bluuebunny/crossref_metadata_2025 huggingface dataset:
Extracellular vesicles derived from mesenchymal stromal cells mitigate intestinal toxicity in a mouse model of acute radiation syndrome.
Authors: Accarie Alison , L'homme Bruno , Benadjaoud Mohamedamine , Lim Sai Kiang , Guha Chadan , Benderitter Marc , Tamarat Radia , SEMONT Alexandra
Published: June 2020

Background: Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods: Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24 and 48 hours after lethal whole-body irradiation (10 Grays). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3) and in vivo permeability to 4 kDa FITC-labeled dextran. Renewal of the small intestinal epithelium was determined by quantifying epithelial cell apoptosis (TUNEL staining) and proliferation (Ki67 immunostaining). Statistical analyses were performed using one-way ANOVA followed by a Tukey test. Statistical analyses of mouse survival were performed using Kaplan-Meier and Cox methods. Results: We demonstrated that MSC-derived extracellular vesicles treatment reduced by 85% the instantaneous mortality risk in mice subjected to 10 Grays whole-body irradiation and so increased their survival time. This effect could be attributed to the efficacy of MSC-derived extracellular vesicles in reducing mucosal barrier disruption. We showed that the MSC-derived extracellular vesicles improved the renewal of the small intestinal epithelium by stimulating proliferation and inhibiting apoptosis of the epithelial crypt cells. The MSC-derived extracellular vesicles also reduced radiation-induced mucosal permeability as evidenced by the preservation of claudin-3 immunostaining at the tight junctions of the epithelium. Conclusions: MSC-derived extracellular vesicles promote epithelial repair and regeneration and preserve structural integrity of the intestinal epithelium in mice exposed to radiation-induced gastrointestinal toxicity. Our results suggest that the administration of MSC-derived extracellular vesicles could be an effective therapy for limiting acute radiation syndrome.
Well Neonate Due For Discharge In Low Resource Setting Must Be Screened For Significant Hyperbilirubinemia
Authors: Carolyn Nasuna , Abdallah Yaser , Charles Karamagi , Jamiru Mugalu
Published: June 2020

Background: Due to lack of comprehensive postnatal care; neonates in low resource settings are at high risk for significant hyperbilirubinemia (SHB) and its complications. We conducted a study to determine the prevalence of SHB, factors associated with it and performance of transcutaneous bilirubin (TCB) measurement compared to visual inspection in identifying these neonates.Methods: We conducted a cross sectional study over a one month period involving 235 neonates 24 to 72 hours of age who were due for discharge in the postnatal ward of Mulago Hospital. Relevant data was captured. Neonates with SHB were referred for treatment. Data was entered in to Epi-data version 3.0 then exported to STAT 14.0 software and analyzed. P-value of <0.05 was considered significant with confidence interval of 95%.Results: Thirty two (13.6%) of the participants had SHB and Three (1.3%) had bilirubin levels at/above exchange transfusion threshold. The means serum bilirubin level among neonates with SHB was 240µmol/l (range 132-481.4µmol/l). Possible causes for SHB included; ABO/Rhesus discordance 11 (34.4%), possible sepsis 8 (25%) due to high CRP without any explanation, significant weight loss 2 (6.25%), cephalohematoma 2 (6.25%) and twelve (37.5%) no immediate cause was identified. Significant hyperbilirubinemia was independently associated with CRP ≥ 10mg/l (AOR 3.96, CI 1.23-12.73, p 0.021), ABO discordance (AOR 3.67, CI 1.28-10.49, p 0.015), jaundice in a previous baby (AOR 3.565, CI 1.10-11.51, p 0.034) and time of initiation of feeds > 1 hour (AOR 2.74, CI 1.10-6.90, p 0.007). The sensitivity, specificity, positive and negative predictive values of TCB were 96.5%, 84.6%, 47.5% and 99.4% respectively compared to 31.2%, 98.5%, 76.9% and 90% respectively for visual assessment.Conclusions: Among well neonates in the post natal ward approximately 1 in 10 have SHB and 1 in 100 have bilirubin level at exchange transfusion threshold between 24 and 72 hours of age hence screening for SHB among such neonates should be emphasized. Transcutaneous bilirubinometry is a suitable screening tool since it identified majority of neonates with SHB. Early initiation of feeding should be promoted. Screening for possible sepsis in neonates with significant hyperbilirubinemia without identifiable reason should be considered.
Complicated hospitalization due to influenza: Results from the Global Hospital Influenza Network for the 2017–2018 season
Authors: Lina Bruno , Georges Alexandre , Burtseva Elena , Nunes Marta C. , Andrew Melissa K. , McNeil Shelly A. , Ruiz-Palacios Guillermo M. , Feng Luzhao , Kyncl Jan , Vanhems Philippe , Ortiz Justin R. , Paget John , Reiner Robert C.
Published: June 2020

