Microbiology

Phage Particles in Ground Arctic Ice Abstract— This is the first report on investigation of bacteriophages in ancient Arctic ground ice of various genesis and geological age. Electron microscopy revealed phage particles in all ice samples. Tailed bacteriophages were the dominant morphotype. A correlation was found between abundances of intact microbial cells and phage particles. Direct microscopic counts revealed the highest phage abundance melted native samples of ice wedge. Dependence of occurrence and abundance of phage particles on genesis of ground ice was observed. The phages, as an integral component of microbial communities, were found to be preserved in extreme low-temperature conditions of ground ancient ice.

Bacterial Adhesion and Biofilm Formation in the Presence of Chitosan and Its Derivatives Abstract— The effect of chitosan and its derivatives on adhesion and biofilm formation by bacteria with diametrically opposite properties of cell surfaces was studied. Treatment of polystyrene surface with chitosan or its quaternized derivatives was shown to decrease its hydrophobicity significantly, resulting with an over fourfold inhibition of M. smegmatis adhesion. On the contrary, E. coli with hydrophilic cell surface showed higher affinity to the polystyrene surface in the presence of chitosan. The possibility of inhibiting formation of M. smegmatis biofilms by chitosan, which increases its antimycobacterial properties after its quaternization, has not been demonstrated previously. At the same time, the increase in the hydrophobicity of quaternized chitosan resulted in its decreased efficiency against E. coli cells with a relatively hydrophilic surface. The succinylated form of chitosan with negatively charged sites in the structure had practically no antibacterial properties due its decreased ability to bind with the target cells.

Phototrophic Communities of the Berikei Highly Mineralized Mesothermal Sulfide Springs (Dagestan, Russia) Abstract— Phototrophic communities forming in the bottom of the Berikei highly mineralized mesothermal sulfide springs (Kayakent region, Dagestan, Russia) were investigated. The Berikei springs are an interesting example of combined effect of such factors as temperature, salinity, pH, and sulfide of occurrence and structure of phototrophic microbial communities. The water was of the sodium chloride type with salinity of 48‒97 g/L, near-neutral brine pH, and sulfide concentration of ~1 mM. The temperature at the stream bottom was as high as 60°C. Elevated temperature and high salinity limited the development of phototrophic communities. Formation of cyanobacterial mats occurred at temperatures below 54°C. Phormidium-like cyanobacteria and unicellular Synechocystis sp. predominated in the mats. The number of cyanobacterial species increased at desalination to 48‒57 g/L with emergence of the species morphologically resembling Spirulina sp., Leptolyngbya sp., and Oscillatoria sp. Among anoxygenic phototrophic bacteria, halophilic purple bacteria Ectothiorhodospira sp., Marichromatium sp., and Rhodovulum sp., green sulfur bacteria Prosthecochloris sp., and unidentified Chloroflexi were present. Oxygenic photosynthesis in the mats was not inhibited by sulfide. Production of cyanobacterial mats was up to 4.7‒53.8 µg/(cm2 h). The contribution of anoxygenic phototrophic bacteria to photosynthetic production varied from 0 to 100%. The composition of this microbial community was compared to those of the phototrophic microbial communities of the mesothermal springs of the Dead Sea coast (Israel), the Washington warm lake (United States), and the Paoha Island hot springs (Mono Lake, United States.

Rhizobacteria Strain from a Hypersaline Environment Promotes Plant Growth of Kengyilia thoroldiana Abstract Kengyilia thoroldiana is a nutritionally rich grass species of the Qinghai-Tibet Plateau. Here, to improve its quality and biomass via biological fertilization, we sought out plant-growth promoting rhizobacteria. Our screening found one Bacillus species capable of nitrogen fixation, indole-3-acetic acid production, and tolerating the extreme saline-alkali soil of Qinghai Province. We determined the strain's growth performance and antagonistic effects with pathogens (Fusarium graminearum, F. acuminatum) and evaluated its impact on K. thoroldiana. The test strain KKLW1 was identified as Bacillusamyloliquefaciens by morphology, adversity culture, and 16S rDNA and gyrB partial sequence analyses. KKLW1 strongly tolerates saline conditions (11% salt, pH 11), and showed stable nitrogen fixation activity and IAA production capacity; its Phl gene, which we amplified, was significant antagonistic to pathogenic pasture fungi. Furthermore, compared with the control, the strain showed clear germination and growth-promoting activity after soaking grass seeds and root-irrigating with the Bacillussuspension, increasing each by 8 and 10–12%, respectively. In sum, the strain KKLW1 has excellent biological properties and stable physiological characteristics in this extreme environment of the Qinghai-Tibet Plateau. We propose KKLW1 for use as a functional strain of microbial fertilizer to increase production and restore vegetation coverage of the Plateau's grassland.

Optimized Fractioning and Structure Analysis of the Reactivating Factor from Luteococcus japonicus subsp. casei Abstract— The chemical structure of the extracellular reactivating factor (RF) from Luteococcus japonicus subsp. casei was determined; this factor promotes survival of a small subpopulation of the producer cells under lethal stress impact. For the isolation and purification of this RF, the previously developed method for RF isolation from Saccharomyces cerevisiae was optimized. A total of 15 fractions were obtained from the culture liquid of Luteococcus casei, two of which (I and IV) exhibited reactivation activity against the cells subjected to a lethal stress impact (UV irradiation). The method included solid-phase extraction of the peptides on a hydrophobic sorbent with the C8 phase and subsequent multistage separation using RP-HPLC. Mass spectral analysis (MALDI-TOF) was used to determine the molecular characteristics of fraction IV. Efficient ionization was not achieved for fraction I. Mass charges for fraction IV were 773.394 and 788.102 Da. Edman automatic sequencing was used to identify these components as peptides: Ala-Pro-Asn-Glu-Asn-Gln-Gly and Ala-Pro-Asn-Glu-Glu-Gln-Gly. No similarity to any known full-size functional peptide molecules in the databases on polypeptide primary structures was revealed. Formation of biologically active peptides by L. casei may be associated with non-template synthesis and probably involves proteolysis of a large protein.

Iron-Reducing Microbial Communities of the Lake Baikal Low-Temperature Bottom Sediments Abstract— Psychroactive enrichment cultures reducing anthraquinone 2,6-disulfonate (AQDS) and soluble complexes of ferric iron at 5–20°C were isolated from the samples of Lake Baikal bottom sediments collected at the depths of 404 to 1396 m. Cultivation resulted in production of up to 6 mM Fe(II), which was over 50% of the initial Fe(III) concentration in the medium, and of 5.5 mM AH2QDS (~30% of the initial quinone concentration). The enrichment culture of iron-reducing bacteria St3 used Fe(III) citrate as the terminal electron acceptor, oxidizing formate from 6.5 to 2.0 g L–1 at 15°C. Phylogenetic analysis showed that the initial samples of the Lake Baikal bottom sediments and the enrichments obtained from these samples contained the taxa of classes Alpha- and Betaproteobacteria, which were closely related to bacteria capable of oxidizing aromatic compounds using inorganic electron acceptors, including ferric iron.

