Eight-year study of antibiotic utilisation in the Republic of Srpska (2010-2017 years); findings and implications

Background: There have been multiple initiatives to improve antibiotic utilisation in the Republic of Srpska in recent years including educational activities with all key stakeholder groups, greater scrutiny over self-purchasing of antibiotics and reimbursement restrictions. This study aimed to analyse total antibiotic utilisation following these initiatives including the quality of use and assess whether additional measures are needed. Methods: Analysis of total outpatient antibiotic utilisation from 2010 to 2017 in DIDs based on data obtained from the Public Health Institute of the Republic of Srpska. Quality indicators based on ESAC, ECDC and WHO recommendations and compared with neighbouring countries in the WHO AMC network. Results: Antibiotic utilisation ranged from 15.6 DIDs to 23.1 DIDs, which is encouraging versus other similar neighbouring countries. Penicillins were the most used antibiotics, accounting for approximately 50-55% of total antibiotic utilisation, with amoxicillin the most used (29 – 41% of total utilisation) versus low use of co-amoxiclav (7 - 11% of total utilisation). This compares favourably with other countries. Cephalosporins were the second most used antibiotic class (13-14%) followed by macrolides (8-9 %) and quinolones (8-9 %). Low use of third and fourth generation cephalosporins (10-20% of total cephalosporins) versus first and second generation. However, rising utilisation of co-amoxiclav and azithromycin (5-10% per years), and higher rates of quinolone utilisation in recent years are noted and are now being addressed through additional interventions. Conclusion: Multiple interventions in the Republic of Srpska have helped enhance the appropriate use of antibiotics. Identified concerns are being addressed

Incidence of Lower Limb Amputation in Diabetic Patients in Osijek-Baranja County

Amputation of the lower limb (LLA) is one of the most feared adverse outcomes among diabetic patients. Our aim was to determine the incidence of amputation in diabetic patients in Osijek-Baranja County and to examine the possible correlationbetween clinical characteristics of the patients and the time elapsed before the first amputation. This was a tertiary-care-based retrospective study and included 925 diabetic patients who underwent non-traumatic lower limb amputation in the University Hospital Osijek from January 1st 2008 to December 31st 2018. Data on associated cardiovascular risk factors and clinical characteristics of the patients were collected from diabetic registry of the Department of diabetes and endocrinology. A total of 278 patients had all data for further analysis. There were 1551 LLAs over a ten year period. The incidence was 6.14 per 1,000 adults with diabetes. LLA rates per 1,000 adults with diabetes decreased by 29% between 2010 and 2013 and then increased by 76% between 2014 and 2018. In ten year period incidence of amputation in diabetic patients varied from 4 to 7.8 per 1000 persons-year. We observed the same pattern in both minor and major LLA but rates of amputation above knee steadily increased 2.7 times between 2010 and 2018 (from 0.69 to 1.83 per 1000 patients-year). The mean age of patients with LLA was 67.2 years, 66% were male, mean BMI was 29.6±4.8 kg/m2 and the mean duration of diabetes was 14.7±8.2 years. There was no association between smoking, arterial hypertension and hyperlipemia, ACE inhibitor use, statin use, antiplatelet use, CVD, neuropathy and duration of diabetes before first amputation. Only sulphonylurea and insulin therapy significantly prolonged the time before the first amputation (p = 0.00001, for each). In conclusion, our study confirmed high rate of lower limb amputation in diabetic patients in Osijek-Baranja County. Incidence rates of LLA in our population are important for further improvements in diabetes care and decisions in health care policy

Imaging Features of Triple N Negative Breast Cancers – Mammography, Ultrasound and Magnetic Resonance Imaging

