ESCADA: Efficient Safety and Context Aware Dose Allocation for Precision Medicine

Finding an optimal individualized treatment regimen is considered one of the most challenging precision medicine problems. Various patient characteristics influence the response to the treatment, and hence, there is no one-size-fits-all regimen. Moreover, the administration of an unsafe dose during the treatment can have adverse effects on health. Therefore, a treatment model must ensure patient \emph{safety} while \emph{efficiently} optimizing the course of therapy. We study a prevalent medical problem where the treatment aims to keep a physiological variable in a safe range and preferably close to a target level, which we refer to as \emph{leveling}. Such a task may be relevant in numerous other domains as well. We propose ESCADA, a novel and generic multi-armed bandit (MAB) algorithm tailored for the leveling task, to make safe, personalized, and context-aware dose recommendations. We derive high probability upper bounds on its cumulative regret and safety guarantees. Following ESCADA's design, we also describe its Thompson sampling-based counterpart. We discuss why the straightforward adaptations of the classical MAB algorithms such as GP-UCB may not be a good fit for the leveling task. Finally, we make \emph{in silico} experiments on the bolus-insulin dose allocation problem in type-1 diabetes mellitus disease and compare our algorithms against the famous GP-UCB algorithm, the rule-based dose calculators, and a clinician.Comment: 23 pages, 12 figure

Antimicrobial, anti-biofilm and cytotoxic properties of methallyl functionalized benzimidazolium-derived Ag(I)-Nheterocyclic carbene complexes

Purpose: To investigate the antimicrobial, antibiofilm, and cytotoxicity properties of methallyl substituted benzimidazolium-based, silver-bound N-heterocyclic carbene (Ag(I)-NHC) complexes, with respect to their potential to act as antimicrobial agents.Methods: The antimicrobial, antibiofilm, and cytotoxicity properties of the four complexes, the synthesis and characterization of which were carried out previously, were investigated. The antimicrobial properties were tested using the broth microdilution method, while their antibiofilm potential were determined by microtiter plate assay. The L-929 cell line was used for cytotoxic studies.Results: Strong antibiofilm and antimicrobial effects were produced by Ag(I)-NHC complexes. Compounds 2 and 3 showed potent activities against E. coli strain, with effects similar to that of positive control antibiotic, while compounds 1 and 4 exhibited antimicrobial activity at a concentration of 31.2 μg/mL. The compounds were effective against biofilms formed at concentrations in the range of 32 – 84 %, and degraded mature biofilms at a concentration range of 14 - 66 %. Compounds 1 and 2 did not significantly affect cell survival (p > 0.05), while compounds 3 and 4 significantly reduced cell survival, when compared with untreated cells in the control group (p < 0.001).Conclusion: This study may be one of the few studies on benzimidazolium-derived NHCs. The compounds which produced antimicrobial, antibiofilm, and cytotoxic properties in this study may be valuable and novel antimicrobial agents. Therefore, there is need for further in vivo and in vitro studies on these compounds

Characteristics of obstetric fistulas and the need for a prognostic classification system

Introduction: To evaluate the need for a prognostic classification system for obstetric fistula (OF) with the data obtained by a voluntarily action for OF repair in a regional hospital and Niger, Africa. Material and methods: Obstetric fistula (OF) characteristics of 51 women with vesicovaginal fistula in a fistula campaign in Maradi Regional Hospital, Niger were evaluated. Initial basic gynecological examination, methylene blue (MBT) test and direct cystoscopy were used to describe the characteristics of the lesions. Demographic and clinical data were compared with the existing literature. Results: In 31 (60 %) cases were the sizes of the fistula greater than 4 cm. The urethra was circumferentially lost in 8 (15.7%) women. In 18 (35.3%) women the trigone was involved. Extensive fibrosis was present in 10 (19.6%) patients. Only in 11(21.6%) patients without any obliterating scarring, neither the trigone nor urethra were damaged. Five (9.8%) patients had severe infection. Five (9.8%) had multiple lesions. Thirty-four (66.6%) had a history of at least one previous attempt for fistula repair. A significant proportion of women were divorced or abandoned from their husband, and socially isolated. Conclusions: A simple, reproducible and universally accepted scientific classification or staging system for OF dealing with outcomes rather than anatomic landmarks should replace the present proposed classification systems for prognostic and ethical purposes