Ability of the Dietzia , Gordonia and Rhodococcus Actinobacteria to Accumulate Nickel Ions Abstract— Accumulation of nickel ions by actinobacterial strains of Dietzia, Gordonia, and Rhodococcus from the Regional Specialized Collection of Alkanotrophic Microorganisms (IEGM; http://www.iegm.ru/iegmcol) was studied. The major physicochemical factors underlying the accumulation of nickel ions are discussed. The strains characterized by high (up to 95%) accumulation of and resistance to increased (up to 10.0 mM) nickel ion concentrations were selected.

Methacrylate-Reducing Activity of Anaerobic Bacteria Anaeromyxobacter dehalogenans and Denitrovibrio acetiphilus Abstract— Periplasmic methacrylate-reducing activity was shown for anaerobic acetate-oxidizing gram-negative bacteria Anaeromyxobacter dehalogenans 2CP-1Т (class Deltaproteobacteria) and Denitrovibrio acetiphilus DSM 12809Т (class Deferribacteres), both possessing homologous genes for methacrylate redox system components. No acrylate reductase activity was revealed in these bacteria. A. dehalogenans and D. acetiphilus were also found to reduce fumarate, exhibiting periplasmic and intracellular fumarate reductase activity, respectively. D. acetiphilus was found to possess nitrate reductase activity of periplasmic and intracellular localization. The possible correspondence between reductase activities and the hypothetical proteins genes in the known genomes of A. dehalogenans and D. acetiphilus are discussed.

Biofilm Formation by Monocultures and Mixed Cultures of Alcaligenes faecalis 2 and Rhodococcus ruber gt 1 Abstract— Biofilm formation by monocultures and mixed cultures of nitrile-hydrolyzing bacteria Alcaligenes faecalis 2 and Rhodococcus ruber gt 1 was studied. Biofilm formation was assessed by staining with Crystal violet, by the energy state of the cells, and by the output of the polymer matrix. A quantitative method for assessment of the output of the polymer matrix by the fluorescence of konA-tetramethylrhodamine was developed. The medium used for obtaining mixed biofilms of Al. faecalis 2 and R. ruber gt 1 contained acetamide and glucose as carbon sources. In mixed biofilms Al. faecalis 2 was shown to act as a primary colonizer, while R. ruber gt 1 was a satellite microorganism. Compared to monoculture biofilms, mixed biofilms exhibited higher output of the polymer matrix and increased biofilm formation by Al. faecalis 2 and R. ruber gt 1 on addition of the culture liquid of the second strain. Daily addition of the toxic substrate acetonitrile to planktonic and biofilm cultures resulted in bacterial adaptation, as was indicated by higher numbers of surviving cells compared to the variants with acetonitrile addition every 10 min, mainly due to nitrile hydratase activity of R. ruber gt 1, which transformed acetonitrile into nontoxic acetamide. Our results show that binary biofilms of amidase-containing Al. faecalis 2 and R. ruber gt 1, a strain with high nitrile hydratase activity, are promising as biocatalysts for acrylic acid production and as the basis for a biofilter for nitrile removal from wastewater.

Characterization of Ultrasmall Chryseobacterium Strains FM1 and FM2 Isolated from Xenopus laevis Skin Abstract— Two strains of ultrasmall gram-negative bacteria (USGNB), FM1 and FM2, were isolated from the skin of the smooth clawed frog Xenopus laevis. The cytological, physiological, biochemical, and genotypic characteristics of the isolates were studied. Based on the sequencing of their 16S rRNA genes and on their phenotypic properties, the isolates were assigned to the genus Chryseobacterium. The cells were extremely small, with cell volumes of ~0.06 and ~0.015 µm3 for developing cultures of strains FM1 and FM2, respectively. Since the USGNB cells were firmly attached to the skin surface and could not be removed by repeated washing with water, these bacteria may be classified as epibionts. Adhesive properties of the fimbria-like appendages revealed in strains FM1 and FM2 by electron microscopy could probably contribute to tight binding of USGNB cells to the skin. Localization of ultrasmall gram-negative bacteria on skin surface of the frogs may indicate their action as a protective bacterial filter; skin surface of Xenopus laevis is thus characterized for the first time as a specific habitat of ultrasmall Chryseobacterium strains. Isolation and characterization of two ultrasmall Chryseobacterium strains, FM1 and FM2, improves our understanding of diversity of the cellular structural and functional characteristics and of the ecological niches of this bacterial genus.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Preventive and Clinical Dental Research

Comparative study of remineralization potential of three different remineralizing agents on demineralized enamel using light fluorescence and confocal fluorescence microscope: An in vitro study Trishagni Chaudhury, S Ananthakrishna, R Veena Kumari, Sukhbir Kour, Aswathi Syam International Journal of Preventive and Clinical Dental Research 2018 5(4):45-49 Aim and Objective: The main objective of this in vitro study was to evaluate the comparative analysis of remineralization potential of three different materials – casein phosphopeptide-amorphous calcium phosphate with fluoride (CPP-ACPF), calcium sucrose phosphate (CaSP), and bioactive glass on demineralized enamel using light fluorescence microscopy and confocal laser scanning fluorescence microscopy. Materials and Methods: A total of 40 single-rooted maxillary and mandibular premolars were selected; 4 mm × 4 mm window was prepared on the buccal surfaces of the teeth, which was then subjected to demineralization for 96 h at 37°C. Teeth were randomly selected and divided into four study groups of 10 teeth each: Group 1 (artificial saliva), Group 2 (CPP-ACPF), Group 3 (bioactive glass), and Group 4 (CaSP). Each group was treated with respective remineralizing agents and sectioned with Struers Minitom diamond saw. Each section obtained was visualized under light fluorescence microscope for detection of remineralized and demineralized zones and also was visualized under confocal laser scanning fluorescent microscope for the quantification of demineralized and remineralized zones. Statistical Analysis: Statistical analysis was done using paired t-test, followed by one-way ANOVA, where P ≤ 0.05. Results: All the groups showed better statistically significant remineralization potential when compared to the control group, but among them Group 4, that is, Toothmin group showed the highest mean remineralized value, followed by Groups 3, 2, and 1, though the values were not statistically significant (P ≤ 0.05). Light fluorescence microscopy was an efficient diagnostic aid in detecting remineralization and demineralization. Conclusion: CaSP (Toothmin) has got the best remineralization potential when compared to other groups.