Background: Since 2011, the Global Influenza Hospital Surveillance Network (GIHSN) has used active surveillance to prospectively collect epidemiological and virological data on patients hospitalized with influenza virus infection. Here, we describe influenza virus strain circulation in the GIHSN participant countries during 2017–2018 season and examine factors associated with complicated hospitalization among patients admitted with laboratory-confirmed influenza illness.Methods: The study enrolled patients hospitalized in a GIHSN hospital in the previous 48 h with acute respiratory symptoms and who had symptoms consistent with influenza within the 7 days before admission. Enrolled patients were tested by reverse transcription-polymerase chain reaction to confirm influenza virus infection. “Complicated hospitalization” was defined as a need for mechanical ventilation, admission to an intensive care unit, or in-hospital death. In each of four age strata (<15, 15–<50, 50–<65, and ≥65 years), factors associated with complicated hospitalization in influenza-positive patients were identified by mixed effects logistic regression and those associated with length of hospital stay using a linear mixed-effects regression model.Results: The study included 12,803 hospitalized patients at 14 coordinating sites in 13 countries, of which 4,306 (34%) tested positive for influenza. Influenza viruses B/Yamagata, A/H3N2, and A/H1N1pdm09 strains dominated and cocirculated, although the dominant strains varied between sites. Complicated hospitalization occurred in 10.6% of influenza-positive patients. Factors associated with complicated hospitalization in influenza-positive patients included chronic obstructive pulmonary disease (15–<50 years and ≥65 years), diabetes (15–<50 years), male sex (50–<65 years), hospitalization during the last 12 months (50–<65 years), and current smoking (≥65 years). Chronic obstructive pulmonary disease (50–<65 years), other chronic conditions (15–<50 years), influenza A (50–<65 years), and hospitalization during the last 12 months (<15 years) were associated with a longer hospital stay. The proportion of patients with complicated influenza did not differ between influenza A and B.Conclusions: Complicated hospitalizations occurred in over 10% of patients hospitalized with influenza virus infection. Factors commonly associated with complicated or longer hospitalization differed by age group but commonly included chronic obstructive pulmonary disease, diabetes, and hospitalization during the last 12 months.
Associations between breastfeeding and cognitive function in children from early childhood to school age: a prospective birth cohort study
Authors: Kim Min Kyoung , Choi Jae-Won
Published: June 2020

Background: Despite the evident benefits of breastfeeding for preventing acute physical illnesses in infants, the evidence for the benefit of breastfeeding on long-term cognitive development is not yet convincing.Methods: The data of nationwide representative sample of 1,752 children born between 2008 and 2009 in Korea were prospectively assessed from the fetal period to examine the benefits of breastfeeding and cognitive development. Breastfeeding duration was prospectively assessed by parents. The Korean Ages and Stages Questionnaire and the Korean version of Denver II were used to assess early development annually from 5.5 to 26.2 months of age. Language development at 3 years of age was assessed with Receptive and Expressive Vocabulary Tests. Cognitive function at 8 years of age was assessed using multifactorial intelligence test.Results: Children who were breastfed 1–3 months displayed significantly higher odds ratios for delayed development assessed at 14.1 months than those breastfed for 3–6 months. Children who were breastfed for >3 months also scored significantly higher on the communication and problem-solving subscales at 14.1 and 26.2 months of age, the expressive language subscale at 3 years, and the vocabulary and language inference vocabulary subscales at 8 years of age than children who were breastfed for <3 months.Conclusion: We found that cognitive development was improved in children that were breastfed for >3 months. Although these results are supported by previous studies, it is important to note that other factors were larger determinants of cognitive development than breastfeeding. Future studies that examine the underlying mechanism for the association between breastfeeding and cognitive development are warranted.
Treatment Effects of Reverse Total Shoulder Arthroplasty – A Simple Method to Measure Outcomes at 6, 12, 24 and 60 Months for Each Patient
Authors: Huber Joerg , Irlenbusch Ulrich , Kääb Max J , Reuther Falk , Kohut Georges , Judge Andy
Published: June 2020

Background Although shoulder arthroplasty is less common than knee or hip arthroplasty, the number of procedures being performed is increasing rapidly. The treatment effect is a simple method to measure outcome of joint replacement. The method was applied to measure results of total hip/knee arthroplasty but not yet for shoulder arthroplasty. Methods Included were patients with unilateral cuff arthropathy (Hamada grades >=2) treated with reversed total shoulder arthroplasty (RSA) in this prospective multicenter study. The patients were assessed with the ASES questionnaire. The treatment effects (TE) was calculated for each patient. TE = score reduction/baseline score. A positive TE means amelioration, TE = 0 unchanged, and a negative TE means worse. The primary aim was to calculate the TE’s for RSA at 6, 12, 24, and 60 months postoperatively. The secondary aim was to analyze the influence of confounders (preoperative Hamada grade, age, gender, dominance, side of the affected shoulder, general co-morbidities measured using ASA grade). Results 203 patients were included for this analysis of whom 183 patients had a complete 2 year follow up. Two years postoperatively the mean ASES score augmented significant from 20.5 to 78.7 (p<0.001). The 2 year TE's ranged from 1 to 0.09. We had no patient with a negative TE. A higher Hamada grade was associated with better TE’s (Hamada grade 4+ vs. 2, p-value 0.042). For age and dominant side there were weak associations where those aged 80+ and dominant side had better TE’s. The patients with higher ASA grade had lower TE’s (ASA grade 4+ vs. 1, p-value 0.013). The mean TE’s were 0.77 at 6-months, 0.81 at 1 year, 0.76 at 2 years and 0.73 at 5 years. Conclusions The outcome for reverse shoulder arthroplasty can be measured with the treatment effect method; the 2 years TE's vary from 1 to 0.09. The mean treatment effects change little in the first five postoperative years (from 0.73 to 0.81). The confounders for better TE’s were: higher severity of cuff arthropathy (Hamada grade 3, 4 and 5), less co-morbidities (ASA Grade 1), higher age (80+) and dominant side. Gender did not influence the 2-year TE’s. Trial registration: Comité intercantonal d'éthique (Jura, Fribourg, Neuchâtel), number 01/2008, 24.09.2008
Long-term preoperative glycemic control restored the perioperative neutrophilic phagocytosis in diabetic mice.
Authors: Fujimoto Daichi , Nomura Yuki , Egi Moritoki , Obata Norihiko , Mizobuchi Satoshi
Published: June 2020

