In this article, the use of an SPME technique is reported for the first time for direct measurement of free drug concentration in solid tissue. In our investigations, we considered doxorubicin (DOX) spiked in homogenized tissue matrix at transient and equilibrium extraction conditions, with subsequent assessment of obtained experimental results by an in silico approach using mathematical models developed in COMSOL Multyphysics. In silico studies were performed on the basis of transported diluted species (tds) and reaction engineering (re) modules from COMSOL Multiphysics, using the same conditions as those used to attain experimental results. To determine the apparent binding affinity of DOX to the tissue matrix which contains multiple binding species, the experimentally determined binding affinity of DOX with human serum albumin (HSA) was considered to simplify the mathematical calculations. Here, the value of the binding affinity was considered for a single binding site and adjusted by fitting the experimental results with the mathematical model. Bovine lung tissue homogenate was selected as a surrogate matrix, and a biocompatible C-8 commercial SPME fiber was used for extraction of DOX. In total, four mathematical models were herein developed to describe the mass transfer kinetics of solid coatings: in agar gel at static conditions, in PBS solution with agitated conditions, extraction in PBS solution in the presence of an HSA binding matrix, and static extraction in homogenized lung tissue. For all conditions, simulated results were in good agreement with experimental results. The developed mathematical model allows for measurements of free drug concentrations inside the tissue matrix and facilitates calculations of local depletion of DOX by a solid SPME coating. Results of the investigations indicate that local depletion of the free form of DOX, even at the kinetic stage, is negligible for tissue extraction, as the release of the heavily bound analyte (over 99% binding to tissue matrix) is very rapid, thus easily compensating for the loss of the drug to the SPME coating. This indicates that the dissociation rate constant of DOX from lung tissue components is very rapid; therefore, the mass transfer of drug to the fiber coating via free from is very efficient. Our results also indicate that thin coating SPME fibers provide a good way to measure drug distribution after dosing, as extractions via thin coating SPME fibers do not affect the free concentration of the drug, which is responsible for drug distribution in tissue.

Abstract Here we present the simple and effective fabrication method of an array of gold microneedles (AuMNs) via the casting of conductive gold ink. To demonstrate the potential of MN arrays as electrochemical biosensors we functionalized AuMNs with an epoxy- and ferrocene-functional polymeric mediator and covalently immobilised urease. The performance of the MN array biosensor for urea detection was assessed in artificial interstitial fluid and epidermal/skin mimic, both spiked with urea. The analytical performance of MN biosensor shows that urea is detected in the range of 50–2500 µM, with a calculated limit of detection of 2.8 µM and sensitivity of 31 nA/mM. The results reveal that these MN-based biosensors may underpin the development of wearable real-time monitoring devices.

Objectives This study aims to investigate the low-resolution human leukocyte antigen (HLA)-B locus polymorphisms between unrelated healthy individuals and patients with diagnosis of seronegative spondyloarthropathies and determine risky and protective allelic groups and genotypes. Patients and methods The study included 104 healthy control individuals (52 males, 52 females; median age 43 years; range 2 to 76 years) and 96 patients (43 males, 53 females; median age 28.5 years; range 2 to 67 years) diagnosed with: ankylosing spondylitis (AS) (n=19), reactive arthritis (n=19), psoriatic arthritis (n=28) and undifferentiated spondyloarthropathies (n=30). Genomic deoxyribonucleic acid was extracted from peripheral blood to detect allelic groups of HLA class I and II. Single-specific-primer polymerase chain reaction was used for HLA genotyping and visualization of products after their separation on 1.5% agarose gel for horizontal gel electrophoresis. Results Significantly increased frequency was found for HLA-A*02 and HLA-B*27 allelic variants in all groups of patients. The increased frequency of the HLA-B*35 allelic group in the control group represents the protective gene variant for the occurrence of AS. The predisposing genotype (HLA-B*27/B*44 and B*27/B*51) for the onset of disease was only found in AS patients. Conclusion This study shows the strong association of HLA-B*27 antigen with spondyloarthropathies, which is considered a risk variant of the gene for the onset of disease. Protective and risky allelic variants and genotypes are rare and their detection as well as increased frequency are possible if larger numbers of patients are involved.

Purpose: The study aimed to determine the impact of communication disorders on discrimination against people who are deaf in the workplace, as well as to find the differences in study participants’ opinions. Method: The study sample consisted of 171 respondents from different industries in Bosnia-Herzegovina- 57 workers who were deaf, 57 workers who could hear, and 57 managers. Both quantitative and qualitative approaches were used in the survey. The opinions of the respondents were elicited through a questionnaire which consisted of 15 statements. The interviews of workers and managers focussed on the presence of discrimination against deaf workers in the workplace. Responses of respondents were converted to quantified values using analysis of discrimination group. The significance of statistical differences among the samples tested is defined at 0.01 level of significance using F-Test. Results: Discriminant analysis tested the null hypothesis that respondents’ answers do not differ regarding discrimination against deaf workers in the workplace. However differences were found between the groups that felt deaf workers did not have equal position at work in comparison to their hearing co-workers. Participants mentioned a number of barriers in workplaces. Workers were of the opinion that there was significant discrimination in the workplace (p>0.01) between groups of participants. Conclusion: There are statistically significant differences in the opinions of respondents regarding statements that workers who are deaf cannot hold positions equal to their co-workers who have regular hearing.

