Kaisa , Castrén Maija L. , Pouladi Mahmoud A.
Published: May 2020

FXS is the most common genetic cause of intellectual (ID) and autism spectrum disorders (ASD). FXS is caused by loss of FMRP, an RNA-binding protein involved in the translational regulation of a large number of neuronal mRNAs. Absence of FMRP has been shown to lead to elevated protein synthesis and is thought to be a major cause of the synaptic plasticity and behavioural deficits in FXS. The increase in protein synthesis results in part from abnormal activation of key protein translation pathways downstream of ERK1/2 and mTOR signalling. Pharmacological and genetic interventions that attenuate hyperactivation of these pathways can normalize levels of protein synthesis and improve phenotypic outcomes in animal models of FXS. Several efforts are currently underway to trial this strategy in patients with FXS. To date, elevated global protein synthesis as a result of FMRP loss has not been validated in the context of human neurons. Here, using an isogenic human stem cell-based model, we show that de novo protein synthesis is elevated in FMRP-deficient neural cells. We further show that this increase is associated with elevated ERK1/2 and Akt signalling and can be rescued by metformin treatment. Finally, we examined the effect of normalizing protein synthesis on phenotypic abnormalities in FMRP-deficient neural cells. We find that treatment with metformin attenuates the increase in proliferation of FMRP-deficient neural progenitor cells but not the neuronal deficits in neurite outgrowth. The elevated level of protein synthesis and the normalization of neural progenitor proliferation by metformin treatment were validated in additional control and FXS patient-derived hiPSC lines. Overall, our results validate that loss of FMRP results in elevated de novo protein synthesis in human neurons and suggest that approaches targeting this abnormality are likely to be of partial therapeutic benefit in FXS.
Magnetic resonance imaging of the female pelvis after Cesarean section: a pictorial review
Authors: Bekiesinska-Figatowska Monika
Published: May 2020

The rate of Cesarean sections (C-sections) in Poland increased from 21.7% in 2001 to 43.85% in 2017 even though the Polish Society of Gynecologists and Obstetricians highlights the negative consequences of C-section for both mother and child and recommends to make every possible effort to reduce its percentage, following the World Health Organization recommendations. There is a long list of possible complications related to the uterine scar after C-section, including uterine scar dehiscence, uterine rupture, abdominal and pelvic adhesions, uterine synechiae, ectopic pregnancy, anomalous location of the placenta, placental invasion, and—rarely—vesicouterine or uterocutaneous fistulas. Ultrasound (US) remains the first-line modality; however, its strong operator- and equipment dependence and other limitations require further investigations in some cases. Magnetic resonance imaging (MRI) is the second-line tool which is supposed to confirm, correct, or complete the sonographic diagnosis thanks to its higher tissue resolution and bigger field of view. This article will discuss the spectrum of C-section complications in the MR image-rich form and will provide a systematic discussion of the possible pathology that can occur, showing comprehensive anatomical insight into the pelvis after C-section thanks to MRI that facilitates clinical decisions.
Extracellular vesicles derived from human ES-MSCs protect retinal ganglion cells and preserve retinal function in a rodent model of optic nerve injury
Authors: Seyedrazizadeh Seyedeh-Zahra , Poosti Sara , Nazari Abdoreza , Alikhani Mehdi , Shekari Faezeh , Pakdel Farzad , Shahpasand Koorosh , Satarian Leila , Baharvand Hossein
Published: May 2020

Background

Retinal and/or optic nerve injury is one of the leading causes of blindness due to retinal ganglion cell (RGC) degeneration. There have been extensive efforts to suppress this neurodegeneration. Various somatic tissue-derived mesenchymal stem cells (MSCs) demonstrated significant neuroprotective and axogenic effects on RGCs. An alternative source of MSCs could be human embryonic stem cells (ES-MSCs), which proliferate faster, express lower levels of inflammatory cytokines, and are capable of immune modulation. It has been demonstrated that MSCs secrete factors or extracellular vesicles that may heal the injury. However, possible therapeutic effects and underlying mechanism of human ES-MSC extracellular vesicles (EVs) on optic nerve injury have not been assessed.

Methods

EVs were isolated from human ES-MSCs. Then, ES-MSC EV was applied to an optic nerve crush (ONC) mouse model. Immunohistofluorescence, retro- and anterograde tracing of RGCs, Western blot, tauopathy in RGCs, and function assessments were performed during 2-month post-treatment to evaluate ONC improvement and underlying mechanism of human ES-MSC EV in in vivo.