A clinical study of incidence, etiology, and pattern of mandibular fractures in K. R. Hospital, Mysore S Sandeep Tejaswi, TS Subash International Journal of Preventive and Clinical Dental Research 2018 5(4):50-52 Introduction: The mandible is the second-most common fractured part of the maxillofacial region after the nasal bone. The incidences, etiology, and pattern of mandibular fractures vary considerably among the different population; there is a need to evaluate aspects of mandibular fracture in Mysore. The main causes of mandible fractures in this study are road traffic accident (RTA), assault, fall, sports-related injuries, and industrial trauma. Materials and Methods: A total of 50 patients records were taken from MLC books who sustained mandibular fracture presenting to the Department of Dentistry, K.R. Hospital from January 2016 to December 2016. A standardized maxillofacial trauma pro forma was used to record the data in relation to age, gender, etiology, and anatomical site. The mandibular fractures were classified based on the anatomical sites such as symphysis, parasymphysis, body, angle, ramus, condyle, coronoid, and dentoalveolar process. Patients were divided into the following age group of <10 years, 11–20 years, 21–30 years, 31–40 years, 41–50 years, and 50 years and above; data were obtained and analyzed using simple descriptive statistical analysis and Pearson's Chi-squared test. Results: A total of 50 patients with 70 fractures were analyzed for the study, in which 32 were male (64%) and 18 (36%) were female. The patients ranged from <10 years to 50 years. The highest prevalence of fracture occurred in the age group of 21–30 (33.3%) years followed by age group of 50 years and above (28.6%). Mandibular fractures are predominantly caused by RTA which consisted of (16/50, 32%). The second-most common was fall (13/50, 26%), followed by assault (10/50, 20%), sports (8/50, 16%), and industrial trauma (3/50, 6%). RTA was the main cause in the age group of 31–40 years. Fall was the second cause in the age group of 40–50 years and above. RTA remains the predominant cause of mandibular fracture in the age group of 31–40 years in this study. Conclusion: Among 70 fracture sites located in this study, sites which fracture were seen was parasymphysis 31.42%, followed by angle 20%, condyle 18.57%, symphysis and dentoalveolar 8.57%, body 7.14%, ramus 4.28%, and the least was coronoid 1.42%. The parasymphysis is the most common site of fracture in this study similar to the other previous studies. In cases with unilateral fractures, parasymphysis was the most common 33.33%, followed by the angle of 19.60%. The most common combination was parasymphysis and condyle.

A comparative evaluation of plastic and metal impression trays on the accuracy of cast Jiji M Edakkalathur, Kurien Varghese, Sony Sebastian, Bilaal Sidhique Abubacker International Journal of Preventive and Clinical Dental Research 2018 5(4):53-56 Background: Defects in making an impression could affect the accuracy and fit of the final prostheses. Aims and Objectives: The present study evaluates whether the rigidity of impression trays made out of two different materials affect the accuracy of cast poured out of same impression material. Materials and Methods: For the present study, metallic perforated rim-lock tray and disposable plastic tray were selected for making the impression. Alginate (Tropicalgin™) was used as the impression material of choice. A master model constructed with stainless steel abutments at 44 and 47 and 34 and 37 region was used for making impressions using metal and plastic impression trays respectively. The cast was poured with type III dental stone and the distance between the reference points were measured using CMM (Coordinate Measuring Machine). The results obtained were compared and statistical analysis done using one sample t – test. Results: The study came out with results showing statistically significant differences (P < 0.05) between casts made out of these two different impression tray materials. Conclusions: The study concluded that rigidity of perforated metal stock trays ensured better results than perforated plastic stock trays for impressions using alginate impression material.

A comparative evaluation of maxillary canine retraction using flap and flapless corticotomy: A clinical study Sarvesh P Agrawal, Shreya Iyengar, Udita A Thakkar, Reema Agrawal, Syed Mohammed Ali, Vinod Sargaiyan International Journal of Preventive and Clinical Dental Research 2018 5(4):57-59 Objective: The objective of this study is to compare and evaluate the effectiveness of maxillary canine retraction using flap and flapless corticotomy. Materials and Methods: A sample of 10 adult patients undergoing orthodontic treatment requiring therapeutic extraction of maxillary first premolars bilaterally were selected, compliant with the inclusion criteria. By random allocation, one site was selected for flap corticotomy-facilitated orthodontics (CFO) and opposite site for flapless CFO. After corticotomy procedure, maxillary canine retractions were done on both the sides using sliding mechanics. A paired t-test was used to determine the statistical significance of the difference in the amount of tooth movement between the flap and flapless sides. Results: There were statistically significant differences (P ≤ 0.01) in the rates of anteroposterior movement of the canines between the flap and flapless sides at all measurement times, and the rates of canine retraction were consistently higher in the flap side than in the flapless side. Conclusions: Flap corticotomy technique is more effective as compared to that of flapless corticotomy technique. Clinical Relevance: Flap corticotomy will be more effective clinically; however, the histologic correlation in regard to the changes in both the technique would be more beneficial.

Prevalence of oral submucous fibrosis among habitual gutkha and areca nut chewers in Dhanbad district Animesh Kumar Shivam, Farrukh Azam, Heena Sadiq International Journal of Preventive and Clinical Dental Research 2018 5(4):60-62 Objectives: To assess the incidence rate of oral submucous fibrosis (OSMF) and its etiology in patients attending outpatient department at Patliputra Medical College and Hospital (PMCH), Dhanbad. Methodology: The diagnosis of OSMF was based on clinical examination and evaluating patient's signs and symptoms. Results: The total number of patients affected by OSMF in this time duration was 270. Of these, 232 (86%) were male, while 38 were female (14%). The greatest proportion of OSMF patients (58.58%) had a habit of chewing areca nut alone or in the form of gutkha. Conclusion: This study reveals that the incidence rate of OSMF in patients visiting PMCH, Dhanbad was 1%. Males were more affected than females. It was seen that the major etiological factors in the development of OSMF was areca nut and gutkha usage by the patients.

Knowledge, attitude, and practice of dentists toward patients with human immunodeficiency virus and hepatitis B virus infections in Bhubaneswar, Odisha, India Rajeev Ranjan, Rudra Joshi, Saurabh Pramanik, Chhaya Jha, Anirban Kundu, Diplina Barman International Journal of Preventive and Clinical Dental Research 2018 5(4):63-67 Background: During routine dental work, dentists and dental students can be exposed to human immunodeficiency virus (HIV) and hepatitis B virus (HBV). The aim of the present study was to assess the knowledge, attitude, and practice of the dentists toward HIV- and HBV-infected patients in Bhubaneswar, Odisha, India. Materials and Methods: A cross-sectional study was conducted among dentists practicing in Bhubaneswar, Odisha, India, from December 2016 to April 2017. A total of 200 practitioners (89 males and 111 females) participated in the study. A pretested validated questionnaire related to the knowledge, attitude, and practices (knowledge – 17, attitude – 13, and practice – 17) of the dentists toward HIV- and HBV-infected patients was distributed among dental practitioners. Results: Almost 80% of the dental practitioners had existing fear and concern of the infection transmission from HIV and HBV patients, and this was the primary cause of refusal to treat these infected patients. Conclusion: The dentists did not have proper knowledge in the field of transmission of HIV and HBV infections. Fear and concern of being infected make them to refuse treating these patients. Therefore, training dentists to improve their attitudes toward the treatment of these patients is necessary.

Appraisal of orthodontic brackets for Adhesive Remnant Index with and without primer: In vitro study Ayub Khan, Sri Sujan Suryadevaraya, B Vengal Rao, Sweta Kattimani, Shaik Kamal Sha, Bindu V Bhaskar International Journal of Preventive and Clinical Dental Research 2018 5(4):68-70 Introduction: The elementary function of the primer is to boost the efficiency of the final bond. The secondary function is to protect the enamel from the ensuing demineralization by the acid-etching and to reduce marginal leakage. Primer computing is a step in the bonding procedure which necessitates increased chair time risk of moisture contamination and an increased procedural cost. Hence, the present study is intended to evaluate the Adhesive Remnant Index (ARI) for the site of bond failure. Methodology: Eighty extracted premolars procured from the department of orthodontics and private clinics divided into two groups with and without primer, after debonding the enamel surfaces, were examined under stereomicroscope of ×20 magnification for ARI, using the 4-point scale described by Artun and Bergland. Results: The frequency distribution of ARI with primer application showed statistically significant results. There were significant differences in debonded locations, between enamel-adhesive with primer and without primer. Conclusions: A conventional adhesive system with primers showed low ARI scores in comparison to adhesive system without primer.

