Overexpression of Neutrophil MMP-9 and HIF-1α May Contribute to the Finger-Like Projections Formation and Histo-Pathogenesis in Nasal Inverted Papilloma.

Abstract:
Background
Nasal inverted papilloma (NIP) is defined based on its histological characteristic of inverted epithelium growth into the stroma. The inversion can result in epithelial growth in the underlying connective tissue stroma when the basement membrane completely separates from the epithelial layer. To date, such inversion mechanism underlying NIP's pathological phenomenon is unknown. Therefore, we hypothesized that mediators and soluble proteins released by neutrophils, the most predominant infiltrating cells in NIP, is vital in causing the epithelial changes and pathogenesis of NIP.

Methods
We collected 37 NIP tissues from patients who underwent surgical removal of NIP and performed hematoxylin-eosin (HE), immunohistochemical, and immunofluorescence staining to analyze in-depth the basic characteristics of NIP, including detecting the expression and distribution of MMPs and associated factors in NIP. Western blotting and quantitative real-time PCR were further performed to analyze the protein and mRNA expression levels of specific factors including MMPs, HIF-1α, and tissue inhibitors of metalloproteinases (TIMPs).

Results
We observed finger-like projections that insert into the epithelium in NIP tissue as its main characteristics. The projections contain fibroblasts, extracellular matrix, capillaries, and infiltrating inflammatory cells. We found abundant neutrophils clustered at the finger-like projection of NIP, and also noted MMP-1 and MMP-9 were up-regulated in NIP (p<0.05), whereas TIMP-1/3 was decreased. The expression level of HIF-1α was also found to be increased in NIP tissue. We further showed that MMP-9 and HIF-1α were mainly expressed by neutrophils and were predominantly observed in the finger-like projections that contribute to the NIP pathology.

Conclusion
Upregulation and release of MMP-9 and HIF-1α from infiltrating neutrophils may cause damage to the epithelial basement membrane and epithelial clefts, forming finger-like projections with angiogenesis and fibroblasts insertion, resulting in epithelial growth in the tissue stroma, a typical histo-pathological characteristic in NIP.

neutrophils
MMP-9
HIF-1α
finger-like projection
nasal inverted papilloma
pathogenesis


Scale-up cultivation enhanced arachidonic acid accumulation by red microalgae Porphyridium purpureum.

Abstract: The present study attempts to cultivate Porphyridium purpureum under different scale-up conditions for further development and commercialization of microalgae-derived PUFAs such as ARA and EPA. Different temperatures (25, 30, and 35 °C) and light intensities (70, 165, and 280 μmol/m2s) were applied to the 50 L pilot-scale cultivation of P. purpureum in ASW. The cultivation under the light intensity of 280 μmol/m2s at 35 °C obtained biomass concentration up to 9.52 g/L, total fatty acid content to 56.82 mg/g, and ARA content to 22.29 mg/g. While the maximum EPA content of 7.00 mg/g was achieved under the light intensity of 280 μmol/m2s at 25 °C and the highest ratio of UFAs to TFAs of 74.66% was also obtained in this trial. Both biomass concentration and TFAs content were improved by increasing light intensity and temperature. Moreover, the ratio of ARA to EPA was enhanced by increasing cultivation temperature under the light intensity of 280 μmol/m2s. In contrast with flask culture, the conversion of linoleic acid (C18:2) to ARA was enhanced in scale-up culture, leading to more ARA content. Phosphate limitation enhanced the synthesis of lipid and LPUFAs. Moreover, the biomass concentration and biosynthesis of palmitic acid were preferred by sufficient C (NaHCO3).

Chang|Jingyu|J| Le|Kai|K| Song|Xiaoqiang|X| Jiao|Kailin|K| Zeng|Xianhai|X| Ling|Xueping|X| Shi|Tuo|T| Tang|Xing|X| Sun|Yong|Y| Lin|Lu|L|

Scale-up cultivation
Enhance
Arachidonic acid
Porphyridium purpureum
Phosphate limitation


Eating Behaviour Predicts Weight Loss Six Months after Bariatric Surgery: A Longitudinal Study.

Abstract: Bariatric surgery is currently the most durable weight loss solution for patients with morbid obesity. The extent of weight loss achieved, however, is subject to variation due to various factors, including patients' behaviour. In this study, we aimed to identify pre- and post-surgical predictors of weight loss following bariatric surgery. This prospective study included 57 participants who went through bariatric surgery (laparoscopic Roux-en-Y gastric bypass: n = 30; laparoscopic sleeve gastrectomy: n = 23; one anastomosis gastric bypass-mini gastric bypass: n = 4) in two tertiary referral hospitals. Consenting participants were assessed prior to surgery (T₀), and three months (T₁) and six months (T₂) after surgery. The assessment included interview and anthropometric measurements. The interview was done with the aid of instruments, including the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression screening and the Dutch Eating Behaviour Questionnaire (DEBQ) for eating behaviour assessment. Baseline comorbidity status was obtained from medical records. A Generalised Estimating Equation (GEE) was developed to determine predictors of weight loss. Participants in the study were mostly women (n = 37, 65%) with a mean age of 39.4 (SD = 10.01) years. The mean excess BMI loss (EBMIL) and total weight loss (TWL) at the sixth month was 63.31% and 23.83%, respectively. Anxiety, depression, and external eating scores reduced over time. Advancing age, high BMI, and higher scores for emotional and external eating emerged as significant negative predictors for TWL%. It can be concluded that the patients experienced substantial weight loss after surgery. Continuous monitoring of psychological well-being and eating behaviour are essential for optimal weight loss.

Subramaniam|Kavitha|K|
Low|Wah-Yun|WY|
Lau|Peng-Choong|PC|0000-0003-2702-0282
Chin|Kin-Fah|KF|
Chinna|Karuthan|K|
Kosai|Nik Ritza|NR|
Taher|Mustafa Mohammed|MM|
Rajan|Reynu|R|0000-0002-3825-2022

eating behaviour
weight loss
bariatric surgery
obesity
psychology


Chemical alterations and regulations of biomolecules in lifestyle-related diseases.

Abstract: We know experientially that not only nutrient factors but also non-nutritive functional food factors are playing important roles in maintenance of homeostasis, health promotion, and disease prevention. Although some of these effective behaviors are supported by accumulating scientific evidences, it is in general difficult to determine properly in human. Therefore, the discovering of novel biomarker and developments of the analytical method are one of the prudent strategies to understand disease etiology and evaluate efficacies of functional food factors via monitoring the pathophysiological alteration in live body, tissue, and cells. This review describes recent our findings on (1) formation mechanism, bioactivities, quantitative determination of cholesterol ozonolysis product, secosterol as possible biomarker for lifestyle-related disease, and (2) chemical biology approach for the investigating molecular mechanisms of most promising cancer chemopreventive food factors, isothiocyanate-inducing bioactivities.

lifestyle-related disease
secosterol
LC-MS
isothiocyanate


Morus alba L. and Morus nigra L. Leaves as a Promising Food Source of Phenolic Compounds with Antioxidant Activity.

Abstract: Bioactivity of mulberry has been widely described, but mostly related to its fruits, while studies with leaves are scarce. Herein, in this study leaves of two mulberry species (Morus alba L. and Morus nigra L.) were characterized, compared, and evaluated in terms of their phenolic composition and antioxidant activity. Aiming to valorize mulberry leaves extracts which can be included in modern diet four different extracts (infusions, decoctions, tinctures and hydromethanolic) were examined. The chemical characterization was done by quantifying total phenolics (TPC), flavonoids (TFC) and phenolic acids (TPAC) content, L( +)ascorbic acid (ASA) and individual phenolic compounds in the extracts by HPLC technique. Moreover, DPPH and FRAP assays were used to assess the antioxidant activity of white and black mulberry leaves. Findings of these studies revealed that black mulberry leaves were richer in TFC and TPAC, while white mulberry leaves contained higher levels of individual phenolic compounds in water extracts. Gallic acid was found in the highest concentrations in two mulberry leave extracts. Correlation analysis showed strong relationships between antioxidant activity and TPC and TFC. This fact suggests the crucial role of phenolic compounds as antioxidant agents in white and black mulberry leaves. The results obtained in this study demonstrate that leaves of both white and black mulberry can be used as a valuable source of phenolic compounds with bioactive potential, which can be applied in the food sector, as foods and as promising source of natural ingredients.

Antioxidant activity
Phenolic composition
Mulberry leaves
Correlation analysis


More inclusive bipolar mixed depression definition by permitting overlapping and non-overlapping mood elevation symptoms.

Abstract:
OBJECTIVE
The objective of this study was to assess the strengths and limitations of a mixed bipolar depression definition made more inclusive than that of the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) by counting not only 'non-overlapping' mood elevation symptoms (NOMES) as in DSM-5, but also 'overlapping' mood elevation symptoms (OMES, psychomotor agitation, distractibility, and irritability).

METHODS
Among bipolar disorder (BD) out-patients assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation, we assessed prevalence, demographics, and clinical correlates of mixed vs. pure depression, using more inclusive (≥3 NOMES/OMES) and less inclusive DSM-5 (≥3 NOMES) definitions.

RESULTS
Among 153 depressed BD, counting not only NOMES but also OMES yielded a three-fold higher mixed depression rate (22.9% vs. 7.2%) and important statistically significant clinical correlates for mixed compared to pure depression (more lifetime anxiety disorder comorbidity, more current irritability, and less current antidepressant use), which were not significant using the DSM-5 threshold.

CONCLUSION
To conclude, further studies with larger numbers of patients with DSM-5 bipolar mixed depression assessing strengths and limitations of more inclusive mixed depression definitions are warranted, including efforts to ascertain whether or not OMES should count toward mixed depression.

Kim|H|H|
Kim|W|W|
Citrome|L|L|
Akiskal|H S|HS|
Goffin|K C|KC|
Miller|S|S|
Holtzman|J N|JN|
Hooshmand|F|F|
Wang|P W|PW|
Hill|S J|SJ|
Ketter|T A|TA|

D039721:Diagnostic and Statistical Manual of Mental Disorders

D011569:Psychiatric Status Rating Scales

depression
bipolar disorder
diagnosis
nosology
psychopathology


Metabolic effects of Crocus sativus and protective action against non-alcoholic fatty liver disease in diabetic rats.

Abstract: Non-alcoholic fatty liver disease (NAFLD) is the result of the accumulation of adipose tissue deposits in the liver and it is associated with type 2 diabetes. Crocus sativus (saffron) is known for its antioxidant and its potential hypoglycemic effects. We investigated the role of saffron on NAFLD in diabetic rats. Thirty adult male rats were allocated into three groups; control (n=10), which received normal diet; streptozotocin (STZ) group (n=10), which received normal chow diet, 10% fructose in their drinking water and STZ (40 mg/kg body weight; STZ-saffron group (n=10), which followed the same dietary and pharmacological pattern as STZ group and were additionally supplemented with saffron (100 mg/kg/day). Metabolic profile was measured and histopathological examination of the liver was evaluated. STZ group exhibited the highest glucose levels at the end of the experiment (P<0.05), while there was no difference between control and STZ-saffron group (584 vs. 213 mg/dl vs. 209 mg/dl, respectively). STZ group revealed higher percentage of steatosis (5-33%) when compared to the other two groups (P<0.005). Saffron exhibits both hypoglycemic and hepatoprotective actions. Yet, further studies enlightening the exact mechanisms of saffron's mode of actions are required.