Results

We found that the ES-MSC EV significantly improved Brn3a+ RGCs survival and retro- and anterograde tracing of RGCs, while preventing retinal nerve fiber layer (RNFL) degenerative thinning compared to the vehicle group. The EVs also significantly promoted GAP43+ axon counts in the optic nerve and improved cognitive visual behavior. Furthermore, cis p-tau, a central mediator of neurodegeneration in the injured RGCs, is detectable after the ONC at the early stages demonstrated tauopathy in RGCs. Notably, after EV treatment cis p-tau was downregulated.

Conclusions

Our findings propose that human ES-MSC EVs, as an off-the-shelf and cell-free product, may have profound clinical implications in treating injured RGCs and degenerative ocular disease. Moreover, the possible mechanisms of human ES-MSC EV are related to the rescue of tauopathy process of RGC degeneration.
RETRACTED ARTICLE: Polydatin improves osteogenic differentiation of human bone mesenchymal stem cells by stimulating TAZ expression via BMP2-Wnt/β-catenin signaling pathway
Authors: Shen Ying-Shan , Chen Xiao-Jun , Wuri Sha-Na , Yang Fan , Pang Feng-Xiang , Xu Liang-Liang , He Wei , Wei Qiu-Shi
Published: May 2020

Objectives

Polydatin (PD), extracted fromPolygonum cuspidatum, has shown potential therapeutic applications due to its antiosteoporotic and anti-inflammatory activities. Our previous study suggested that PD promotes the osteogenesis of human bone marrow stromal cells (hBMSCs) via the BMP2-Wnt/β-catenin pathway. The aim of our present study was to further explore the role of PD-mediated regulation of Tafazzin (TAZ), a transcriptional coactivator with a PDZ-binding motif, in osteogenesis.

Materials and methods

hBMSCs were isolated and treated with PD at various concentrations. Alizarin red staining and RT-qPCR were performed to identify calcium complex deposition in hBMSCs as well as the expression of specific osteoblast-related markers, respectively, in each group. Next, TAZ-silenced hBMSCs were generated by lentivirus-produced TAZ shRNA. After treatment with PD, the osteogenic abilities of the TAZ-silenced and control hBMSCs were estimated by ALP activity assay, and expression of the TAZ protein was detected by Western blot analysis and immunofluorescence staining. In vitro, an ovariectomized (OVX) mouse model was established and used to evaluate the effect of PD on bone destruction by micro-CT, immunohistochemistry, and ELISA.

Results

In vitro, 30 μM PD significantly improved the proliferation and calcium deposition of hBMSCs and markedly stimulated the expression of the mRNAsRUNX2,Osteopontin,DLX5,β-catenin,TAZ, andOsteocalcin(OCN). Osteogenic differentiation induced by PD was blocked by lentivirus-mediated TAZ shRNA. Furthermore, Noggin (a regulator of bone morphogenic protein 2 (BMP2)) and DKK1 (an inhibitor of the Wnt/β-catenin pathway) were found to inhibit the increase in TAZ expression induced by PD. In vivo, PD prevented estrogen deficiency-induced bone loss in the OVX mouse model.

Conclusion

Taken together, our findings suggest that PD improved the osteogenic differentiation of hBMSCs and maintained the bone matrix in the OVX mouse model through the activation of TAZ, a potential target gene of the BMP2-Wnt/β-catenin pathway.
How effective are digital interventions in increasing flu vaccination amongst pregnant women? A systematic review protocol
Authors: Parsons Joanne , Atherton Helen
Published: May 2020

Background

Pregnant women and their unborn babies are at increased risk of complications as a result of flu, yet uptake of the flu vaccination in the UK remains low. Digital interventions have proven effectiveness in changing health behaviour, but their effectiveness in increasing flu vaccination amongst pregnant women has not been examined. This protocol details the design and methodology of a systematic review and meta-analysis, examining the effectiveness of digital interventions in increasing flu vaccination amongst pregnant women.

Methods

Bibliographic databases will be searched using appropriate search terms related to vaccination, pregnancy and flu. Randomised, non-randomised, quasi randomised controlled trials and other quantitative study designs will be eligible for inclusion, and studies will present the rate of flu vaccination amongst pregnant women of digital interventions compared to non-digital interventions, or usual care. No date or study country restrictions will be put on included studies, but studies will be published in English.

Discussion

This is the first known systematic review to examine the effectiveness of digital interventions in increasing the rate of flu vaccination amongst pregnant women. This review has the potential to inform whether digital interventions are an appropriate and successful method of increasing flu vaccination amongst pregnant women, and to determine which mode of digital intervention is most effective.