Chitosan hydrogel: Its applications in medicine and dentistry Guljot Singh, Umang Jamwal International Journal of Preventive and Clinical Dental Research 2018 5(4):71-76 Since times immemorial, there has been an interactive interdependence of man on nature. The world of technology has overpowered him, yet technology and nature go hand in hand to help mankind fulfill his day-to-day necessities. The developing civilization has once again led to a quest to turn to nature in search for materials that are ecofriendly and economical. Chitosan is one such polymer. The combination of properties of chitosan such as biocompatibility, biodegradability, nontoxicity, and antibacterial properties open many possibilities for its application in medicine and dentistry. This article overviews the applications of chitosan in the form of hydrogels that can be applied effectively and give promising results for target delivery of drugs, the reduction of toxicity, and its uses focused towards the advancement of dentistry.

Restoring biomechanics in immature young maxillary permanent central incisor MR Amith, P Venugopal, CM Jayashankara, S Anil Kumar, P Sharath Kumar, SA Girish International Journal of Preventive and Clinical Dental Research 2018 5(4):77-80 Treatment of immature young permanent tooth is complex owing to the presence of open apex and thin fragile dentinal walls. To create an apical seal, the treatment of choice would be apexification. The present clinical case is a report of immature permanent young central incisor associated with the periapical lesion treated with single-visit Biodentine® apexification and restored with glass fiber post in the aid of dual-cured resin composite to achieve monobloc effect. The concept of accomplishing monobloc with root dentin is imperative for the durability of the foundation.

Software-guided predictable endodontic management of three-rooted lower right second premolar Purnil B Shah, Nili Shah, Pratik Kariya International Journal of Preventive and Clinical Dental Research 2018 5(4):81-83 It is essential in endodontics to understand the morphological anatomy of the roots and root canal systems of the teeth to increase the success rate of root canal therapy. Advanced diagnostic imaging modalities like cone-beam computed tomography (CBCT) and the assistive software like three-dimensional (3D) Endo Software (by Dentsply Sirona) are very helpful aids in understanding the anatomy of the teeth, especially the complicated premolars. Most commonly mandibular first and second premolars have a single root and root canal system. However, multiple roots and canals have also been reported in few cases which are considered as a challenging task for an endodontist. The present case report discusses the complete endodontic management of a three-rooted mandibular second premolar using CBCT imaging and assistive guidance by 3D Endo Software (by Dentsply Sirona).

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Ultrasounds

Transient periportal hyperechogenicity in feverish patients: a novel ultrasonographic finding Abstract Purpose Periportal hyperechogenicity has been recorded in many inflammatory and infectious diseases, including viral hepatitis, inflammatory bowel diseases, toxic shock syndrome of staphylococcus infection, typhoid fever, and schistosomiasis. We aimed to evaluate the echogenicity of the portal tracts of the liver by abdominal ultrasound imaging in patients with fever irrespective of the cause. Methods Abdominal ultrasound examination was performed in 277 consecutive patients presented with fever at their first visit and repeated 2 weeks later after their recovery. Results Transient periportal hyperechogenicity was present in 39% (108 patients) of the feverish patients studied irrespective of the cause of the fever. Conclusion Transient periportal hyperechogenicity is a frequent ultrasonographic finding in feverish patients irrespective of the cause of fever, and hence should not be misdiagnosed as liver disease or chronic periportal fibrosis unless the hyperechogenicity persists after recovery from the febrile or inflammatory condition.

Paediatric neck ultrasonography: a pictorial essay Abstract The neck structures are located very superficially and are therefore easy to explore by ultrasound examination. Ultrasonography is crucial for the detection of neck pathologies in children. High-frequency probes (10–15 MHz) are used for the ultrasound examination on the patient lying in supine decubitus and with their neck stretched out. The outcome of the exam depends mainly on the child's cooperation—hence the need for warm sonographic gel and a comfortable cushion to place under the patient's shoulders. The complete scan of the neck includes the evaluation of the thyroid and salivary glands and the vascular structures as well as the lymph node analysis. In children and adolescents, the thymus is often visualised in the supraclavicular and jugular scans. It appears as a structure, usually hypoechoic, with thin hyperechoic straps, though echogenicity increases with age. In this pictorial essay, the main pathological conditions of the neck in paediatric age will be examined, such as thyroid dysgenesis, thyroiditis, thyroid nodules, lymphadenopathies, cystic lesions, haemangiomas and vascular malformation, cervical thymus, fibromatosis colli and pilomatrixoma.

Spinal cord ultrasonography of the newborn Abstract Ultrasound represents the first-line survey for the assessment of spinal cord development abnormalities. In fact, within 6 months of life, the non-ossification of neuronal arcs provides an excellent acoustic window that allows a detailed depiction of the spinal canal, its content and of the surrounding soft tissues. Nevertheless, an accurate ultrasound examination requires a complete knowledge of the anatomy, the condition of normality, the frequent anatomical variants and the main pathologies involved. This review is intended to briefly summarize the US technique, the main clinical indication and the key notions that could help to properly perform this type of ultrasound examination.

Treatment of thyroid nodules with radiofrequency: a 1-year follow-up experience Abstract Purpose The aim of this study is to assess the effectiveness and safety of radiofrequency ablation (RFA) in debulking benign solid thyroid nodules. Materials and methods This is a retrospective review of 77 patients with predominantly solid thyroid nodules treated with RFA in a single center between 2013 and 2016. All patients declined or were not eligible for surgery. Benign proven thyroid nodules causing compressive symptoms and cosmetic concerns were considered for treatment. Nodule volume, thyroid nodule related compressive symptoms, cosmetic concerns and thyroid function were evaluated. Results All patients underwent a single treatment session. Mean nodule volume decreased from 17.9 ± 15.6 mL at baseline to 5.2 ± 7.4 after 12 months with a volume reduction ratio (VRR) of 70.9% ± 20.8%. There were no identifiable factors predictive of response to RFA. Median cosmetic and symptom scores of the entire population decreased from 3 [2–4] and 3 [0–10] to 1 [1–3] (p < 0.001) and 0 [0–5] (p < 0.001), respectively. No major complications occurred and RFA did not affect thyroid function when normal. Conclusion RFA induces substantial volume reduction of predominantly solid thyroid nodules and improves compressive symptoms and cosmetic concerns. RFA does not impact normal thyroid function and has an acceptable safety profile.