BACKGROUND: The risk of surgical site infection has been reported to be higher in patients with poorly controlled diabetes. Since chronic hyperglycemia impairs neutrophil functions, preoperative glycemic control may restore neutrophil function. However, long-term insulin therapy may lead to a delay in surgery, which may be a problem, especially in cancer surgery. It is therefore unfortunate that　there have been few studies in which the optimal duration of perioperative glycemic control for diabetes with chronic hyperglycemia was investigated. Therefore, we investigated the effects of preoperative long-term insulin therapy and short-term insulin therapy on perioperative neutrophil functions in diabetic mice with chronic hyperglycemia. METHODS: Five-week-old male C57BL/6J mice were divided into four groups (Untreated (Diabetes Mellitus: DM), Short-term (DM), Long-term (DM), and Non-diabetic groups). Diabetes was established by administrating repeated low-dose streptozotocin. The Short-term (DM)group received insulin therapy for 6 hours before the operation and the Long-term (DM)group received insulin therapy for 5 days before the operation. The Untreated (DM) group and the Non-diabetic group did not receive insulin therapy. At 14 weeks of age, abdominal surgery with intestinal manipulation was performed in all four groups. We carried out a phagocytosis assay with fluorescent microspheres and a reactive oxygen species (ROS) production assay with DCFH-DA (2’,7’-dichlorodihydrofluorescein diacetate) before and 24 hours after the operation using FACSVerse™ with BD FACSuite™ software. RESULTS: Blood glucose was lowered by insulin therapy in the Short-term (DM) and Long-term (DM) groups before the operation. Neutrophilic phagocytosis activities before and after the operation were significantly restored in the Long-term (DM) group compared with those in the Untreated (DM) group (before: p = 0.0008, after: p = 0.0005). However, they were not significantly restored in the Short-term (DM) group. Neutrophilic ROS production activities before and after the operation were not restored in either the Short-term (DM) group or Long-term (DM) group. CONCLUSIONS: Preoperative and postoperative phagocytosis activities are restored by insulin therapy for 5 days before the operation but not by insulin therapy for 6 hours before the operation.
Risk of stroke after unilateral or bilateral TKA in 327,438 matched patients using data from the National Health Insurance Claims for South Korea
Authors: Han Seung-Beom , Yoon Jung-Ro , Cheong Ji-Young , Lee Sang-Soo , Shin Young-Soo
Published: June 2020

Background: This study aims to investigate the incidence rate and risk factors of stroke in patients treated with bilateral TKA compared with patients with unilateral TKA. Methods: In this retrospective nationwide cohort study, we compared patients undergoing unilateral TKA or bilateral TKA using data from the Korean National Health Insurance claims database between January 1, 2009 and August 31, 2017 and included patients older than 40 years of age who underwent primary TKA by the index date as documented primary diagnosis and first additional diagnosis without a history of stroke during the preceding 1 year. We used matched Cox regression models to compare the incidence rate and risk factors of newly acquired stroke among patients treated with unilateral TKA or bilateral TKA after propensity score (PS) matching. Results: In the present study, 163,719 patients who received unilateral TKA were matched to 163,719 patients with bilateral TKA based on PS. The risk of stroke during the study period was lower in patients treated with bilateral TKA than in patients with unilateral TKA (adjusted hazard ratio [HR] 0.79). Patients who received bilateral TKA were at decreased risk of stroke when the following variables were present: advanced age (70-79 years, HR 0.76), female sex (HR 0.75), rural area (HR 0.77), small- or medium-sized hospital (HR 0.75), health insurance (HR 0.77), history of hypertension drug use (HR 0.75), congestive heart failure (HR 0.70), connective tissue disease (HR 0.71), diabetes (HR 0.77), and diabetes with complication (HR 0.76). Conclusions: The risk of stroke was lower in patients treated with bilateral TKA than in patients with unilateral TKA. Patients treated with bilateral TKA were at decreased risk of stroke when the following variables were present: age (70-79 years), female sex, health insurance, history of hypertension drug use, and comorbidities, such as congestive heart failure, connective tissue disease, and diabetes. More importantly, we do state that those with simultaneous bilateral TKA and staged bilateral TKA without discharge could have been healthier. Therefore, those who underwent 2 unilateral TKAs could have been at more risk of stroke, especially in the 2nd unilateral TKA.
Investigating the healthcare pathway through patients’ experience and profiles: implications for breast cancer healthcare providers
Authors: CHERIF Emna , VERDIER Elisabeth MARTIN , ROCHETTE Corinne
Published: June 2020

