The role of tonic glycinergic conductance in cerebellar granule cell signalling and the effect of gain-of-function mutation.

Abstract:
KEY POINTS
A T258F mutation of the glycine receptor increases the receptor affinity to endogenous agonists, modifies single-channel conductance and shapes response decay kinetics. Glycine receptors of cerebellar granule cells play their functional role not continuously, but when the granule cell layer starts receiving a high amount of excitatory inputs. Despite their relative scarcity, tonically active glycine receptors of cerebellar granule cells make a significant impact on action potential generation and inter-neuronal crosstalk, and modulate synaptic plasticity in neural networks; extracellular glycine increases probability of postsynaptic response occurrence acting at NMDA receptors and decreases this probability acting at glycine receptors. Tonic conductance through glycine receptors of cerebellar granule cells is a yet undiscovered element of the biphasic mechanism that regulates processing of sensory inputs in the cerebellum. A T258F point mutation disrupts this biphasic mechanism, thus illustrating the possible role of the gain-of-function mutations of the glycine receptor in development of neural pathologies.

ABSTRACT
Functional glycine receptors (GlyRs) have been repeatedly detected in cerebellar granule cells (CGCs), where they deliver exclusively tonic inhibitory signals. The functional role of this signalling, however, remains unclear. Apart from that, there is accumulating evidence of the important role of GlyRs in cerebellar structures in development of neural pathologies such as hyperekplexia, which can be triggered by GlyR gain-of-function mutations. In this research we initially tested functional properties of GlyRs, carrying the yet understudied T258F gain-of-function mutation, and found that this mutation makes significant modifications in GlyR response to endogenous agonists. Next, we clarified the role of tonic GlyR conductance in neuronal signalling generated by single CGCs and by neural networks in cell cultures and in living cerebellar tissue of C57Bl-6J mice. We found that GlyRs of CGCs deliver a significant amount of tonic inhibition not continuously, but when the cerebellar granule layer starts receiving substantial excitatory input. Under these conditions tonically active GlyRs become a part of neural signalling machinery allowing generation of action potential (AP) bursts of limited length in response to sensory-evoked signals. GlyRs of CGCs support a biphasic modulatory mechanism which enhances AP firing when excitatory input intensity is low, but suppresses it when excitatory input rises to a certain critical level. This enables one of the key functions of the CGC layer: formation of sensory representations and their translation into motor output. Finally, we have demonstrated that the T258F mutation in CGC GlyRs modifies single-cell and neural network signalling, and breaks a biphasic modulation of the AP-generating machinery.

cerebellar granule cells
gain-of-function mutation
glycine receptor
tonic inhibitory current


Reduced growth velocity from the mid-trimester is associated with placental insufficiency in fetuses born at a normal birthweight.

Abstract:
BACKGROUND
Fetal growth restriction (FGR) due to placental insufficiency is a major risk factor for stillbirth. While small-for-gestational-age (SGA; weight < 10th centile) is a commonly used proxy for FGR, detection of FGR among appropriate-for-gestational-age (AGA; weight ≥ 10th centile) fetuses remains an unmet need in clinical care. We aimed to determine whether reduced antenatal growth velocity from the time of routine mid-trimester ultrasound is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency among term AGA infants.

METHODS
Three hundred and five women had biometry measurements recorded from their routine mid-trimester (20-week) ultrasound, at 28 and 36 weeks' gestation, and delivered an AGA infant. Mid-trimester, 28- and 36-week estimated fetal weight (EFW) and abdominal circumference (AC) centiles were calculated. The EFW and AC growth velocities between 20 and 28 weeks, and 20-36 weeks, were examined as predictors of four clinical indicators of placental insufficiency: (i) low 36-week cerebroplacental ratio (CPR; CPR < 5th centile reflects cerebral redistribution-a fetal adaptation to hypoxia), (ii) neonatal acidosis (umbilical artery pH < 7.15) after the hypoxic challenge of labour, (iii) low neonatal body fat percentage (BF%) reflecting reduced nutritional reserve and (iv) placental weight < 10th centile.

RESULTS
Declining 20-36-week fetal growth velocity was associated with all indicators of placental insufficiency. Each one centile reduction in EFW between 20 and 36 weeks increased the odds of cerebral redistribution by 2.5% (odds ratio (OR) = 1.025, P = 0.001), the odds of neonatal acidosis by 2.7% (OR = 1.027, P = 0.002) and the odds of a < 10th centile placenta by 3.0% (OR = 1.030, P < 0.0001). Each one centile reduction in AC between 20 and 36 weeks increased the odds of neonatal acidosis by 3.1% (OR = 1.031, P = 0.0005), the odds of low neonatal BF% by 2.8% (OR = 1.028, P = 0.04) and the odds of placenta < 10th centile by 2.1% (OR = 1.021, P = 0.0004). Falls in EFW or AC of > 30 centiles between 20 and 36 weeks were associated with two-threefold increased relative risks of these indicators of placental insufficiency, while low 20-28-week growth velocities were not.

CONCLUSIONS
Reduced growth velocity between 20 and 36 weeks among AGA fetuses is associated with antenatal, intrapartum and postnatal indicators of placental insufficiency. These fetuses potentially represent an important, under-recognised cohort at increased risk of stillbirth. Encouragingly, this novel fetal assessment would require only one additional ultrasound to current routine care, and adds to the potential benefits of routine 36-week ultrasound.

D000222:Adaptation, Physiological
D000328:Adult
D001724:Birth Weight
D015331:Cohort Studies
D005260:Female
D047109:Fetal Development
D005317:Fetal Growth Retardation
D020567:Fetal Weight
D005865:Gestational Age
D006801:Humans
D056865:Ideal Body Weight
D007231:Infant, Newborn
D008297:Male
D010927:Placental Insufficiency
D011247:Pregnancy
D011262:Pregnancy Trimester, Second
D012307:Risk Factors
D016216:Ultrasonography, Prenatal
D014469:Umbilical Arteries
D055815:Young Adult

Growth velocity
Mid-trimester
Placental insufficiency
Fetal growth restriction
Small-for-gestational-age
Appropriate-for-gestational-age
Antenatal ultrasonography


Cardiovascular comorbidities as predictors for severe COVID-19 infection or death.

Abstract:
AIMS
Pre-existing cardiovascular diseases (CVDs) have been proposed to identify patients at higher risk of adverse coronavirus disease 2019 (COVID-19) outcomes, but existing evidence is conflicting. Thus, it is unclear whether pre-existing CVDs are independently important predictors for severe COVID-19.

METHODS AND RESULTS
In a nationwide Danish cohort of hospital-screened COVID-19 patients aged ≥40, we investigated if pre-existing CVDs predict the 30-day risk of (i) composite outcome of severe COVID-19 and (ii) all-cause mortality. We estimated 30-day risks using a Cox regression model including age, sex, each CVD comorbidity, chronic obstructive pulmonary disease-asthma, diabetes, and chronic kidney disease. To illustrate CVD comorbidities' importance, we evaluated the predicted risks of death and severe infection, for each sex, along ages 40-85. In total, 4090 COVID-19 hospital-screened patients were observed as of 26 August 2020; 22.1% had ≥1 CVD, 23.7% had severe infection within 30 days and 12.6% died. Predicted risks of both outcomes at age 75 among men with single CVD comorbidities did not differ in clinically meaningful amounts compared with men with no comorbidities risks for the composite outcome of severe infection; women with heart failure (28.2%; 95% CI 21.1-37.0%) or atrial fibrillation (30.0%; 95% CI: 24.2-36.9%) showed modest increases compared with women with no comorbidities (24.0%; 95% CI: 21.4-26.9%).

CONCLUSIONS
The results showing only modest effects of CVDs on increased risks of poor COVID-19 outcomes are important in allowing public health authorities and clinicians to provide more tailored guidance to cardiovascular patients, who have heretofore been grouped together as high risk due to their disease status.

Phelps|Matthew|M|
Christensen|Daniel Mølager|DM|
Gerds|Thomas|T|
Fosbøl|Emil|E|
Torp-Pedersen|Christian|C|
Schou|Morten|M|
Køber|Lars|L|
Kragholm|Kristian|K|
Andersson|Charlotte|C|
Biering-Sørensen|Tor|T|
Christensen|Helle Collatz|HC|
Andersen|Mikkel Porsborg|MP|
Gislason|Gunnar|G|

D029424:Pulmonary Disease, Chronic Obstructive

Cardiovascular comorbidities
COVID-19
Mortality
Morbidity
Pre-existing conditions
Severe outcomes


Plant Adaptation to Acid Soils: The Molecular Basis for Crop Aluminum Resistance.

Abstract: Aluminum (Al) toxicity in acid soils is a significant limitation to crop production worldwide, as approximately 50% of the world's potentially arable soil is acidic. Because acid soils are such an important constraint to agriculture, understanding the mechanisms and genes conferring resistance to Al toxicity has been a focus of intense research interest in the decade since the last article on crop acid soil tolerance was published in this journal. An impressive amount of progress has been made during that time that has greatly increased our understanding of the diversity of Al resistance genes and mechanisms, how resistance gene expression is regulated and triggered by Al and Al-induced signals, and how the proteins encoded by these genes function and are regulated. This review examines the state of our understanding of the physiological, genetic, and molecular bases for crop Al tolerance, looking at the novel Al resistance genes and mechanisms that have been identified over the past ten years. Additionally, it examines how the integration of molecular and genetic analyses of crop Al resistance is starting to be exploited for the improvement of crop plants grown on acid soils via both molecular-assisted breeding and biotechnology approaches.

Kochian|Leon V|LV|
Piñeros|Miguel A|MA|
Liu|Jiping|J|
Magalhaes|Jurandir V|JV|

D018506:Gene Expression Regulation, Plant

aluminum resistance
ALMT
MATE
aluminum exclusion
aluminum tolerance
root organic acid exudation


The relationship between negative expressivity, anger, and PTSD symptom clusters.

Abstract: More investigation is needed to understand how specific posttraumatic stress disorder (PTSD) symptom clusters relate to the internal experience of anger and overt negative behaviors in response to anger (negative expressivity). We investigated whether anger mediated relations between PTSD symptom clusters and negative expressivity. Multiple regression revealed lower PTSD intrusion symptoms associated with higher levels of negative expressivity. Anger mediated this relationship. Higher avoidance symptoms related to higher negative expressivity. Clinical implications, limitations, and strengths are discussed.

Claycomb|Meredith|M|
Roley|Michelle E|ME|
Contractor|Ateka A|AA|
Armour|Cherie|C|
Dranger|Paula|P|
Wang|Li|L|
Elhai|Jon D|JD|


Assisted Suicide as a Remedy for Suffering? The End-of-Life Preferences of British "Suicide Tourists".

Abstract: The highly charged debate about the moral status of assisted suicide features regularly in the news media in medically advanced countries. In the United Kingdom, the debate has been dominated in recent years by a new mode of death: assisted suicide in Switzerland, so-called suicide tourism. Drawing on in-depth interviews with people who were actively planning on 'going to Switzerland,' alongside participant-observation at a do-it-yourself self-deliverance workshop, I discuss how participants arrived at their decision to seek professionalized assistance. In doing so, I explore the constituent elements of people's suffering, examining how participants justified, rationalized, or sought authentication from a doctor for their decision to die in light of their own belief systems and aesthetic preferences for a good death.