Trial registration

This systematic review is registered on the international prospective register of systematic reviews (PROSPERO). Registration number pending.
Measure of noncompactness and a generalized Darbo’s fixed point theorem and its applications to a system of integral equations
Authors: Parvaneh Vahid , Khorshidi Maryam , De La Sen Manuel , Işık Hüseyin , Mursaleen Mohammad
Published: May 2020

Işık et al. (Mathematics 7:862, 2019) presented an interesting generalization of the Banach contraction principle. In this paper, motivated by Işık et al., we give a new extension of the well-known Darbo inequality in a Banach space. Our results provide several generalizations of the Darbo inequality. As an application, we study the existence of solutions for a system of functional integral equations in$C[0,T]$C[0,T]. Finally, we expose a genuine example to support the effectiveness of our results.
On a fractional hybrid multi-term integro-differential inclusion with four-point sum and integral boundary conditions
Authors: Baleanu Dumitru , Etemad Sina , Rezapour Shahram
Published: May 2020

We investigate the existence of solutions for a fractional hybrid multi-term integro-differential inclusion with four-point sum and integral boundary value conditions. By using Dhage’s fixed point results, we prove our main existence result. Finally, we give an example to illustrate our main result.
The effect of a 5-year hand hygiene initiative based on the WHO multimodal hand hygiene improvement strategy: an interrupted time-series study
Authors: Suzuki Yumi , Morino Motoko , Morita Ichizo , Yamamoto Shigenori
Published: May 2020

Background

A World Health Organization (WHO) guideline-based multimodal hand hygiene (HH) initiative was introduced hospital-wide to a nonteaching Japanese hospital for 5 years. The objective of this study was to assess the effect of this initiative in terms of changes in alcohol-based hand rub (ABHR) consumption and the Hand Hygiene Self-Assessment Framework (HHSAF) score.

Methods

The consumption of monthly hospital-wide ABHR was calculated in L per 1000 patient days (PDs). The change in ABHR consumption was analysed by an interrupted time series analysis with a pre-implementation period of 36 months and an implementation period of 60 months. The correlation between annual ABHR consumption and the HHSAF score was estimated using Pearson’s correlation coefficients.

Results

The annual ABHR consumption was 4.0 (L/1000 PDs) to 4.4 in the pre-implementation period and 10.4 to 34.4 in the implementation period. The HHSAF score was 117.5 (out of 500) in the pre-implementation period and 267.5 to 445 in the implementation period. A statistically significant increase in the monthly ABHR consumption (change in slope: + 0.479 L/1000 PDs, p <  0.01) was observed with the implementation of the initiative. Annual ABHR consumption was strongly correlated with the annual HHSAF score (r = 0.971, p <  0.01).

Conclusions

A 5-year WHO-based HH initiative significantly increased ABHR consumption. Our study suggested that the HHSAF assessment can be a good process measure to improve HH in a single facility, as ABHR consumption increased with the HHSAF score.
Clinical characteristics and risk factors of polymicrobial Staphylococcus aureus bloodstream infections
Authors: Zheng Cheng , Zhang Shufang , Chen Qingqing , Zhong Li , Huang Tiancha , Zhang Xijiang , Zhang Kai , Zhou Hongwei , Cai Jiachang , Du Linlin , Wang Changming , Cui Wei , Zhang Gensheng
Published: May 2020

Background

Although Staphylococcus aureus bloodstream infections (SA-BSI) are a common and important infection, polymicrobial SA-BSI are infrequently reported. The aim of this study was to investigate the clinical characteristics and risk factors of polymicrobial SA-BSI in comparison with monomicrobial SA-BSI.

Methods

A single-center retrospective observational study was performed between Jan 1, 2013, and Dec 31, 2018 at a tertiary hospital. All patients with SA-BSI were enrolled, and their clinical data were gathered by reviewing electronic medical records.

Results

A total of 349 patients with SA-BSI were enrolled including 54 cases (15.5%) with polymicrobial SA-BSI. In multivariable analysis, burn injury (adjusted odds ratio [OR], 7.04; 95% confidence interval [CI], 1.71–28.94), need of blood transfusion (aOR, 2.72; 95% CI, 1.14–6.50), use of mechanical ventilation (aOR, 3.11; 95% CI, 1.16–8.30), the length of prior hospital stay (aOR, 1.02; 95% CI, 1.00–1.03), and pneumonia as primary site of infection (aOR, 4.22; 95% CI, 1.69–10.51) were independent factors of polymicrobial SA-BSI. In comparison with monomicrobial SA-BSI, patients with polymicrobial SA-BSI had longer length of ICU stay [median days, 23(6.25,49.25) vs. 0(0,12), p < 0.01] and hospital stay [median days, 50(21.75,85.75) vs. 28(15,49), p < 0.01], and showed a higher 28-day mortality (29.6% vs. 15.3%, p = 0.01).