Background: Healthcare systems are facing many changes. Particularly, patients are more engaged in the care process. The medical perspective of the process is insufficient to provide patients with high quality care and service personalisation. This research presents an attempt to complete this medical perspective through an experiential perspective, especially for chronic diseases such as cancer. We investigated patients’ experiences and profiles to reach a deeper understanding of their needs and expectations when they confront the disease. The objectives of this research were to model the key stages underling the patient pathway and to identify the challenging touch points of the interactions between patients and healthcare providers. Bringing together findings of patient experience, pathway, and profiles would help all the stakeholders involved to develop better practices for the healthcare process. Methods: A qualitative observational nethnography on a French specialized forum for breast cancer patients “ les Impatientes” was conducted. A total of 967 reviews were collected over a complete year period from all over France. Thematic and lexicometric content analysis were performed according to the experience dimensions, the pathway stages and touch points, as well as the patients’ profiles. Results: Data analysis shows that the healthcare pathway experienced by the patients is built around three stages. The discovery stage is closely related to the emotional dimension regarding the patient and physician relationship. The examination stage is characterized by a more technical and informational needs for the types of treatments. The follow-up and survivorship stage illustrates the patients’ need to assess the treatments’ effectiveness and the quality of the follow-up. Moreover, three profiles of patients were identified. The newcomers, the altruists and the autonomous are characterized by different attitudes depending on the stage of the healthcare pathway they were living. Conclusions: Our research presents an original modelling of the patient pathway and profiles beyond the medical process. It gives practical tracks to improve the healthcare pathway. Patients expect healthcare providers to integrate and strengthen several challenging touch points in order to create satisfactory patient experiences and high quality service.
Bioassay and molecular monitoring of insecticide resistance status in Aedes albopictus populations from Greece, to support evidence-based vector control
Authors: Balaska Sofia , Fotakis Emmanouil Alexandros , Kioulos Ilias , Grigoraki Linda , Mpellou Spyridoula , Chaskopoulou Alexandra , Vontas John
Published: June 2020

Background: Aedes albopictus has a well-established presence in southern European countries, associated with recent disease outbreaks (e.g. chikungunya). Development of insecticide resistance in the vector is a major concern as its control mainly relies on the use of biocides. Data on the species’ resistance status are essential for efficient and sustainable control. To date the insecticide resistance status of Ae. albopictus populations from Greece against major insecticides used in vector control remains largely unknown. Methods: We investigated the insecticide resistance status of 19 Ae. albopictus populations from 11 regions of Greece. Bioassays were performed against diflubenzuron (DFB), Bacillus thuringiensis var. israelensis (Bti), deltamethrin and malathion. Known insecticide resistance loci were molecularly analysed, i.e. voltage-gated sodium channel (VGSC) mutations associated with pyrethroid resistance; presence and frequency of carboxylesterases 3 (CCEae3a) and 6 (CCEae6a) gene amplification associated with organophosphate (OP) resistance and; chitin synthase-1 (CHS-1) for the possible presence of DFB resistance mutations. Results: Bioassays showed full susceptibility to DFB, Bti and deltamethrin, but resistance against the OP malathion (range of mortality: 55.30–91.40%). VGSC analysis revealed a widespread distribution of the mutations F1534C (in all populations, with allelic frequencies between 6.6–68.3%), and I1532T (in 6 populations; allelic frequencies below 22.70%), but absence of V1016G. CCE gene amplifications were recorded in 8 out of 11 populations (overall frequency: 33%). Co-presence of the F1534C mutation and CCEae3a amplification was reported in 39 of the 156 samples analysed by both assays. No mutations at the CHS-1 I1043 locus were detected. Conclusions: The results indicate: (i) the suitability of larvicides DFB and Bti for Ae. albopictus control in Greece; (ii) possible incipient pyrethroid resistance due to the presence of kdr mutations; and (iii) possible reduced efficacy of OPs, in a scenario of re-introducing them for vector control. The study highlights the need for systematic resistance monitoring for developing and implementing appropriate evidence-based control programmes.
Ovarian reserve after three-step laparoscopic surgery for endometriomas utilizing dienogest: a non-randomized prospective pilot study.
Authors: Kitajima Michio , Matsumoto Kanako , Murakami Naoko , Harada Ayumi , Kitajima Yuriko , Masuzaki Hideaki , Miura Kiyonori
Published: June 2020

Background Surgery for endometriomas may cause detrimental effects on ovarian reserve. In this study, we evaluated the safety of three-step laparoscopic surgery for endometriomas utilizing novel progestin, dienogest in terms of post -surgical ovarian reserve.Methods Twelve women received first look laparoscopy (FLL) with fenestration and drainage. Immediately after the surgery, they took oral dienogest 2mg for three months, then they received second look laparoscopy (SLL) with cystectomy. We compared the effects on ovarian reserve by serum AMH levels between women had three step management with dienogest and another twelve women had　conventional one-step surgery without medications. In women had three-step surgery with dienogest, the changes in concentration of proinflammatory cytokines and chemokines (interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1) in peritoneal fluids were evaluated.Results Serum AMH levels were significantly decreased after three months of dienogest following FLL. AMH levels were also significantly decreased 3-6 month both after SLL and after one-step surgery, however, recovery of serum AMH levels at 9-12 months after surgery were evident in women had three-step surgery comparing to those of women had one-step surgery. Proinflammatory cytokines and chemokines in peritoneal fluids were down regulated at the time of SLL comparing to those of FLL.Conclusions Three-step surgery with dienogest may be a beneficial approach to protect ovarian reserve. Dienogest may exert its effects in part by lowering proinflammatory cytokines and chemokines.
Sports activity participation after curved periacetabular osteotomy for acetabular dysplasia
Authors: Takahashi Yoshiki , Takahira Naonobu , Uchiyama Katsufumi , Fukushima Kensuke , Moriya Mitsutoshi , Shibuya Manaka , Tsuda Kouji , Tozaki Kiyoshi , Kudo Sho , Kaneda Hiroaki , Sekita Junya , Takaso Masashi
Published: June 2020