Assisted suicide
suffering
death and dying
decision-making
euthanasia
right-to-die


Application of response surface methodology to optimize the extracellular fungal mediated nanosilver green synthesis.

Abstract: This study aims to optimize the biosynthesis of nanosilver particles mediated by Trichoderma viride ATCC36838 using response surface methodology (RSM). Silver nanoparticles (AgNPs) were biosynthesized effectively in terms of the factors impacting silver ion (Ag+) reduction to metallic nanosilver (Ag0) using culture filtrate under shaking condition. The results of statistics calculations revealed that 2 mM silver nitrate and 28% (v/v) of culture filtrate at pH 7.0 for 34 h were the optimum values for AgNPs biosynthesis. The characterization of the produced AgNPs was conducted using electron microscopy, energy dispersive X-ray analysis, UV/visible spectrophotometry, and Fourier transform infrared spectroscopy. Round to oval AgNPs were detected with aspects of TEM within diameter range of 4-16 nm. The results of this study could help in developing a reliable ecofriendly, simple, and low cost process for microbial assisted AgNPs green synthesis especially with the continuous increase in its application fields.

Othman|Abdelmageed M|AM|
Elsayed|Maysa A|MA|
Elshafei|Ali M|AM|
Hassan|Mohamed M|MM|

Response surface methodology
Nanosilver
Biosynthesis
Trichoderma viride
Characterization


AKI in hospitalized children: comparing the pRIFLE, AKIN, and KDIGO definitions.

Abstract:
BACKGROUND AND OBJECTIVES
Although several standardized definitions for AKI have been developed, no consensus exists regarding which to use in children. This study applied the Pediatric RIFLE (pRIFLE), AKI Network (AKIN), and Kidney Disease Improving Global Outcomes (KDIGO) criteria to an anonymized cohort of hospitalizations extracted from the electronic medical record to compare AKI incidence and outcomes in intensive care unit (ICU) and non-ICU pediatric populations.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Observational, electronic medical record-enabled study of 14,795 hospitalizations at the Lucile Packard Children's Hospital between 2006 and 2010. AKI and AKI severity stage were defined by the pRIFLE, AKIN, and KDIGO definitions according to creatinine change criteria; urine output criteria were not used. The incidences of AKI and each AKI stage were calculated for each classification system. All-cause, in-hospital mortality and total hospital length of stay (LOS) were compared at each subsequent AKI stage by Fisher exact and Kolmogorov-Smirnov tests, respectively.

RESULTS
AKI incidences across the cohort according to pRIFLE, AKIN, and KDIGO were 51.1%, 37.3%, and 40.3%. Mortality was higher among patients with AKI across all definitions (pRIFLE, 2.3%; AKIN, 2.7%; KDIGO, 2.5%; P<0.001 versus no AKI [0.8%-1.0%]). Within the ICU, pRIFLE, AKIN, and KDIGO demonstrated progressively higher mortality at each AKI severity stage; AKI was not associated with mortality outside the ICU by any definition. Both in and outside the ICU, AKI was associated with significantly higher LOS at each AKI severity stage across all three definitions (P<0.001). Definitions resulted in differences in diagnosis and staging of AKI; staging agreement ranged from 76.7% to 92.5%.

CONCLUSIONS
Application of the three definitions led to differences in AKI incidence and staging. AKI was associated with greater mortality and LOS in the ICU and greater LOS outside the ICU. All three definitions demonstrated excellent interstage discrimination. While each definition offers advantages, these results underscore the need to adopt a single, universal AKI definition.

Sutherland|Scott M|SM|
Byrnes|John J|JJ|
Kothari|Manish|M|
Longhurst|Christopher A|CA|
Dutta|Sanjeev|S|
Garcia|Pablo|P|
Goldstein|Stuart L|SL|

children
mortality
acute renal failure
kidney failure


Uninvestigated dyspepsia and associated factors of patients with gastrointestinal disorders in Dessie Referral Hospital, Northeast Ethiopia.

Abstract:
BACKGROUND
Dyspepsia is a common problem in the community and clinical practice with symptom(s) considered arising from the gastroduodenal region. Dyspepsia burden and associated factors vary from country to country. The aim of this study was to determine the prevalence of uninvestigated dyspepsia (UD) using Rome III criteria, associated risk factors and self-reported dyspepsia symptoms' correlation with H. pylori infection.

METHODS
A cross-sectional study was conducted among randomly selected 318 out patients with gastrointestinal complaints during the period from September 1 to December 30, 2015. All patients completed a questionnaire for collecting data regarding sociodemographic, lifestyle and functional gastrointestinal disorders. Diagnosis of dyspepsia was made according to the Rome III criteria. H. pylori infection was assessed using stool antigen test. SPSS version 20.0 statistical software package was used for data analysis.

RESULTS
From a total of 318 patients, 48.4% had UD according to Rome III criteria; with 42.1% symptoms of epigastric pain/burning, 26.1% postprandial fullness and 22.6% early satiation. Epigastric pain/burning (AOR = 1.92, 95% CI 1.07-3.43), early satiation (AOR = 2.68, 95% CI 1.38-5.20) and belching (AOR = 4.7, 95% CI 1.54-14.40) were significantly correlated with H. pylori infection. H. pylori infection (AOR = 4.33, 95% CI 2.41-7.76) and aspirin/NSAIDs consumption (AOR = 5.29, 95% CI 2.82-9.93) were independent risk factors for UD. However, consumption of raw fruits/ vegetables at least once a week (AOR = 0.48, 95% CI 0.24-0.98) and taking two or more cups of tea a day (AOR = 0.339, 95% CI 0.17-0.70) were inversely associated with UD.

CONCLUSIONS
UD is highly prevalent among adults with gastrointestinal complaints. H. pylori infection is significantly associated with UD and correlates with its symptoms. Individuals with epigastric pain/burning, early satiation and belching should be primary focus of H. pylori infection diagnosis and treatment. The role of consumption of tea, raw fruits and vegetables on dyspepsia needs further large scale study.

Uninvestigated dyspepsia
Ethiopia
Rome III
Self-reported
H. pylori


The Southern Illinois Twins/Triplets and Siblings Study (SITSS): A Longitudinal Study of Early Child Development.

Abstract: This article reviews the Southern Illinois Twins/Triplets and Siblings Study (SITSS) and describes some of the findings related to recent projects that were completed using this sample. At this time, the SITSS has enrolled 375 twin pairs, 12 triplet families, 1 family of quadruplets, 98 nontwin sibling pairs and 287 singletons. Testing begins for twins and triplets as young as age 1 and then occurs yearly on their birthdays until 5 years of age. Through age 20, various follow-up studies have been conducted on the SITSS sample to examine their social, emotional, and cognitive development across childhood and adolescence from a behavioral genetic perspective. A variety of methodologies have been used to investigate gene-environment correlations (rGE) and gene-environment interactions (GxE). Advanced statistical procedures (e.g., genetic likelihood indices and multilevel modeling) have been utilized to further investigate genetic underpinnings of behavior. Recent results have indicated genetic influences on the aggressiveness of preschoolers' media preferences, increased problem behaviors related to young children's overestimation of self-competence, and the influence of early life temperament and internalizing problems on adolescent health behaviors. Additionally, the SITSS has provided evidence for evocative rGE for various behaviors (aggression, prosocial and play), as well as findings supporting interactions between the dopamine receptor D4 gene (DRD4) and the environment (peer victimization, prenatal birth complications and parental sensitivity). Together, by use of multitrait and multimethodological investigations, this behavior genetic data set assists in furthering our understanding of biological and environmental influences on children's development.

DiLalla|Lisabeth Fisher|LF|
Jamnik|Matthew R|MR|

internalizing and externalizing problems


5-Aminosalicylic acid intolerance is associated with a risk of adverse clinical outcomes and dysbiosis in patients with ulcerative colitis.

Abstract:
BACKGROUND/AIMS
5-Aminosalicylic acid (ASA) causes intolerance reactions in some patients. This study was performed to examine the prognosis of patients with ulcerative colitis (UC) and 5-ASA intolerance, and to evaluate the potential interaction between 5-ASA intolerance and the intestinal microbiota.

METHODS
We performed a retrospective cohort study of patients with UC who visited participating hospitals. The primary endpoint was to compare the incidence of hospitalization within 12 months between the 5-ASA intolerance group and the 5-ASA tolerance group. The secondary endpoint was to compare the risk of adverse clinical outcomes after the start of biologics between the 2 groups. We also assessed the correlation between 5-ASA intolerance and microbial change in an independently recruited cohort of patients with UC.

RESULTS
Of 793 patients, 59 (7.4%) were assigned to the 5-ASA intolerance group and 734 (92.5%) were assigned to the 5-ASA tolerance group. The admission rate and incidence of corticosteroid use were significantly higher in the intolerance than tolerance group (P< 0.001). In 108 patients undergoing treatment with anti-tumor necrosis factor biologics, 5-ASA intolerance increased the incidence of additional induction therapy after starting biologics (P< 0.001). The 5-ASA intolerance group had a greater abundance of bacteria in the genera Faecalibacterium, Streptococcus, and Clostridium than the 5-ASA tolerance group (P< 0.05).

CONCLUSIONS
In patients with UC, 5-ASA intolerance is associated with a risk of adverse clinical outcomes and dysbiosis. Bacterial therapeutic optimization of 5-ASA administration may be important for improving the prognosis of patients with UC.

Mizuno|Shinta|S| Ono|Keiko|K| Mikami|Yohei|Y| Naganuma|Makoto|M| Fukuda|Tomohiro|T| Minami|Kazuhiro|K| Masaoka|Tatsuhiro|T| Terada|Soichiro|S| Yoshida|Takeshi|T| Saigusa|Keiichiro|K| Hirahara|Norimichi|N| Miyata|Hiroaki|H| Suda|Wataru|W| Hattori|Masahira|M| Kanai|Takanori|T|

5-Aminosalicylic acid
Dysbiosis
Prognosis
Colitis, ulcerative


What is the effect of initial implant position on the crestal bone level in flap and flapless technique during healing period?

Abstract:
PURPOSE
The level of the implant above the marginal bone and flap design have an effect on the bone resorption during the healing period. The aim of this study is to detect the relationship between the level of the implant at the implant placement and the bone level at the healing period in the mesial and distal side of implants placed with flapless (FL) and full-thickness flap (FT) methods.

METHODS
Twenty-two nonsubmerged implants were placed with the FL and FT technique. Periapical radiographs were taken of the patient at implant placement, and at 6 and 12 weeks. By using computer software, bone level measurements were taken from the shoulder of the healing cap to the first bone implant contact in the mesial and distal side of the implant surface.