Konstantopoulos|Panagiotis|P|
Doulamis|Ilias P|IP|
Tzani|Aspasia|A|
Korou|Maria-Laskarina|ML|
Agapitos|Emmanouil|E|
Vlachos|Ioannis S|IS|
Pergialiotis|Vasilios|V|
Verikokos|Christos|C|
Mastorakos|George|G|
Katsilambros|Nicholas L|NL|
Perrea|Despina N|DN|

metabolism
non-alcoholic fatty liver
diabetes
rats
saffron


Spermatozoa morphology changes during reproduction and first observation of acrosomal contact in two dioecious species of Macrobiotidae (Tardigrada: Eutardigrada).

Abstract: Mating behaviours for two species of dioecious eutardigrades: a strain of Paramacrobiotus sp. and Macrobiotus shonaicus (Stec et al., 2018) have been recorded previously, and observations have indicated that spermatozoa of both species are first released into the environment, then swim through the cloaca of the females and into the spermatheca. The fusion of gamete nuclei has not yet occurred in a laid egg. Therefore, it has been suggested that fertilization is completed externally as the egg is released into the environment before the nuclei of the gametes fuse. In the present study, the spermatozoa of both Paramacrobiotus sp. and M. shonaicus spermatozoa underwent morphological changes during reproduction. In morphometrical analyses of testicular spermatozoa, the tail, mid-piece, nucleus, and acrosome were significantly longer in Paramacrobiotus sp. compared with M. shonaicus. The nuclei of both the testicular and spermathecal spermatozoa were equally coiled, but the latter had shorter tails in both species. These spermatozoa were present on the surface of the egg chorion after oviposition. The tip of the acrosomes lay buried in the chorion, suggesting that penetration had occurred. We also proposed that the reduced tail is a conserved trait, at least in Macrobiotidae.

Reproduction
Paramacrobiotus sp.
Macrobiotus shonaicus
Fertilization
Gametes morphology


Structural, Magnetic and Catalytic Properties of a New Vacancy Ordered Perovskite Type Barium Cobaltate BaCoO2.67.

Abstract: A new vacancy ordered, anion deficient perovskite modification with composition of BaCoO2.67 (Ba3 Co3 O8 □1 ) has been prepared via a two-step heating process. Combined Rietveld analysis of neutron and X-ray powder diffraction data shows a novel ordering of oxygen vacancies not known before for barium cobaltates. A combination of neutron powder diffraction, magnetic measurements, and density functional theory (DFT) studies confirms G-type antiferromagnetic ordering. From impedance measurements, the electronic conductivity of the order of 10-4  S cm-1 is determined. Remarkably, the bifunctional catalytic activity for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR) is found to be comparable to that of Ba0.5 Sr0.5 Co0.8 Fe0.2 O3-y , confirming that charge-ordered anion deficient non-cubic perovskites can be highly efficient catalysts.

magnetism
perovskite
ab initio calculations
bifunctional catalyst
neutron diffraction


Diagnosis of spinal xanthomatosis by next-generation sequencing: identifying a rare, treatable mimic of hereditary spastic paraparesis.

Abstract: Cerebrotendinous xanthomatosis is an autosomal recessive disorder of bile acid metabolism causing a range of progressive neurological symptoms. Even in the presence of the classical triad of neurological dysfunction, tendon xanthoma and early onset cataracts, the diagnosis is often missed. It can mimic more common conditions such as hereditary spastic paraparesis or multiple sclerosis, particularly if the phenotype is spinal xanthomatosis where the disease causes a spastic paraplegia. Early recognition and treatment with chenodeoxycholic acid may prevent irreversible neurological damage. The introduction of next-generation sequencing to screen for a large number of genetic disorders associated with progressive spastic paraparesis will allow earlier identification and treatment of these patients and their families, and will particularly help in atypical cases such as the patient described here.

Nicholls|Zoe|Z|
Hobson|Esther|E|
Martindale|Joanne|J|
Shaw|Pamela J|PJ|

SPASTICITY
GENETICS
HEREDIT SPASTIC PARAPLEGIA
METABOLIC DISEASE
NEUROGENETICS


Cellulosome Localization Patterns Vary across Life Stages of Anaerobic Fungi.

Abstract: Anaerobic fungi (Neocallimastigomycota) isolated from the guts of herbivores are powerful biomass-degrading organisms that enhance their degradative ability through the formation of cellulosomes, multienzyme complexes that synergistically colocalize enzymes to extract sugars from recalcitrant plant matter. However, a functional understanding of how fungal cellulosomes are deployed in vivo to orchestrate plant matter degradation is lacking, as is knowledge of how cellulosome production and function vary throughout the morphologically diverse life cycle of anaerobic fungi. In this work, we generated antibodies against three major fungal cellulosome protein domains, a dockerin, scaffoldin, and glycoside hydrolase (GH) 48 protein, and used them in conjunction with helium ion and immunofluorescence microscopy to characterize cellulosome localization patterns throughout the life cycle of Piromyces finnis when grown on simple sugars and complex cellulosic carbon sources. Our analyses reveal that fungal cellulosomes are cell-localized entities specifically targeted to the rhizoids of mature fungal cells and bodies of zoospores. Examination of cellulosome localization patterns across life stages also revealed that cellulosome production is independent of growth substrate in zoospores but repressed by simple sugars in mature cells. This suggests that further exploration of gene regulation patterns in zoospores is needed and can inform potential strategies for derepressing cellulosome expression and boosting hydrolytic enzyme yields from fungal cultures. Collectively, these findings underscore how life cycle-dependent cell morphology and regulation of cellulosome production impact biomass degradation by anaerobic fungi, insights that will benefit ongoing efforts to develop these organisms and their cellulosomes into platforms for converting waste biomass into valuable bioproducts. IMPORTANCE Anaerobic fungi (Neocallimastigomycota) isolated from the guts of herbivores excel at degrading ingested plant matter, making them attractive potential platform organisms for converting waste biomass into valuable products, such as chemicals and fuels. Major contributors to their biomass-hydrolyzing power are the multienzyme cellulosome complexes that anaerobic fungi produce, but knowledge gaps in how cellulosome production is controlled by the cellular life cycle and how cells spatially deploy cellulosomes complicate the use of anaerobic fungi and their cellulosomes in industrial bioprocesses. We developed and used imaging tools to observe cellulosome spatial localization patterns across life stages of the anaerobic fungus Piromyces finnis under different environmental conditions. The resulting spatial details of how anaerobic fungi orchestrate biomass degradation and uncovered relationships between life cycle progression and regulation of cellulosome production will benefit ongoing efforts to develop anaerobic fungi and their cellulosomes into useful biomass-upgrading platforms.

Lillington|Stephen P|SP|
Chrisler|William|W|
Haitjema|Charles H|CH|
Gilmore|Sean P|SP|
Smallwood|Chuck R|CR|
Shutthanandan|Vaithiyalingam|V|
Evans|James E|JE|
O'Malley|Michelle A|MA|

cellulosome
anaerobic fungi
enzyme
antibody
immunofluorescence
cellulase


Ultrasound-guided ablation for hepatocellular carcinoma: time for a reappraisal?

Abstract: Ultrasound-guided techniques play a key role in the clinical management of hepatocellular carcinoma. Among these, percutaneous ethanol injection (PEI) was the first technique to be proposed for the treatment of nodular-type hepatocellular carcinoma: the role of PEI was first discussed during the European Association for the Study of the Liver conference held in Barcelona in 2000, 15 years ago. Since then, other techniques have been introduced and radiofrequency ablation now represents the most widely used percutaneous technique. PEI and radiofrequency ablation are widely used in clinical practice. However, only scant progresses in the application of these techniques have been performed over the past 15 years, and percutaneous approaches are often only marginally discussed and studied. Here, we discuss the most relevant clinical issues regarding PEI and radiofrequency ablation that have emerged in the past years.

Cabibbo|Giuseppe|G| Antonucci|Michela|M| Sacco|Rodolfo|R| Sciarrino|Elio|E|

D006528:Carcinoma, Hepatocellular
D017115:Catheter Ablation
D000431:Ethanol
D006801:Humans
D008113:Liver Neoplasms
D018084:Ultrasonography, Interventional


UV induced reversible chain extension of 1-(2-anthryl)-1-phenylethylene functionalized polyisobutylene.

Abstract: The synthesis of novel 1-(2-anthryl)-1-phenylethylene (APE) di-telechelic polyisobutylenes is described. Utilization of a difunctional cationic initiator and the in situ addition of the non-homopolymerizable APE lead to the formation of di-anthryl telechelic polyisobutylenes. Products were characterized by 1H NMR spectroscopy and Size Exclusion Chromatography. The polymers were UV irradiated at 365 and 254 nm and the reversible photocycloaddition of anthryl moieties was investigated. The chain extension of di-anthryl telechelic PIBs through photocoupling at 365 nm produced higher molecular weight products from low molecular weight precursors. The effect of precursor polymer concentration on the degree of chain extension was investigated, and intermolecular interactions leading to the formation of tetramers was observed. The photocoupled products were UV irradiated at 254 nm to induce the reversal of photocycloaddition of anthryl groups and to follow the consequent photoscission of polymers.

polyisobutylene
Anthracene
cationic polymerization
photochemistry
reversible chain-extension


Celecoxib, a cyclooxygenase-2 inhibitor, offers chemoprevention against reproductive and neurobehavioural abnormalities induced by atrazine in male Wistar rats.

Abstract: The cyclooxygenase-2/prostanoid pathway (COX-2) serves as a potential therapeutic target in various pathological conditions. Thus, the modulatory effect of celecoxib (CXB), a COX-2 inhibitor, in atrazine-induced toxicity was investigated. Five groups (n = 6 rats per group) of adult male Wistar rats received corn oil (2 ml/kg), atrazine (ATZ, 300 mg/kg) and CXB (5.7 mg/kg) respectively and their combinations via the oral route. Results obtained showed reduced (p < 0.05) sperm motility (25.8%) and counts (27.6%), testosterone (29.9%), luteinizing (33%) and follicle stimulating hormones (78.7%) plus elevated total cholesterol (112.3%), triglyceride (115.7%), malondialdehyde levels respectively in ATZ-treated rats. Similarly, ATZ administration causes reduced locomotion (33.6%), spontaneous motor activity (46.6%) and catalepsy effects (157.3%) respectively. However, CXB divided doses moderately reverse reproductive abnormalities, modulate neurobehavioural deficits and slightly preserved COX-2 elevation following ATZ intoxication. Furthermore, histopathology of testis shows improvement in treated rats. Overall, our data suggest chemopreventive actions via pharmacological inhibition of COX-2 activity during ATZ toxicity.