Background: Curved periacetabular osteotomy (CPO) was developed to treat acetabular dysplasia. Given that CPO can improve physical function in the early post-operative period, patients might be able to participate in sports activities post-operatively. Therefore, this study examined the post-operative sports activity participation and characteristics of acetabular dysplasia patients who have undergone CPO.Methods: A total of 52 patients who underwent CPO for acetabular dysplasia were given a questionnaire on pre- and post-operative sports activities; 43 patients responded. We surveyed patients’ sports activities, satisfaction, and physical function. Patients were divided according to whether they participated in sports activities after CPO. Physical function was compared before and after CPO.Results: The pre- and post-operative sports activity participation rates were 55.8% and 72.1%, respectively. Patients mostly performed low-impact sports activities. Moreover, patients who participated in sports activities post-operatively had smaller pre-operative range of motion of hip flexion and returned to full weight bearing earlier.Conclusions: Among acetabular dysplasia patients who underwent CPO, 72.1% participated in sports activities post-operatively. Post-operatively, patients participated not only in low-impact sports activities, but also in high-impact ones. These findings might be useful for advising patients who are concerned about participating in sports activities after CPO.
Qualitative analysis of clinicians’ perspectives on the use of a computerized decision aid in the treatment of psychotic disorders
Authors: Roebroek Lukas , Bruins Jojanneke , Delespaul Philippe A. , Boonstra Albert , Castelein Stynke
Published: June 2020

Background: Clinical decision aids are used in various medical fields to support patients and clinicians when making healthcare decisions. Few attempts have been made to implement such tools in psychiatry. We developed Treatment E-Assist (TREAT); a routine outcome monitoring based computerized clinical decision aid, which generates personalized treatment recommendations in the care of people with psychotic disorders. The aim of this study is to investigate how TREAT is used and evaluated by clinicians and how this tool can be improved. Methods: Clinicians working with TREAT during a clinical trial were asked to participate in semi-structured interviews. The unified theory of acceptance and use of technology (UTAUT) was used as a sensitizing theory to structure a part of the interview questions. The transcripts were coded. An inductive thematic analysis was followed to identify the main themes. Results: 13 clinicians (mean age: 49) of which eight psychiatrists and five nurse practitioners, participated in this study. Eight clinicians experienced TREAT as beneficial, whereas five experienced no additional benefits. Thematic analysis revealed five themes about how TREAT was used and evaluated by clinicians, views on TREAT’s visual structuring of routine outcome monitoring results, guideline based treatment recommendations, contextual factors, effects on patients and effects on shared decision-making. Performance and effort expectancy were perceived as high by clinicians. The facilitating conditions were optimal and perceived social influence was low. Conclusion: This article presents a qualitative evaluation by clinicians of a computerized clinical decision aid in psychosis care. TREAT was viewed by most clinicians as beneficial during their consultations. The visual representation of routine outcome monitoring results was well-appreciated and provided input to discuss treatment planning with patients. The treatment recommendations did not change most treatment decisions but supported clinical reasoning. However, some clinicians were unconvinced about TREAT’s benefits. The delivery, applicability and the availability of resources require improvement to increase TREAT’s efficacy. Not all patients responded well to TREAT but the observed facilitation of shared decision-making is promising. All four predictors of the unified theory of acceptance and use of technology were positively evaluated by the majority of clinicians..
Temperature, Precipitation, Ozone Pollution, and Daily Fatal Unintentional Injuries in Jiangsu Province, China during 2015-2017
Authors: Robertson Leon , Zhou Lian , Chen Kai
Published: June 2020

Background The correlation of unintentional injury mortality to rising temperatures found in several studies could result from changes in behavior that increases exposure to hazards or risk when exposed. Temperature, precipitation and air pollutants may contribute to symptoms and distractions that increase risk or avoidance behavior that reduces risk. This study examines data that allows estimates of the relation of daily maximum temperature, precipitation and ozone pollution to injury mortality risk, each corrected statistically for the correlation with the others.Methods Daily data on unintentional injury deaths and exposures to temperature, precipitation and ozone in 9 cities in Jiangsu Province, China during 2015-2017 were analyzed using Poisson regression. The regression estimates were adjusted for weekends, holidays, an anomalous difference in death rates in Nanjing, and population size.Results Non transport injury death risk increased substantially in relation to higher temperatures when temperatures were in the moderate range and even more so at temperatures 35 degrees (C) and higher. Transport deaths were related to increasing deaths when temperatures were low but the correlation reversed at higher temperatures. Deaths were lower on rainy days when temperatures were cool and moderate with the exception of non-transport injuries when temperatures were moderate. Higher ozone concentrations were associated with more deaths except when temperatures were low. Injury mortality on weekends and holidays varied in relation to temperature as well. Conclusions The variations in deaths in relation to temperature, precipitation and ozone suggest that people are behaving differently or are in different environments when specific combinations of the predictor variables are prevalent, putting them at greater or less risk. More study of the behaviors and circumstances that result in injury under those conditions is needed.
Ex-Utero Intrapartum Treatment (EXIT): indications and outcome in fetal cervical and oropharyngeal masses
Authors: García-Díaz Lutgardo , Chimenea Ángel , de Agustín Juan Carlos , Pavón Antonio , Antiñolo Guillermo
Published: June 2020