Strain elastography in Crohn's disease: the role of visual observation and semiquantitative parameters Abstract Strain elastography is a recently developed ultrasound method that seems to contribute to the diagnosis and monitoring of inflammatory bowel diseases. This pictorial essay aims to present the feasibility of strain elastography in clinical practice by comparing visual observation and semiquantitative parameters with endoscopic or radiological images in some common cases of Crohn's disease. In our opinion, strain elastography with visual observation is easily performed in connection with B-mode ultrasound and color Doppler imaging and may provide relevant information. Strain elastography with the elaboration of semiquantitative parameters is not as immediate as the visual observation method, but it seems to provide more objective data and seems more appropriate for monitoring the evolution of the disease. However, for the elastographic method to extensively contribute in inflammatory bowel diseases, standardization and further studies are required to confirm the promising results already reported in the literature.

A role for ultrasound in the fabrication of carbohydrate-supported nanomaterials Abstract Nowadays, sonication is a well-known technique for the fabrication and surface modification of nanomaterials with various sizes, shapes, and chemical and physical properties. In addition to conducting catalyst-mediated chemical reactions and enhancing medicinal properties, such as antibacterial and antifungal activities, nanoparticles made from biodegradable and biocompatible carbohydrate coatings and glycosidic frameworks offer exciting opportunities for the development of biomaterials, optical sensors, packaging materials, agricultural products, and food. This review article discusses the synthesis of carbohydrate-coated nanoparticles by ultrasound radiation as well as the many applications of these nanoparticles. Graphical abstract

Pancake kidney, a rare and often misdiagnosed malformation: a case report and radiological differential diagnosis Abstract Renal ectopia and fusion anomalies are Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) that are usually incidentally detected and asymptomatic. Patients affected present a higher risk of complications like recurrent urinary tract infections or obstruction. Pancake kidney (PK) is one of the rarest types of renal anomaly with complete fusion of the superior, mild and inferior poles of both kidneys in the pelvic cavity. Each kidney has its own excretory system with two ureters that do not cross the midline. In the asymptomatic cases, a conservative approach should be performed. Surgical management may be needed when urological problems occur. PK is often associated with congenital anomalies of other organs. Ultrasound is the first line radiological examination for the diagnosis and the follow-up of kidney malformations. The main sonographic findings suggesting PK diagnosis are a large and lobulated renal mass consisting of two fused lateral lobes without an intervening septum located in the pelvic cavity. Each lobe usually has a separate pelvicalyceal system, the renal pelvis is anteriorly placed and the ureters are usually short and enter the bladder normally without crosses the midline. Ultrasonography gives useful information on the morphology and volume of the organ, and on its vascularization through the use of the Color- and Power-Doppler. Computer Tomography and Magnetic Resonance Urography are second level techniques used to confirm the diagnosis and to evaluate the presence of other abnormalities. The knowledge of the imaging findings and the anatomy of congenital renal malformations is important to avoid diagnostic pitfalls and misinterpretations. We report the case of a 14-years old female with PK who was misdiagnosed with a horseshoe kidney (HSK) during an abdominal ultrasound.

Increased renal cortical stiffness obtained by share-wave elastography imaging significantly predicts the contrast-induced nephropathy in patients with preserved renal function Abstract Purpose We aimed to investigate the relation between renal cortical stiffness (CS) obtained by shear-wave elastography (SWE) and contrast-induced nephropathy (CIN) development in interventional treatment-planned acute coronary syndrome (ACS) patients. Methods Our study group consisted of 465 ACS patients. Routine laboratory assessments, B-mode, Doppler, and SWE renal ultrasonography (USG) evaluations were performed. Renal resistive index (RRI), renal pulsatility index (RPI), and acceleration time (AT) and CS were measured. Patients were grouped as with and without CIN. Results Among the study group, 55 patients (11.8%) had CIN. Age, diabetes mellitus (DM), hypertension (HT), basal creatinine, CK-MB and troponin I levels, contrast volume, contrast volume/weight ratio, SYNTAX score, RRI, RPI, AT, and CS values were significantly higher in patients with CIN. eGFR was lower in patients who developed CIN. Age, contrast volume/weight ratio, and CS were determined as independent predictors of CIN occurrence in logistic regression analysis. In multivariate logistic analysis, increase of age (each year), contrast volume/weight (each 0.2 mL/kg), and CS (each 1 kPa) were found to augment the development of CIN by 7.1, 59.5, and 62.3%, respectively. In the ROC analysis, CS had the highest AUROC value. The cutoff value of CS obtained by the ROC curve analysis was 7 kPa for the CIN development (sensitivity: 74.5%, specificity: 72.5%). Conclusion CS value is a simple, cheap, reproducible, noninvasive, and objective parameter for the detection of CIN development. ACS patients should be directed to renal USG, and routine CS value should be written besides USG measurements in reports.

Contrast-enhanced ultrasound patterns of hepatocellular adenoma: an Italian multicenter experience Abstract Purpose Hepatocellular adenoma (HCA) is a rare benign monoclonal neoplasm, recently categorized on genetic and histopathological basis into four subtypes with different biological behaviors. Since contrast-enhanced ultrasonography (CEUS) is nowadays a well-established technique for liver nodule characterization, the aim of our study was to assess CEUS features of HCAs to identify criteria that correlate with different HCA subtypes as compared to histopathologic examination and other imaging modalities. Methods We retrospectively analyzed data of patients with histology-proven HCA who underwent CEUS, computed tomography or magnetic resonance imaging (MRI) in seven different Italian ultrasound units. Results The study enrolled 19 patients (16 females; 69% with concomitant/prior use of oral contraceptives): the mean size of all HCAs was 4.2 cm (range 1.6–7.1 cm); 14/19 had inflammatory HCAs (I-HCA), 1/19 β-catenin-activated HCA, and the others unclassified HCAs. On CEUS, during the arterial phase, all but one HCA displayed a rapid enhancement, with 89% of these showing centripetal and 11% centrifugal filling pattern, whereas during the portal and late venous phase 58% of HCA showed washout and the remaining 42% displayed persistent enhancement. In particular, among I-HCAs 7/14 showed no washout, 3/14 and 4/14 showed washout in the portal or late phase, respectively. Conclusions This dataset represents one of the few published experiences on HCAs and CEUS in Italy and shows that HCAs are hypervascularized in the arterial phase usually with a centripetal flow pattern and have a heterogeneous behavior in portal and late phase. In particular, occurrence of delayed washout on CEUS but not on MRI is frequently observed in the subtype of I-HCA.

Neonatal and pediatric thoracic ultrasonography Abstract Ultrasound examination of the thorax (TUS) can be quite suitable for children because their unique thoracic anatomy provides many acoustic windows into the chest. This review article covers techniques, indications, and applications of TUS in neonates, infants, and children, including common aspects and applications, like pulmonary consolidation and atelectasis, pleural effusion and pneumothorax and main neonatal pathologies such as respiratory distress syndrome (RDS) and transitory tachypnea of the newborn (TTN).