Kale|O E|OE|
Oyesola|T O|TO|
Raji|F S|FS|

Celecoxib
Cyclooxygenase-2
Atrazine
Neurobehavioural deficit
Male reproduction
Oxidative stress


Synthesis of polymers containing 3-hydroxypyridin-4-one bidentate ligands for treatment of iron overload.

Abstract: Iron overload is a clinical problem which can be prevented by using iron chelating agents. An alternative method of relieving iron overload is to reduce iron absorption from the intestine by administering specific iron chelating agents, which can bind iron to form nonabsorbable complexes. Based on this strategy, a series of polymeric ligands containing the chelating moiety 3-hydroxypyridin-4-ones (HPOs) were synthesized. The synthetic route involves the benzylation of hydroxyl group of (2-methyl-3-hydroxypyran-4-one (maltol) and conversion of benzylated maltol to 3-benzyloxypyridin-4-one derivatives by using three suitable primary amines (2,6-diaminohexanoic acid (lysine) and 1,6-diaminohexane and 5-aminopentanol). The resulted compounds incorporated into polymer by copolymerization with acryloyl chloride using 2, 2'-azobisisobutyronitrile (AIBN) as the initiator. Finally, the benzyl groups of polymers were removed by catalytic hydrogenation (Pd/C). In this work, three final polymers of HPO derivatives namely poly-2-propylamido-6-(3- hydroxy -1,4-dihydro-2-methy-4-oxopyrid-1-yl) hexanoic acid, 6-(3-hydroxy-1, 4-dihydro-2-methyl-4-oxopyrid-1-yl) hexyl-1-polypropylamide and 5-(3-hydroxy-1-,4-dihydro-2-methyl-4-oxopyrid-1-yl)-1-polyacrylate pentane were synthesized. Identification and structural elucidation of compounds were achieved by proton nuclear magnetic resonance ((1)H NMR), carbon nuclear magnetic resonance ((13)C NMR) and infrared (IR) spectroscopy.

Saghaie|Lotfollah|L|
Liu|Dy|D|
Hider|Robert C|RC|

3-Hydroxypyridin-4-ones
Iron overload
Iron chelating agents


Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients.

Abstract: The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use. Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely. This position paper represents the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO. The aim of this paper is to provide physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients. Importantly, this will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions. Given the need for further evidence, we encourage restraint in the widespread use of ECMO until we have a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.

Combes|Alain|A|
Brodie|Daniel|D|
Bartlett|Robert|R|
Brochard|Laurent|L|
Brower|Roy|R|
Conrad|Steve|S|
De Backer|Daniel|D|
Fan|Eddy|E|
Ferguson|Niall|N|
Fortenberry|James|J|
Fraser|John|J|
Gattinoni|Luciano|L|
Lynch|William|W|
MacLaren|Graeme|G|
Mercat|Alain|A|
Mueller|Thomas|T|
Ogino|Mark|M|
Peek|Giles|G|
Pellegrino|Vince|V|
Pesenti|Antonio|A|
Ranieri|Marco|M|
Slutsky|Arthur|A|
Vuylsteke|Alain|A|
|||

extracorporeal membrane oxygenation
acute respiratory distress syndrome
critical care networks
hospital organization
position article


Tibiotalar Incongruency in Clubfoot Treated Operatively Is a Predictor of Worse Outcome at a Mean of 26 Years.

Abstract: The traditional approach to congenital talipes equinovarus (CTEV) has relied on stepwise manipulations, followed by surgery in severe or recurrent cases. The 3 aims of this study were: (1) to report long-term results of clubfoot treated by posterior capsulectomy and selective release (PCSR); (2) to determine the reliability of a visual scale in the assessment of intraoperative tibiotalar incongruency (TTI); and, (3) to assess the role of TTI as a prognostic factor. We reviewed data regarding 95 CTEV (65 patients) treated by PCSR at a minimum follow-up of 20 years. Patients underwent a physical and radiographic examination, and were assessed through multiple clinical scores. The inter- and intraobserver reliability for TTI evaluation was calculated on clinical photographs. Based on TTI, 52 CTEV were divided in 2 groups (30 congruent vs 22 incongruent) and compared. At a mean follow-up of 26.8 (from 24 to 31) years, 52 CTEV (38 patients) were available for the analysis. Functional results were globally satisfactory. The inter- (κ = 0.748) and intraobserver analysis (κ = 0.688) for the TTI visual assessment showed substantial agreement. In patients with incongruency, patient reported outcomes were significantly worse, with also a greater development of subtalar (p = .02), talonavicular and calcaneocuboid arthritis (p < .001 for both). In treating severe CTEV, the surgical PCSR performed in the first year of life obtains satisfactory clinical and patient-recorded outcomes at over 25 years of follow-up. The visual assessment of TTI is reproducible and potentially represents a long-term prognostic factor.

Bernasconi|Alessio|A| Iorio|Paolino|P| Lintz|François|F| Ray|Robbie|R| Sadile|Francesco|F|

D000071066:Patient Reported Outcome Measures

clubfoot
operative
ankle
long term
talipes equinus
talus


Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model.

Abstract:
AIM
Antiepileptic drugs that modulate GABA have the potential to aggravate or improve the symptoms of absence epilepsy. PF-06372865 is a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines. The aim of this study was to assess the antiepileptic effect of PF-06372865 in a preclinical model of absence seizures.

METHODS
Genetic absence epilepsy rats from Strasbourg (GAERS) was implanted with four cortical electrodes over the frontoparietal cortex, and the number and cumulated duration of spike-and-wave discharges (SWDs) were recorded for 10-90 minutes following administration of vehicle, PF-06372865, and positive controls diazepam and valproate.

RESULTS
PF-06372865 (0.3, 1, 2, 10 mg kg-1 ) dose-dependently reduced the expression of SWDs, including full suppression at the highest doses by 30 minutes after administration.

CONCLUSIONS
PF-06372865 demonstrated robust efficacy in suppressing SWDs in the GAERS model of absence epilepsy. To our knowledge, this is the first demonstration of antiepileptic activity of an α2/3/5-subtype-selective GABAA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.

Duveau|Venceslas|V|
Buhl|Derek L|DL|
Evrard|Alexis|A|
Ruggiero|Céline|C|
Mandé-Niedergang|Betty|B|
Roucard|Corinne|C|
Gurrell|Rachel|R|0000-0002-4209-4821

GAERS
absence
epilepsy
GABA
PF-06372865 (total ≥5
≤8)


What We Know and Do Not Know About Actin.

Abstract: Seven decades of research have revealed much about actin structure, assembly, regulatory proteins, and cellular functions. However, some key information is still missing, so we do not understand the mechanisms of most processes that depend on actin. This chapter summarizes our current knowledge and explains some examples of work that will be required to fill these gaps and arrive at a mechanistic understanding of actin biology.

D051376:Actin-Related Protein 2-3 Complex

Actin
Arp2/3 complex
Capping protein
Cofilin
Profilin


Scoring Performance on the Y-Balance Test Using a Deep Learning Approach.

Abstract: The Y Balance Test (YBT) is a dynamic balance assessment typically used in sports medicine. This work proposes a deep learning approach to automatically score this YBT by estimating the normalized reach distance (NRD) using a wearable sensor to register inertial signals during the movement. This paper evaluates several signal processing techniques to extract relevant information to feed the deep neural network. This evaluation was performed using a state-of-the-art human activity recognition system based on recurrent neural networks (RNNs). This deep neural network includes long short-term memory (LSTM) layers to learn features from time series by modeling temporal patterns and an additional fully connected layer to estimate the NRD (normalized by the leg length). All analyses were carried out using a dataset with YBT assessments from 407 subjects, including young and middle-aged volunteers and athletes from different sports. This dataset allowed developing a global and robust solution for scoring the YBT in a wide range of applications. The experimentation setup considered a 10-fold subject-wise cross-validation using training, validation, and testing subsets. The mean absolute percentage error (MAPE) obtained was 7.88 ± 0.20%. Moreover, this work proposes specific regression systems to estimate the NRD for each direction separately, obtaining an average MAPE of 7.33 ± 0.26%. This deep learning approach was compared to a previous work using dynamic time warping and k-NN algorithms, obtaining a relative MAPE reduction of 10%.

Y Balance Test
wearable sensors
recurrent neural networks
time series data


How to assess scapular dyskinesis precisely: 3-dimensional wing computer tomography--a new diagnostic modality.

Abstract:
BACKGROUND
Aberrations in scapular motion are believed to be associated with the presence of shoulder or elbow pathologies. There are many methods to evaluate scapular kinematics, but they have certain limitations. Nevertheless, it is believed that appropriate rehabilitation for each type of scapular dyskinesis is important.

METHODS
Eighty-nine athletes were videotaped and seven blinded observers categorized scapular dyskinesis into 4 types, which was followed by 3-dimensional (3D) wing computer tomography (CT). Four blinded examiners evaluated 5 angles [upward rotation (UR), internal rotation (IR), anterior tilting (AT), superior translation (ST), and protraction (PRO)] on the 3D wing CT. Inter-rater reliability (IRR) was calculated for both the methods. CT scan measurements were compared with the 4 observational types to establish the validity.

RESULTS
The IRR with observational assessment of scapular dyskinesis into 4 types was good, 0.780. The 3D wing CT analysis had a very high IRR, 0.972. There was a statistically significant correlation between observational assessment and 3D wing CT analysis. The UR angle, ST angle in type 3 scapular dyskinesis, and AT angle in type 1 scapular dyskinesis were increased as compared with those in the other types of scapular dyskinesis. All these measurements were made in the resting position of the scapula.

CONCLUSION
The 3D wing CT analysis allows precise quantification of a position associated with scapular dyskinesis. Therefore, 3D wing CT can be considered as an alternative method for assessing scapular dyskinesis.

Park|Jin-Young|JY|
Hwang|Jung-Taek|JT|
Kim|Kwang-Mo|KM|
Makkar|Dheeraj|D|
Moon|Sung Gyu|SG|
Han|Kyung-Jin|KJ|

Scapular dyskinesis
3D wing CT
inter-rater reliability
observational assessment
3D analysis
Diagnostic Study
Level III
scapular movement


Evaluation of Purdue Improved Crop Storage Triple Layer Hermetic Storage Bag against Prostephanus truncatus (Horn) (Coleoptera: Bostrichidae) and Sitophilus zeamais (Motsch.) (Coleoptera: Curculionidae).