Validity and Reliability of The Authentic Happiness Scale

Studies on the concept of happiness have led to questions about whether all symptoms of happiness correspond to a real and healthy emotional state. Therefore, in this research, a scale was developed to examine the concept of “authentic happiness” coined by Seligman. Firstly, literature that explains authentic happiness and defines its relationship to other psychological concepts was reviewed, and then a theoretical framework was developed based on this information and the psychometric characteristics of the scale were introduced. The results of the confirmatory factor analysis revealed that the fit indices were compatible with twodimensional structure. These two dimensions have been entitled as “Authentic Happiness” and “Fluctuating Happiness”. Based on the findings of the present study, the Authentic Happiness Scale (AHS) is a reliable and valid scale to determine the authentic happiness levels of university students

The sufficiency of 6 core sextant prostate biopsy in patients with prostate specific antigen (PSA) values over 20 ng/mL

Objective: In this study, we aimed to investigate sufficiency of 6 core prostate biopsy in patients with PSA levels elevated above 20 ng/mL. Materials and methods: The medical record of the patients who received prostate biopsy at our institution between August 2011 to August 2016 who had serum total PSA values above 20 ng/mL, were reviewed retrospectively. In this study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy. A total number of 80 patients were enrolled in this study. Patients were divided into two groups, a 6 core biopsy group and a 12 core biopsy group. These groups are compared according to age, total PSA, prostate volume and final pathological diagnosis. Results: Based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had PCa in both group 1 and 2. The cancer detection rate in both groups was 95%. Although there were higher values of mean age, mean total PSA, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in both groups. Conclusion: Although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with PSA values above 20 ng/mL

Preparation of Silicon-Antimony based Anode Materials for Lithium-Ion Batteries

I n this study, SixSb immiscible composite blend as anode materials have been synthesized using micron-sized silicone and antimony particles in different compositions through chemical reduction-mechanical alloying method CR-MA . The obtained microstructures have been investigated by X-ray diffraction XRD and Scanning Electron Microscopy SEM with Energy Dispersive X-Ray analysis EDX . Spectroscopic characterizations of the composite materials showed that a traditional intermetallic compound could not be achieved. However a novel immiscible composite blend system have been developed. One of the newly prepared composite materials, Si0.65Sb, exhibits an initial capacity of 790 mAh g-1 and a good cyclic stability compared to the pure silicone. The battery performance results of the micron-sized Si0.65Sb blend system have been compared with the commercially used graphite and the nano-sized Si/Sb alloy systems. The cycling stability of the micron-sized Si0.65Sb blend system showed an improvement compared to nano-sized Si/Sb alloy systems. Moreover its specific capacity is slightly higher than the commercial graphite anode material. These results portray the importance of micron sized Si/Sb system in large-scale applications due to its low cost