Conclusions

Burn injury, blood transfusion, mechanical ventilation, the length of prior hospital stay, and pneumonia as a primary site of infection are independent risk factors for polymicrobial SA-BSI. In addition, patients with polymicrobial SA-BSI might have worse outcomes compared with monomicrobial SA-BSI.
Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms
Authors: Qin Chuan , Lu Yalan , Wang Kewei , Bai Lin , Shi Guiying , Huang Yiying , Li Yongning
Published: May 2020

Background

Alzheimer’s disease is a neurodegenerative disorder. Therapeutically, a transplantation of bone marrow mesenchymal stem cells (BMMSCs) can play a beneficial role in animal models of Alzheimer’s disease. However, the relevant mechanism remains to be fully elucidated.

Main body

Subsequent to the transplantation of BMMSCs, memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease (AD). Potential mechanisms involved neurogenesis, apoptosis, angiogenesis, inflammation, immunomodulation, etc. The above mechanisms might play different roles at certain stages. It was revealed that the transplantation of BMMSCs could alter some gene levels. Moreover, the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease, which could be used to construct gene-specific patterns.

Conclusions

Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models. Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect. The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.
Electrically stimulable indium tin oxide plate for long-term in vitro cardiomyocyte culture
Authors: Moon Sung-Hwan , Cho Young-Woo , Shim Hye-Eun , Choi Jae-Hak , Jung Chan-Hee , Hwang In-Tae , Kang Sun-Woong
Published: May 2020

Background

We investigated whether electrical stimulation via indium tin oxide (ITO) could enhance the in vitro culture of neonatal rat ventricular myocytes (NRVMs), which are important in vitro models for studying the mechanisms underlying many aspects of cardiology.

Methods

Cardiomyocytes were obtained from 1-day-old neonatal rat heart ventricles. To evaluate function of NRVMs cultured on ITO with electrical stimulation, the cell viability, change of cell morphology, immunochemistry using cardiac-specific antibodies, and gene expression were tested.

Results

Defined sarcomeric structure, cell enlargement, and increased distribution of NRVMs appeared in the presence of electrical stimulation. These characteristics were absent in NRVMs cultured under standard culture conditions. In addition, the expression levels of cardiomyocyte-specific and ion channel markers were higher in NRVMs seeded on ITO-coated dishes than in the control group at 14 days after seeding. ITO-coated dishes could effectively provide electrical cues to support the in vitro culture of NRVMs.

Conclusions

These results provide supporting evidence that electrical stimulation via ITO can be effectively used to maintain culture and enhance function of cardiomyocytes in vitro.
Construction of reporter gene assays using CWP and PDR mutant yeasts for enhanced detection of various sex steroids
Authors: Ito-Harashima Sayoko , Matano Mami , Onishi Kana , Nomura Tomofumi , Nakajima Saki , Ebata Shingo , Shiizaki Kazuhiro , Kawanishi Masanobu , Yagi Takashi
Published: May 2020

Background

Sex steroid hormone receptors are classified into three classes of receptors: estrogen receptors (ER) α and β, androgen receptor (AR), and progesterone receptor (PR). They belong to the nuclear receptor superfamily and activate their downstream genes in a ligand-dependent manner. Since sex steroid hormones are involved in a wide variety of physiological processes and cancer development, synthetic chemical substances that exhibit sex steroid hormone activities have been applied as pharmaceuticals and consumed in large amounts worldwide. They are potentially hazardous contaminants as endocrine disruptors in the environment because they may induce inappropriate gene expression mediated by sex steroid hormone receptors in vivo.

Results

To develop simple reporter gene assays with enhanced sensitivity for the detection of sex steroid hormones, we newly established mutant yeast strains lacking the CWP and PDR genes encoding cell wall mannoproteins and plasma membrane drug efflux pumps, respectively, and expressing human ERα, ERβ, AR, and PR. Reporter gene assays with mutant yeast strains responded to endogenous and synthetic ligands more strongly than those with wild-type strains. Sex steroid hormone activities in some pharmaceutical oral tablets and human urine were also detectable in these yeast assays.

Conclusions

Yeast reporter gene assay systems for all six steroid hormone receptors, including previously established glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) assay yeasts, are now available. Environmental endocrine disrupters with steroid hormone activity will be qualitatively detectable by simple and easy procedures. The yeast-based reporter gene assay will be valuable as a primary screening tool to detect and evaluate steroid hormone activities in various test samples. Our assay system will strongly support the detection of agonists, antagonists, and inverse agonists of steroid hormone receptors in the field of novel drug discovery and assessments of environmental pollutants.
Mitigation of adverse effects of salinity stress on sunflower plant (Helianthus annuus L.) by exogenous application of chitosan
Authors: Bakhoum Gehan Shaker , Sadak Mervat Shamoon , Badr Elham Abd El Moneim
Published: May 2020

Background

Most developing countries are suffering from a decline in agricultural area and fresh water supply due to the adverse effects of climate change. Sunflower has been considered as having the ability to grow under various environmental conditions, tolerating levels considered stresses to other plants.