Abstract: Hermetic technologies are being promoted in Africa as safer and more effective methods of grain storage on smallholder farms. However, farmers and policy makers lack knowledge of their efficacy in controlling major stored grain pests. An on-station study was conducted to evaluate the triple layer Purdue Improved Crop Storage (PICS) airtight bags against two major storage insect pests. Two sets each of PICS, jute and polypropylene bags were filled with 50 kg maize grain per bag. Each set was replicated four times. One set of PICS bags was each infested with 50 insects each of the larger grain borer P. truncatus and the maize weevil S. zeamais; while the other set was not. One set of jute and polypropylene woven bags was treated with a cocktail of 1.6% Pirimiphos methyl and 0.3% Permethrin, serving as positive controls; while the remaining sets with untreated maize grain formed negative controls. Gas analysis in the PICS bags followed the expected trend with oxygen levels falling sharply below 10% and carbon dioxide increasing to almost 10% after 12 weeks hence resulting in insect death. After 16 weeks, increase in oxygen levels may be attributed to perforation of the bags from outside by the P. truncatus. Results showed that PICS bags were significantly (P < 0.05) superior to treated and untreated controls of polypropylene and jute bags in suppressing insect development, maize grain damage and weight loss during storage. Weight loss in polypropylene and jute bags reached 40% and 41%, respectively, at 24 weeks after storage compared to PICS (2.4-2.9%). These results demonstrate that PICS bags can be used to store maize against P. truncatus and S. zeamais attack.

Mutambuki|Kimondo|K| Affognon|Hippolyte|H| Likhayo|Paddy|P| Baributsa|Dieudonne|D|

Prostephanus truncatus
Sitophilus zeamais
grain storage
PICS bags
smallholder farmers


The Sweetener-Sensing Mechanisms of the Ghrelin Cell.

Abstract: Carbohydrate administration decreases plasma levels of the 'hunger hormone' ghrelin. The ghrelin cell is co-localized with the sweet taste receptor subunit, TAS1R3, and the gustatory G-protein, gustducin, both involved in the sensing of sweeteners by entero-endocrine cells. This study investigated the role of gustducin-mediated sweet taste receptor signaling on ghrelin secretion in a gastric ghrelinoma cell line, tissue segments and mice. The monosaccharide d-glucose and low-intensity sweetener oligofructose (OFS) decreased (p < 0.001) ghrelin secretion while the high-intensity sweetener sucralose increased (p < 0.001) ghrelin secretion in vitro. These effects were not mediated via the sweet taste receptor or glucose transporters (the sodium-dependent glucose cotransporter SGLT-1 and GLUT2). The effect of these compounds was mimicked ex vivo in gastric and jejunal segments from both wild type (WT) and α-gustducin knockout (α-gust-/-) mice. In vivo, the sensing of d-glucose was polarized since intragastric but not intravenous administration of d-glucose decreased (p < 0.05) ghrelin levels in an α-gustducin independent manner which involved inhibition of duodenal ghrelin release. In contrast, neither OFS nor sucralose affected ghrelin secretion in vivo. In conclusion, α-gustducin-mediated sweet taste receptor signaling does not play a functional role in the sensing of carbohydrates, or low- or high-intensity sweeteners by the ghrelin cell.

ghrelin
sweet taste receptor
gustducin
sweeteners
glucose


Olfaction preservation after removal of large tuberculum sellae meningiomas via a superior interhemispheric approach. A quantitative and qualitative study.

Abstract:
INTRODUCTION
We present a prospective series of tuberculum sellae meningioma (TSM) resected via a superior interhemispheric (IH) approach in 10 patients who preoperatively and postoperatively underwent extensive olfaction testing using a standardised test battery.

PATIENTS AND METHODS
This prospective longitudinal study evaluated the olfactory function after TSM resection. The resection was performed via a superior interhemispheric (IH) approach. The quantitative and qualitative analyses of the olfactory function were assessed with the Biolfa(®) olfactory test (at 6 months).

RESULTS
Between November 2009 and April 2012, 10 consecutive patients with symptomatic TSM and preserved olfactory function were operated via a superior IH approach. For the self-evaluation criteria of the olfactory function, the mean preoperative visual analog scale score was 8.8. The mean preoperative total quantitative (/27) scored 18.2 ± 6.3 for this cohort of 10 patients. In the postoperative period, the mean total score decreased non-significantly to 15.8 ± 8.8 (Wilcoxon test, P = 0.085). The mean preoperative qualitative score (/8) was 5.5 ± 1.7 and in the postoperative period decreased, non-significantly, to 4.7 ± 2.6 (Wilcoxon test, P = 0.12). The olfactory function was quantitatively and qualitatively preserved in 6 patients (60%), but a postoperative deterioration occurred in 2 (20%) and an anosmia in 2 (20%). Size and invasive characteristics of the meningioma determined the post-surgical deterioration.

CONCLUSION
Olfaction is an important factor of emotional and social life, which needs to be integrated into the challenge regarding the resection of TSM. The risks of nerve damage are reviewed.

Hannequin|P|P| Paviot|A|A| Chaussy|O|O| Gilard|V|V| Cébula|H|H| Marie|J-P|JP| Proust|F|F|

Olfaction
Meningioma
Méningiome
Sellar tuberculum
Tubercule sellaire


p21CIP1 Induces Apoptosis via Binding to BCL2 in LNCaP Prostate Cancer Cells Treated with MCS-C3, A Novel Carbocyclic Analog of Pyrrolopyrimidine.

Abstract:
BACKGROUND
Previously, we synthesized a new carbocyclic analog of pyrrolo[2,3-d]pyrimidine nucleoside, designated MCS-C3. Recently, we found that LNCaP androgen-responsive prostate cancer cells treated with MCS-C3 rapidly undergo intrinsic apoptosis through dramatic up-regulation of p21(CIP1). The present study aimed to evaluate the cellular functions and underlying molecular mechanisms of p21(CIP1) on apoptotic induction in LNCaP cells treated with 6 μM MCS-C3.

MATERIALS AND METHODS
Western blots, flow cytometric assay, immunoprecipitation, and transmission electron microscopy analysis were used to measure apoptotic induction in 6-μM MCS-C3-treated LNCaP cells. Effects of MCS-C3 on gene expression of p21(CIP1) were measured by semi-quantitative real-time polymerase chain reaction, and small interfering RNA transfection.

RESULTS
MCS-C3 induced appreciable caspase-dependent apoptosis associated with the significant up-regulation of p53-dependent p21(CIP1) in LNCaP cells. Moreover, this apoptotic induction was caused by direct binding of p21(CIP1) to anti-apoptotic B-cell lymphoma 2 (BCL2) protein, and antagonizing BCL2 function. In addition, MCS-C3-mediated apoptotic induction, and up-regulation of p21(CIP1) were almost completely blocked by the treatment of androgen-responsive LNCaP cells with flutamide, an androgen receptor (AR) antagonist.

CONCLUSION
We identified that induction of intrinsic apoptosis in LNCaP cells by 6 μM MCS-C3 is associated not only with p53 activation but also with mediation of AR. In the present study, we identified the cellular functions and underlying molecular mechanisms of p53-dependent and AR-associated p21(CIP1) on apoptotic induction via direct binding to BCL2 in LNCaP cells treated with 6 μM MCS-C3.

Choi|Ko-Woon|KW|
Suh|Hyewon|H|
Oh|Ha Lim|HL|
Ryou|Chongsuk|C|
Lee|Chul-Hoon|CH|


Cognitive Dysfunction in Asian Patients with Depression (CogDAD): A Cross-Sectional Study.

Abstract:
Background
Cognitive dysfunction is a predominant symptom of Major Depressive Disorder (MDD), contributing to functional impairment.

Objective
The primary objective of this study was to assess and describe perceived cognitive dysfunction amongst Asian patients diagnosed with MDD. The secondary objective was to explore the associations between depression severity, perceived cognitive dysfunction and functional disability.

Methods
This was a multi-country, multi-centre, cross-sectional study. Adults with a current episode of MDD were recruited from 9 university/general hospital clinics in Asia. During a single study visit, psychiatrists assessed depression severity (Clinical Global Impression-Severity, CGI-S); patients completed questionnaires assessing depression severity (Patient Health Questionnaire-9 items, PHQ-9), perceived cognitive dysfunction (Perceived Deficit Questionnaire-Depression, PDQ-D) and functional disability (Sheehan Disability Scale, SDS).

Results
Patients (n=664), predominantly women (66.3%), were aged 46.5±12.5 years, lived in urban areas (81.3%) and were employed (84.6%). 51.5% of patients were having their first depressive episode; 86.7% were receiving treatment; 82.2% had a current episode duration >8 weeks. Patients had mild-to-moderate depression (CGI-S=3.3±1.0; PHQ-9=11.3±6.9). Patients reported perceived cognitive dysfunction (PDQ-D=22.6±16.2) and functional disability (SDS=11.3±7.9). PHQ-9, PDQ-D and SDS were moderately-to-highly correlated (PHQ-9 and SDS: r=0.72; PHQ-9 and PDQ-D: r=0.69; PDQ-D and SDS, r=0.63). ANCOVA showed that after controlling for patient-reported depression severity (PHQ-9), perceived cognitive dysfunction (PDQ-D) was significantly associated with functional disability (SDS) (p<0.001).

Conclusions
Asian patients with MDD reported perceived cognitive dysfunction. There is a need for physicians to evaluate cognitive dysfunction in the clinical setting in order to reach treatment goals, including functional recovery beyond remission of mood symptoms.

Manit|Srisurapanont|S|
Yee Ming|Mok|M|
Yen Kuang|Yang|Y|
Herng-Nieng|Chan|C|
Constantine D|Della|D|
Zuraida|Zainal Nor|ZN|
Stephen|Jambunathan|J|
Nurmiati|Amir|A|
Pranabi|Kalita|K|

Cognition
Depression
Symptom
Functioning
Perceived cognitive dysfunction
Asia


Physician Characteristics Strongly Predict Patient Enrollment In Hospice.

Abstract: Individual physicians are widely believed to play a large role in patients' decisions about end-of-life care, but little empirical evidence supports this view. We developed a novel method for measuring the relationship between physician characteristics and hospice enrollment, in a nationally representative sample of Medicare patients. We focused on patients who died with a diagnosis of poor-prognosis cancer in the period 2006-11, for whom palliative treatment and hospice would be considered the standard of care. We found that the proportion of a physician's patients who were enrolled in hospice was a strong predictor of whether or not that physician's other patients would enroll in hospice. The magnitude of this association was larger than that of other known predictors of hospice enrollment that we examined, including patients' medical comorbidity, age, race, and sex. Patients cared for by medical oncologists and those cared for in not-for-profit hospitals were significantly more likely than other patients to enroll in hospice. These findings suggest that physician characteristics are among the strongest predictors of whether a patient receives hospice care-which mounting evidence indicates can improve care quality and reduce costs. Interventions geared toward physicians, both by specialty and by previous history of patients' hospice enrollment, may help optimize appropriate hospice use.

Obermeyer|Ziad|Z|
Powers|Brian W|BW|
Makar|Maggie|M|
Keating|Nancy L|NL|
Cutler|David M|DM|


Effectiveness of Yi-Zhi-An-Shen granules on cognition and sleep quality in older adults with amnestic mild cognitive impairment: protocol for a randomized, double-blind, placebo-controlled trial.