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182

Orthodontics and Dentofacial Orthopedics

Directory: AAO Officers and Organizations Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s):

Leena Peck, 1945-2019 Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Sheldon Peck

May 2019:155(5) Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Allen H. Moffitt

Searching the literature for studies for a systematic review. Part 4: Searching with the use of text words Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Anne Littlewood, Dimitrios Kloukos

Got milk? Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Laurance Jerrold

Precision of 3D-printed splints with different dental model offsets Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Niansong Ye, Tingting Wu, Ting Dong, Lingjun Yuan, Bing Fang, Luoguo Xia Introduction The purpose of this study was to assess the precision of 3D-printed splints generated from different dental model offsets. Methods Ten maxillary models were offset by given distances (0.05 mm, 0.1 mm, and 0.2 mm). Digital splints were created by means of the boolean operation. The physical splints were fabricated by means of digital light-processing (DLP) rapid prototyping technologies. A layer of impression material, which could be weighed by means of an electronic analytical balance, was placed in the airspace between the splint and the teeth. We also calculated the shell-to-shell deviations by measuring the 3-dimensional (3D) euclidean distances between the surface points of the scanned splints and the original digital splint and evaluating the results with color-mapping methods. Results There was a statistically significant difference in the amounts of impression material remaining in the airspace between the 0.0-mm group and the 0.05-mm, 0.1-mm, and 0.2-mm groups (P < 0.05), between the 0.05-mm and the 0.1-mm and 0.2-mm groups (P < 0.05), and between the 0.0-mm group and the 0.05-mm, 0.1-mm, and 0.2-mm groups (P < 0.05). There was a statistically significant difference in shell-to-shell deviations between the 0.05-mm and the 0.1-mm and 0.2-mm groups (P < 0.05). Conclusions 3D-printed splints generated from offset dental models (offset 0.05 mm, 0.1 mm, and 0.2 mm) can fit better on the teeth than splints from no-offset dental models. An offset of 0.1 mm is the best choice of parameter for generating the splint.

Maxillary molar mesialization with the use of palatal mini-implants for direct anchorage in an adolescent patient Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Benedict Wilmes, Sivabalan Vasudavan, Dieter Drescher A unique clinical challenge presents when dealing with a compromised first permanent molar. A compelling treatment option for consideration is the removal of a nonrestorable first permanent molar, with the subsequent "replacement" through controlled mesial tooth movement of viable second and third molars. To reinforce the anchorage support associated with such a planned movement, indirect or direct implant-supported mechanics may be used. With the use of direct anchorage, orthodontic brackets are not required and space closure can be commenced immediately. In this article, we report the clinical procedure and design of direct-anchorage mechanics used for the successful closure of a maxillary first permanent molar space with the use of an implant-supported appliance (Mesialslider). Treatment was completed in just under 12 months, with successful mesial movement of the maxillary second and third molars without the need for the bonding of orthodontic brackets on the anterior dentition. The result was determined to be stable over a 3-year period.

Hemimandibular hyperplasia treated with orthognathic surgery and mandibular body osteotomy Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Han-Lim Kim, Young-Jun Choi, Hyewon Kim Surgical treatment of facial asymmetry usually involves 2-jaw orthognathic surgery. But when the size of the mandible differs a great deal between the right and left sides, as in hemimandibular hyperplasia, additional contouring surgery is required. A 20-year-old woman presented with facial asymmetry, showing marked mandibular hyperplasia of the right side. She was treated with the use of 2-jaw surgery with mandibular body osteotomy in conjunction with orthodontic intrusion. Good esthetic outcome and functional occlusion were achieved.

A complex orthognathic surgical approach correcting a Class III malocclusion involving traumatic dental injuries and a maxilla fracture Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Renato Barcellos Rédua, Robson Almeida de Rezende, Carlos Eduardo de Almeida Ferreira, Márcio Rodrigues Bittencourt This case report describes a complex approach to orthodontic preparation for surgical treatment of a Class III facial skeletal deformity in a patient who suffered a unilateral maxilla fracture that also featured maxillary left central incisor avulsion, maxillary right central incisor extrusion, and maxillary right lateral luxation. A 12-mm negative overjet was formed by extraction of the maxillary right lateral incisor and closure of the residual space by retraction of the maxillary right central incisor, maxillary left lateral incisors, and maxillary right and left canines. Forward and impaction movement of the maxilla and retrusion and a counterclockwise turning movement of the mandible were then performed. Maxillary first premolars were reshaped to establish a maxillary canine shape, maxillary canines were reshaped to be maxillary lateral incisors, and a maxillary left lateral incisor received a central incisor crown, with a Class II molar relationship with good occlusion after 2 years of follow-up. This case was a great challenge that included complex multidisciplinary procedures, and the results indicated successful treatment of an orthodontic preparation for surgical treatment in a patient after maxillary fracture associated with dental trauma.

3D stereophotogrammetry versus traditional craniofacial anthropometry: Comparing measurements from the 3D facial norms database to Farkas's North American norms Publication date: May 2019 Source: American Journal of Orthodontics and Dentofacial Orthopedics, Volume 155, Issue 5 Author(s): Seth M. Weinberg Introduction Datasets of soft-tissue craniofacial anthropometric norms collected with the use of different methods are available, but there is little understanding of how the measurements compare. Here we compare a set of standard facial measurements between 2 large datasets: the 3D Facial Norms (3DFN) dataset collected with the use of 3D stereophotogrammetry (n = 2454), and the Farkas craniofacial norms collected with the use of direct anthropometry (n = 2326). Methods A common set of 24 craniofacial linear distances were compared by computing standardized effect sizes (Cohen d) for each measurement to describe the overall direction and magnitude of the difference between the 2 datasets. Results Variables with higher mean d values (suggesting greater discrepancy across datasets) included measurements involving the ear landmark tragion, the landmark nasion, the width of nasolabial structures, the vermilion portion of the lips, and palpebral fissure length. Variables with lower mean d values included smaller midline measurements involving the lips and lower face and horizontal distance measures between the eyes. Eight measurements showed a significant negative correlation (P < 0.05) between Cohen d and age, indicating greater similarity across the 2 datasets as age increased. Conclusions There are considerable differences between the 3DFN and Farkas norms. In addition to the measurement methods, other factors accounting for discrepancies may include secular trends in craniofacial morphology or differences in ethnic composition.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

BioDrugs

Correction to: Vestronidase Alfa: A Review in Mucopolysaccharidosis VII The article Vestronidase Alfa: A Review in Mucopolysaccharidosis VII, written by Emma H. McCafferty and Lesley J. Scott, was originally published Online First without open access.

PARP Inhibitors and the Evolving Landscape of Ovarian Cancer Management: A Review Abstract As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, as it has high rates of homologous recombination (HR) deficiency. PARP inhibition exploits this cancer vulnerability by further disrupting DNA repair, thus leading to genomic catastrophe. Early clinical data demonstrated the effectiveness of PARP inhibition in women with recurrent EOC harbouring BRCA1/2 mutations and those with platinum-sensitive recurrences. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with recurrent EOC. Based upon randomised controlled trials, PARP inhibitors are in use as "maintenance" therapy for those with platinum-sensitive and platinum-responsive recurrences (irrespective of BRCA1/2 mutation status). Among women with BRCA1/2 mutations (either germline or somatic), maintenance PARP inhibitor therapy for those with recurrence has led to a nearly fourfold prolongation of progression-free survival compared to placebo control. Those without BRCA1/2 mutations experience an approximately twofold increase in progression-free survival. The latest clinical data demonstrate that women with BRCA1/2 mutations who respond to first-line chemotherapy and go on to have maintenance olaparib experience a doubling of the rate of freedom from death at 3 years when compared to placebo (60% vs 27%). PARP inhibitors are also approved as active therapy for women with germline or tumour BRCA1/2 mutations and recurrent EOC treated with three or more prior lines of therapy. Apart from the presence of a BRCA1/2 mutation (germline or somatic) and clinical factors such as platinum sensitivity and responsiveness, other predictive biomarkers are not in routine clinical use. Assays to identify genomic aberrations caused by HR deficiency, or mutations in genes involved in HR, have not been sufficiently sensitive to identify all patients who benefit from treatment. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, capable of re-establishing the DNA open-reading frame and leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair may also be important. This review focuses on the rationale for the use of PARP inhibitors in EOC. The data that have shaped clinical research are presented, and the trials that have changed management standards are reviewed and discussed. Highlighted are the past and ongoing efforts to further improve and explore the use of PARP inhibitors in EOC.