Materials and Methods

Thus, two field experiments were conducted in the screen of National Research Centre during two successive summer seasons 2018 and 2019, respectively to investigate the effect of soaking seeds of sunflower plant in different concentrations of chitosan (control, 25, 50 and 75 mg/L) on growth, some physiological parameters, yield and its components and some chemical composition of the yielded seeds of sunflower under different salinity levels (control, 4000 and 8000 mg/l).

Results

The obtained results showed that salt stress with 4000 mg/L recorded the highest values of all the studied growth characters, photosynthetic pigments, some physiological aspects, seed yield/plant and oil %. On the other hand, the highest values of head diameter, head circumference, weight 50 seed and crude protein were obtained by control treatment. Meanwhile, the highest values of proline and free amino acid were recorded under higher salinity level (8000 mg/L). On the other hand, all chitosan treatments significantly enhanced growth and productivity of sunflower plant. Also, the obtained data that, chitosan concentration (50 mg/L) recorded the highest values of all the studied growth and yield quantity and quality via enhancing photosynthetic pigments and the studied physiological aspects, as compared with other treatments. As for interaction effect, plants treated with chitosan concentration (50 mg/L) under salinity level (4000 mg/L) recorded the highest growth characters, photosynthetic pigments and IAA. While the interaction between chitosan concentrations (50 mg/L) under salinity level (8000 mg/L) recorded the highest yield characters, except for crude protein (75 mg/L chitosan) in control plants (those plants irrigated with tap water).

Conclusion

In conclusion, chitosan treatments did not only improve plant growth and productivity but also could enhance the reducing effects of salinity stress on growth and productivity of sunflower plant. The most effective concentrations was 50 mg/L on increasing growth and yield of sunflower plant.
Reducing work pressure and IT problems and facilitating IT integration and audit & feedback help adherence to perioperative safety guidelines: a survey among 95 perioperative professionals
Authors: Emond Yvette E. J. J. M. , Wolff André P. , Peters Yvonne A. S. , Bloo Gerrit J. A. , Westert Gert P. , Damen Johan , Calsbeek Hiske , Wollersheim Hub C.
Published: May 2020

Background

To improve perioperative patient safety, guidelines for the preoperative, peroperative, and postoperative phase were introduced in the Netherlands between 2010 and 2013. To help the implementation of these guidelines, we aimed to get a better understanding of the barriers and drivers of perioperative guideline adherence and to explore what can be learned for future implementation projects in complex organizations.

Methods

We developed a questionnaire survey based on the theoretical framework of Van Sluisveld et al. for classifying barriers and facilitators. The questionnaire contained 57 statements derived from (a) an instrument for measuring determinants of innovations by the Dutch Organization for Applied Scientific Research, (b) interviews with quality and safety policy officers and perioperative professionals, and (c) a publication of Cabana et al. The target group consisted of 232 perioperative professionals in nine hospitals. In addition to rating the statements on a five-point Likert scale (which were classified into the seven categories of the framework: factors relating to the intervention, society, implementation, organization, professional, patients, and social factors), respondents were invited to rank their three most important barriers in a separate, extra open-ended question.

Results

Ninety-five professionals (41%) completed the questionnaire. Fifteen statements (26%) were considered to be barriers, relating to social factors (N = 5), the organization (N = 4), the professional (N = 4), the patient (N = 1), and the intervention (N = 1). An integrated information system was considered an important facilitator (70.4%) as well as audit and feedback (41.8%). The Barriers Top-3 question resulted in 75 different barriers in nearly all categories. The most frequently reported barriers were as follows: time pressure (16% of the total number of barriers), emergency patients (8%), inefficient IT structure (4%), and workload (3%).

Conclusions

We identified a wide range of barriers that are believed to hinder the use of the perioperative safety guidelines, while an integrated information system and local data collection and feedback will also be necessary to engage perioperative teams. These barriers need to be locally prioritized and addressed by tailored implementation strategies. These results may also be of relevance for guideline implementation in general in complex organizations.

Trial registration

Dutch Trial Registry: NTR3568.
Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening
Authors: Yamaguchi Takeshi , Nakamura Akie , Nakayama Kanako , Hishimura Nozomi , Morikawa Shuntaro , Ishizu Katsura , Tajima Toshihiro
Published: May 2020

Purpose

Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood.

Methods

We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity.

Results

We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group.