Abstract:
BACKGROUND
Amnestic mild cognitive impairment (aMCI) is a syndrome characterized by significant forgetfulness that does not meet the criteria of dementia. Individuals with aMCI are at greater risk of progressing to dementia. Current studies suggest that good sleep quality is linked with preserved cognition in the elderly, and sleep complaints are common among the elderly with amnesia. Therefore, improving their sleep may be helpful for maintaining and improving their cognitive capacity. According to the theory of traditional Chinese medicine, Yi-Zhi-An-Shen is an herbal compound which may ameliorate forgetfulness and sleep disorders. As growing evidence indicates that the gut microbiome is associated with major mental symptoms, a hypothesis was proposed that Yi-Zhi-An-Shen granules (YZASG) might work by alternating microbial abundance and diversity. In this study, the investigators intend to assess the efficacy of YZASG on global cognition in the elderly suffering from aMCI and evaluate its safety as well as its potential mechanisms via sleep quality, fecal microbial 16S ribosomal DNA and metagenomics analyses, and serum markers.

METHODS/DESIGN
This study is a randomized, double-blind, placebo-controlled clinical trial. A total of 80 patients (aged 60-85 years) will be recruited and allocated randomly to a treatment group and a placebo group in a 1:1 ratio and will then be administered YZASG or isodose placebo three times a day. The intervention course is 16 weeks, with an 18 months follow-up. The primary outcome is the Alzheimer's Disease Assessment Scale-Cognitive Subscale. Secondary outcome measures are the Mini-Mental State Examination, Montreal Cognitive Assessment, Pittsburgh Sleep Quality Index, serum concentrations of immunological factors and inflammatory cytokines, and fecal microbiota. Fecal microbiota will only be collected at the baseline and endpoint of the intervention.

DISCUSSION
The results of this trial will be conducive to assessing the safety and effectiveness on cognition of YZASG in intervening aMCI among the elderly and determining if it takes effect via the improvement of sleep quality, regulation of gut microbiota, and concentration of certain serum markers.

TRIAL REGISTRATION
ClinicalTrials.gov, NCT03601000 . Registered on 26 July 2018.

D016032:Randomized Controlled Trials as Topic

Sleep
Older adults
Amnestic mild cognitive impairment
Gut microbiome


The effectiveness of memory remediation strategies after traumatic brain injury: Systematic review and meta-analysis.

Abstract:
BACKGROUND
Traumatic brain injury (TBI) is a steadily rising health concern associated with significant risk of emotional, behavioral and cognitive impairments. Cognitive memory impairment is one of the most concerning outcomes after TBI, affecting a wide range of everyday activities, social interactions and employment. Several comparative and comprehensive reviews on the effects of cognitive interventions in individuals with TBI have been conducted but usually with a qualitative rather than quantitative approach. Thus, evidence synthesis of the effects of TBI interventions on memory difficulties is limited.

OBJECTIVE
In this meta-analysis, we examined the memory-remediating effects of internal and external interventions, injury severity and the interaction of both factors for patients with TBI.

METHODS
Data were extracted from studies published between 1980 and 2020 that used objective memory measures (computerized or pencil-and-paper), and multiple meta-analyses were conducted to compare effectiveness across these interventions. Publication bias was assessed, as was quality of evidence using the Cochrane Risk of Bias tool for randomized controlled studies. Our final meta-analysis included 16 studies of 17 interventions classified into 3 categories: internal, external and mixed.

RESULTS
Mixed interventions demonstrated the highest average effect size for memory difficulties (Morris d=0.79). An evaluation of injury severity yielded 2 categories: mild-moderate and moderate-severe. Analyses demonstrated a homogenous medium effect size of improvement across injury severity, with moderate-severe injury with the largest average effect size (Morris d=0.65). Further evaluation of injury severity interaction with intervention type revealed a mediating effect for both factors, demonstrating the largest effect size for mixed interventions with moderate-severe injury (Morris d=0.81).

CONCLUSION
This study highlights the effectiveness of memory remediation interventions on memory impairment after TBI. A wide range of interventions are more effective because they address individual variability for severity and memory deficits. The study further supports and expands existing intervention standards and guidelines.

Memory remediation
Meta-analysis
TBI
Interventions
Injury severity


Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial.

Abstract:
BACKGROUND
Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance.

METHODS
This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships.

RESULTS
Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events.

CONCLUSIONS
The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.

Sunitinib
Pediatric
Gastrointestinal stromal tumor
Pharmacokinetics
Safety


Correlations between the Type of Aggregates in the Bulk Phase and the Functionality and Safety of All-Purpose Cleaners.

Abstract: The article shows that the type and concentration of inorganic salt can be translated into the structure of the bulk phase and the performance properties of ecological all-purpose cleaners (APC). A base APC formulation was developed. Thereafter, two types of salt (sodium chloride and magnesium chloride) were added at various concentrations to obtain different structures in the bulk phase. The salt addition resulted in the formation of spherical micelles and-upon addition of more electrolyte-of aggregates having a lamellar structure. The formulations had constant viscosities (ab. 500 mPa·s), comparable to those of commercial products. Essential physical-chemical and performance properties of the four formulations varying in salt types and concentrations were evaluated. It was found that the addition of magnesium salt resulted in more favorable characteristics due to the surface activity of the formulations, which translated into adequately high wettability of the investigated hydrophobic surfaces, and their ability to emulsify fat. A decreasing relationship was observed in foaming properties: higher salt concentrations lead to worse foaming properties and foam stability of the solutions. For the magnesium chloride composition, the effect was significantly more pronounced, as compared to the sodium chloride-based formulations. As far as safety of use is concerned, the formulations in which magnesium salt was used caused a much lesser irritation compared with the other investigated formulations. The zein value was observed to decrease with increasing concentrations of the given type of salt in the composition.

functionality
safety
all-purpose cleaners
detergency
eco-friendly cleaning products1
electrolytes
skin irritation
volume phase


Extracellular vesicles as a platform for membrane-associated therapeutic protein delivery.

Abstract: Membrane proteins are of great research interest, particularly because they are rich in targets for therapeutic application. The suitability of various membrane proteins as targets for therapeutic formulations, such as drugs or antibodies, has been studied in preclinical and clinical studies. For therapeutic application, however, a protein must be expressed and purified in as close to its native conformation as possible. This has proven difficult for membrane proteins, as their native conformation requires the association with an appropriate cellular membrane. One solution to this problem is to use extracellular vesicles as a display platform. Exosomes and microvesicles are membranous extracellular vesicles that are released from most cells. Their membranes may provide a favourable microenvironment for membrane proteins to take on their proper conformation, activity, and membrane distribution; moreover, membrane proteins can cluster into microdomains on the surface of extracellular vesicles following their biogenesis. In this review, we survey the state-of-the-art of extracellular vesicle (exosome and small-sized microvesicle)-based therapeutics, evaluate the current biological understanding of these formulations, and forecast the technical advances that will be needed to continue driving the development of membrane protein therapeutics.

Yang|Yoosoo|Y|
Hong|Yeonsun|Y|
Cho|Eunji|E|
Kim|Gi Beom|GB|
Kim|In-San|IS|

Extracellular vesicle
Membrane protein
Exosomes
Microdomain
Protein therapeutics


Development and evaluation of antimicrobial herbal formulations containing the methanolic extract of Samadera indica for skin diseases.

Abstract: Samadera indica Gaetrn (Simaroubaceae) is claimed to possess various pharmacological activities like antioxidant, antifungal, antitumor, antiviral, and so on, but its taste is bitter. The aim of the present study is to investigate the toxicity of the methanolic extract and to develop suitable herbal formulations of the methanolic extract of Samadera indica, having efficient antimicrobial activity. The methanolic extract prepared from the dried leaves of Samadera indica by continuous hot percolation, were used to examine the toxicity, according to the OECD 423 guidelines, in Swiss Albino mice. Topical formulations were prepared by incorporating Samadera indica (5% w / w) in an emulsifying ointment and a carbopol gel base and evaluated for physical parameters and in-vitro antimicrobial activity (S. aureus, P. aeruginosa and C. albicans). The study reveals that no animals under the study showed any clinical signs of toxicity or mortality when administered a dose of 5 - 2000 mg / kg body weight. Therefore, the maximum tolerated dose of the methanolic extract of Samadera indica was above 2000 mg / kg body weight. The formulated ointment and gel had acceptable physical parameters that showed that they were compatible with the skin, and in addition to this, these formulations passed the short-term stability studies. The in-vitro antimicrobial activity studies showed that the formulated ointment showed significantly strong (p < 0.05) activity against S. aureus, P. aeruginosa and C. albicans than the formulated gel. Thus, the present study concludes that the formulated ointment and gel are safe and efficient antimicrobial formulations for the topical delivery of the methanolic extract of Samadera indica.

Viswanad|Vidya|V|
Aleykutty|N A|NA|
Jayakar|B|B|
Zacharia|Subin Mary|SM|
Thomas|Litha|L|

Samadera indica
ointment
gel
Acute toxicity
antibacterial activity
antifungal activity


Study on Low-Velocity Impact Damage and Residual Strength of Reinforced Composite Skin Structure.

Abstract: In order to better understand the damage tolerance of reinforced composite plates, the impact damage of the reinforced composite plates was investigated under low-velocity impact test. The experimental results show that the impact of different positions and energies causes different degrees of damage to the specimens, including but not limited to ply fracture, internal delamination of the skin, and debonding of the stiffeners and skin. After impacting, the specimens were tested in an axial compression. The results show that the ultimate bearing capacity of the specimen is also affected by different forms of impact. The impact point has the greatest influence on the specimen while it locates at the intersection of longitudinal and transverse bars. Compared with the intact specimen, the ultimate load carrying capacity was reduced by 16.83% and 44.02%, while the specimen impacted by 15 J and 30 J, respectively. The compression failure mode of the damaged specimen is mainly the breakage of the stiffeners and the delamination of the skin.

Li|Hanhua|H| Zhang|Qiuhua|Q| Jia|Jiale|J| Ji|Chunming|C|0000-0001-5345-1719 Wang|Bing|B| Yan|Shi|S|

low-velocity impact
reinforced composite plate
compression after impact


Health literacy.

Abstract: Health literacy skills are cognitive and social skills which determine the motivation and ability of individuals to gain access to, understand, and use information in ways which promote and maintain good health'. Patients use these literacy skills to critically analyze information; to allow them to exert greater control over life events and situations. An understanding of health literacy is also important for those developing and delivering healthcare programmes, especially vaccination programmes, as both the information and the actions required to use the information are complex requiring sophisticated health literacy skills beyond the capacity of a significant proportion of the population. There are simple steps which can be taken to make the information in vaccination materials easier to understand and use. The complex concepts of reading and numeracy skills in relation to health will be discussed and strategies described which can improve access to healthcare information for all patients, whatever their literacy level.

health literacy
vaccination
health information


Antimicrobial resistance in commensal Escherichia coli and Enterococcus spp. is influenced by production system, antimicrobial use, and biosecurity measures on Spanish pig farms.