RESULTS
At 6 weeks, the correlation between the crestal bone level at the implant placement and crestal bone level of the FT mesially was significant (Pearson correlation coefficient=0.675, P<0.023). At 12 weeks, in the FT mesially, the correlation was nonsignificant (Spearman correlation coefficient=0.297, P<0.346). At 6 weeks in the FT distally, the correlation was nonsignificant (Pearson correlation coefficient=0.512, P<0.107). At 12 weeks in the FT distally, the correlation was significant (Spearman correlation coefficient=0.730, P<0.011). At 6 weeks in the FL mesially, the correlation was nonsignificant (Spearman correlation coefficient=0.083, P<0.809). At 12 weeks in the FL mesially, the correlation was nonsignificant (Spearman correlation coefficient=0.062, P<0.856). At 6 weeks in the FL distally, the correlation was nonsignificant (Spearman correlation coefficient=0.197, P<0.562). At 12 weeks in the FL distally, the correlation was significant (Pearson correlation coefficient=0.692, P<0.018).

CONCLUSIONS
A larger sample size is recommended to verify the conclusions in this preliminary study. The bone level during the healing period in the FT was more positively correlated with the implant level at implant placement than in the FL.

Al-Juboori|Mohammed Jasim|MJ|
Ab Rahman|Shaifulizan|S|
Hassan|Akram|A|
Bin Ismail|Ikmal Hisham|IH|
Tawfiq|Omar Farouq|OF|

Bone resorption
Clinical trial
Dental implantation
Oral surgical procedures


Effect of Asian dust on respiratory symptoms among children with and without asthma, and their sensitivity.

Abstract: There has been little study on the effect of Asian dust exposure on respiratory symptoms among children who are vulnerable to environmental factors. In this panel study, we investigated the effect of Asian dust on respiratory symptoms among children with and without asthma, and their sensitivity. Children attending two elementary schools (137 total), and 23 children with asthma from cooperating medical institutions in Fukuoka prefecture were recruited. Subjects measured peak expiratory flow rate (PEF), and recorded asthma-like symptoms, cough, nasal symptoms and use of medication in a diary from April 1, 2013 to June 30, 2013. To assess exposure to Asian dust, we used Light Detection and Ranging (LIDAR) data. For the analysis of the association between Asian dust and respiratory symptoms, the case-crossover design and generalized estimating equation (GEE) models were used. Taking individual sensitivity to respiratory aggravation into consideration, the subjects were classified into three groups: children without asthma, children with asthma who do not use long-term preventive medication (CA) and children with asthma who use long-term preventive medication (CA-LTM). For CA, Asian dust exposure was significantly associated with asthma-like symptoms, with a hazard ratio of 5.17 (95%CI: 1.02=26.12) at Lag0, and the change in %maxPEF, -1.65% (95%CI:-2.82, -0.48) at Lag0. For children without asthma, a statistically significant association was found between Asian dust exposure and the change in %maxPEF, -0.56% (95%CI: -1.31, -0.08) at Lag1. However, no adverse effects were observed in CA-LTM. Temperature had significant effects on %maxPEF for three groups. Asian dust, photochemical oxidant and pollen caused simultaneously additive adverse effects on nasal symptoms for children without asthma. This study suggests the possibility that long-term preventive medication to manage asthma may suppress aggravation of respiratory symptoms due to Asian dust and may be an effective prevention.

Hasunuma|Hideki|H|
Takeuchi|Ayano|A|
Ono|Rintaro|R|
Amimoto|Yuko|Y|
Hwang|Yoon Ha|YH|
Uno|Itsushi|I|
Shimizu|Atsushi|A|
Nishiwaki|Yuji|Y|
Hashizume|Masahiro|M|
Askew|David J|DJ|
Odajima|Hiroshi|H|

Asian dust
Peak expiratory flow rate
Prevention
Asthma medication
Desert dust
Epidemiology


Possible basis for the emergence of H1N1 viruses with pandemic potential from avian hosts.

Abstract: Influenza A viruses of the H1N1 subtype have emerged from the avian influenza gene pool in aquatic birds and caused human pandemics at least twice during the past century. Despite this fact, surprisingly little is known about the H1N1 gene pool in the aquatic bird reservoir. A preliminary study showed that an H1N1 virus from a shorebird of the Charadriiformes order was transmitted between animals through the airborne route of infection, whereas an H1N1 virus from a bird of the Anseriformes order was not. Here we show that two of the three H1N1 viruses isolated from Charadriiformes species in 2009 were transmitted between animals through the airborne route of infection, and five H1N1 isolates from Anseriformes species were not. The one H1N1 virus from a Charadriiformes species that failed to transmit through the airborne route was a reassortant possessing multiple internal gene segments from Anseriformes species. The molecular differences between the airborne-transmissible and non-airborne-transmissible H1N1 viruses were multigenic, involving the selection of virus with human-like receptor-binding specificity (α2-6 sialic acid) and multiple differences in the polymerase complex, mainly in the PB2, PB1-F2, and nonstructural genes.

Koçer|Zeynep A|ZA|
Krauss|Scott|S|
Zanin|Mark|M|
Danner|Angela|A|
Gulati|Shelly|S|
Jones|Jeremy C|JC|
Friedman|Kimberly|K|
Graham|Allison|A|
Forrest|Heather|H|
Seiler|Jon|J|
Air|Gillian M|GM|
Webster|Robert G|RG|

H1N1
avian
Charadriiformes
Anseriformes
ferret model transmission


Prognostic significance of the lymph node ratio regarding recurrence and survival in rectal cancer patients treated with postoperative chemoradiotherapy.

Abstract:
BACKGROUND/AIMS
TO EVALUATE THE PROGNOSTIC IMPACT OF THE LYMPH NODE RATIO (LNR: the ratio of positive lymph nodes to the total number of lymph nodes examined) on disease recurrence and survival among rectal cancer patients who received curative surgery and postoperative chemoradiotherapy (CRT).

METHODS
Between 1995 and 2008, 124 patients with pathologic T3-4 or node-positive rectal cancer underwent curative surgery and postoperative CRT. Postoperative radiotherapy was delivered at a median dose of 50.4 Gy (range, 45 to 59.4 Gy) for 6 weeks. Chemotherapy consisted of a bolus injection of 5-fluorouracil and leucovorin in the first and last week of radiotherapy (91.9%) or daily capecitabine during radiotherapy (8.1%). Further adjuvant chemotherapy was administered after chemoradiation.

RESULTS
The median follow-up was 5.1 years. In the multivariate analysis, pathologic N (pN) stage and lymphovascular invasion were significantly associated with disease-free survival and disease-specific survival (p<0.05). However, when the LNR with a cutoff value of 0.2 was included as a covariate in the model, the LNR was highly significant (p<0.001), and the pN stage lost its significance (p>0.05).

CONCLUSIONS
The LNR predicts recurrence and survival more accurately than pN stage. The pN stage and the LNR should be considered together when estimating the risk of disease recurrence among rectal cancer patients.

Kim|Ji-Yoon|JY| Chung|Su-Mi|SM| Choi|Byung-Ock|BO| Lee|In-Kyu|IK| An|Chang-Hyeok|CH| Won|Jong-Man|JM| Ryu|Mi-Ryeong|MR|

Lymph nodes
Combined modality therapy
Rectal neoplasms


Error Analysis of the K-Rb-21Ne Comagnetometer Space-Stable Inertial Navigation System.

Abstract: According to the application characteristics of the K-Rb-21Ne comagnetometer, a space-stable navigation mechanization is designed and the requirements of the comagnetometer prototype are presented. By analysing the error propagation rule of the space-stable Inertial Navigation System (INS), the three biases, the scale factor of the z-axis, and the misalignment of the x- and y-axis non-orthogonal with the z-axis, are confirmed to be the main error source. A numerical simulation of the mathematical model for each single error verified the theoretical analysis result of the system's error propagation rule. Thus, numerical simulation based on the semi-physical data result proves the feasibility of the navigation scheme proposed in this paper.

Cai|Qingzhong|Q|0000-0002-9956-4740 Yang|Gongliu|G| Quan|Wei|W| Song|Ningfang|N| Tu|Yongqiang|Y| Liu|Yiliang|Y|

error analysis
comagnetometer
space-stable inertial navigation system
inertial navigation


Novel use of the medtronic micro vascular plug for PDA closure in preterm infants.

Abstract:
OBJECTIVES
To describe a single institution experience with a new endovascular occlusion device used for transcatheter patent ductus arteriosus (PDA) closure in preterm infants.

BACKGROUND
The PDA is a defect largely treated via cardiac catheterization except for the smallest patients.

METHODS
Medical records and catheterization reports of all premature neonates who underwent PDA device closure with the Medtronic Micro Vascular Plug (MVP) (Medtronic, Minneapolis, MN) between September 2015 and June 2016 were reviewed. Procedural details, complications, and short term outcomes were recorded.

RESULTS
Eight premature neonates born at a median gestational age of 28 weeks (23 to 35 weeks) underwent PDA closure with a Medtronic MVP. All devices were deployed via a 4F angled Glide catheter in prograde fashion without arterial access. Median age and weight was 52 days (15-112 days) and 2,550 g (1,800-3,500 g), respectively. Fluoroscopy and echocardiography were utilized for the procedure. Complete closure was achieved in all patients with no procedural complications, pulmonary artery or aortic obstruction or death. One device embolized 9 days after deployment and was successfully retrieved.

CONCLUSIONS
This study describes transcatheter PDA closure with the Medtronic MVP. The major advantage is the ability to deliver the device via a standard catheter in prograde fashion, and avoid the hemodynamic instability produced by rigid delivery sheaths. It also further validates the ability to close the PDA without arterial access, providing improved access to this procedure to smaller and more vulnerable children. © 2016 Wiley Periodicals, Inc.

Wang-Giuffre|Elizabeth W|EW|
Breinholt|John P|JP|

patent ductus arteriosus
congenital heart disease
vascular occlusion


Economic evaluation of a cluster randomized trial of interventions to improve health workers' practice in diagnosing and treating uncomplicated malaria in Cameroon.

Abstract:
BACKGROUND
Malaria rapid diagnostic tests (RDTs) are a valid alternative to malaria testing with microscopy and are recommended for the testing of febrile patients before prescribing an antimalarial. There is a need for interventions to support the uptake of RDTs by health workers.

OBJECTIVE
To evaluate the cost-effectiveness of introducing RDTs with basic or enhanced training in health facilities in which microscopy was available, compared with current practice.

METHODS
A three-arm cluster randomized trial was conducted in 46 facilities in central and northwest Cameroon. Basic training had a practical session on RDTs and lectures on malaria treatment guidelines. Enhanced training included small-group activities designed to change health workers' practice and reduce the consumption of antimalarials among test-negative patients. The primary outcome was the proportion of febrile patients correctly treated: febrile patients should be tested for malaria, artemisinin combination therapy should be prescribed for confirmed cases, and no antimalarial should be prescribed for patients who are test-negative. Individual patient data were obtained from facility records and an exit survey. Costs were estimated from a societal perspective using project reports and patient exit data. The analysis used bivariate multilevel modeling and adjusted for imbalance in baseline covariates.

RESULTS
Incremental cost per febrile patient correctly treated was $8.40 for the basic arm and $3.71 for the enhanced arm. On scale-up, it was estimated that RDTs with enhanced training would save $0.75 per additional febrile patient correctly treated.

CONCLUSIONS
Introducing RDTs with enhanced training was more cost-effective than RDTs with basic training when each was compared with current practice.