Breast cancer (BC) is a highly heterogeneous disease. Aim was to evaluate imaging features of triple negative breast cancers (TNBC) in comparison to non-TNBC. We reviewed data of 30 patients who had been diagnosed as having TNBC and 37 patients with non-TNBC (control group) using criteria described for mammography (MMG), ultrasound (US) and magnetic resonance imaging (MRI) in Breast Imaging-Reporting and Data System (BI-RADS) lexicon for image interpretation. Age of patients, size of tumor, multifocality, histological type, tumor grade and status of lymph nodes were reviewed. TNBC were more often histological grade 3 and had significantly more positive lymph nodes at the time of diagnosis on pathology reports. On MMG, US and MRI TNBC mostly appeared as regularly shaped masses. On US as hypoechogenic masses with no posterior acoustic features and on MRI as masses with rim type of enhancement, fast wash-in and plateau type of curves. Most frequent category reported after MMG and US was BI RADS 4, and after MRI BI RADS 5. In conclusion, our study confirmed higher histological grade of TNBC, as well as more frequent lymph node involvement in comparation to the non-TNBC. TNBC showed tendency to affect younger women and to be larger than non-TNBC. Although, they most often presented as a mass on mammography and sonography, in a significant number of cases they remained miscategorized, due to the benign imaging features. All cases are recognized on MRI where they appear as rim enhancing masses

TREATMENT OF LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN

Histiocitoza Langerhansovih stanica (HLS) jest bolest karakterizirana patološkim nakupljanjem i umnožavanjem stanica monocitno-makrofagnog sustava u tkivima. Bolest može zahvatiti bilo koji organski sustav. U ovoj retrospektivnoj studiji analizirani su podatci pacijenata liječenih u Zavodu za dječju hematologiju i onkologiju Klinike za pedijatriju Medicinskog fakulteta u Zagrebu kojima je potvrđena dijagnoza HLS-a u petnaestogodišnjem razdoblju od 1. 1. 1996 do 31. 12. 2010. g. Liječeno je 22-je djece oboljele od HLS-a kod koje je bilo potrebno sustavno liječenje. Izliječeno je 19-ero (86%), a umrlo je troje (14%) djece, sve troje mlađe od 2 godine s multisustavnom bolešću. Kod postavljanja dijagnoze 12-ero djece imalo je bolest samo jednog organskog sustava (55%), i to u najvećoj mjeri zahvaćen je bio koštani sustav, kod 8 bolesnika (36%). Sva su djeca liječena prema protokolima LCH-I i LCH-III. Blaže posljedice bolesti i liječenja imalo je osmero djece. Kod četvero djece zaostao je dijabetes insipidus.Langerhans’ cell histiocytosis (LCH) is a disease characterised by pathologic accumulation and proliferation of histiocytes, cells from the monocyte-macrophage system, in various tissues and organs. In this retrospective study we analyzed patients charts treated in the Department of pediatric hematology and oncology at the University Hospital Zagreb with the diagnosis of LCH. Twenty-two children were diagnosed between January 1st 1996 and December 31st 2010, and all were treated with chemotherapy. 19 patients survived (86%) and the remaining 3 (14%), all under the age of 2 with multisystem disease, died. At the time of diagnosis 12 children (55%) presented with single-system disease, the most common were bone lesions in 8 children (36%). All children were treated according to protocols LCH-I and LCH –III. Eight children had mild complications of treatment and the disease itself. Diabetes insipidus remains in 4 children

Association of sclerostin, dickkopf 1 and functional genetic aromatase inhibitors polymorphisms with interpatient variability in the frequency and intensity of adverse effects