Background

The “Ex-Utero Intrapartum Treatment” (EXIT) procedure allows to ensure fetal airway before completion of delivery and umbilical cord clamping, while keeping uteroplacental circulation. Airway obstruction in fetal oropharyngeal and cervical masses can be life-threatening at birth. In those situations, a controlled access to fetal airway carried out by a trained multidisciplinary team allows a safe airway management, while feto-maternal circulation is preserved. We aim to review the indications and outcome of EXIT procedure in a cases series of fetal cervical and oropharyngeal masses.

Methods

We performed a retrospective review of all patients with fetal cervical and oropharyngeal masses who underwent an EXIT procedure between 2008 and 2019. Variables evaluated included indication for EXIT, ultrasound and MRI findings, need of amnioreduction, gestational age at EXIT, birth weight, complications, operative time, survival rate, pathological findings and postnatal evolution. Five patients are included in this series. One additional case has already been published.

Results

The diagnosis were cervical teratoma (n=1), epulis (n=1) and lymphangioma (n=3). Polyhydramnios was present in 2 patients, requiring amnioreduction in one of them. Mean gestational age at EXIT was 36-37 weeks (range, 34-38 weeks). Median EXIT time in placental support was 9 minutes (range, 3-22 minutes). Access to airway was successfully established in EXIT in all cases. All children born by EXIT are currently healthy and without complications.

Conclusion

The localization and characteris­tics of the mass, its relationship to the airway and the presence of polyhydramnios seems to be major factors determining indications for EXIT and clinical outcome.
New Mechanisms to Fund Independent Clinical Trials for Repurposing Off-Patent or Generic Medicines
Authors: Verbaanderd Ciska , Rooman Ilse , Huys Isabelle
Published: June 2020

Finding new therapeutic uses for approved, off-patent or generic medicines could lead to safe, affordable and timely new treatment options for patients with high medical needs. However, due to a lack of economic incentives, pharmaceutical developers are rarely interested to invest in this type of research. Consequently, potential new uses for off-patent or generic medicines are mainly studied in independent proof-of-concept clinical trials initiated and led by researchers from academia, research institutes or collaborative groups. Yet, these researchers need additional financial support to conduct expensive phase III clinical trials to confirm the results from exploratory research. In this study, scientific and grey literature was searched to identify and evaluate new mechanisms for funding clinical trials with repurposed medicines. Semi-structured interviews were conducted with 16 European stakeholders with expertise in clinical research, funding mechanisms and/or drug repurposing between November 2018 and February 2019 to consider the future perspectives of applying new funding mechanisms. Traditional grant funding awarded by government and philanthropic organisations or companies is well known and widely implemented in all research fields. In contrast, the application potential of newer mechanisms to fund independent clinical research, such as social impact bonds or crowdfunding, is not yet known. Interviewees stated that there is a substantial need for additional financial support in health research, especially in disease domains where there is limited commercial interest. However, the implementation of new funding mechanisms is facing several practical and financial challenges, such as a lack of expertise and guidelines, high transaction costs and difficulties to measure health outcomes. Furthermore, increased collaboration and centralisation at a European and international level is recommended to make clinical research more efficient and reduce the need for additional funding. New funding mechanisms to support clinical research may become more important in the future, but the unresolved issues warrant further exploration in pilot projects.
TILT: Time-Lapse Imaging Trial: A pragmatic, Multi-Centre, Three-Arm Randomised Controlled Trial to Assess the Clinical Effectiveness and Safety of Time-Lapse Imaging in in-Vitro Fertilisation Treatment.
Authors: Bhide Priya , Srikanthara Arasaratnam , Lanz Doris , Dodds Julie , Collins Bonnie , Zamora Javier , Chan David YL , Thangaratinam Shakila , Khan Khalid
Published: June 2020

• Background: Subfertility is a common problem for which in-vitro fertilisation (IVF) treatment is commonly recommended. Success rates following IVF are suboptimal and have remained static over the last few years. This imposes a considerable financial burden on overstretched healthcare resources. Time-lapse imaging (TLI) of developing embryos in IVF treatment is hypothesised to improve the success rates of treatment. This may be either by providing undisturbed culture conditions and/or improving the predictive accuracy for optimal embryo selection from a cohort of available embryos. However, current best evidence for its effectiveness is inconclusive. • Methods: The time-lapse imaging trial is a pragmatic, multi-centre, three-arm parallel group randomised controlled trial using re-randomisation. The primary objective of the trial is to determine if the use of TLI or undisturbed culture in IVF treatment results in a higher live birth rate when compared to current standard methods of embryo incubation and assessment. Secondary outcomes include measures of clinical efficacy and safety. The trial will randomise 1575 participants to detect an increase in live birth from 26.5% to 35.25%.• Discussion: In the absence of high quality evidence, there is no current national guidance, recommendation or policy for the use of TLI. The use of TLI is not consistently incorporated into standard IVF care. A large, pragmatic, multicentre, trial will provide much needed definitive evidence regarding the effectiveness of TLI. If proven to be effective, its incorporation into standard care would translate into significant clinical and economic benefits. If not, it would allow allocation of resources to more effective interventions.• Trial registration: ISRCTN registry, ISRCTN17792989, 18/04/2018, prospectively registered.
Lipidomics Profiling of Skin Surface Lipids in Senile Pruritus
Authors: Ma xiaolei , Lu Lulu , Zhao Zheng , Cai Mingru , Gao Na , Han Gangwen
Published: June 2020