Conclusions

The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.
Quantitative single-cell interactomes in normal and virus-infected mouse lungs
Authors: Cain Margo P. , Hernandez Belinda J. , Chen Jichao
Published: May 2020

Mammalian organs consist of diverse, intermixed cell types that signal to each other via ligand-receptor interactions – an interactome – to ensure development, homeostasis and injury-repair. Dissecting such intercellular interactions is facilitated by rapidly growing single-cell RNA sequencing (scRNA-seq) data; however, existing computational methods are often not readily adaptable by bench scientists without advanced programming skills. Here, we describe a quantitative intuitive algorithm, coupled with an optimized experimental protocol, to construct and compare interactomes in control and Sendai virus-infected mouse lungs. A minimum of 90 cells per cell type compensates for the known gene dropout issue in scRNA-seq and achieves comparable sensitivity to bulk RNA sequencing. Cell lineage normalization after cell sorting allows cost-efficient representation of cell types of interest. A numeric representation of ligand-receptor interactions identifies, as outliers, known and potentially new interactions as well as changes upon viral infection. Our experimental and computational approaches can be generalized to other organs and human samples.
The Lumiptosome, an engineered luminescent form of the apoptosome can report cell death by using the same Apaf-1 dependent pathway
Authors: Hosseini Elaheh Sadat , Nikkhah Maryam , Hamidieh Amir Ali , Fearnhead Howard O. , Concordet Jean-Paul , Hosseinkhani Saman
Published: May 2020

Detection of the apoptosis signature becomes central in understanding cell death modes. We present here a whole-cell biosensor that detects Apaf-1 association and apoptosome formation using a split-luciferase complementary assay. Fusion of N-terminal (Nluc) and C-terminal (Cluc)-fragments of firefly luciferase to the N-terminus of human Apaf-1 was performed in HEK293 cells by using CRISPR-Cas9 technology. This resulted in a luminescent form of the apoptosome that we named ‘Lumiptosome’. During Apaf-1 gene editing, a high number of knock-in events were observed without selection, suggesting that the Apaf-1 locus is important for the integration of exogenous transgenes. Since activation of caspase-9 is directly dependent on the apoptosome formation, measured reconstitution of luciferase activity should result from the cooperative association of Nluc-Apaf-1 and Cluc-Apaf-1. Time-response measurements also confirmed that formation of the apoptosome occurs prior to activation of caspase-3. Additionally, overexpression of the Bcl2 apoptosis regulator in transgenic and normal HEK293 cells confirmed that formation of the Lumiptosome depends on release of cytochrome c. Thus, HEK293 cells that stably express the Lumiptosome can be utilized to screen pro- and anti-apoptotic drugs, and to examine Apaf-1-dependent cellular pathways.
Cajuputs candy impairs Candida albicans and Streptococcus mutans mixed biofilm formation in vitro
Authors: Septiana Siska , Bachtiar Boy Muchlis , Yuliana Nancy Dewi , Wijaya Christofora Hanny
Published: May 2020

Background: Cajuputs candy (CC), an Indonesian functional food, utilizes the bioactivity of Melaleuca cajuputi essential oil (MCEO) to maintain oral cavity health. Synergistic interaction between Candida albicans and Streptococcus mutans is a crucial step in the pathogenesis of early childhood caries. Our recent study revealed several alternative MCEOs as the main flavors in CC. The capacity of CC to interfere with the fungus-bacterium relationship remains unknown. This study aimed to evaluate CC efficacy to impair biofilm formation by these dual cariogenic microbes.

Methods: The inhibition capacity of CC against mixed-biofilm comprising C. albicans and S. mutans was assessed by quantitative (crystal violet assay, tetrazolium salt [MTT] assay, colony forming unit/mL counting, biofilm-related gene expression) and qualitative analysis (light microscopy and scanning electron microscopy).

Result: Both biofilm-biomass and viable cells were significantly reduced in the presence of CC. Scanning electron microscopy imaging confirmed this inhibition capacity, demonstrating morphology alteration of C. albicans, along with reduced microcolonies of S. mutans in the biofilm mass. This finding was related to the transcription level of selected biofilm-associated genes, expressed either by C. albicans or S. mutans. Based on qPCR results, CC could interfere with the transition of C. albicans yeast form to the hyphal form, while it suppressed insoluble glucan production by S. mutans. G2 derived from Mojokerto MCEO showed the greatest inhibition activity on the relationship between these cross-kingdom oral microorganisms (p < 0.05).