Cilj: Anastrozol jelijek prvog izbora u liječenju poslijemenopauzalnih žena s hormonski ovisnim rakom dojke (HR-BC).Citokrom P450 (CYP) i UDP-glukuronoziltransferaza(UGT)imaju ključnu ulogu u deaktivaciji i uklanjanjuanastrozola. Negativanjeučinak anastrozola na koštani metabolizam dokazan, dok se učinak na Wnt inhibitore još uvijek istražuje. Cilj je istraživanja bio odrediti cirkulirajuće razine Wnt inhibitora u bolesnica s HR-BC liječenih anastrozolom i usporediti ih s bolesnicama oboljelima od raka dojke prije uvođenja terapije.Također smo ispitali povezanost Wnt inhibitora s mineralnom gustoćom kosti (BMD) te prehrambenim i životnim navikama. Polimorfizmijednog nukleotida (SNPs) u genima koji kodirajuCYP i UGTmogu imati ključnu ulogu u individualnim odgovorima na anastrozol. Cilj je bio utvrditi učestalost mutiranih CYP3A4*1B, CYP3A5*3 i UGT1A4*2 alela teistražiti njihovu povezanost s ishodom liječenjate pojavom nuspojava. Bolesnici i metode: U opažajno presječno istraživanje slučaja i kontrola je uključena 141 poslijemenopauzalna ispitanicas HR-BC,od kojih je 85 liječeno s 1 mg anastrozola, dok je 56 uključeno prije adjuvantne hormonske terapije. Serumske koncentracije Wnt inhibitora mjerene su pomoću komercijalno dostupnih ELISA testova. BMD; g/cm² izmjerena je denzitometrijom dvoenergetskim rendgenskim zrakama (eng. dual-energy X-ray absorptiometry, DXA) pomoću uređaja Lunar Prodigy (GE Healthcare, SAD), a upitnik je korišten za istraživanje osobitosti životnog stila i prehrambenih navikaispitanica. Genomska je DNA izolirana iz uzoraka periferne krvni upotrebom komercijalno dostupnog kompleta (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Njemačka). PCR u realnom vremenu upotrijebljen je za otkrivanje polimorfizama, uz primjenu specifičnog testa TaqMan® SNP genotipizacije (Applied Biosystems). Rezultati: Serumskesurazine sklerostina bile znatno više u skupini ispitanica liječenih anastrozolom (31,8 pmol/l) u usporedbi sa skupinom prije uvođenja hormonske terapije (24,1 pmol/l, p <0,001). Nasuprot tomu, razina DKK1 u serumu bilajeznatno niža u skupini liječenoj anastrozolom (24,3 pmol/l prema 26,02 pmol/l, p<0,001). BMD kuka i vrata bedrene kosti bio jeznatno niži u skupini liječenih anastrozolom. Statistički značajna negativna korelacija između sklerostina i DKK1 (rho=-0,287, p <0,001) zabilježena je u svih ispitanika. CYP3A5*3 predominantanjealel u hrvatskoj populaciji bolesnica s HR-BC. Dokazano je i istodobno postojanje heterozigotnog CYP3A4 *1B i CYP3A5*3 haplotipa u istoj skupini ispitanica.Zaključak: Povećanje serumske razine sklerostinai smanjenje razine DKK1 povezano je s liječenjemanastrozolom. Povezanost ispitivanihpolimorfizama s nastankom nuspojava liječenja nije dokazana.Objectives: Anastrozole is the first choice treatmentinpostmenopausal women with hormone-dependent breast cancer (HR-BC). Cytokine P450 (CYP) and UDP-Glucuronosyltransferase (UGT) have a key role in deactivating and eliminating anastrozole. The negative effect of anastrozole on bone metabolism has been demonstrated, while the effect on Wnt inhibitors is still being investigated. The aim of the study was to determine the circulating levels of Wnt inhibitors in HR-BC patients treated with anastrozole and compare them with patients with breast cancer prior to theintroduction of the adjuvant hormonal therapy. We also investigated the association of Wnt inhibitors with bone mineral density (BMD) and dietary and life habits of participants. Single nucleotide polymorphisms (SNPs) in genes encoding CYP and UGT may play a key role in individual responses to anastrozole. The aim was to determine the frequency of mutated CYP3A4*1B, CYP3A5*3 and UGT1A4*2 alleles and to investigate their correlation with the outcome of adjuvant hormonal treatment and the occurrence of side effects. Participants and methods: Cross-sectional study included 141 postmenopausal HR-BC patients, of whom 85 were treated with 1 mg of anastrozole, and 56 were included prior to the introduction adjuvant hormonal therapy. Serum concentrations of Wntinhibitors were measured using commercially available ELISA assays. BMD; g/cm2 was measured by dual-energy x-ray absorptiometry (DXA) imaging (Lunar Prodigy, GE Healthcare, SAD) and a self-reported questionnaire was used to investigate the lifestyle and eating habits of the examinees. Genomic DNA was isolated from peripheral blood samples using commercially available kit (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Germany). A real-time PCR was used for the detection of polymorphisms, with the application of the specific TaqMan® SNP Genotyping Assay (Applied Biosystems). Results: Serum levels of sclerostin were significantly higher in the group of participants treated with anastrozole (31.8 pmol/l) compared to the w/o anastrozole therapy group (24.1 pmol/l,p<0.001). In contrast, the serum DKK1 level was significantly lower in the anastrozole treated group (24.3 pmol/l at 26.02 pmol/l, p <0.001). Total hip and femoral neckBMD were significantly lower in the group treated with anastrozole. Statistically significant negative correlation between sclerostin and DKK1 (rho=-0.287, p<0.001) was observed in all participants. CYP3A5*3 was found to be predominant in theCraotian population of HR-BC patients. We have demonstrateda strong linkage disequilibrium betweenCYP3A5*3 andCYP3A4*1B alleles in the same group of participants. Conclusion: Increased serum levels of sclerostin and decreased levels of DKK1 are associated with the anastrozole treatment. The correlation of the investigated polymorphisms with the onset of treatment side effects has not been established