Abstract:
BACKGROUND
Antimicrobial resistance (AMR) is a global public health threat consequence of antimicrobial use (AMU) in human and animal medicine. In food-producing animals factors such as management, husbandry or biosecurity may impact AMU. Organic and extensive Iberian swine productions are based on a more sustainable and eco-friendly management system, providing an excellent opportunity to evaluate how sustained differences in AMU impact the AMR in indicator bacteria. Here, we evaluate the usefulness of commensal Escherichia coli and Enterococcus spp. isolates as AMR bioindicators when comparing 37 Spanish pig farms from both intensive and organic-extensive production systems, considering the effect of AMU and biosecurity measures, the last only on intensive farms.

RESULTS
The production system was the main factor contributing to explain the AMR differences in E. coli and Enterococcus spp. In both bacteria, the pansusceptible phenotype was more common (p < 0.001) on organic-extensive farms when compared to intensive herds. The microbiological resistance in commensal E. coli was, for most of the antimicrobials evaluated, significantly higher (p < 0.05) on intensive farms. In enterococci, the lincosamides usage revealed the association between AMR and AMU, with an increase in the AMR for erythromycin (p < 0.01), quinupristin-dalfopristin (p < 0.01) and the multidrug-resistant (MDR) phenotype (p < 0.05). The biosecurity measures implemented on intensive farms influenced the AMR of these bioindicators, with a slightly lower resistance to sulfamethoxazole (p < 0.01) and the MDR phenotype (p < 0.05) in E. coli isolated from farms with better cleaning and disinfection protocols. On these intensive farms, we also observed that larger herds had a higher biosecurity when compared to smaller farms (p < 0.01), with no significant associations between AMU and the biosecurity scores.

CONCLUSIONS
Overall, this study evidences that the production system and, to a lesser extent, the biosecurity measures, contribute to the AMR development in commensal E. coli and Enterococcus spp., with antimicrobial usage as the main differential factor, and demonstrates the potential value of these bacteria as bioindicators on pig farms in AMR surveillance programs.

Escherichia coli
Enterococcus spp.
Swine
Bioindicator
Antibiotic usage
One health
Sustainable farming


Targeting Macrophage for the Treatment of Amyotrophic Lateral Sclerosis.

Abstract:
BACKGROUND & OBJECTIVE
Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that specifically affects motor neurons in the brain and in the spinal cord. Patients with amyotrophic lateral sclerosis usually die from respiratory failure within 3 to 5 years from when the symptoms first appear. Currently, there is no cure for amyotrophic lateral sclerosis. Accumulating evidence suggests that dismantling of neuromuscular junction is an early event in the pathogenesis of amyotrophic lateral sclerosis.

CONCLUSION
It is starting to realized that macrophage malfunction contributes to the disruption of neuromuscular junction. Modulation of macrophage activation states may stabilize neuromuscular junction and provide protection against motor neuron degeneration in amyotrophic lateral sclerosis.


Efficacy and safety of endometrial ablation for treating abnormal uterine bleeding in pre- and postmenopausal women with liver cirrhosis.

Abstract:
AIM
Abnormal uterine bleeding (AUB) occurs in 10-30% of women of reproductive age and up to 61% of cirrhotic women. We evaluated the efficacy and safety of endometrial ablation (NovaSure therapy) for AUB in cirrhotic women.

METHODS
This prospective, two-arm, observational study enrolled patients for NovaSure treatment, and they were followed for 12 months. Primary measurements were the amenorrhea rate and changes of pictorial blood loss assessment chart (PBLAC) scores at 1-month post-therapy. Key secondary end-points included the longevity of amenorrhea at 12 months, safety profile, and progression of cirrhosis.

RESULTS
Among 88 women, 26 were cirrhotic and 62 were non-cirrhotic. At 1-month post-NovaSure treatment, a significant reduction of mean PBLAC scores was observed in cirrhotic patients compared to those at baseline (0.4 ± 1.3 vs 215.2 ± 410.9, P < 0.001), and the amenorrhea rate was 88.5%. The efficacy outcomes of the PBLAC scores and amenorrhea rate were maintained until the end of the 12-month follow-up. A significant improvement in quality of life scores was observed 1-month post-therapy compared to those at baseline (5.4 ± 3.1 vs 20.5 ± 5.5, P < 0.001). Patients' satisfaction rates were 100% and 92.31% at 6 and 12 months, respectively. The aforementioned outcomes were comparable with those in non-cirrhotic patients. No significant progression of cirrhosis or safety concern was reported.

CONCLUSION
Cirrhotic patients on NovaSure therapy had a high rate of amenorrhea 1-month post-treatment, which maintained longevity for 12 months. The safety profile was similar to that in non-cirrhotic patients.

Liu|Qing|Q|
Li|Xiu-Lan|XL|
Liu|Ji-Juan|JJ|
Song|Xiao-Hong|XH|
Jiang|Xiao-Ying|XY|
Li|Wei|W|
Zhang|Hua|H|
Pan|Calvin Q|CQ|

endometrial ablation
abnormal uterine bleeding
NovaSure
hepatic cirrhosis


Speech Characteristics of Patients with Parkinson's Disease-Does Dopaminergic Medications Have a Role?

Abstract: Objective  The present study aimed to investigate the effects of dopaminergic medication on voice, speech motor functions, and motor impairment in patients with Parkinson's disease (PD). Materials and Methods  Twenty-five individuals (16 males and 9 females) with PD underwent comprehensive assessment of voice, speech, and motor functions in levodopa medication ON and medication OFF conditions. Age- and gender-matched healthy controls were recruited to compare speech and acoustic parameters. Multi-Dimensional Voice Program (MDVP) from Computerized Speech Laboratory (Model: 4500) was utilized for acoustic analysis of voice and the Voice Handicap Index (VHI) for the self-assessment of vocal function. Frenchay Dysarthria Assessment (FDA-2) and Unified Parkinson's Disease Rating Scale-III (UPDRS III) were used to evaluate speech motor and motor functions, respectively. Statistical Analysis  The mean and standard deviation were used as descriptive statistics measures. Raw scores were obtained for FDA-2, DRS, VHI, MDVP parameters, and UPDRS-III in either medication condition. The Wilcoxon signed-rank test was performed to determine the statistical significance of the above measures in both genders across the medication conditions. Spearman's rank correlation coefficient was used to determine the relationship between motor speech function and motor impairment and between VHI and MDVP parameters across both medication conditions. The interrater reliability rating was established using Cohen's kappa. Results  An improvement in lip and laryngeal functioning was found in the medication ON over medication OFF state in both males and females with PD. A few frequency and amplitude-related measures improved in the medication-ON state over the medication-OFF state. UPDRS-III scores reduced from the OFF state to the ON state, and no change in dysarthria severity or VHI was found in either gender or medication condition. No correlation was found between speech motor function and motor function or between VHI and acoustic parameters of voice in either medication condition. Conclusions  Improvement in motor symptoms with levodopa was predominantly observed when compared with the minor improvements in a few aspects of speech motor function and vocal parameters. The results of this study suggest the need for speech therapy as a nonpharmacological treatment method for speech impairments in PD.

speech
dopaminergic medication
Parkinson's disease
Voice Handicap Index


A simulation study to quantify the impacts of exposure measurement error on air pollution health risk estimates in copollutant time-series models.

Abstract:
BACKGROUND
Exposure measurement error in copollutant epidemiologic models has the potential to introduce bias in relative risk (RR) estimates. A simulation study was conducted using empirical data to quantify the impact of correlated measurement errors in time-series analyses of air pollution and health.

METHODS
ZIP-code level estimates of exposure for six pollutants (CO, NOx, EC, PM2.5, SO4, O3) from 1999 to 2002 in the Atlanta metropolitan area were used to calculate spatial, population (i.e. ambient versus personal), and total exposure measurement error. Empirically determined covariance of pollutant concentration pairs and the associated measurement errors were used to simulate true exposure (exposure without error) from observed exposure. Daily emergency department visits for respiratory diseases were simulated using a Poisson time-series model with a main pollutant RR = 1.05 per interquartile range, and a null association for the copollutant (RR = 1). Monte Carlo experiments were used to evaluate the impacts of correlated exposure errors of different copollutant pairs.

RESULTS
Substantial attenuation of RRs due to exposure error was evident in nearly all copollutant pairs studied, ranging from 10 to 40% attenuation for spatial error, 3-85% for population error, and 31-85% for total error. When CO, NOx or EC is the main pollutant, we demonstrated the possibility of false positives, specifically identifying significant, positive associations for copollutants based on the estimated type I error rate.

CONCLUSIONS
The impact of exposure error must be considered when interpreting results of copollutant epidemiologic models, due to the possibility of attenuation of main pollutant RRs and the increased probability of false positives when measurement error is present.

Exposure measurement error
Copollutant
Bias
Exposure assessment
Exposure modeling


Neurobiology of Pediatric Anxiety Disorders.

Abstract: While the fear-based anxiety disorders (i.e., generalized anxiety disorder, social phobia and separation anxiety disorder) are among the most common psychiatric conditions in children and adolescents, only recently has an integrated understanding of the neurobiology of these disorders developed. In this regard, both structural and functional neuroimaging studies have demonstrated neuroanatomic and functional abnormalities within the amygdala and prefrontal cortex in youth with fear-based anxiety disorders, and have also suggested altered functional connectivity among components of the anterior limbic network (ALN), as well as alterations in neurochemistry within the anterior cingulate cortex. Additionally, several prefrontal structures and regions (e.g., medial prefrontal cortex) appear to be dysregulated in youth who are at risk of developing anxiety disorders (e.g., youth with inhibited temperament, behavioral inhibition, etc.). Finally, emerging data raise the possibility that functional activity within these amygdala-prefrontal networks may be affected by successful psychopharmacologic and psychotherapeutic treatment and may predict outcome.

Strawn|Jeffrey R|JR|
Dominick|Kelli C|KC|
Patino|Luis R|LR|
Doyle|Christopher D|CD|
Picard|Lara S|LS|
Phan|K Luan|KL|

Anxiety disorders
1H MRS
Generalized anxiety disorder (GAD)
Separation anxiety disorder (SAD)
Social phobia (SoP)
fMRI


Future Challenges in Cancer Resistance to Immunotherapy.

Abstract: Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

van Elsas|Marit J|MJ|
van Hall|Thorbald|T|0000-0002-9115-558X
van der Burg|Sjoerd H|SH|

immunotherapy
primary resistance
secondary resistance


Development of in vitro resistance to chitosan is related to changes in cell envelope structure of Staphylococcus aureus.