Immunogenicity of Chimeric Antigen Receptor T-Cell Therapeutics Abstract Chimeric antigen receptor (CAR) T-cell immunotherapy has gained significant attention in the past decade due to its considerable potential in the treatment of various types of malignancies, particularly hematological. While success has been achieved in a number of studies, and two CAR-T-cell products were recently approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) (YESCARTA®, KYMRIAH®), this treatment modality continues to present challenges for clinical development. One major potential side effect is the ability of CAR-T products to induce host immune responses. Immunogenicity induction risk factors have been shown to be associated with the presence of non-human or partially human sequences in the CAR construct, suicide domain, or other components of the CAR-T, and also with the presence of residual viral proteins or other non-human origin proteins utilized as part of the gene editing step of CAR-T production. Both humoral (antibody-based) and cellular-type responses have been described, leading to various degrees of impact on CAR-T expansion and persistence, and therefore the overall safety and clinically meaningful response of the treatment. In this article we discuss various types of immune responses specific to CAR-T therapy, their impact on treatment outcome, and methodologies used to detect them.

Different Policy Measures and Practices between Swedish Counties Influence Market Dynamics: Part 1—Biosimilar and Originator Infliximab in the Hospital Setting Abstract Background Decentralisation of healthcare budgets and issuance of local guidelines means that the use of biosimilars can vary by region within a particular country, for example between the 21 counties of Sweden. Objectives This study aimed to analyse the county-level market dynamics of biosimilar and originator infliximab, which are hospital products, and to examine how local policy measures and practices, in addition to national policy, influenced market dynamics. Methods We first conducted a literature review on (biosimilar) policies in Sweden, then analysed market data provided by IQVIA™ on uptake of originator and biosimilar infliximab within the different counties (Q2 2012 to Q4 2017), including discounts from (tender) contracts. Biosimilar market shares were calculated with volume data (measured as defined daily doses [DDDs]). We then discussed our findings in semi-structured interviews with the national pricing and reimbursement agency, key experts within the county councils of Skåne, Västra Götaland, and Stockholm, and an industry representative. Results Market shares of biosimilar infliximab vary widely between counties (range 18–96% in 2017). The initial uptake of biosimilar infliximab was slow and variable, with abrupt increments in biosimilar market shares coinciding with expiration of contracts for the originator product. Different approaches taken by counties to achieve a low cost per DDD of infliximab were identified, i.e., a rapid switch to the biosimilar (Skåne), a delayed switch to the biosimilar (Stockholm), or no switch to the biosimilar when a favourable price on the originator product could be obtained (Västra Götaland). Quantitative analysis showed that 59% of the variability in biosimilar market shares could be explained by the relative difference in discounted price between the biosimilar and the originator product. In addition, qualitative analysis indicated the presence of key opinion leaders, local guidelines and initiatives, and whose budget it affects as drivers in the decision-making process. Conclusions Variations in the market share of biosimilar infliximab between the Swedish counties is largely explained by the discounted price difference between biosimilar and originator product, and counties used different strategies to leverage such biosimilar competition. Additionally, the presence of key opinion leaders, local guidelines and gainsharing arrangements appeared to play a role in infliximab market dynamics in counties.

A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin ® ) in Healthy Male Subjects Abstract Objective BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects. Methods This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUC0–inf). Biosimilarity of the study drugs was confirmed if the two-sided 90% confidence interval (CI) ratios of the geometric means for the three pairwise comparisons were contained within the range 80–125%. Other pharmacokinetic parameters including area under the concentration curve to time t (AUC0–t), maximum concentration of drug in plasma (Cmax), half-life (t½), and time to Cmax (tmax) were also measured. Results The pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUC0–inf was 99–112% for BAT1706 versus EU-BEV, 97–110% for BAT1706 vs US-BEV and 92–104% for EU-BEV versus US-BEV comparisons, respectively, demonstrating biosimilarity. There were no significant adverse events attributable to BAT1706, as compared to EU-BEV and US-BEV. BAT1706 demonstrated a similar safety profile to EU-BEV and US-BEV. In addition, no anti-drug antibody positive result was reported for any subject included in the study. Conclusion In this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion. Trial Registration NCT03030430.

Adalimumab Biosimilars in Europe: An Overview of the Clinical Evidence Abstract Adalimumab, the first fully humanised monoclonal antibody against tumour necrosis factor alpha (TNF-α), has played a leading role in the revolution brought about by the introduction of biologics, and has received the widest range of indications among TNF-α inhibitors. Post-registration, observational and registry studies of real-life use have largely supported the outcomes seen in registrational clinical trials. With the recent loss of exclusivity for the originator medicinal product in Europe, a number of biosimilar adalimumab molecules have been licensed for use in the same indications as the originator molecule across rheumatology, dermatology, gastroenterology and ophthalmology. Clinicians in these areas first gained experience with biosimilar infliximab, followed by etanercept and rituximab. However, adalimumab is likely to present unique challenges given the numbers of patients treated and the range of biosimilar adalimumab products available. The biosimilar approval pathway has an emphasis on the pre-clinical analytic data in combination with clinical studies conducted to confirm therapeutic equivalence. To date, several adalimumab biosimilars have entered the EU market following successful marketing authorisation applications and recent expiration of originator patent protection. This overview covers the extent of use of adalimumab and summarises the regulatory process involved in the development of biosimilars as well as their use in clinical practice. The authors also discuss clinical data available so far on adalimumab biosimilars and their envisaged impact in the field of immune-mediated inflammatory diseases.

Assessing Analytical and Functional Similarity of Proposed Amgen Biosimilar ABP 980 to Trastuzumab Abstract Background ABP 980 has been developed as a biosimilar to Herceptin® (trastuzumab). Comprehensive analytical characterization incorporating orthogonal analytical techniques was used to compare ABP 980 to trastuzumab reference products sourced from the United States (US) and the European Union (EU). Methods Physicochemical property comparisons included the following: primary structure related to amino acid sequence and post-translational modifications, including glycans; higher-order structure; product-related substances and impurities, including size and charge variants; subvisible and submicron particles, and protein content. In addition, functional similarity was assessed for Fab-mediated, Fc-mediated, and combined Fab- and Fc-mediated activities. Results ABP 980 has the same amino acid sequence as and similar post-translational modification profiles to trastuzumab (US) and trastuzumab (EU). Importantly, ABP 980 was found to be highly similar to trastuzumab for all functional activities related to the mechanism(s) of action. Higher-order structure, product-related substances and impurities, particles and aggregates were also highly similar between ABP 980 and trastuzumab. Where minor differences were noted, they were evaluated and found unlikely to impact clinical performance. The totality of evidence, including the pharmacokinetic clinical similarity of ABP 980, further supports that ABP 980 is highly similar to trastuzumab. Conclusion Based on the comprehensive analytical similarity assessment, ABP 980 is analytically highly similar to the reference product, trastuzumab.