Expression of CK-19 and CEA mRNA in peripheral blood of gastric cancer patients

Aim: To investigate the clinical and pathological relevance of detection of circulating tumor cells (CTC) in the peripheral blood of gastric carcinoma patients before operation. Patients and Methods: Fifty patients with gastric adenocarcinoma were analysed prospectively. Patients were divided into two groups according to the extent of the tumor. Group I (unresectable) consisted of 22, and group II (resectable) consisted of 28 patients. Peripheral blood samples were collected pre-operatively from all 50 patients as well as from ten healthy controls and analyzed for carcinoembryonic antigen (CEA) and cytokeratin-19 (CK-19) messenger ribonucleic acids (mRNAs). Tumor localisation, stage, presence of signet cell formation, nodal metastases, serousal and lymphovascular invasion were recorded for all patients. Results: Expression of CK-19 was detected in 24 (48%), and CEA in 10 (20%) cases. Nine patients (40%) in group I and 15 (53.6%) in group II were positive for CK-19 expression. CEA expression was more frequent among group I patients (6 vs. 4 cases). There was no significant difference between the groups in the expression of CK-19 and CEA mRNA, tumor localisation, presence of signet formation, and presence and extent of nodal metastases. Patients with major vascular invasion (MVI) expressed significantly higher levels of CTC mRNA compared to those without MVI (p = 0.023 for CEA, and p = 0.009 for CK-19). The median 1 and 2-year survival was 9.5 and 10.5 months for group I, and 20 and 28.5 months for group II, respectively (p = 0.001). The mean survival was 6.7 months for patients with MVI, and 30.2 months for those without MVI (p = 0.0001). Conclusions: High levels of CTCs were observed in patients with MVI invasion, rather than other causes of unresectability. It can be suggested that expression of both CEA and CK-19 in the peripheral blood of gastric cancer patients are strong predictors of MVI and significantly worse survival rates. Copyright © Experimental Oncology, 2010

Di­hydro­oxazolones and di­hydro­imidazolo­nes derived from acyl­glycines: syntheses, mol­ecular structures and supra­molecular assembly

Syntheses and structures are described for some alkyl­idene-substituted di­­hydro­oxazolones and di­hydro­imidazoles derived from simple acyl­glycines. A second, triclinic, polymorph of 4-benzyl­idene-2-(4-methyl­phen­yl)-1,3-oxazol-5(4H)-one, C17H13NO2, (I), has been identified and the structure of 2-methyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one, C9H7NO2S, (II), has been rerefined taking into account the orientational disorder of the thienyl group in each of the two independent mol­ecules. The reactions of phenyl­hydrazine with 2-phenyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one or 2-(4-methyl­phen­yl)-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one yield, respectively, 3-anilino-2-phenyl-5-[(thio­phen-2-yl)methyl­idene]-3,5-di­hydro-4H-imid­azol-4-one, C10H15N3OS, (III), and 3-anilino-2-(4-methyl­phen­yl)-5-[(thio­phen-2-yl)methyl­idene]-3,5-di­hydro-4H-imidazol-4-one, C21H17N3OS, (IV), which both exhibit orientational disorder in their thienyl groups. The reactions of 2-phenyl-4-[(thio­phen-2-yl)methyl­idene]-1,3-oxazol-5(4H)-one with hydrazine hydrate or with water yield, respectively, N-[3-hydrazinyl-3-oxo-1-(thio­phen-2-yl)prop-1-en-2-yl]benzamide and 2-(benzoyl­amino)-3-(thio­phen-2-yl)prop-2-enoic acid, which in turn react, respectively, with thio­phene-2-carbaldehyde to form 2-phenyl-5-[(thio­phen-2-yl)methyl­idene]-3-{[(E)-(thio­phen-2-yl)methyl­idene]­amino}-3,5-di­hydro-4H-imidazol-4-one, C19H13N3OS2, (V), which exhibits orientational disorder in only one of its thienyl groups, and with methanol to give methyl (2Z)-2-(benzoyl­amino)-3-(thio­phen-2-yl)prop-2-enoate, C15H13NO3S, (VI). There are no direction-specific inter­molecular inter­actions in the crystal structure of the triclinic polymorph of (I), but the mol­ecules of (II) are linked by two independent C—H⋯O hydrogen bonds to form C22(14) chains. Compounds (III) and (IV) both form centrosymmetric R22(10) dimers built from N—H⋯O hydrogen bonds, while compound (V) forms a centrosymmetric R22(10) dimer built from C—H⋯O hydrogen bonds. In the structure of compound (VI), a combination of N—H⋯O and C—H⋯π(arene) hydrogen bonds links the mol­ecules into sheets. Comparisons are made with some similar compounds

Expression of CK-19 and CEA MRNA in peripheral blood of gastric cancer patients

The aim of this paper is to investigate the clinical and pathological relevance of detection of circulating tumor cells (CTC) in the peripheral blood of gastric carcinoma patients before operation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London