Mangham-Jefferies|Lindsay|L|
Wiseman|Virginia|V|
Achonduh|Olivia A|OA|
Drake|Thomas L|TL|
Cundill|Bonnie|B|
Onwujekwe|Obinna|O|
Mbacham|Wilfred|W|

practice
malaria
Cameroon
cluster-randomized trial
cost-effectiveness analysis
health worker training


The Utility of EEG in Attention Deficit Hyperactivity Disorder: A Replication Study.

Abstract: The routine use of stimulants in pediatrics has increased dramatically over the past 3 decades and the long-term consequences have yet to be fully studied. Since 1978 there have been 7 articles identifying electroencephalogram (EEG) abnormalities, particularly epileptiform discharges in children with attention deficit hyperactivity disorder (ADHD). Many have studied the prevalence of these discharges in this population with varying results. An article published in 2011 suggests that EEG technology should be considered prior to prescribing stimulants to children diagnosed with ADHD due to a high prevalence of epileptiform discharges. The 2011 study found a higher prevalence (26%) of epileptiform discharges when using 23-hour and sleep-deprived EEGs in comparison with other methods of activation (hyperventilation or photostimulation) and conventional EEG. We sought to replicate the 2011 results using conventional EEG with the added qEEG technologies of automatic spike detection and low-resolution electromagnetic tomography analysis (LORETA) brain mapping. Our results showed 32% prevalence of epileptiform discharges, which suggests that an EEG should be considered prior to prescribing stimulant medications.

Swatzyna|Ronald J|RJ|
Tarnow|Jay D|JD|
Roark|Alexandra|A|
Mardick|Jacob|J|

D001289:Attention Deficit Disorder with Hyperactivity


Predictive value of CRP/albumin ratio in major abdominal surgery.

Abstract:
INTRODUCTION
Surgical site infection (SSI) is a major cause of morbidity, resulting in significant healthcare and economic implications. The ability to predict patients at high risk of SSI may enable targeted follow-up and management. This study sought to examine the relationship between the CRP/albumin ratio in the prediction of SSI in patients undergoing emergency major abdominal surgery.

METHODS
A retrospective study of all patients who underwent emergency major abdominal surgery in our institution over 2 years was performed. Patients were identified from a prospectively maintained database of SSI's and cross-referenced with hospital records. Patient demographics including age, gender, ASA grade, and wound classification (clean, clean/contaminated, contaminated, and dirty) were collated.

RESULTS
CRP preoperatively of greater than 5 was statistically significant in predicting an SSI (P < 0.05). In addition, preoperative serum albumin of < 32 was also significant in predicting a superficial site infection. Interestingly, preoperative CRP/albumin ratio did not predict SSI, but postoperative CRP/albumin ratio was predictive at both 24 and 48 hour time points (P < 0.05). Median length of stay in the SSI group was statistically significantly longer at 27.88 days (range 7-76) versus 18.32 days (1-56) (P < 0.01).

CONCLUSIONS
Though CRP and albumin have merit in isolation in preoperative identification of patients at risk of SSI, CRP/albumin ratio is a useful postoperatively adjunct in predicting SSI postoperatively at 24 and 48hrs postoperatively.

Donlon|Noel E|NE|
Mohan|Helen|H|
Free|Ross|R|
Elbaghir|Badr|B|
Soric|Igor|I|
Fleming|Christina|C|
Balasubramanian|Ischwaria|I|
Ivanovski|Ivan|I|
Schmidt|Karl|K|
Mealy|Ken|K|

CRP
Albumin
Major abdominal surgery
Surgical site infection
Laparotomy


Cancer Cachexia Induces Preferential Skeletal Muscle Myosin Loss When Combined With Denervation.

Abstract: Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (-69%) that was significantly lower than DEN (-53%) or CCX (-36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.

Yamada|Takashi|T| Ashida|Yuki|Y| Tatebayashi|Daisuke|D| Abe|Masami|M| Himori|Koichi|K|

cancer cachexia
denervation
muscle atrophy
anabolism
catabolism


Do health literacy and patient empowerment affect self-care behaviour? A survey study among Turkish patients with diabetes.

Abstract:
OBJECTIVE
This study aimed to assess the impact of health literacy and patient empowerment on diabetes self-care behaviour in patients in metropolitan Turkish diabetes centres. The conceptual background is provided by the psychological health empowerment model, which holds that health literacy without patient empowerment comes down to wasting health resources, while empowerment without health literacy can lead to dangerous or suboptimal health behaviour.

DESIGN, SETTING AND PARTICIPANTS
A cross-sectional study was conducted with 167 patients over the age of 18 from one of two diabetes clinics in a major Turkish City. Self-administered questionnaires were distributed to eligible outpatients who had an appointment in one of the clinics. Health literacy was measured by a newly translated Turkish version of the Short Test of Functional Health Literacy in Adults (S-TOFHLA) and the Chew self-report scale. Patient empowerment was measured by a 12-item scale based on Spreitzer's conceptualisation of psychological empowerment in the workplace. Self-care behaviour was measured by the Self-care behaviours were measured by the Summary of Diabetes Self-Care Activities Measure (SDSCA). Level of diabetes knowledge was measured by Diabetes Knowledge Test.

RESULTS
Two subscales of empowerment, impact and self-determination, predicted self-reported frequency of self-care behaviours. Neither health literacy nor diabetes knowledge had an effect on self-care behaviours.

CONCLUSIONS
Health literacy might be more effective in clinical decisions while empowerment might exert a stronger influence on habitual health behaviours.

D007722:Health Knowledge, Attitudes, Practice

health literacy
patient empowerment
diabetes management behaviors


NIHSS 24 h After Mechanical Thrombectomy Predicts 90-Day Functional Outcome.

Abstract:
BACKGROUND
Mechanical thrombectomy (MT) for large vessel occlusion (LVO) ischemic stroke is a safe and effective treatment modality. The National Institute of Health Stroke Scale (NIHSS) 24 h after MT (24 h-NIHSS) was shown to serve as the strongest surrogate for 90-day functional outcome. Here, we seek to externally validate 24 h-NIHSS as predictor for 90-day functional outcome and explore additional variables in this context.

METHODS
Patients treated for anterior LVO between February 2016 and August 2020 with premorbid mRS < 3 were included. Receiver operating characteristics were used to compare different NIHSS-related surrogates, such as baseline (B) NIHSS, 24 h-NIHSS, Δ‑NIHSS and percent (%) change NIHSS to predict favorable function outcome (mRS 0-2). Additional analysis was performed to assess predictors associated with poor outcome despite reaching the best predictor threshold.

RESULTS
A total of 337 eligible cases were identified. The 24 h-NIHSS outperformed B‑NIHSS, Δ‑NIHSS, and %‑NIHSS in terms of 90-day mRS 0-2 prediction. A 24-NIHSS ≤ 8 was identified as the optimal binary threshold. Multivariable analysis demonstrated that 24-NIHSS ≤ 8 and younger patient age were independently associated with mRS 0-2. Despite achieving 24 h-NIHSS ≤ 8, 23/143 (16.1%) cases experienced poor outcome (mRS 4-6). Older age, higher baseline NIHSS, coexisting chronic kidney disease, and longer hospital stay were independent predictors for poor outcome despite achieving 24 h-NIHSS ≤ 8.

CONCLUSION
An NIHSS of 8 or less 24 h after MT was validated to serve as an independent, strong surrogate for favorable functional outcome; however, cofactors such as older age, higher baseline NIHSS and coexisting comorbidities appear to mitigate this clinical adjunct.

Hendrix|Philipp|P|
Melamed|Itay|I|
Collins|Malie|M|
Lieberman|Noah|N|
Sharma|Vaibhav|V|
Goren|Oded|O|
Zand|Ramin|R|
Schirmer|Clemens M|CM|
Griessenauer|Christoph J|CJ|

Mechanical thrombectomy
Large vessel occlusion
Stroke
Predictors
Ischemia


Ancient Duplications and Expression Divergence in the Globin Gene Superfamily of Vertebrates: Insights from the Elephant Shark Genome and Transcriptome.

Abstract: Comparative analyses of vertebrate genomes continue to uncover a surprising diversity of genes in the globin gene superfamily, some of which have very restricted phyletic distributions despite their antiquity. Genomic analysis of the globin gene repertoire of cartilaginous fish (Chondrichthyes) should be especially informative about the duplicative origins and ancestral functions of vertebrate globins, as divergence between Chondrichthyes and bony vertebrates represents the most basal split within the jawed vertebrates. Here, we report a comparative genomic analysis of the vertebrate globin gene family that includes the complete globin gene repertoire of the elephant shark (Callorhinchus milii). Using genomic sequence data from representatives of all major vertebrate classes, integrated analyses of conserved synteny and phylogenetic relationships revealed that the last common ancestor of vertebrates possessed a repertoire of at least seven globin genes: single copies of androglobin and neuroglobin, four paralogous copies of globin X, and the single-copy progenitor of the entire set of vertebrate-specific globins. Combined with expression data, the genomic inventory of elephant shark globins yielded four especially surprising findings: 1) there is no trace of the neuroglobin gene (a highly conserved gene that is present in all other jawed vertebrates that have been examined to date), 2) myoglobin is highly expressed in heart, but not in skeletal muscle (reflecting a possible ancestral condition in vertebrates with single-circuit circulatory systems), 3) elephant shark possesses two highly divergent globin X paralogs, one of which is preferentially expressed in gonads, and 4) elephant shark possesses two structurally distinct α-globin paralogs, one of which is preferentially expressed in the brain. Expression profiles of elephant shark globin genes reveal distinct specializations of function relative to orthologs in bony vertebrates and suggest hypotheses about ancestral functions of vertebrate globins.

Opazo|Juan C|JC|
Lee|Alison P|AP|
Hoffmann|Federico G|FG|
Toloza-Villalobos|Jessica|J|
Burmester|Thorsten|T|
Venkatesh|Byrappa|B|
Storz|Jay F|JF|

globin
Chondrichthyes
neuroglobin
myoglobin
gene duplication
gene family evolution


Could a Midwife Leading Health Behavior Counseling Improve Self-Care of Women During Perimenopause? A Quasi-Experimental Study.

Abstract:
Background
Promoting the health and providing a sense of well-being in each period of a woman's life could improve her life quality and would bring lots of benefits to the community. Menopause has a remarkable impact on quality of life during the climacteric stage and the early stages of post menopause.

Aims
This study aims to evaluate the effectiveness of a behaviour change counselling program based on the model A, which is planned in order to improve the women self-care during the climacteric stage.

Methods
The study is quasi-experimental type, conducted before and after counselling intervention, to evaluate effect of the health behaviour counselling of model 5A on self-care of 42 women aged 39-51 (during climacteric stage) in areas of general health, physical activity, nutrition, sleep, psycho-social health, body image and sexual health. After obtaining permission from the ethics of Alborz University of Medical Sciences, a clinical trial registry (IRCT2016042427557N1) was performed.

Results
Results of non-parametric Fridman test showed a change in score average grade of self-care before and after the health behaviour counselling in the area studied (P < 0.0001). There was a significant difference between the self-care score before counselling, and one and three months later, in all areas except body image and sleep.

Conclusions
Multidimensional changes of women in climacteric stage may affect their life quality. They need more information about menopause process to manage its symptoms. Results of this study highlight more the effectiveness of health behaviour change counselling planned by emphasizing the individual's self-care level.