Conclusion: In general, all CC formulas showed biofilm inhibition capacity. Candy derived from Mojokerto MCEO showed the greatest capacity to maintain the yeast form of C. albicans and to inhibit extracellular polysaccharide production by S. mutans. Therefore, the development of dual-species biofilms can be impaired effectively by the CC tested.
Recent advances in de-intensification of radiotherapy in elderly cancer patients
Authors: Desideri Isacco , Salvestrini Viola , Livi Lorenzo
Published: May 2020

Cancer in the elderly remains an evolving issue and a health challenge. Several improvements in the radiotherapy field allow the delivery of higher doses/fractions with a safe toxicity profile, permitting the reduction of radiation treatment protocols in the elderly. Regarding breast, prostate, and lung cancer, the under-representation of older patients in clinical trials limits the extension of treatment recommendations to elderly patients in routine clinical practice. Among the feasible alternatives to standard whole breast radiotherapy (WBRT) in older patients are shorter courses using higher hypofractionation (HF) and accelerated partial breast irradiation (APBI). The boost continues to be used in women at high risk of local recurrence but is less widely accepted for women at lower risk and patients over 70 years of age. Regarding prostate cancer, there are no published studies with a focus on the elderly. Current management decisions are based on life expectancy and geriatric assessment. Regimens of HF and ultra-HF protocols are feasible strategies for older patients. Several prospective non-randomized studies have documented the safe delivery of ultra-HF for patients with localized prostate cancer, and multiple phase III trials and meta-analyses have confirmed that the HF regimen should be offered with similar acute toxicity regardless of patient age and comorbidity. A recent pooled analysis from two randomized trials comparing surgery to stereotactic body radiation therapy (SBRT) in older adult patients with early stage non-small cell lung cancer did show comparable outcomes between surgery and SBRT. Elderly cancer patients are significantly under-represented in all clinical trials. Thus, the inclusion of older patients in clinical studies should be strongly encouraged to strengthen the evidence base for this age group. We suggest that the creation of oncogeriatric coordination units may promote individualized care protocols, avoid overtreatment with aggressive and unrecommended therapies, and support de-escalating treatment in elderly cancer patients.
Differential dynamics of early stages of platelet adhesion and spreading on collagen IV- and fibrinogen-coated surfaces
Authors: Horev Melanie B. , Zabary Yishaia , Zarka Revital , Sorrentino Simona , Medalia Ohad , Zaritsky Assaf , Geiger Benjamin
Published: May 2020

Background:Upon wound formation, platelets adhere to the neighboring extracellular matrix and spread on it, a process which is critical for physiological wound healing. Multiple external factors, such as the molecular composition of the environment and its mechanical properties, play a key role in this process and direct its speed and outcome.

Methods:We combined live cell imaging, quantitative interference reflection microscopy and cryo-electron tomography to characterize, at a single platelet level, the differential spatiotemporal dynamics of the adhesion process to fibrinogen- and collagen IV-functionalized surfaces.

Results:Initially, platelets sense both substrates by transient rapid extensions of filopodia. On collagen IV, a short-term phase of filopodial extension is followed by lamellipodia-based spreading. This transition is preceded by the extension of a single or couple of microtubules into the platelet’s periphery and their apparent insertion into the core of the filopodia. On fibrinogen surfaces, the filopodia-to-lamellipodia transition was partial and microtubule extension was not observed leading to limited spreading, which could be restored by manganese or thrombin.

Conclusions:Based on these results, we propose that interaction with collagen IV stimulate platelets to extend microtubules to peripheral filopodia, which in turn, enhances filopodial-to-lamellipodial transition and overall lamellipodia-based spreading. Fibrinogen, on the other hand, fails to induce these early microtubule extensions, leading to full lamellipodia spreading in only a fraction of the seeded platelets. We further suggest that activation of integrin αIIbβ3 is essential for filopodial-to-lamellipodial transition, based on the capacity of integrin activators to enhance lamellipodia spreading on fibrinogen.
The Normalization of Consumer Valuations: Context-Dependent Preferences from Neurobiological Constraints
Authors: Webb Ryan , Glimcher Paul W. , Louie Kenway
Published: May 2020

Consumer valuations are shaped by choice sets, exemplified by patterns of substitution between alternatives as choice sets are varied. Building on recent neuroeconomic evidence that valuations are transformed during the choice process, we incorporate the canonical divisive normalization computation into a discrete choice model and characterize how choice behaviour depends on both size and composition of the choice set. We then examine evidence for such behaviour from two choice experiments that vary the size and composition of the choice set. We find that divisive normalization more accurately captures observed behaviour than alternative models, including an example range normalization model. These results are robust across experimental paradigms. Finally, we demonstrate that Divisive Normalization implements an efficient means for the brain to represent valuations given neurobiological constraints, yielding the fewest choice errors possible given those constraints.