Background: Senile pruritus is common, yet its etiology remains unknown. Aging-associated skin barrier defects and skin surface lipids (SSL) alterations have been postulated to play important roles in its occurrence. In the present study, the lipidomic profiles of SSLs in elderly patients were examined to better understand the potential causes of senile pruritus. Methods: Transepidermal water loss (TEWL) was evaluated to assess the skin barrier function. The Ameliorated Kawashima Itch Scale score was used to measure the pruritus severity. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and multivariate data analysis were employed to investigate SSL alterations. Results: The results showed that senile pruritus patients had higher TEWL values than control subjects (13.13±4.28 versus 6.71±2.45, P<0.01). LC-MS/MS revealed significant differences in the lipidomic profiles and identified 81 species of SSLs that differed between the two groups. Compared with control subjects, senile pruritus patients had increased levels of ceramides (Cers), diacylglycerols, fatty acids, phosphatidylcholines, phosphatidylethanolamines, phytosphingosines, sphingosines, diacylceryl-3-O-carboxyhydroxymethylcholine, diacylglyceryl trimethylhomoserine, and unsaturated free fatty acids, but decreased levels of triacylglycerol. Cer-EOS, Cer-NDS, and Cer-NS were positively correlated with TEWL value (P<0.05). Pruritus severity score was positively correlated with sphingomyelin, Cer-NP, Cer-AS, Cer-NDS, and Cer-NS, but negatively correlated with Cer-BS, Cer-EODS, Cer-EOS, and Cer-AP. Conclusions: The present study indicated that patients with senile pruritus have impaired skin barrier function and altered SSL composition. Certain SSL species identified in this study may be potential targets for future studies on the pathogenesis of senile pruritus.Trial registration: Peking University International Hospital (Number: YN2018QN04; date: January 2019).
Development of an in vitro 3D model for investigating ligamentum flavum hypertrophy
Authors: Lin Cheng-Li , Kuo Yi-Ting , Tsao Che-Hao , Shyong Yan-Jye , Shih Shu-Hsien , Tu Ting-Yuan
Published: June 2020

Background
Ligamentum flavum hypertrophy (LFH) is one of the most crucial factors in degenerative lumbar spinal stenosis, which can cause back pain, lower extremity pain, cauda equina syndrome and neurogenic claudication. The exact pathogenesis of LFH remains elusive, despite extensive research. Most in vitro studies of LFH have been carried out using conventional 2D cell cultures, which do not resemble in vivo conditions, as they lack crucial pathophysiological factors found in three-dimensional (3D) LFH tissue, such as enhanced cell proliferation and cell cluster formation. In this study, we generated LF clusters using spheroid cultures derived from primary LFH tissue.
Results
The cultured LF spheroids exhibited good viability and growth on the ULA 96-plate platform according to live/dead staining. Our results showed that 100-cell culture continued to grow in size, while 1000-cell culture maintained the size and 5000-cell culture exhibited a decreasing trend as the culture time increased, and long-term culture was validated for at least 28 days. The LF spheroids also maintained the extracellular matrix (ECM) phenotype, i.e. fibronectin, elastin, and collagen I and III. 2D culture and 3D culture were further compared by cell cycle and Western blot analyses. Finally, we utilized hematoxylin and eosin (H&E) staining to demonstrate 3D spheroids has resembled part of the cell arrangement in LF hypertrophic tissue.
Conclusions
The developed LF spheroid model has great potential, as it provides a stable culture platform in a 3D model that can further improve our understanding of the pathogenesis of LFH and has applications in future studies.
Aggresome Formation and Liquid-liquid Phase Separation Independently Induce Cytoplasmic Aggregation of TAR DNA-binding protein 43
Authors: Yamanaka Koji , Watanabe Seiji , Inami Hidekazu , Oiwa Kotaro , Murata Yuri , Sakai Shohei , Komine Okiru , Sobue Akira , Iguchi Yohei , Katsuno Masahisa
Published: June 2020