Faraji|Katayoon|K|
Kamrani|Mahnaz Akbari|MA|
Saeieh|Sara Esmaelzade|SE|
Farid|Malihe|M|

health behavior counseling
self-care
Climacteric


Irisin immunohistochemistry in gastrointestinal system cancers.

Abstract: Cancer is the leading cause of morbidity and mortality worldwide. Some studies have shown that high heat kills cancer cells. Irisin is a protein involved in heat production by converting white into brown adipose tissue, but there is no information about how its expression changes in cancerous tissues. We used irisin antibody immunohistochemistry to investigate changes in irisin expression in gastrointestinal cancers compared to normal tissues. Irisin was found in human brain neuroglial cells, esophageal epithelial cells, esophageal epidermoid carcinoma, esophageal adenocarcinoma and neuroendocrine esophageal carcinoma, gastric glands, gastric adenosquamous carcinoma, gastric neuroendocrine carcinoma, gastric signet ring cell carcinoma, neutrophils in vascular tissues, intestinal glands of colon, colon adenocarcinoma, mucinous colon adenocarcinoma, hepatocytes, hepatocellular carcinoma, islets of Langerhans, exocrine pancreas, acinar cells and interlobular and interlobular ducts of normal pancreas, pancreatic ductal adenocarcinoma, and intra- and interlobular ducts of cancerous pancreatic tissue. Histoscores (area × intensity) indicated that irisin was increased significantly in gastrointestinal cancer tissues, except liver cancers. Our findings suggest that the relation of irisin to cancer warrants further investigation.

Aydin|S|S|
Kuloglu|T|T|
Ozercan|M R|MR|
Albayrak|S|S|
Aydin|S|S|
Bakal|U|U|
Yilmaz|M|M|
Kalayci|M|M|
Yardim|M|M|
Sarac|M|M|
Kazez|A|A|
Kocdor|H|H|
Kanat|B|B|
Ozercan|İ H|İH|
Gonen|M|M|
Bilgen|M|M|
Balgetir|F|F|

D015972:Gene Expression Regulation, Neoplastic

irisin
immunohistochemistry
gastrointestinal system
cancer


Population Genomics Training for the Next Generation of Conservation Geneticists: ConGen 2018 Workshop.

Abstract: The increasing availability and complexity of next-generation sequencing (NGS) data sets make ongoing training an essential component of conservation and population genetics research. A workshop entitled "ConGen 2018" was recently held to train researchers in conceptual and practical aspects of NGS data production and analysis for conservation and ecological applications. Sixteen instructors provided helpful lectures, discussions, and hands-on exercises regarding how to plan, produce, and analyze data for many important research questions. Lecture topics ranged from understanding probabilistic (e.g., Bayesian) genotype calling to the detection of local adaptation signatures from genomic, transcriptomic, and epigenomic data. We report on progress in addressing central questions of conservation genomics, advances in NGS data analysis, the potential for genomic tools to assess adaptive capacity, and strategies for training the next generation of conservation genomicists.

Stahlke|Amanda|A|
Bell|Donavan|D|
Dhendup|Tashi|T|
Kern|Brooke|B|
Pannoni|Samuel|S|
Robinson|Zachary|Z|
Strait|Jeffrey|J|
Smith|Seth|S|
Hand|Brian K|BK|
Hohenlohe|Paul A|PA|
Luikart|Gordon|G|

D003247:Conservation of Natural Resources

adaptive capacity
conservation genetics pedagogy
effective population size
evolutionary significant units
population genomic data analysis


Assay Systems for Profiling Deubiquitinating Activity.

Abstract: Deubiquitinating enzymes regulate various cellular processes, particularly protein degradation, localization, and protein-protein interactions. The dysregulation of deubiquitinating enzyme (DUB) activity has been linked to several diseases; however, the function of many DUBs has not been identified. Therefore, the development of methods to assess DUB activity is important to identify novel DUBs, characterize DUB selectivity, and profile dynamic DUB substrates. Here, we review various methods of evaluating DUB activity using cell lysates or purified DUBs, as well as the types of probes used in these methods. In addition, we introduce some techniques that can deliver DUB probes into the cells and cell-permeable activity-based probes to directly visualize and quantify DUB activity in live cells. This review could contribute to the development of DUB inhibitors by providing important information on the characteristics and applications of various probes used to evaluate and detect DUB activity in vitro and in vivo.

activity-based probes
Ub-probes
cell permeability
deubiquitination assay


Numerical analysis of tooth movement in different plans of transparent tooth correction therapies.

Abstract:
BACKGROUND
The objective of this study was to investigate how treatment strategies in the same treatment affected the canine's initial displacement and the stress in periodontal ligament using three-dimensional finite element analysis. And to find out the way to design an effective treatment plan.

METHODS
Based on computed tomography images of the teeth and their supporting tissues, solid models were used to build finite element models. Three treatment plans of three different transparent tooth correction therapies finite element-analyses were operated.

RESULTS
The canine's initial displacement and stresses' distribution in periodontal ligament were obtained.

CONCLUSIONS
For rotation movement, the canine should rotate along tooth long axis, and not combine with other kinds of tooth movement as possible. For translation movement, the combination of translation and inclination movement is helpful for the treatment.

Cai|Yong-Qing|YQ| Yang|Xiao-Xiang|XX| He|Bing-Wei|BW| Yao|Jun|J|

D001696:Biomechanical Phenomena
D003198:Computer Simulation
D020342:Finite Element Analysis
D006801:Humans
D007180:Incisor
D008954:Models, Biological
D009970:Orthodontics
D010513:Periodontal Ligament
D013314:Stress, Mechanical
D014087:Tooth Movement Techniques

stress
Finite element method
center of rotation
initial movement
movement combination


Vitamin C therapy for patients with sepsis or septic shock: a protocol for a systematic review and a network meta-analysis.

Abstract:
INTRODUCTION
Vasoplegia is common and associated with a poor prognosis in patients with sepsis and septic shock. Vitamin C therapy in combination with vitamin B1 and glucocorticoid, as well as monotherapy in various doses, has been investigated as a treatment for the vasoplegic state in sepsis, through targeting the inflammatory cascade. However, the combination effect and the relative contribution of each drug have not been well evaluated. Furthermore, the best combination between the three agents is currently unknown. We are planning a systematic review (SR) with network meta-analysis (NMA) to compare the different treatments and identify the combination with the most favourable effect on survival.

METHODS AND ANALYSIS
We will include all randomised controlled trials comparing any intervention using intravenous vitamin C, vitamin B1 and/or glucocorticoid with another or with placebo in the treatment of sepsis. We are interested in comparing the following active interventions. Very high-dose vitamin C (≥12 g/day), high-dose vitamin C (≥6 g/day), vitamin C (<6 g/day); low-dose glucocorticoid (<400 mg/day of hydrocortisone (or equivalent)), vitamin B1 and combinations of the drugs above. The primary outcome will be all-cause mortality at the longest follow-up within 1 year but 90 days or longer postrandomisation. All relevant studies will be sought through database searches and trial registries. All reference selection and data extraction will be conducted by two independent reviewers. We will conduct a random-effects NMA to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. We will use the surface under the cumulative ranking curve and the mean ranks to rank the various interventions. To differentiate between the effect of combination therapies and the effect of a component, we will employ a component NMA.

ETHICS AND DISSEMINATION
This SR does not require ethical approval. We will publish findings from this systematic review in a peer-reviewed scientific journal and present these at scientific conferences.

PROSPERO REGISTRATION NUMBER
CRD42018103860.

D000305:Adrenal Cortex Hormones
D001205:Ascorbic Acid
D004359:Drug Therapy, Combination
D006801:Humans
D015201:Meta-Analysis as Topic
D000071076:Network Meta-Analysis
D012107:Research Design
D012772:Shock, Septic
D000078202:Systematic Reviews as Topic
D013831:Thiamine
D016896:Treatment Outcome
D056987:Vasoplegia

adult intensive & critical care
clinical trials
statistics & research methods


Motor Function Test Reliability During the NeuroNEXT Spinal Muscular Atrophy Infant Biomarker Study.

Abstract:
BACKGROUND
The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1.

OBJECTIVE
To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS).

METHODS
Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with 'expert' consensus scores was examined using Pearson's correlation coefficients.

RESULTS
Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with 'expert' consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability.

CONCLUSIONS
Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

Krosschell|Kristin J|KJ|
Bosch|Michael|M|
Nelson|Leslie|L|
Duong|Tina|T|
Lowes|Linda P|LP|
Alfano|Lindsay N|LN|
Benjamin|Danielle|D|
Carry|Terri B|TB|
Devine|Ginger|G|
Kelley|Carolyn|C|
Gadekan|Rebecca|R|
Malkus|Elizabeth C|EC|
Pasternak|Amy|A|
Provance-Orr|Stephanie|S|
Roemeiser-Logan|Lynne|L|
Nicorici|Alina|A|
Trussell|Donata|D|
Young|Sally Dunaway|SD|
Fetterman|Jennifer R|JR|
Montes|Jacqueline|J|
Powers|Penny J|PJ|
Quinones|Rebecca|R|
Quigley|Janet|J|
Coffey|Christopher S|CS|
Yankey|Jon W|JW|
Bartlett|Amy|A|
Kissel|John T|JT|
Kolb|Stephen J|SJ|
|||

D014897:Spinal Muscular Atrophies of Childhood

motor function testing
reliability
NeuroNEXT
Spinal muscular atrophy
TIMPSI
CHOP-INTEND
AIMS
clinical evaluator
neuromuscular diseases
outcome measures


Influence of lipids with hydroxyl-containing head groups on Fe2+ (Cu2+)/H2O2-mediated transformation of phospholipids in model membranes.

Abstract: Under condition of ROS formation in lipid membranes, free radical reactions can proceed in both hydrophobic (peroxidation of lipids, POL) and polar (free radical fragmentation) parts of the bilayer. Free-radical fragmentation is typical for the lipids containing a hydroxyl group in β-position with respect to an ester or amide bond. The present study has been undertaken to investigate free-radical transformations of phospholipids in model membranes containing lipids able to undergo fragmentation in their polar part. Liposomes from egg yolk lecithin containing saturated or monounsaturated glycero- and sphingolipids were subjected to the action of an HO* - generating system - Fe(2+)(Cu(2+))/H2O2/Asc, and the POL products were investigated. In parallel with this, the effects of monoacylglycerols and scavengers of reactive species on Fe(2+)(Cu(2+))/H2O2/Asc - mediated free-radical fragmentation of phosphatidylglycerols were studied. Hydroxyl-containing sphingolipids and glycerolipids, which undergo free-radical fragmentation under such conditions, manifested antioxidant properties in the model membranes. In the absence of HO groups in the lipid structure, the effect was either pro-oxidant or neutral. Monoacylglycerols slowed down the rate of both peroxidation in the hydrophobic part and free-radical fragmentation in the hydrophilic part of phospholipid membrane. Scavengers of reactive species inhibited the fragmentation of phosphatidylglycerol substantially. Thus, the ability of hydroxyl-containing lipids to undergo free-radical fragmentation in polar part apparently makes a substantial contribution to the mechanism of their protector action.