Association of sclerostin, dickkopf 1 and functional genetic aromatase inhibitors polymorphisms with interpatient variability in the frequency and intensity of adverse effects

Cilj: Anastrozol jelijek prvog izbora u liječenju poslijemenopauzalnih žena s hormonski ovisnim rakom dojke (HR-BC).Citokrom P450 (CYP) i UDP-glukuronoziltransferaza(UGT)imaju ključnu ulogu u deaktivaciji i uklanjanjuanastrozola. Negativanjeučinak anastrozola na koštani metabolizam dokazan, dok se učinak na Wnt inhibitore još uvijek istražuje. Cilj je istraživanja bio odrediti cirkulirajuće razine Wnt inhibitora u bolesnica s HR-BC liječenih anastrozolom i usporediti ih s bolesnicama oboljelima od raka dojke prije uvođenja terapije.Također smo ispitali povezanost Wnt inhibitora s mineralnom gustoćom kosti (BMD) te prehrambenim i životnim navikama. Polimorfizmijednog nukleotida (SNPs) u genima koji kodirajuCYP i UGTmogu imati ključnu ulogu u individualnim odgovorima na anastrozol. Cilj je bio utvrditi učestalost mutiranih CYP3A4*1B, CYP3A5*3 i UGT1A4*2 alela teistražiti njihovu povezanost s ishodom liječenjate pojavom nuspojava. Bolesnici i metode: U opažajno presječno istraživanje slučaja i kontrola je uključena 141 poslijemenopauzalna ispitanicas HR-BC,od kojih je 85 liječeno s 1 mg anastrozola, dok je 56 uključeno prije adjuvantne hormonske terapije. Serumske koncentracije Wnt inhibitora mjerene su pomoću komercijalno dostupnih ELISA testova. BMD; g/cm² izmjerena je denzitometrijom dvoenergetskim rendgenskim zrakama (eng. dual-energy X-ray absorptiometry, DXA) pomoću uređaja Lunar Prodigy (GE Healthcare, SAD), a upitnik je korišten za istraživanje osobitosti životnog stila i prehrambenih navikaispitanica. Genomska je DNA izolirana iz uzoraka periferne krvni upotrebom komercijalno dostupnog kompleta (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Njemačka). PCR u realnom vremenu upotrijebljen je za otkrivanje polimorfizama, uz primjenu specifičnog testa TaqMan® SNP genotipizacije (Applied Biosystems). Rezultati: Serumskesurazine sklerostina bile znatno više u skupini ispitanica liječenih anastrozolom (31,8 pmol/l) u usporedbi sa skupinom prije uvođenja hormonske terapije (24,1 pmol/l, p <0,001). Nasuprot tomu, razina DKK1 u serumu bilajeznatno niža u skupini liječenoj anastrozolom (24,3 pmol/l prema 26,02 pmol/l, p<0,001). BMD kuka i vrata bedrene kosti bio jeznatno niži u skupini liječenih anastrozolom. Statistički značajna negativna korelacija između sklerostina i DKK1 (rho=-0,287, p <0,001) zabilježena je u svih ispitanika. CYP3A5*3 predominantanjealel u hrvatskoj populaciji bolesnica s HR-BC. Dokazano je i istodobno postojanje heterozigotnog CYP3A4 *1B i CYP3A5*3 haplotipa u istoj skupini ispitanica.Zaključak: Povećanje serumske razine sklerostinai smanjenje razine DKK1 povezano je s liječenjemanastrozolom. Povezanost ispitivanihpolimorfizama s nastankom nuspojava liječenja nije