Background Cytoplasmic inclusion of TAR DNA-binding protein 43 (TDP-43) is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and a subtype of frontotemporal lobar degeneration (FTLD). Recent studies have suggested that the formation of cytoplasmic TDP-43 aggregates is dependent on a liquid-liquid phase separation (LLPS) mechanism. However, it is unclear whether TDP-43 pathology is induced through a single intracellular mechanism such as LLPS.Methods We established a TDP-43 aggregation screening system using a cultured neuronal cell line stably expressing EGFP-fused TDP-43 and a mammalian expression library of the inherited ALS/FTLD causative genes. We performed a screening to identify the intracellular mechanisms responsible for TDP-43 aggregation. An immunofluorescence study was conducted using the sporadic ALS spinal cord sections.Results We found that microtubule-related proteins (MRPs) and RNA-binding proteins (RBPs) co-aggregated with TDP-43. MRPs and RBPs sequestered TDP-43 into the cytoplasmic aggregates through distinct mechanisms such as microtubules and LLPS, respectively. The MRPs-induced TDP-43 aggregates were co-localized with aggresomal markers and dependent on histone deacetylase 6 (HDAC6), suggesting that aggresome formation induced the co-aggregation. However, the MRPs-induced aggregates were not affected by 1,6-hexanediol, an LLPS inhibitor. On the other hand, the RBPs-induced TDP-43 aggregates were sensitive to 1,6-hexanediol, but not dependent on microtubules or HDAC6. In sporadic ALS patients, approximately half of skein-like TDP-43 inclusions were co-localized with HDAC6, but round and granular type inclusion were not. Moreover, HDAC6-positive and HDAC6-negative inclusions were found in the same ALS patient, suggesting that the two distinct pathways are both involved in TDP-43 pathology.Conclusion Our findings suggest that at least two distinct pathways (i.e., aggresome formation and LLPS ) are involved in inducing the TDP-43 pathologies.
Rat epidermal stem cells promote the angiogenesis of full-thickness wound
Authors: Huang Shaobin , Hu Zhicheng , Wang Peng , zhang Yi , Cao Xiaoling , Dong Yunxian , Cheng Pu , Xu Hailin , Zhu Wenkai , Tang Bing , Zhu Jiayuan
Published: June 2020

Background: Full-thickness wounds are a serious problem which badly affects patients’ life quality and also become the difficult problem for clinicians. Stem cells have great prospects in the treatment of wounds. Our previous experiments proved that autologous basal cell suspension can promote wound healing, and there are epidermal stem cells (ESCs) in basal cell suspension. We then conducted experiments to explore the effect of ESCs on full-thickness wound. Methods: In our study, the rat ESCs were isolated and expanded, and transfected with lentivirus to stably express EGFP. Experimental rats were randomly divided into 2 groups, in the ESCs group, the rat ESCs were sprayed on the Full-thickness wounds of the rats, while in control group, sprayed the PBS on the wound. Wound healing and neovascularization were then evaluated. Colonization, division and differentiation of ESCs on the wound were discovered by immunofluorescence.Results: The result suggested that rat ESCs can colonize, divide and proliferate in the wound. What’s more, the rat ESCs around blood vessels can differentiate into vascular endothelial cells and form a lumen-like structure. Compared with the control group, spraying the rat ESCs on the wound bed can promote angiogenesis and accelerate wound healing. Conclusions: Our study proved that rat ESCs were safe and effective for treating full-thickness wounds, and under certain conditions, ESCs can differentiate into vascular endothelial cells to promote angiogenesis and wound healing.
Umbilical cord-derived mesenchymal stromal cells immunomodulate and restore actin dynamics and phagocytosis of LPS-activated microglia via PI3K/Akt/Rho GTPase pathway
Authors: Mukai Takeo , Martino Elena Di , Tsuji Shunichiro , Blomgren Klas , Nagamura-Inoue Tokiko , Ådén Ulrika
Published: June 2020

Background: Microglia are the immune cells in the central nervous system constantly surveying their environment and reacting to various injuries. Activated microglia may cause impaired synaptic plasticity, therefore modulating and restoring them to more neutral phenotype is crucial to counteract a pro-inflammatory, neurotoxic state. In this study, we focused on elucidating whether human umbilical cord (UC) tissue-derived mesenchymal stromal cells (MSCs) can exert immunomodulatory effect and change the phenotype of activated microglia. Methods: Primary culture of microglia was activated by lipopolysaccharide (LPS) and was co-cultured with three lots of MSCs. We investigated immunomodulation, actin dynamics and phagocytic capacity of activated microglia, and examined change of Rho GTPase in microglia as the mechanism. Results: MSCs suppressed the expression of IL-1β and pNFκB in LPS-activated microglia, and conversely elevated the expression of IL-1β in resting-surveying microglia with lot-to-lot variation. Morphological and phagocytotic analyses revealed that LPS stimulation significantly increased active Rho GTPase, Rac1, and Cdc42 levels in the microglia, and their morphology changed to amoeboid in which F-actin spread with ruffle formation. The F-actin spreading persisted after removal of LPS stimulation and reduced phagocytosis. On the other hand, MSC co-culture induced bimodal increase in active Rac1 and Cdc42 levels in LPS-activated microglia. Moreover, extended ruffles of F-actin shrinked and concentrated to form an actin ring, thereby restoring phagocytosis. We confirmed that inhibition of the PI3K/Akt pathway attenuated F-actin dynamics and phagocytosis restored by MSCs. Conclusions: Overall, we demonstrated that MSCs immunomodulated microglia with lot-to-lot variation, and changed the phenotype of LPS-activated microglia, thereby restoring actin dynamics and phagocytosis by increase of active Rho GTPase. Modulation of the phenotype of activated microglia by MSCs can be a novel therapeutic strategy for the treatment of neurological disorders accompanied by inflammation.