Olshyk|Viktoriya N|VN|
Melsitova|Inna V|IV|
Yurkova|Irina L|IL|

Phospholipids
Free-radical fragmentation
Sphingolipids
Copper
Lipid peroxidation
Reactive oxygen species


Highly Selective Olefin-Assisted PdII -Catalyzed Oxidative Alkynylation of Enallenes.

Abstract: An olefin-assisted, palladium-catalyzed oxidative alkynylation of enallenes for regio- and stereoselective synthesis of substituted trienynes has been developed. The reaction shows a broad substrate scope and good tolerance for various functional groups on the allene moiety, including carboxylic acid esters, free hydroxyls, imides, and alkyl groups. Also, a wide range of terminal alkynes with electron-donating and electron-withdrawing aryls, heteroaryls, alkyls, trimethylsilyl, and free hydroxyl groups are tolerated.

olefin-assisted oxidation alkynylation enallene palladium


Solid state stability and solubility of triethylenetetramine dihydrochloride.

Abstract: The API triethylenetetramine dihydrochloride used as an alternative treatment of Wilson's disease is sensitive to water and it exhibits polymorphism. As this may become an issue for the drug formulation, the physical stability has been studied by differential scanning calorimetry, high-pressure thermal analysis, dynamic vapor sorption, and X-ray diffraction as a function of temperature. In addition, high-pressure liquid chromatography and mass spectrometry have been used to study the purity and chemical stability of the API. A pressure-temperature phase diagram of the pure compound has been constructed and it can be concluded that form II is monotropic in relation to form I, which is the only stable solid. The solubilities of the different solid forms have been determined with the help of a temperature - composition phase diagram. The API is very soluble, at 20° C about 10% of the saturated solution with respect to the dihydrate consists of API and the solubility of the pure form I is twice as high. Moreover, it has been shown that at 20°C, a relative humidity above 40% induces the formation of the dihydrate and at 70% a saturated solution appears. At higher temperatures, the formation of the dihydrate appears at lower relative humidity values. A clear link has been established between the API's chemical stability, its physical stability and the relative humidity in the air. Humidity levels above 40% are detrimental to the quality of the API.

Henriet|Théo|T|
Gana|Inès|I|
Ghaddar|Carine|C|
Barrio|Maria|M|
Cartigny|Yohann|Y|
Yagoubi|Najet|N|
Do|Bernard|B|
Tamarit|Josep-Lluis|JL|
Rietveld|Ivo B|IB|

Physical stability
Chemical stability
Phase diagram
Phase behavior
Phase equilibrium
Thermodynamics
Water vapor


A cluster randomised controlled trial of an intervention based on the Health Action Process Approach for increasing fruit and vegetable consumption in Iranian adolescents.

Abstract:
OBJECTIVE
To evaluate an intervention programme based on the Health Action Process Approach and designed to increase the intake of fruit and vegetables (F&V) among Iranian adolescents aged 13 to 18.

DESIGN
A randomised controlled trial with three arms examined the short- (1 month) and long-term (6 months) effects of the intervention. There were two intervention groups (one included adolescents only [A group; n = 510]; the second included mothers and adolescents [M + A group; n = 462]) and a control group (n = 483). All participants were recruited from schools.

MAIN OUTCOME MEASURES
Social cognitions, self-regulatory processes and F&V intake.

RESULTS
The intervention led to an increase in F&V intake for adolescents in the short and long terms. Adolescents in the M + A group increased their F& V intake more than adolescents in the A group. Outcome expectancies, self-monitoring, intentions, action and coping planning, perceived social support and behavioural automaticity mediated the effect of the intervention on F&V intake.

CONCLUSION
The theory-based intervention led to an increase in F&V intake and promoted more positive social cognitions and self-regulatory processes among Iranian adolescents. The findings also provide evidence that involving mothers in an intervention can confer additional benefit.

Lin|Chung-Ying|CY|
Scheerman|Janneke F M|JFM|
Yaseri|Mehdi|M|
Pakpour|Amir H|AH|
Webb|Thomas L|TL|

intervention
fruit and vegetable
adolescent
behaviour
randomised-controlled trial


Combining mutation and horizontal gene transfer in a within-host model of antibiotic resistance.

Abstract: Antibiotics are used extensively to control infections in humans and animals, usually by injection or a course of oral tablets. There are several methods by which bacteria can develop antimicrobial resistance (AMR), including mutation during DNA replication and plasmid mediated horizontal gene transfer (HGT). We present a model for the development of AMR within a single host animal. We derive criteria for a resistant mutant strain to replace the existing wild-type bacteria, and for co-existence of the wild-type and mutant. Where resistance develops through HGT via conjugation we derive criteria for the resistant strain to be excluded or co-exist with the wild-type. Our results are presented as bifurcation diagrams with thresholds determined by the relative fitness of the bacteria strains, expressed in terms of reproduction numbers. The results show that it is possible that applying and then relaxing antibiotic control may lead to the bacterial load returning to pre-control levels, but with an altered structure with regard to the variants that comprise the population. Removing antimicrobial selection pressure will not necessarily reduce AMR and, at a population level, other approaches to infection prevention and control are required, particularly when AMR is driven by both mutation and mobile genetic elements.

Roberts|M G|MG|
Burgess|S|S|
Toombs-Ruane|L J|LJ|
Benschop|J|J|
Marshall|J C|JC|
French|N P|NP|

Horizontal gene transfer
Antimicrobial resistance
Dynamical systems
Escherichia coli
Plasmid dynamics


Assessment of slow wave propagation in multichannel electrogastrography by using noise-assisted multivariate empirical mode decomposition and cross-covariance analysis.

Abstract: Electrogastrography (EGG) is a noninvasive technique for recording the myoelectrical activity of the stomach. An electrogastrographic signal recorded by using a four-channel system with electrodes placed on the surface of the skin is a mixture of a low-frequency gastric pacesetter potential known as a slow wave, electrical activity from other organs, and random noise. The aim of this work was to investigate the possibility of detecting the propagation of the gastric slow wave from multichannel EGG data. Noise-assisted multivariate empirical mode decomposition (NA-MEMD) and cross-covariance analysis (CCA) are proposed as new detection tools. NA-MEMD was applied to attenuate the noise and extract the EGG signal from four channels, while CCA was performed to assess the time shift between the EGG signal channels. Validation of the method was performed using synthetic EGG signals and the methodology was tested on four young, healthy adults. After validation, the proposed method was applied for two kinds of human EGG data: 10-min (short) EGG data from the preprandial phase and 90-120-min (long) EGG data from the preprandial phase as well as the postprandial phase. The results obtained for both synthetic and human EGG data confirm that the proposed method could be a useful tool for assessing the propagation of slow waves. The time shift calculation from the preprandial phase of the EGG examination yielded more consistent results than the postprandial phase. The mean value of the slow wave time lag between neighbouring channels for synthetic data was found to be 4.99±0.47 s. In addition, it was confirmed that the proposed method, that is, NA-MEMD and CCA together, are robust to noise.

Noise-assisted empirical mode decomposition


A comparison of robotic arm versus gantry linear accelerator stereotactic body radiation therapy for prostate cancer.

Abstract: Prostate cancer is the most prevalent cancer diagnosed in men in the United States besides skin cancer. Stereotactic body radiation therapy (SBRT; 6-15 Gy per fraction, up to 45 minutes per fraction, delivered in five fractions or less, over the course of approximately 2 weeks) is emerging as a popular treatment option for prostate cancer. The American Society for Radiation Oncology now recognizes SBRT for select low- and intermediate-risk prostate cancer patients. SBRT grew from the notion that high doses of radiation typical of brachytherapy could be delivered noninvasively using modern external-beam radiation therapy planning and delivery methods. SBRT is most commonly delivered using either a traditional gantry-mounted linear accelerator or a robotic arm-mounted linear accelerator. In this systematic review article, we compare and contrast the current clinical evidence supporting a gantry vs robotic arm SBRT for prostate cancer. The data for SBRT show encouraging and comparable results in terms of freedom from biochemical failure (>90% for low and intermediate risk at 5-7 years) and acute and late toxicity (<6% grade 3-4 late toxicities). Other outcomes (eg, overall and cancer-specific mortality) cannot be compared, given the indolent course of low-risk prostate cancer. At this time, neither SBRT device is recommended over the other for all patients; however, gantry-based SBRT machines have the abilities of treating larger volumes with conventional fractionation, shorter treatment time per fraction (~15 minutes for gantry vs ~45 minutes for robotic arm), and the ability to achieve better plans among obese patients (since they are able to use energies >6 MV). Finally, SBRT (particularly on a gantry) may also be more cost-effective than conventionally fractionated external-beam radiation therapy. Randomized controlled trials of SBRT using both technologies are underway.

Avkshtol|Vladimir|V|
Dong|Yanqun|Y|
Hayes|Shelly B|SB|
Hallman|Mark A|MA|
Price|Robert A|RA|
Sobczak|Mark L|ML|
Horwitz|Eric M|EM|
Zaorsky|Nicholas G|NG|

stereotactic body radiation therapy
prostate cancer
technology
quality of life


Preparation and characterization of triamterene complex with ascorbic acid derivatives.

Abstract: The purpose of this study was to prepare solid dispersions of triamterene (TRT) with ascorbic acid (AA) or ascorbic acid 2 glucoside (AA2G) and to evaluate their physical properties. Solid dispersions were prepared by dissolving each sample in an organic solvent and evaporation (EVP). Powder X-ray diffraction (PXRD) revealed a halo pattern for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1). In differential scanning calorimetry (DSC), endothermic peaks due to the melting of TRT and AA disappeared for EVP1 (AA/TRT = 1/1), and the melting peaks of TRT and AA2G disappeared for EVP2 (AA2G/TRT = 1/1). Fourier transform infrared (FT-IR) spectroscopy revealed broadened peaks for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1) due to the hydroxyl groups (-OH) of AA and the amino groups (-NH2) of TRT and also revealed a peak shift due to the pteridine skeleton (C = N) of TRT. In near-infrared absorption (NIR) spectroscopy, peaks due to the hydroxyl groups (-OH) of AA and AA2G were found for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT = 1/1), respectively. A peak due to the amino groups (-NH2) was evident. This suggested the formation of an evaporation, in which TRT interacted with AA or AA2G. In the dissolution test, the dissolved fraction of TRT alone after 3 min was 30%, whereas the fractions were enhanced to approximately 90% for EVP1 (AA/TRT = 1/1) and EVP2 (AA2G/TRT= 1/1). Results confirmed that dissolution properties were improved as a result of complex formation. The above findings indicated improvement the dissolution properties of TRT.

Onoda|Hirotaka|H| Inoue|Yutaka|Y| Ezawa|Toshinari|T| Murata|Isamu|I| Chantadee|Takron|T| Limmatvapirat|Sontaya|S| Oguchi|Toshio|T| Kanamoto|Ikuo|I|

D017550:Spectroscopy, Fourier Transform Infrared

triamterene
solid dispersion
evaporation
dissolution
Ascorbic acid 2-glucoside


Advances in Nod-like receptors (NLR) biology.