dokazana.Objectives: Anastrozole is the first choice treatmentinpostmenopausal women with hormone-dependent breast cancer (HR-BC). Cytokine P450 (CYP) and UDP-Glucuronosyltransferase (UGT) have a key role in deactivating and eliminating anastrozole. The negative effect of anastrozole on bone metabolism has been demonstrated, while the effect on Wnt inhibitors is still being investigated. The aim of the study was to determine the circulating levels of Wnt inhibitors in HR-BC patients treated with anastrozole and compare them with patients with breast cancer prior to theintroduction of the adjuvant hormonal therapy. We also investigated the association of Wnt inhibitors with bone mineral density (BMD) and dietary and life habits of participants. Single nucleotide polymorphisms (SNPs) in genes encoding CYP and UGT may play a key role in individual responses to anastrozole. The aim was to determine the frequency of mutated CYP3A4*1B, CYP3A5*3 and UGT1A4*2 alleles and to investigate their correlation with the outcome of adjuvant hormonal treatment and the occurrence of side effects. Participants and methods: Cross-sectional study included 141 postmenopausal HR-BC patients, of whom 85 were treated with 1 mg of anastrozole, and 56 were included prior to the introduction adjuvant hormonal therapy. Serum concentrations of Wntinhibitors were measured using commercially available ELISA assays. BMD; g/cm2 was measured by dual-energy x-ray absorptiometry (DXA) imaging (Lunar Prodigy, GE Healthcare, SAD) and a self-reported questionnaire was used to investigate the lifestyle and eating habits of the examinees. Genomic DNA was isolated from peripheral blood samples using commercially available kit (QIAamp DNA Blood Midi Kit, Qiagen, Hilden, Germany). A real-time PCR was used for the detection of polymorphisms, with the application of the specific TaqMan® SNP Genotyping Assay (Applied Biosystems). Results: Serum levels of sclerostin were significantly higher in the group of participants treated with anastrozole (31.8 pmol/l) compared to the w/o anastrozole therapy group (24.1 pmol/l,p<0.001). In contrast, the serum DKK1 level was significantly lower in the anastrozole treated group (24.3 pmol/l at 26.02 pmol/l, p <0.001). Total hip and femoral neckBMD were significantly lower in the group treated with anastrozole. Statistically significant negative correlation between sclerostin and DKK1 (rho=-0.287, p<0.001) was observed in all participants. CYP3A5*3 was found to be predominant in theCraotian population of HR-BC patients. We have demonstrateda strong linkage disequilibrium betweenCYP3A5*3 andCYP3A4*1B alleles in the same group of participants. Conclusion: Increased serum levels of sclerostin and decreased levels of DKK1 are associated with the anastrozole treatment. The correlation of the investigated polymorphisms with the onset of treatment side effects has not been established