Purpose The immune checkpoint inhibitors (ICIs) have resulted in subgroups of patients with metastatic melanoma achieving high-quality durable responses. Metastatic melanoma survivors are a new population in the era of cancer survivorship. The aim of this study was to evaluate metastatic melanoma survivors in terms of health-related quality of life (HRQoL), immune-related adverse events (irAEs) and exposure to immunosuppressive agents in a large single centre in the UK. Methods We defined the survivor population as patients with a diagnosis of metastatic melanoma who achieved a durable response to an ICI and had been followed-up for a minimum of 12 months from initiation of ICI without disease progression. HRQoL was assessed using SF-36. Electronic health records were accessed to collect data on demographics, treatments, irAEs and survival. HRQoL data was compared with two norm-based datasets. Results Eighty-four metastatic melanoma survivors were eligible and 87% ( N  = 73) completed the SF-36. ICI-related toxicity of any grade occurred in 92% of patients and 43% had experienced a grade 3 or 4 toxicity. Almost half (49%) of the patients required steroids for the treatment of ICI-related toxicity, whilst 14% required treatment with an immunosuppressive agent beyond steroids. Melanoma survivors had statistically significant lower HRQoL scores with regard to physical, social and physical role functioning and general health compared with the normative population. There was a trend towards inferior scores in patients with previous exposure to ipilimumab compared with those never exposed to ipilimumab. Conclusions Our results show that metastatic melanoma survivors have potentially experienced significant ICI-related toxicity and experience significant impairments in specific HRQoL domains. Future service planning is required to meet this population’s unique survivorship needs.

Introduction: Many factors affect the growth and development of the mandible. The most common one is micrognathia; this can pose and neonatal emergency. Early recognition of mandibular and other face anomalies could provide immediate care for these infants, and presence of neonatologist or other doctors in the delivery room. The aim: Aim of this study was to develop normal ranges of the facial markers: mandibular length, jaw index and the facial angle in the fetus using 3D ultrasound. Material and methods: The research was conducted as a cross-sectional study in the second trimester of pregnancy. Fetuses (female n=23 and male n=27) from singleton pregnancy between 29-37 week of gestation were examined by ultrasound. All images were acquired transabdominally, using Voluson E16. Ultrasound was performed by an experienced operator (SM) and measured the values of head circumference, abdominal circumference, biparietal diameter, femur length, body mass. For mandibular length, inferior facial angle, and the jaw index was calculated (Jaw Index =AP mandibular diameter / BPD * 100), the profile images were used (only images in the exact midsagittal plane were used). The characteristics of the fetal profiles were determined by the Schwartz and Ricketts profile analysis using soft tissue landmarks and analysis of the profile photographs. Results: The results show that the jaw index ranged from 25.33 and 34.06 with an average of 26.00 for all examined fetuses. Conclusion: The physiological position of the mandible is retrognathic and that the average physiological length of the mandible in the third trimester is 2.31cm. There is no difference in mandibular length between genders. Corresponding Author: Samra Salga-Nefic Rosenweg 2a, 3125 Toffen, Switzerland, e-mail: samrasalaga@gmail.com A determination of the standards of morphometrics variables of the stomatognathic system of a fetus INTRODUCTION Many factors affect the growth and development of the mandible: genes, irregular cell migration, low growth potential, feeding habits, and other habits acquired by newborns.1 The most common anomalies are microgenia (weak mandible growth) and retrogenia (small mandible growth in the sagittal plane).1 Deviation of physiological mandibular growth and development may incapacitate the essential functions of the stomatognathic system. Fetuses with mandible anomalies are at risk of airway obstruction through retro-positioning of the tongue-base into posterior pharyngeal airway.2 Micrognathia is frequently seen in Pierre Robin sequence, however it can be found in many genetic syndromes.3 Antenatal diagnosis of anomalies by ultrasound is widely used nowadays. The aim of this study was to develop normal ranges of the facial marker: mandibular length, jaw index and the facial angle in the fetus using 3D ultrasound. MATERIAL AND METHODS The research was conducted as a cross-sectional study in the second trimester of pregnancy. Fetuses (female n=23 and male n=27) from singleton pregnancy between 29-37 week of gestation were examined by ultrasound. All images were acquired transabdominally, using ultrasound Voluson E16, GE Healthcare, Austria GmbH & Co OG. Salaga-Nefic S., Mehmedbasic S., Kozadra J., Zukanovic A., Tiro, A., Dzemidzic, V., Nakas E. A determination of the standards of morphometrics variables of the stomatognathic system of a fetus. South Eur J Orthod Dentofac Res. 2019;6(1):6-11. Submitted: July 30, 2018; Revised: March 7, 2019; Published: April 30, 2019 6 South Eur J Orthod Dentofac Res Salaga-Nefic S. et al. Morphometrics variables of the fetus

Ultra-high performance concrete (UHPC) is a durable material that allows the construction of innovative structural elements and conforms with accelerated bridge construction (ABC) goals. The main idea of this research is to utilize UHPC to prefabricate a shell that acts as a stay-in-place form for bridge columns. The prefabricated shell eliminates the conventional formwork while reducing the on-site construction time and acting as a durable protective layer for the normal concrete inside the shell against environmental attacks. In addition, the UHPC shell provides additional confinement to the column concrete, which improves the column’s structural performance. During construction and after completing the column reinforcement work onsite, based on the conventional construction methods, the prefabricated UHPC shell is placed around the column reinforcement, followed by casting a portion of UHPC for a column-to-footing connection, which improves the capacity of the connection and shifts the plastic hinge zone above the connection. Once the UHPC portion hardens, normal concrete is placed inside the shell, forming a permanent concrete-filled UHPC shell. The construction process is finalized by placing and connecting a prefabricated cap beam to the column through the same developed connection as that in this research. This technical note presents the development of two test specimens using an UHPC shell in lieu of a conventional formwork with the advantage of improving the column performance and durability.