Abstract: The bacterial cell envelope is believed to be a principal target for initiating the staphylocidal pathway of chitosan. The present study was therefore designed to investigate possible changes in cell surface phenotypes related to the in vitro chitosan resistance development in the laboratory strain S. aureus SG511-Berlin. Following a serial passage experiment, a stable chitosan-resistant variant (CRV) was identified, exhibiting >50-fold reduction in its sensitivity towards chitosan. Our analyses of the CRV identified phenotypic and genotypic features that readily distinguished it from its chitosan-susceptible parental strain, including: (i) a lower overall negative cell surface charge; (ii) cross-resistance to a number of antimicrobial agents; (iii) major alterations in cell envelope structure, cellular bioenergetics and metabolism (based on transcriptional profiling); and (iv) a repaired sensor histidine kinase GraS. Our data therefore suggest a close nexus between changes in cell envelope properties with the in vitro chitosan-resistant phenotype in S. aureus SG511-Berlin.

Raafat|Dina|D| Leib|Nicole|N| Wilmes|Miriam|M| François|Patrice|P| Schrenzel|Jacques|J| Sahl|Hans-Georg|HG|

D000900:Anti-Bacterial Agents
D048271:Chitosan
D008826:Microbial Sensitivity Tests
D013211:Staphylococcus aureus

Chitosan
Antibiotic resistance
Microarray analysis
Phospholipids analysis


Exploring the occurrence of classic selective sweeps in humans using whole-genome sequencing data sets.

Abstract: Genome-wide scans for selection have identified multiple regions of the human genome as being targeted by positive selection. However, only a small proportion has been replicated across studies, and the prevalence of positive selection as a mechanism of adaptive change in humans remains controversial. Here we explore the power of two haplotype-based statistics--the integrated haplotype score (iHS) and the Derived Intraallelic Nucleotide Diversity (DIND) test--in the context of next-generation sequencing data, and evaluate their robustness to demography and other selection modes. We show that these statistics are both powerful for the detection of recent positive selection, regardless of population history, and robust to variation in coverage, with DIND being insensitive to very low coverage. We apply these statistics to whole-genome sequence data sets from the 1000 Genomes Project and Complete Genomics. We found that putative targets of selection were highly significantly enriched in genic and nonsynonymous single nucleotide polymorphisms, and that DIND was more powerful than iHS in the context of small sample sizes, low-quality genotype calling, or poor coverage. As we excluded genomic confounders and alternative selection models, such as background selection, the observed enrichment attests to the action of recent, strong positive selection. Further support to the adaptive significance of these genomic regions came from their enrichment in functional variants detected by genome-wide association studies, informing the relationship between past selection and current benign and disease-related phenotypic variation. Our results indicate that hard sweeps targeting low-frequency standing variation have played a moderate, albeit significant, role in recent human evolution.

Fagny|Maud|M|
Patin|Etienne|E|
Enard|David|D|
Barreiro|Luis B|LB|
Quintana-Murci|Lluis|L|
Laval|Guillaume|G|

D044466:Asians
D044383:Blacks
D030541:Databases, Genetic
D014644:Genetic Variation
D005828:Genetics, Population
D015894:Genome, Human
D006801:Humans
D008957:Models, Genetic
D020641:Polymorphism, Single Nucleotide
D012641:Selection, Genetic
D017422:Sequence Analysis, DNA
D044465:Whites

whole-genome sequence data
positive selection
human populations
neutrality statistics


Can dogs use vocal intonation as a social referencing cue in an object choice task?

Abstract: Evidence from the literature indicates that dogs' choices can be influenced by human-delivered social cues, such as pointing, and pointing combined with facial expression, intonation (i.e., rising and falling voice pitch), and/or words. The present study used an object choice task to investigate whether intonation conveys unique information in the absence of other salient cues. We removed facial expression cues and speech information by delivering cues with the experimenter's back to the dog and by using nonword vocalizations. During each trial, the dog was presented with pairs of the following three vocal cues: Positive (happy-sounding), Negative (sad-sounding), and Breath (neutral control). In Experiment 1, where dogs received only these vocal cue pairings, dogs preferred the Positive intonation, and there was no difference in choice behavior between Negative or Breath. In Experiment 2, we included a point cue with one of the two vocal cues in each pairing. Here, dogs preferred containers receiving pointing cues as well as Negative intonation, and preference was greatest when both of these cues were presented together. Taken together, these findings indicate that dogs can indeed extract information from vocal intonation alone, and may use intonation as a social referencing cue. However, the effect of intonation on behavior appears to be strongly influenced by the presence of pointing, which is known to be a highly salient visual cue for dogs. It is possible that in the presence of a point cue, intonation may shift from informative to instructive.

Colbert-White|Erin N|EN|
Tullis|Alexa|A|
Andresen|David R|DR|
Parker|Kiona M|KM|
Patterson|Kaylana E|KE|

Dogs
Intonation
Social referencing
Object choice task
Pointing
Canis familiaris


A New Species of Micryletta (Amphibia: Anura) from Sumatra, Indonesia.

Abstract: Micryletta inornata is a complex species that is widely distributed from Sumatra to mainland Asia, including the Thai-Malay Peninsula and Indochina. Recently, this species was confirmed to be endemic to regions near the type locality in Sumatra, and the populations from other regions were suggested to be different species. We examined phenotypic and genotypic characters of the Sumatran populations and found an unnamed lineage in addition to the true M. inornata. The newly found lineage can be distinguished from M. inornata and other congeners by both molecular and morphological traits and has been named Micryletta sumatrana sp. nov. The new species is characterized by having a small body size, golden brown dorsum with scattered dark spots, dark brown ventrum with diffuse cream mottling, dark brown lateral head with cream spots on lips and the tympanum region extending to the axilla, and tibiotarsal articulation reaching to the front of the eye. We discuss the taxonomic status of so-called M. inornata occurring outside of its type locality, especially of M. inornata lineata.

Munir|Misbahul|M|
Hamidy|Amir|A|
Matsui|Masafumi|M|
Kusrini|Mirza Dikari|MD|
Nishikawa|Kanto|K|

Sumatra
Micryletta inornata
Micryletta sumatrana sp. nov
mtDNA phylogeny
systematics
taxonomy


Assessment of a personalized and distributed patient guidance system.

Abstract:
OBJECTIVES
The MobiGuide project aimed to establish a ubiquitous, user-friendly, patient-centered mobile decision-support system for patients and for their care providers, based on the continuous application of clinical guidelines and on semantically integrated electronic health records. Patients would be empowered by the system, which would enable them to lead their normal daily lives in their regular environment, while feeling safe, because their health state would be continuously monitored using mobile sensors and self-reporting of symptoms. When conditions occur that require medical attention, patients would be notified as to what they need to do, based on evidence-based guidelines, while their medical team would be informed appropriately, in parallel. We wanted to assess the system's feasibility and potential effects on patients and care providers in two different clinical domains.

MATERIALS AND METHODS
We describe MobiGuide's architecture, which embodies these objectives. Our novel methodologies include a ubiquitous architecture, encompassing a knowledge elicitation process for parallel coordinated workflows for patients and care providers; the customization of computer-interpretable guidelines (CIGs) by secondary contexts affecting remote management and distributed decision-making; a mechanism for episodic, on demand projection of the relevant portions of CIGs from a centralized, backend decision-support system (DSS), to a local, mobile DSS, which continuously delivers the actual recommendations to the patient; shared decision-making that embodies patient preferences; semantic data integration; and patient and care provider notification services. MobiGuide has been implemented and assessed in a preliminary fashion in two domains: atrial fibrillation (AF), and gestational diabetes Mellitus (GDM). Ten AF patients used the AF MobiGuide system in Italy and 19 GDM patients used the GDM MobiGuide system in Spain. The evaluation of the MobiGuide system focused on patient and care providers' compliance to CIG recommendations and their satisfaction and quality of life.

RESULTS
Our evaluation has demonstrated the system's capability for supporting distributed decision-making and its use by patients and clinicians. The results show that compliance of GDM patients to the most important monitoring targets - blood glucose levels (performance of four measurements a day: 0.87±0.11; measurement according to the recommended frequency of every day or twice a week: 0.99±0.03), ketonuria (0.98±0.03), and blood pressure (0.82±0.24) - was high in most GDM patients, while compliance of AF patients to the most important targets was quite high, considering the required ECG measurements (0.65±0.28) and blood-pressure measurements (0.75±1.33). This outcome was viewed by the clinicians as a major potential benefit of the system, and the patients have demonstrated that they are capable of self-monitoring - something that they had not experienced before. In addition, the system caused the clinicians managing the AF patients to change their diagnosis and subsequent treatment for two of the ten AF patients, and caused the clinicians managing the GDM patients to start insulin therapy earlier in two of the 19 patients, based on system's recommendations. Based on the end-of-study questionnaires, the sense of safety that the system has provided to the patients was its greatest asset. Analysis of the patients' quality of life (QoL) questionnaires for the AF patients was inconclusive, because while most patients reported an improvement in their quality of life in the EuroQoL questionnaire, most AF patients reported a deterioration in the AFEQT questionnaire.

DISCUSSION
Feasibility and some of the potential benefits of an evidence-based distributed patient-guidance system were demonstrated in both clinical domains. The potential application of MobiGuide to other medical domains is supported by its standards-based patient health record with multiple electronic medical record linking capabilities, generic data insertion methods, generic medical knowledge representation and application methods, and the ability to communicate with a wide range of sensors. Future larger scale evaluations can assess the impact of such a system on clinical outcomes.

CONCLUSION
MobiGuide's feasibility was demonstrated by a working prototype for the AF and GDM domains, which is usable by patients and clinicians, achieving high compliance to self-measurement recommendations, while enhancing the satisfaction of patients and care providers.

Peleg|Mor|M|
Shahar|Yuval|Y|
Quaglini|Silvana|S|
Broens|Tom|T|
Budasu|Roxana|R|
Fung|Nick|N|
Fux|Adi|A|
García-Sáez|Gema|G|
Goldstein|Ayelet|A|
González-Ferrer|Arturo|A|
Hermens|Hermie|H|
Hernando|M Elena|ME|
Jones|Val|V|
Klebanov|Guy|G|
Klimov|Denis|D|
Knoppel|Daniel|D|
Larburu|Nekane|N|
Marcos|Carlos|C|
Martínez-Sarriegui|Iñaki|I|
Napolitano|Carlo|C|
Pallàs|Àngels|À|
Palomares|Angel|A|
Parimbelli|Enea|E|
Pons|Belén|B|
Rigla|Mercedes|M|
Sacchi|Lucia|L|
Shalom|Erez|E|
Soffer|Pnina|P|
van Schooten|Boris|B|

D020000:Decision Support Systems, Clinical


Efficacy of coating activated carbon with milk proteins to prevent binding of bacterial cells from foods for PCR detection.