Implementation of Elastography Score and Strain Ratio in Combination with B-mode Ultrasound Avoids Unnecessary Biopsies of Breast Lesions

The aim of this study was to evaluate whether the combination of B-mode ultrasound, elastography score (ES) and strain ratio (SR) improves diagnostic performance with respect to breast lesions. One hundred thirty lesions were prospectively evaluated by B-mode ultrasound and strain elastography, followed by fine-needle aspiration cytology/biopsy in 117 woman who were scheduled for regular breast BUS. The median ES (4.5 vs. 2.9, p , 0.001) and SR (4.9 vs. 2.3, p , 0.001) were significantly higher for malignant than for benign lesions. A sensitivity of 90.5% and specificity of 93.2% for the ES (cutoff point53.8) and a sensitivity of 87.5% and specificity of 87.6% for the SR (cutoff point53.5) were obtained. Elastography combined with B-mode ultrasound improved the specificity, accuracy and positive predictive value. Receiver operating characteristic curves yielded a higher value for the combined technique for diagnosis of breast lesions. Routine use of such a diagnostic algorithm could reduce the number of unnecessary biopsies

Exploring Association of Breast Pain, Pregnancy, and Body Mass Index with Breast Tissue Elasticity in Healthy Women: Glandular and Fat Differences

Breast sonoelastography is a relatively novel ultrasound (US) method that enables estimation of tissue stiffness to estimate the elasticity of normal breast tissue and seek to correlate it with well-known breast cancer risk factors. Two hundred women of different age were included in the study and completed a questionnaire about personal, familiar, and reproductive history. Glandular and fatty tissue elasticity in all breast quadrants was measured by shear wave elastography (SWE). Mean elastographic values of breast tissue were calculated and compared to personal history risk factors. Elasticity of normal glandular tissue (66.4 kilopascals (kPa)) was higher than fatty tissue (26.1 kPa) in all breast quadrants and in both breasts. Lower outer quadrant (LOQ) had the lowest elasticity values of both parenchyma and fat. Higher elasticity values of breast tissue were confirmed in the left breast than in the right breast. Glandular and fat tissue elasticity negatively correlated with body mass index (BMI). Women with mastodynia had higher glandular elastographic values compared to subjects without breast pain. Nuliparity was also associated with higher elasticity of glandular breast tissue. The results of this study are promising and could, over time, contribute to a better understanding of glandular breast tissue elasticity as a potential risk factor for breast cancer

Elastic Modulus and Elasticity Ratio of Malignant Breast Lesions with Shear Wave Ultrasound Elastography: Variations with Different Region of Interest and Lesion Size

Shear wave elastography (SWE) is a type of ultrasound elastography with which the elastic properties of breast tissues can be quantitatively assessed. The purpose of this study was to determine the impact of different regions of interest (ROI) and lesion size on the performance of SWE in differentiating malignant breast lesions. The study included 150 female patients with histopathologically confirmed malignant breast lesions. Minimal (Emin), mean (Emean), maximal (Emax) elastic modulus and elasticity ratio (e-ratio) values were measured using a circular ROI size of 2, 4 and 6 mm diameters and the lesions were divided into large (diameter ≥ 15 mm) and small (diameter < 15 mm). Highest Emin, Emean and e-ratio values and lowest variability were observed when using the 2 mm ROI. Emax values did not differ between different ROI sizes. Larger lesions had significantly higher Emean and Emax values, but there was no difference in e-ratio values between lesions of different sizes. In conclusion, when measuring the Emin, Emean and e-ratio of malignant breast lesions using SWE the smallest possible ROI size should be used regardless of lesion size. ROI size has no impact on Emax values while lesion size has no impact on e-ratio values

Models of Drug Induced Liver Injury (DILI) - Current Issues and Future Perspectives

BACKGROUND: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases. METHODS: A structured search of bibliographic databases - Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described. RESULTS: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described. CONCLUSION: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well