Abstract: The innate immune system is composed of a wide repertoire of conserved pattern recognition receptors (PRRs) able to trigger inflammation and host defense mechanisms in response to endogenous or exogenous pathogenic insults. Among these, nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are intracellular sentinels of cytosolic sanctity capable of orchestrating innate immunity and inflammatory responses following the perception of noxious signals within the cell. In this review, we elaborate on recent advances in the signaling mechanisms of NLRs, operating within inflammasomes or through alternative inflammatory pathways, and discuss the spectrum of their effector functions in innate immunity. We describe the progressive characterization of each NLR with associated controversies and cutting edge discoveries.

D036341:Intercellular Signaling Peptides and Proteins

NLR
Innate immunity
Inflammation
Inflammasome
Cell death


Indole alkaloids from leaves of Alstonia scholaris (L.) R. Br. protect against emphysema in mice.

Abstract:
ETHNOPHARMACOLOGICAL RELEVANCE
Alstonia scholaris (L.) R. Br. (Apocynaceae) is a medicinal plant in China traditionally used to treat pulmonary diseases, including bronchitis, whooping cough, asthma and chronic obstructive pulmonary disease.

AIM OF THE STUDY
To provide experimental data supporting clinical adaptation of total indole alkaloids ( TA) from A. scholaris leaves for treating emphysema.

MATERIALS AND METHODS
An emphysema model was induced by a single intratracheal instillation of porcine pancreatic elastase followed by administration of TA and four main alkaloid components (scholaricine, 19-epischolaricine, vallesamine, and picrinine) for 30 consecutive days. Cytokine levels, histopathological parameters and protein expression in lung tissues were examined.

RESULTS
Administering the TA, picrinine, scholaricine, 19-epischolaricine and vallesamine for 30 days effectively inhibited inflammatory cell accumulation and invasion in the lung tissue and relieved pulmonary tissue injury. Oxygen saturation was enhanced, and interleukin (IL)-1β, monocyte-chemo attractive peptide 1, IL-11, matrix metalloproteinase-12, transforming growth factor-β and vascular endothelial growth factor levels were significantly reduced, likely by suppressing overactivation of alveolar macrophages and pulmonary fibrosis. The elastin content was markedly elevated, and fibronectin was reduced. Bcl-2 expression was significantly increased, and nuclear factor-κB and β-catenin levels were decreased.

CONCLUSIONS
TA can be potentially used as an effective novel drug for pulmonary emphysema and exerts its effects through not only inhibiting inflammation of the airway wall and airflow resistance but also promoting lung elastic recoil and protease/anti-protease balance.

Zhao|Yun-Li|YL| Yang|Zi-Feng|ZF| Wu|Bai-Fen|BF| Shang|Jian-Hua|JH| Liu|Ya-Ping|YP| Wang|Xin-Hua|XH| Luo|Xiao-Dong|XD|

D042461:Vascular Endothelial Growth Factor A

Indole alkaloids
Pulmonary emphysema
Inflammation
Alstonia scholaris leaf
Apoptosis
Protease/antiproteinase balance


Therapeutic strategy for functional tricuspid regurgitation in patients undergoing mitral valve repair for severe mitral regurgitation.

Abstract:
BACKGROUND
The aim of this study was to determine optimal patient selection and selection of a prosthetic ring size for tricuspid valve (TV) repair at the time of mitral valve (MV) repair.

METHODS
We prospectively enrolled 167 consecutive patients undergoing MV repair. TV repair was indicated if patients had at least one of the following conditions representing tricuspid annular dilatation: (1) tricuspid regurgitation (TR)≥moderate, (2) history of right heart failure, (3) atrial fibrillation, and (4) pulmonary hypertension. The size of the ring was targeted to a normal-sized systolic tricuspid annuls in relation to the patient's body surface area (BSA). Serial echocardiographic studies were performed preoperatively, at discharge, and at 1, 3, and 5years postoperatively.

RESULTS
Overall, 100 (60%) patients required TV repair, while it was not indicated for 67 (40%) patients. During follow-up, 26 patients showed progression or recurrent TR≥moderate. The TR grade at 5years after MV surgery was 0.8±0.9 in patients with TV repair and 0.9±0.7 in those without TV repair (P=0.69). There were no significant differences between patients with and without TV repair in a composite endpoint of death from any cause, re-do MV or TV surgery, and recurrence or progression of TR≥moderate (P=0.46).

CONCLUSIONS
Patient selection for TV repair considering not only the grade of TR but clinical signs representing tricuspid annular dilatation is feasible at the time of MV repair. TV repair targeting a normal systolic size in relation to the BSA is a simple and reproducible procedure.

Kitai|Takeshi|T| Furukawa|Yutaka|Y| Murotani|Kenta|K| Krittanawong|Chayakrit|C| Kaji|Shuichiro|S| Koyama|Tadaaki|T| Okada|Yukikatsu|Y|

D019918:Heart Valve Prosthesis Implantation

Tricuspid regurgitation
Tricuspid valve
Mitral valve surgery


Referral patterns, treatment and outcome of high-grade malignant bone sarcoma in Scandinavia--SSG Central Register 25 years' experience.

Abstract:
AIMS
The objectives of this study were to present changes in referral patterns, treatment and survival in patients with high-grade malignant bone sarcoma in Sweden and Norway based on data in the Scandinavian Sarcoma Group (SSG) Central Register.

METHOD
Data on 1,437 patients with diagnosis 1986-2010 was analyzed.

RESULTS
Osteosarcoma was the most frequentl diagnosis (45%), followed by Ewing sarcoma (21%) and chondrosarcoma (17%). Thirty-one percent of Swedish and 41% of Norwegian patients had tumors in the axial skeleton. Eighty-six percent of extremity tumors and 66% of axial tumors were referred to a sarcoma center prior to unplanned surgery or biopsy. During the past decade, limb salvage surgery has risen from under 50% to over 80%. Five-year overall survival in non-metastatic osteosarcoma was 70% for extremity tumors, and 35% for axial tumors. No improvement in osteosarcoma survival was observed during the last decade. Five-year survival in Ewing sarcoma improved from 50% to 69%.

CONCLUSION
Referral patterns in bone sarcomas have improved. However, greater efforts should be dedicated to improving referral of patients with possible tumors in the axial skeleton to multidisciplinary teams (MDTs). Overall survival of patients with high-grade malignant bone sarcomas in Sweden and Norway is in line with other reports.

Zaikova|Olga|O|
Sundby Hall|Kirsten|K|
Styring|Emelie|E|
Eriksson|Mikael|M|
Trovik|Clement S|CS|
Bergh|Peter|P|
Bjerkehagen|Bodil|B|
Skorpil|Mikael|M|
Weedon-Fekjaer|Harald|H|
Bauer|Henrik C F|HC|

referral pattern
bone sarcoma
SSG
osteosarcoma
Ewing sarcoma
chondrosarcoma
overall survival


A high level of serum neopterin is associated with rapidly progressive interstitial lung disease and reduced survival in dermatomyositis.

Abstract: Neopterin is primarily synthesized and released by activated macrophages/monocytes upon stimulation with interferon-γ and is considered as a marker for macrophage activation. This study aimed to analyze the serum levels of neopterin in patients with dermatomyositis (DM) in association with clinical manifestations, laboratory data and patient prognosis. One hundred and eighty-two consecutive DM patients and 30 healthy controls were retrospectively enrolled into the study. Serum levels of neopterin were significantly increased in DM patients compared to healthy controls (P < 0·001). High serum neopterin levels were associated with anti-melanoma differentiation-associated gene (MDA5) antibody, rapidly progressive interstitial lung disease (RP-ILD) and characteristic DM cutaneous involvement. Longitudinal assessment of serum samples revealed that the serum neopterin levels were closely correlated with disease severity (β = 30·24, P < 0·001). In addition, a significant increase in serum neopterin concentration of non-survivors was observed when compared to that of survivors (P < 0·001). Receiver operator characteristic curves showed that serum neopterin could distinguish non-survivors and survivors at an optimal cut-off level of 22·1 nmol/l with a sensitivity and specificity of 0·804 and 0·625, respectively (P < 0·001). Kaplan-Meier survival curves revealed that DM patients with serum neopterin > 22·1 nmol/l had a significantly higher mortality compared to the patient group with serum neopterin < 22·1 nmol/l (log-rank P < 0·001). Multivariate regression analysis identified high serum neopterin concentration to be an independent risk factor for poor prognosis in DM (adjusted hazard ratio = 4·619, 95% confidence interval = 2·092-10·195, P < 0·001). In conclusion, increased serum levels of neopterin were significantly associated with RP-ILD and reduced survival in DM patients, suggesting it as a promising biomarker in disease evaluation of DM.

Peng|Q-L|QL|0000-0002-1271-1729 Zhang|Y-M|YM| Liang|L|L| Liu|X|X| Ye|L-F|LF| Yang|H-B|HB| Zhang|L|L| Shu|X-M|XM| Lu|X|X| Wang|G-C|GC|


Real Workload-Situated Training in COVID-19 Prevention of General Practice Residents in China: A Situated Cognition Study.

Abstract: Objective: The participation of general practice (GP) residents in COVID-19 prevention and control tasks touched workload participation in public health and disease prevention and control and was also a rare, valuable training experience for the residents and research material for medical education. This experience contributed to the understanding of three key points: First, was the content of the COVID-19 prevention task suited to them, or did it overload them in the present? Second, their competence in the COVID-19 prevention task reflected whether the early medical school training was sufficient or not. Third, what can be drawn from this study to promote public health training in the future? This study aimed to explore these issues by conducting a real epidemic situated training (REST) program. Methods: A situated cognition study was designed that included situational context design, legitimate peripheral participation, and the construction of a community of practice. The Task Cognitive Load Scale (NASA-TLX Scale) and self-developed questionnaires were adopted to conduct a questionnaire survey of resident doctors in a GP training program from West China Hospital of Sichuan University, and 183 questionnaires were collected. SPSS 23.0 statistical software was used for the statistical analysis of data. Results: The NASA scale showed that the intensity of field epidemic prevention and control (training) was tolerable. In particular, there was statistical difference in the cognitive load intensity of training before and after the epidemic occurred at different time points (P < 0.05). This shows that they were early trained and well-prepared before sudden outbreak of the COVID-19. Before the outbreak of the epidemic, the public health knowledge and training received came from undergraduate education (83.16%), early residents program training (69.47%), online self-study (49.16%), and continuing education (20.53%). Conclusion: Former medical school education and training at the regulatory training stage have a good effect and enable residents to master the skills required for epidemic prevention and control and to physically and mentally prepare for the task. After this stage, epidemic prevention and control training in real situations will make important contributions to the self-assessment and performance improvement of public health training.

Xin|Rao|R| Li|Luo|L| Qiaoli|Su|S| Xingyue|Wang|W|

COVID-19
general practice
resident
situated cognition
workload


Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo.