Different Policy Measures and Practices between Swedish Counties Influence Market Dynamics: Part 2—Biosimilar and Originator Etanercept in the Outpatient Setting Abstract Background Diverging approaches towards market entry and uptake of biosimilars, even within a country, leads to regional variation in biosimilar use. This is the case in Sweden, where the 21 county councils control the healthcare budget and offer regional guidance. Objectives This study aimed to analyse the market dynamics of originator and biosimilar etanercept (outpatient setting) in the different counties of Sweden, and examine the influence of local policy measures and practices, in addition to national policy. Methods This study was performed in three steps: (1) a structured review of the literature on (biosimilar) policies in Sweden; (2) analysis of market data on the counties' originator and biosimilar etanercept uptake (quarter two 2012 to quarter four 2017) provided by IQVIA™; and (3) discussion of findings in face-to-face semi-structured interviews with the national pricing and reimbursement agency, key experts in the county councils of Skåne, Västra Götaland and Stockholm, and an industry representative. Results Notwithstanding the existence of a national managed entry agreement for etanercept, wide variations in biosimilar market shares between counties were observed (40–82% in 2017). Over time, early and late adopters of biosimilar etanercept can be distinguished. In quarter four 2017, biosimilar market shares of all counties slightly decreased in accordance with the lower priced originator product from 1 October 2017. As prescriptions for treatment with etanercept are often provided for a year, two approaches are possible to switch patients: active pullback of prescriptions resulting in additional workload, or wait until the patient's next visit. Qualitative analysis indicated that the choice to use the biosimilar or the originator product depends on differences in rebated prices of the biosimilar and originator product, the presence of key opinion leaders, local guidelines, and financial streams and local gainsharing arrangements. Our estimates of current rebated prices and costs after gainsharing for the county councils and Government reveal only limited price differences between products. Conclusions Regional variations in use of biosimilar etanercept can be seen although prices are coordinated nationally. This suggests that counties react differently to price differences and highlights the role of local policy and attitudes of stakeholders towards biosimilars and switching. It seems that some counties are hesitant to switch patients, as it is associated with an increased administrative workload that might not be compensated for by savings associated with a lower priced product.

Physicochemical and Biological Characterization of RTXM83, a New Rituximab Biosimilar Abstract Background RTXM83 is a rituximab biosimilar with proven clinical safety and efficacy. It is the first rituximab biosimilar developed and approved in South America and is currently marketed in several Latin American, Middle Eastern and African countries. Objective The aim of this study was to present the physicochemical and biological characterization studies utilized to demonstrate the similarity between RTXM83 and its reference product. Methods Primary and higher order protein structures were analysed using peptide mapping with liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS), fluorescence spectroscopy and circular dichroism, and micro-differential scanning calorimetry, among other techniques. Charge variants were determined by cation-exchange chromatography (CEX) and capillary isoelectric focusing (cIEF). Glycosylation and glycoforms distribution were analysed using MS, normal phase high-performance liquid chromatography (NP-HPLC) and high-performance anion-exchange chromatography with pulsed amperometric detection (HPAE-PAD). Size variants were evaluated by size-exclusion chromatography (SEC), sedimentation velocity analytical ultracentrifugation (SV-AUC), dynamic light scattering (DLS), and capillary electrophoresis-sodium dodecyl sulfate (CE-SDS). Biological characterization included binding assays for complement C1q, CD20, and several Fc receptors (FcRs), as well as potency determination for in vitro apoptosis induction, complement-dependent cytotoxicity (CDC), and antibody-dependent cell-mediated cytotoxicity (ADCC). Results RTXM83 and the reference product showed identical primary sequences and disulfide bridge patterns, and similarity at higher order protein structures, post-translational modification profiles (amino acid modifications, charge variants, and glycosylation) and levels of purity and process-related impurities. Functional studies demonstrated that RTXM83 is similar to the reference product regarding the three known mechanisms of action of rituximab: CDC, ADCC, and apoptosis induction. Binding affinities to CD20, complement component C1q, and different FcRs were also equivalent. Conclusion RTXM83 is similar to its reference product in all critical quality attributes.

Analysis of Pharmacokinetic and Pharmacodynamic Parameters in EU- Versus US-Licensed Reference Biological Products: Are In Vivo Bridging Studies Justified for Biosimilar Development? Abstract Background Bridging studies are mandatory in the EU and USA if the reference biological product used in the biosimilar comparability exercise is foreign sourced. However, it has been argued that the duplication of bridging studies may limit biosimilar development. Objective The aim of the study was to explore whether it is necessary to conduct pharmacokinetic (PK)/pharmacodynamic (PD) bridging studies for biosimilars. This study examines similarities and differences between EU- and US-licensed reference biological products, based on literature-reported PK and/or PD data. Methods We searched PubMed, Drugs@FDA, and European Medicines Agency (EMA) databases to identify biosimilar bridging studies designed to evaluate similarities between EU- and US-licensed reference biological products. PK and/or PD parameters were retrieved; the ratio of the parameter value of the EU-licensed product to that of the US-licensed product and its corresponding 90% confidence intervals (CIs) were calculated. Similarity was declared if the 90% CIs for the ratios of the PK or PD parameters were within the range of 80–125%. Results Thirty-one bridging studies were identified for 11 biosimilars, including adalimumab (n = 10), bevacizumab (n = 4), epoetin alfa (n = 1), etanercept (n = 2), filgrastim (n = 1), infliximab (n = 3), insulin glargine (n = 1), insulin lispro (n = 1), PEGfilgrastim (n = 2), rituximab (n = 2), and trastuzumab (n = 4). Most studies showed PK and/or PD similarities between the EU- and US-licensed reference biological products. However, among the 31 studies, only three studies (accounting for two biologics, PEGfilgrastim and adalimumab) showed dissimilarity between the EU and US reference products. Although one bridging study on PEGfilgrastim (Sandoz) indicated dissimilar PKs (maximum observed plasma concentration [Cmax] and area under the concentration–time curve [AUC]) between the reference products, the other study (Mylan) demonstrated similar PK. Moreover, two of ten studies involving adalimumab failed to demonstrate similarities between the reference products. However, for both cases, PK similarities were later confirmed in the follow-up bridging studies with larger sample sizes. Conclusion Our analysis reveals that, in most cases, the reference biological products originated from the EU and those from the USA are almost indistinguishable in terms of PK/PD properties. Additional in vivo bridging studies between reference products from different global regions may not be required if similar physicochemical and structural properties are evident in vitro.

ALEXANDROS SFAKIANAKIS ANAPAFSEOS 5 AGIOS NIKOLAOS CRETE 72100 GREECE +306932607174 +302841026182