This paper was accepted by Elke Weber, judgment and decision making.
Fluorescence imaging and Raman spectroscopy applied for the accurate diagnosis of breast cancer with deep learning algorithms
Authors: Shang Lin-Wei , Ma Dan-Ying , Fu Juan-Juan , Lu Yan-Fei , Zhao Yuan , Xu Xin-Yu , Yin Jian-Hua
Published: May 2020

Deep learning is usually combined with a single detection technique in the field of disease diagnosis. This study focused on simultaneously combining deep learning with multiple detection technologies, fluorescence imaging and Raman spectroscopy, for breast cancer diagnosis. A number of fluorescence images and Raman spectra were collected from breast tissue sections of 14 patients. Pseudo-color enhancement algorithm and a convolutional neural network were applied to the fluorescence image processing, so that the discriminant accuracy of test sets, 88.61%, was obtained. Two different BP-neural networks were applied to the Raman spectra that mainly comprised collagen and lipid, so that the discriminant accuracy of 95.33% and 98.67% of test sets were gotten, respectively. Then the discriminant results of fluorescence images and Raman spectra were counted and arranged into a characteristic variable matrix to predict the breast tissue samples with partial least squares (PLS) algorithm. As a result, the predictions of all samples are correct, with minor error of predictive value. This study proves that deep learning algorithms can be applied into multiple diagnostic optics/spectroscopy techniques simultaneously to improve the accuracy in disease diagnosis.
Registration of fluorescein angiography and optical coherence tomography images of curved retina via scanning laser ophthalmoscopy photographs
Authors: Almasi Ramin , Vafaei Abbas , Ghasemi Zeinab , Ommani Mohammad Reza , Dehghani Ali Reza , Rabbani Hossein
Published: May 2020

Accurate and automatic registration of multimodal retinal images such as fluorescein angiography (FA) and optical coherence tomography (OCT) enables utilization of supplementary information. FA is a gold standard imaging modality that depicts neurovascular structure of retina and is used for diagnosing neurovascular-related diseases such as diabetic retinopathy (DR). Unlike FA, OCT is non-invasive retinal imaging modality that provides cross-sectional data of retina. Due to differences in contrast, resolution and brightness of multimodal retinal images, the images resulted from vessel extraction of image pairs are not exactly the same. Also, prevalent feature detection, extraction and matching schemes do not result in perfect matches. In addition, the relationships between retinal image pairs are usually modeled by affine transformation, which cannot generate accurate alignments due to the non-planar retina surface. In this paper, a precise registration scheme is proposed to align FA and OCT images via scanning laser ophthalmoscopy (SLO) photographs as intermediate images. For this purpose, first a retinal vessel segmentation is applied to extract main blood vessels from the FA and SLO images. Next, a novel global registration is proposed based on the Gaussian model for curved surface of retina. For doing so, first a global rigid transformation is applied to FA vessel-map image using a new feature-based method to align it with SLO vessel-map photograph, in a way that outlier matched features resulted from not-perfect vessel segmentation are completely eliminated. After that, the transformed image is globally registered again considering Gaussian model for curved surface of retina to improve the precision of the previous step. Eventually a local non-rigid transformation is exploited to register two images perfectly. The experimental results indicate the presented scheme is more precise compared to other registration methods.
Generation of 0.7 mJ multicycle 15 THz radiation by phase-matched optical rectification in lithium niobate
Authors: Jang Dogeun , Sung Jae Hee , Lee Seong Ku , Kang Chul , Kim Ki-Yong
Published: May 2020

We demonstrate efficient multicycle terahertz pulse generation at 14.6 THz from large-area lithium niobate crystals by using high-energy (up to 2 J) femtosecond Ti:sapphire laser pulses. Such terahertz radiation is produced by phase-matched optical rectification in lithium niobate. Experimentally, we achieve maximal terahertz energy of 0.71 mJ with conversion efficiency of

∼

0.04
%

. Our experimental setup is simple and easily upscalable to produce multi-millijoule, multicycle terahertz radiation with proper lithium niobate crystals.
Las Cumbres de las Américas: una nueva plataforma para la sociedad civil
Authors: Tussie Diana , Botto Mercedes
Published: May 2020

RESUMEN: Este artículo analiza los avances logrados por las Cumbres de las Américas en materia de incorporación de los actores no gubernamentales en la definición de la agenda hemisférica. La descripción identifica los alcances de la apertura a nivel regional y a nivel nacional. En la conclusión, se evalúan los desafíos que enfrentan los foros de participación de la sociedad civil para institucionalizarse como plataformas democráticas de consulta y diálogo entre gobiernos y actores no gubernamentales de la región.ABSTRACT: This article analyzes the accomplishments of the Summits of the Americas regarding the inclusion of non-governmental actors in the definition of the hemispheric agenda. The description identifies the reach of the opening at both the regional and national levels. In the conclusion, the authors assess the challenges faced by the civil society participatory forums in order to get institutionalized as democratic platforms for dialogue between governmental and non-governmental actors across the region.