Abstract: Foods contaminated with pathogens are common sources of illness. Currently, the most common and sensitive rapid detection method involves the PCR. However, food matrices are complex and contain inhibitors that limit the sensitivity of the PCR. The use of coated activated carbon can effectively facilitate the removal of PCR inhibitors without binding targeted bacterial cells from food samples. With the use of activated carbon coated with milk proteins, a cell recovery at pH 7.0 of 95.7%±2.0% was obtained, compared to control uncoated activated carbon, which yielded a cell recovery of only 1.1%±0.8%. In addition, the milk protein coated activated carbon was able to absorb similar amounts of soluble compounds as uncoated activated carbon, with the exception of bovine hemoglobin. This suggests that the use of milk proteins to coat activated carbon may therefore serve as a suitable replacement for bentonite in the coating of activated carbon, which has previously been used for the removal of PCR inhibitors from food.

D053000:Analytic Sample Preparation Methods

tryptic Soy Agar supplemented with 0.5% glucose

tryptic Soy Broth supplemented with 0.5% glucose


MHCSeqNet: a deep neural network model for universal MHC binding prediction.

Abstract:
BACKGROUND
Immunotherapy is an emerging approach in cancer treatment that activates the host immune system to destroy cancer cells expressing unique peptide signatures (neoepitopes). Administrations of cancer-specific neoepitopes in the form of synthetic peptide vaccine have been proven effective in both mouse models and human patients. Because only a tiny fraction of cancer-specific neoepitopes actually elicits immune response, selection of potent, immunogenic neoepitopes remains a challenging step in cancer vaccine development. A basic approach for immunogenicity prediction is based on the premise that effective neoepitope should bind with the Major Histocompatibility Complex (MHC) with high affinity.

RESULTS
In this study, we developed MHCSeqNet, an open-source deep learning model, which not only outperforms state-of-the-art predictors on both MHC binding affinity and MHC ligand peptidome datasets but also exhibits promising generalization to unseen MHC class I alleles. MHCSeqNet employed neural network architectures developed for natural language processing to model amino acid sequence representations of MHC allele and epitope peptide as sentences with amino acids as individual words. This consideration allows MHCSeqNet to accept new MHC alleles as well as peptides of any length.

CONCLUSIONS
The improved performance and the flexibility offered by MHCSeqNet should make it a valuable tool for screening effective neoepitopes in cancer vaccine development.

D015395:Histocompatibility Antigens Class I

Deep learning
MHC epitope prediction
Recurrent neural networks


Dietary Sphingolipids Contribute to Health via Intestinal Maintenance.

Abstract: As sphingolipids are constituents of the cell and vacuole membranes of eukaryotic cells, they are a critical component acquired from our daily diets. In the present review, we highlight the knowledge regarding how dietary sphingolipids affect our health, particularly our intestinal health. Animal- and plant-derived foods contain, respectively, sphingomyelin (SM) and glucosylceramide (GlcCer) as their representative sphingolipids, and the sphingoid base as a specific structure of sphingolipids also differs depending upon the source and class. For example, sphingosine is predominant among animal sphingolipids, and tri-hydroxy bases are present in free ceramide (Cer) from plants and fungi. Dietary sphingolipids exhibit low absorption ratios; however, they possess various functions. GlcCer facilitates improvements in intestinal impairments, lipid metabolisms, and skin disorders, and SM can exert both similar and different effects compared to those elicited by GlcCer. We discuss the digestion, absorption, metabolism, and function of sphingolipids while focused on the structure. Additionally, we also review old and new classes in the context of current advancements in analytical instruments.

intestine sphingomyelin glucosylceramide sphingosine ceramide inflammation


Protein Supramolecular Structures: From Self-Assembly to Nanovaccine Design.

Abstract: Life-inspired protein supramolecular assemblies have recently attracted considerable attention for the development of next-generation vaccines to fight against infectious diseases, as well as autoimmune diseases and cancer. Protein self-assembly enables atomic scale precision over the final architecture, with a remarkable diversity of structures and functionalities. Self-assembling protein nanovaccines are associated with numerous advantages, including biocompatibility, stability, molecular specificity and multivalency. Owing to their nanoscale size, proteinaceous nature, symmetrical organization and repetitive antigen display, protein assemblies closely mimic most invading pathogens, serving as danger signals for the immune system. Elucidating how the structural and physicochemical properties of the assemblies modulate the potency and the polarization of the immune responses is critical for bottom-up design of vaccines. In this context, this review briefly covers the fundamentals of supramolecular interactions involved in protein self-assembly and presents the strategies to design and functionalize these assemblies. Examples of advanced nanovaccines are presented, and properties of protein supramolecular structures enabling modulation of the immune responses are discussed. Combining the understanding of the self-assembly process at the molecular level with knowledge regarding the activation of the innate and adaptive immune responses will support the design of safe and effective nanovaccines.

Zottig|Ximena|X| Côté-Cyr|Mélanie|M| Arpin|Dominic|D| Archambault|Denis|D| Bourgault|Steve|S|

protein
supramolecular structure
self-assembly
nanovaccine
vaccine
immune response
adjuvant
nanoassemblies


Neurological Soft Signs Predict Auditory Verbal Hallucinations in Patients With Schizophrenia.

Abstract: Neurological soft signs (NSS) are well documented in individuals with schizophrenia (SZ), yet so far, the relationship between NSS and specific symptom expression is unclear. We studied 76 SZ patients using magnetic resonance imaging (MRI) to determine associations between NSS, positive symptoms, gray matter volume (GMV), and neural activity at rest. SZ patients were hypothesis-driven stratified according to the presence or absence of auditory verbal hallucinations (AVH; n = 34 without vs 42 with AVH) according to the Brief Psychiatric Rating Scale. Structural MRI data were analyzed using voxel-based morphometry, whereas intrinsic neural activity was investigated using regional homogeneity (ReHo) measures. Using ANCOVA, AVH patients showed significantly higher NSS in motor and integrative functions (IF) compared with non-hallucinating (nAVH) patients. Partial correlation revealed that NSS IF were positively associated with AVH symptom severity in AVH patients. Such associations were not confirmed for delusions. In region-of-interest ANCOVAs comprising the left middle and superior temporal gyri, right paracentral lobule, and right inferior parietal lobule (IPL) structure and function, significant differences between AVH and nAVH subgroups were not detected. In a binary logistic regression model, IF scores and right IPL ReHo were significant predictors of AVH. These data suggest significant interrelationships between sensorimotor integration abilities, brain structure and function, and AVH symptom expression.

Wolf|Robert C|RC|
Rashidi|Mahmoud|M|
Schmitgen|Mike M|MM|
Fritze|Stefan|S|
Sambataro|Fabio|F|
Kubera|Katharina M|KM|
Hirjak|Dusan|D|

neurological soft signs
auditory verbal hallucinations
MRI
gray matter volume
regional homogeneity


Familial PDGFRA-mutation syndrome: somatic and gastrointestinal phenotype.

Abstract: Germline activating platelet-derived growth factor receptor alpha (PDGFRA) mutations have been described in four families. All the index patients have presented with multiple mesenchymal tumors of the gastrointestinal tract. We identified a fifth family with four first-degree relatives that harbor a PDGFRA exon 18 (D846V) germline mutation. The affected kindred have a unique phenotype including coarse facies and skin, broad hands and feet, and previously undescribed premature tooth loss. While the index patient presented with multiple small bowel inflammatory fibroid polyps (IFPs) and has a gastric gastrointestinal stromal tumor (GIST), no tumors have yet been identified in other family members. We describe the pathology, genetics, the incomplete penetrance and variable expressivity of the familial PDGFRA-mutation syndrome referencing the mouse knock-in Pdgfra model. We speculate on the role of the telocyte, a recently described CD34, PDGFRA+ stromal cell, in the development of inflammatory fibroid polyps and the somatic phenotype.

Manley|Paul N|PN|
Abu-Abed|Suzy|S|
Kirsch|Richard|R|
Hawrysh|Andrea|A|
Perrier|Nicole|N|
Feilotter|Harriet|H|
Pollett|Aaron|A|
Riddell|Robert H|RH|
Hookey|Lawrence|L|
Walia|Jagdeep S|JS|

D020022:Genetic Predisposition to Disease

D020796:Receptor, Platelet-Derived Growth Factor alpha

PDGFRA
Inflammatory fibroid polyp
GIST
Telocyte
Dysmophology


Distribution, sources and chemical screening-level assessment of toxic metals in the northern Bay of Bengal, Bangladesh.

Abstract: The present study aims to examine the distribution, sources and potential risks of toxic metals in the northern Bay of Bengal, Bangladesh. We found Cu, Pb, Zn and Hg exhibited similar spatial distribution pattern. Influenced by the Ganges-Brahmaputra River and the Karnafuli River, there were higher concentrations of these metals associated with the finer sediment and higher TOC in the northeastern portion of the study area. Moreover, coal transportation was assumed to account for the distinctive spatial distribution of As with higher concentration down the Port of Chittagong in the eastern boundary. Chemical-screening level assessment demonstrated the majority of the metals exceeded the threshold effect values, indicating certain possibility of adverse effect. The concentrations of Ni were higher than the possible hazardous values, suggesting high possibility of harmful consequences. The uncontaminated sediments mainly distributed in northwestern and the central portions affected by the delta erosion and marine transported sediments.

Liu|Shengfa|S|
Wu|Bin|B|
Seddique|Ashraf Ali|AA|
Zhang|Hui|H|
Zhu|Aimei|A|
Liu|Jianguo|J|
Shi|Xuefa|X|

Sources
Toxic metals
Bay of Bengal
Sediment
Risk assessment


Feasibility and Value of Radiographic Union Score Hip Fracture after Treatment with Intramedullary Nail of Stable Hip Fractures.

Abstract:
INTRODUCTION
Given the importance of fracture healing on patient outcome in clinical practice, it is critical to assess fracture healing.

AIM
The aim of this study was to evaluate the feasibility of the Radiographic Union Score Hip fracture after treatment with intramedullary nail of stable hip fractures.

PATIENTS AND METHODS
We retrospectively collected the data from the clinical records of our institution of the 47 patientswho had undergone intertrochanteric hip fracture treatment using an intramedullary nail. Pain visual analogic score (VAS) was collected the same day that X-rays were taken. Plain hip X-rays were performed, in two radiographic views, at 40 and 90 days after the surgical procedure. The correlation between the RUSH and VAS score was evaluated.

RESULTS
Mean RUSH and VAS scores showed a strong statistical improvement between the 40 and 90 day follow-ups. RUSH value at 40 days fitted an inverse linear regression with VAS, p-value of 0.0063 and r2 of 0.15. At 90 days the regression between RUSH and VAS scores was not significant.

CONCLUSION
RUSH could be proposed as an objective system to evaluate union in hip fractures treated with intramedullary nail.

Maiettini|Daniele|D| Bisaccia|Michele|M| Caraffa|Auro|A| Rinonapoli|Giuseppe|G| Piscitelli|Luigi|L| Bisaccia|Olga|O| Rollo|Giuseppe|G| Meccariello|Luigi|L| Ceccarini|Paolo|P| Rebonato|Alberto|A|

Union
Intramedullary Nail
Stable Hip Fractures
RUSH
Delay Union
Non Union
Radiographic Value