Abstract: GBA1 mutations that encode lysosomal β-glucocerebrosidase (GCase) cause the lysosomal storage disorder Gaucher disease (GD) and are strong risk factors for synucleinopathies, including Parkinson's disease and Lewy body dementia. Only a subset of subjects with GBA1 mutations exhibit neurodegeneration, and the factors that influence neurological phenotypes are unknown. We find that α-synuclein (α-syn) neuropathology induced by GCase depletion depends on neuronal maturity, the physiological state of α-syn, and specific accumulation of long-chain glycosphingolipid (GSL) GCase substrates. Reduced GCase activity does not initiate α-syn aggregation in neonatal mice or immature human midbrain cultures; however, adult mice or mature midbrain cultures that express physiological α-syn oligomers are aggregation prone. Accumulation of long-chain GSLs (≥C22), but not short-chain species, induced α-syn pathology and neurological dysfunction. Selective reduction of long-chain GSLs ameliorated α-syn pathology through lysosomal cathepsins. We identify specific requirements that dictate synuclein pathology in GD models, providing possible explanations for the phenotypic variability in subjects with GCase deficiency.

glycosphingolipids
Gaucher disease
α-synuclein
Parkinson’s disease
lysosomal storage disease


Static Magnetic Field Stimulation over the Visual Cortex Increases Alpha Oscillations and Slows Visual Search in Humans.

Abstract: Transcranial static magnetic field stimulation (tSMS) was recently introduced as a promising tool to modulate human cerebral excitability in a noninvasive and portable way. However, a demonstration that static magnetic fields can influence human brain activity and behavior is currently lacking, despite evidence that static magnetic fields interfere with neuronal function in animals. Here we show that transcranial application of a static magnetic field (120-200 mT at 2-3 cm from the magnet surface) over the human occiput produces a focal increase in the power of alpha oscillations in underlying cortex. Critically, this neurophysiological effect of tSMS is paralleled by slowed performance in a visual search task, selectively for the most difficult target detection trials. The typical relationship between prestimulus alpha power over posterior cortical areas and reaction time (RT) to targets during tSMS is altered such that tSMS-dependent increases in alpha power are associated with longer RTs for difficult, but not easy, target detection trials. Our results directly demonstrate that a powerful magnet placed on the scalp modulates normal brain activity and induces behavioral changes in humans.

Gonzalez-Rosa|Javier J|JJ|
Soto-Leon|Vanesa|V|
Real|Pablo|P|
Carrasco-Lopez|Carmen|C|
Foffani|Guglielmo|G|
Strange|Bryan A|BA|
Oliviero|Antonio|A|

static magnetic field
visual search
EEG
NIBS
TMS
occipital cortex


Neoadjuvant Chemoradiotherapy for Stage III Non-Small Cell Lung Cancer.

Abstract: The local management of stage III non-small cell lung cancer is controversial. Although definitive chemoradiotherapy (CRT) is considered a standard-of-care in the curative management of the disease, inadequate local control outcomes have led to various treatment strategies that incorporate surgical resection. Surgery alone has long been recognized as insufficient for this stage, and thus neoadjuvant strategies have been developed to treat micrometastatic disease and increase the probability of a complete resection. The optimal induction strategy has not yet been defined, however, with arguments favoring either preoperative chemotherapy or CRT. In this article, the data supporting the use of neoadjuvant CRT and the randomized literature comparing the two approaches will be reviewed. The article will conclude with summary comparisons of these induction paradigms.

stage III non-small cell lung cancer
lung cancer
combined modality therapy
neoadjuvant therapy
radiation therapy


Context-dependent functional compensation between Ythdf m6A reader proteins.

Abstract: The N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional mRNA modification, regulating mRNA decay and splicing. It plays a major role during normal development, differentiation, and disease progression. The modification is regulated by a set of writer, eraser, and reader proteins. The YTH domain family of proteins consists of three homologous m6A-binding proteins, Ythdf1, Ythdf2, and Ythdf3, which were suggested to have different cellular functions. However, their sequence similarity and their tendency to bind the same targets suggest that they may have overlapping roles. We systematically knocked out (KO) the Mettl3 writer, each of the Ythdf readers, and the three readers together (triple-KO). We then estimated the effect in vivo in mouse gametogenesis, postnatal viability, and in vitro in mouse embryonic stem cells (mESCs). In gametogenesis, Mettl3-KO severity is increased as the deletion occurs earlier in the process, and Ythdf2 has a dominant role that cannot be compensated by Ythdf1 or Ythdf3, due to differences in readers' expression pattern across different cell types, both in quantity and in spatial location. Knocking out the three readers together and systematically testing viable offspring genotypes revealed a redundancy in the readers' role during early development that is Ythdf1/2/3 gene dosage-dependent. Finally, in mESCs there is compensation between the three Ythdf reader proteins, since the resistance to differentiate and the significant effect on mRNA decay occur only in the triple-KO cells and not in the single KOs. Thus, we suggest a new model for the Ythdf readers function, in which there is profound dosage-dependent redundancy when all three readers are equivalently coexpressed in the same cell types.

D018507:Gene Expression Regulation, Developmental


Health Status in Long-Term Survivors of Hepatoblastoma.

Abstract: The aim of this study was to evaluate the health status of children cured from hepatoblastoma. Forty-five patients with hepatoblastoma treated between 1996-2014 were assessed. The recorded data included sex, age at diagnosis, disease stage, treatment methods, time since diagnosis, and the evaluation of health status domains which included performance status, growth development, hearing, cardiovascular, skeletal, gastrointestinal, genitourinary, neurological, and hematological function. There were 30 boys and 15 girls. The age at diagnosis ranged from one month to 14 years (median one year). At the time of the health status evaluation, the youngest patient was 5.5 years old and the oldest was 21 years of age (median-10 years). All patients were treated according to the Childhood Liver Tumors Strategy Group-SIOPEL recommendations, though they were not active participants of the studies. The median cumulative dose of cisplatin was 520 mg/m2 and 360 mg/m2 for doxorubicin. Thirty-six patients underwent partial hepatectomy, and nine total hepatectomy and liver transplantation. At a median of nine years from diagnosis, 68% of hepatoblastoma survivors had experienced at least one chronic health condition of any grade. The most frequent late complication was ototoxicity (28.8%), and the most serious were second malignancies (6.6%) and cardiomyopathy (4.4%). Conclusion: Survivors of hepatoblastoma are at risk for long-term complications. They require long-term monitoring for late effects.

Dembowska-Bagińska|Bożenna|B| Więckowska|Jolanta|J| Brożyna|Agnieszka|A|0000-0002-2255-3066 Święszkowska|Ewa|E| Ismail|Hor|H| Broniszczak-Czyszek|Dorota|D| Stefanowicz|Marek|M| Grajkowska|Wiesława|W| Kaliciński|Piotr|P|0000-0003-0555-2229

survivors
hepatoblastoma
children
follow-up
long-term health status


The P2X7 Receptor, Cathepsin S and Fractalkine in the Trigeminal Subnucleus Caudalis Signal Persistent Hypernociception in Temporomandibular Rat Joints.

Abstract: Temporomandibular joint (TMJ) is frequently involved with rheumatoid arthritis with a high prevalence that could result in a chronic pain state. Once the disease is established in the joint, the antigen-specific immune reaction initiates a neuro-immune cascade of events that causes sensitization of the central nervous system. This study establishes animal experimental models that evaluate the chronicity of albumin-induced arthritis hypernociception in the TMJ. Antigen-induced arthritis was generated in rats with methylated bovine serum albumin (mBSA) diluted in complete Freund's. Intra-articular injection of mBSA (10 µg/TMJ/week) during 3 weeks resulted in a persistent inflammatory hypernociception which was characterized by an inflammatory episode characterized by the increased of lymphocytes, macrophages and pro-inflammatory interleukins IL-12 and IL-18. The persistent model of inflammatory hypernociception induced by arthritis in the TMJ elicited protein levels of P2X7 receptors, cathepsin S and fractalkine in the trigeminal subnucleus caudalis. Overall, the results of the present work suggest that a persistent inflammatory hypernociception of albumin-induced arthritis in the TMJ leads to the activation of the central nervous system signaling by P2X7/cathepsin S/fractalkine pathway.

Bonfante|Ricardo|R|
Napimoga|Marcelo Henrique|MH|
Macedo|Cristina Gomes|CG|
Abdalla|Henrique Ballassini|HB|
Pieroni|Victor|V|
Clemente-Napimoga|Juliana Trindade|JT|

temporomandibular joint
arthritis
sensitization
inflammation
microglial cells
persistent pain


Multi-Drug Resistant Surgical Site Infection Due to Mycobacterium abscessus Complex.

Abstract: M. abscessus complex is notoriously resistant to most antimicrobial agents. The complex is differentiated into 3 subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. Skin and soft tissue infections due to this organism can be acquired by direct contact with contaminated material through traumatic injury, surgical wound and environmental exposure or by secondary involvement of skin/soft tissue during disseminated disease. We report a case of Mycobacterium abscessus infection recovered from a post-operative mid-line abdominal wound to illustrate the diagnostic and management difficulties encountered in such patients.

Misra|Richa|R|
Jain|Vidhi|V|
Tejan|Nidhi|N|
Negi|Aarti|A|
Umrao|Jyoti|J|
Dhole|Tapan Nirodhechand|TN|

multi-drug resistant
surgical site infection
M. abscessus complex


Correlations between serum levels of 25-hydroxyvitamin D and carotid atherosclerosis in patients with type 2 diabetes in Shanghai.

Abstract:
OBJECTIVE
To explore the potential association between the serum levels of 25-hydroxyvitamin D [25(OH)D] and carotid atherosclerosis in patients with type 2 diabetes.

MATERIAL AND METHODS
Three hundred and fifty patients with type 2 diabetes were enrolled in this study in Shanghai, China. B-mode ultrasound was used to detect carotid plaques as indicators of atherosclerosis and measure carotid artery intima-media wall thickness (C-IMT) at two sites of carotid artery. Subjects were divided into group A (patients with carotid plaques) and group B (patients without carotid plaques) and be assessed clinically. Serum levels of 25(OH)D and other clinical parameters were measured. Multivariate logistic regression was performed to find predictors of carotid atherosclerosis in the entire group.

RESULTS
The levels of serum 25(OH)D were lower in group A than in group B[19.60 (13.30-25.73) vs 23.19 (18.10-30.06)ng/ml, P<0.001]. The C-IMT levels [(1.00±0.17 vs 0.88±0.20)mm, Ptrend<0.001] and proportion of people with carotid plaques(44/88 vs 20/87, Ptrend<0.001) in the lowest quartile of 25(OH)D were higher than in the highest quartile. Vitamin D concentrations were inversely associated with HbA1c in women(r=-0.194, P=0.006), and C-IMT in men(r=-0.409, P<0.001). Logistic regression analysis showed age, male sex, current smoke, history of hypertension, SBP, LDL-C and lg[25(OH)D] (OR: 0.924, 95%CI: 0.893-0.955, P<0.001) were independently associated with the presence of carotid plaques in T2DM.

CONCLUSIONS
Serum vitamin D level is significantly and independently associated with carotid atherosclerosis in patients with T2DM in Shanghai, China.

Chen|Rui-hua|RH| Jiang|Xiao-zhen|XZ| Jiang|Quan|Q| Gu|Zhe|Z| Gu|Pei-li|PL| Zhou|Bin|B| Zhu|Zhen-hong|ZH| Xu|Lin-yan|LY| Zou|Yu-feng|YF|

25-hydroxyvitamin D
25-hydroxyvitamin D
Atherosclerosis
25-hydroxyvitamine D
Athérosclérose subclinique
Carotid intima-media thickness
Diabetes mellitus type 2
Diabète de type 2
Épaisseur intima-média carotidienne