University Clinical Hospital Center "Sestre Milosrdnice"
Recent publications
Background: Diabetic kidney disease (DKD) is the main cause of end�stage renal disease in patients with diabetes mellitus type I (DM-T1). Microalbuminuria and estimated glomerular filtration rate (eGFR) are standard predictors of DKD. However, these predictors have serious weaknesses. Our study aimed to analyze cystatin C, renal resistance index, and urinary kidney injury molecule-1 (KIM-1) as predictors of DKD. Methods: We conducted a cross-sectional study in 2019 on a consecutive sample of children and adolescents (10–18 years) diagnosed with DM-T1. The outcome was a risk for DKD estimated using standard predictors: age, urinary albumin, eGFR, serum creatinine, DM-T1 duration, HbA1c, blood pressure, and body mass index (BMI). We conducted the analysis using structural equation modeling. Results: We enrolled 75 children, 36 girls and 39 boys with the median interquartile range (IQR) age of 14 (11–16) years and a median (IQR) duration of DM-T1 of 6 (4–9) years. The three focal predictors (cystatin C, resistance index, and urinary KIM-1) were significantly associated with the estimated risk for DKD. Raw path coefficients for cystatin C were 3.16 [95% CI 0.78; 5.53; p = 0.009, false discovery rate (FDR) < 5%], for renal resistance index were – 8.14 (95% CI –15.36; –0.92; p = 0.027; FDR < 5%), and for urinary KIM-1 were 0.47 (95% CI 0.02; 0.93; p = 0.040; FDR < 5%). Conclusion: Cystatin C, renal resistance index, and KIM-1 may be associated with the risk for DKD in children and adolescents diagnosed with DM-T1. We encourage further prospective cohort studies to test our results.
Purpose This systematic review and meta-analysis aimed to evaluate the immune response to anti-SARS-CoV-2 prime-vaccination in patients with cancer. Methods We performed a systematic literature search using PubMed, Embase, and Cochrane Library until 28/09/2021, and conference proceedings from ASCO and ESMO 2021 annual meetings. We screened for observational or interventional studies including subjects ≥ 16 years old with cancer diagnosis who were vaccinated against SARS-CoV-2. Prime-vaccination was defined as one dose of Ad26.COV2-S vaccine or two doses of BNT162b2, mRNA-1273, ChAdOx1-S or inactivated SARS-CoV-2 vaccine. The outcomes were humoral and adaptive immune responses (proportion of subjects with positive titers of antibody anti-SARS-CoV-2 spike protein and anti-SARS-CoV-2 cellular responses, respectively). Results We included 89 records reporting data from 30,183 subjects. The overall seropositive rate within the first month after complete anti-SARS-CoV-2 prime-vaccination was 80% [95% confidence interval (CI), 72–86%], 60% (95%CI, 53–67%) in patients with hematological malignancies (HM) versus 94% (95%CI, 88–97%) in patients with solid malignancies (SM). The diagnosis of HM was significantly associated with a lower seropositive rate on multivariate meta-regression (odds ratio 0.35, 95% CI 0.18–0.69, HM versus both, p = 0.002). The overall humoral response was 49% (95% CI, 42–56%) after incomplete prime-vaccination and 79% (95% CI, 70–86%) at 2 months after complete prime-vaccination. These responses were also lower in patients with HM at these time points. The overall cellular response rate at any time after vaccination was 61% (95% CI, 44–76%). Conclusion This meta-analysis provides compelling evidence of humoral and adaptive immune responses against SARS-CoV-2 in patients with cancer, which last for at least 2 months following complete prime-vaccination.
Today, in the era of precision medicine, the determination of genomic instability or other potentially targetable mutations, along with BRCA 1 and BRCA 2, is a crucial component of the diagnosis and treatment management of advanced ovarian cancer. Advanced technologies such as next-generation sequencing (NGS) have enabled comprehensive genomic profiling (CGP) analysis to become more feasible for routine use in daily clinical work. Here, we present the results for the first two years of an analysis of patients with advanced ovarian cancer on a national level. The aim was to establish the position of CGP in the daily clinical practice of treating ovarian cancer. We performed a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients who were newly diagnosed with locally advanced or metastatic ovarian cancer or whose initial disease had progressed from 1 January 2020 to 1 December 2021, and whose tumors underwent CGP analysis. All 86 patients (100%) analyzed with CGP had at least one genomic alteration (GA). The median LOH was 14.6 (IQR 6.8–21.7), with 35 patients (41%) having an LOH ≥ 16. We found BRCA-positive status in 22 patients (26%). Conventional testing, which detects only BRCA mutations, would have opted for therapy with PARP inhibitors in 22 (26%) of our patients. However, CGP revealed the need for PARP inhibitors in 35 patients (41%). The results identified a significantly higher number of women who would achieve a possible benefit from targeted therapy. Hence, we believe that CGP should be a backbone diagnostic tool in the management of ovarian cancer.
Background: Ichthyosis uteri is an extremely rare condition in which the entire or extensive parts of endometrial lining are replaced by stratified squamous epithelium. Malignant potential of this entity is unclear and its association with dysplastic changes and primary squamous cell carcinoma of the endometrium and endometrial adenocarcinoma has been reported. However, lack of data makes difficult to interpret the significance of neoplasms arising from this condition. Patients and methods: We report a case of ichthyosis uteri associated with squamous cell carcinoma of the endometrium in a 62-year-old female who presented with postmenopausal bleeding and thin endometrium on ultrasound. Results: Endometrial curettage was performed and revealed high grade squamous intraepithelial lesion. The patient underwent total laparoscopic hysterectomy with bilateral salpingo-oophorectomy and bilateral pelvic lymph node dissection. Microscopic examination of sections revealed squamous cell cancer along with extensive replacement of the endometrial lining by stratified squamous epithelium, consistent with ichthyosis uteri. Conclusion: If ichthyosis uteri is suspected we recommend hysterectomy in order to rule out possibility of coexisting carcinoma. Also, thin endometrium in women with postmenopausal bleeding does not reliably exclude endometrial cancer.
Purpose: Dilated cardiomyopathy (DCM) is a primary disorder of the cardiac muscle, characterised by dilatation of the left ventricle and contractile dysfunction. About 50% of DCM cases can be attributed to monogenic causes, whereas the aetiology in the remaining patients remains unexplained. Methods: We report a family with two brothers affected by severe DCM with onset in the adolescent period. Using exome sequencing, we identified a homozygous premature termination variant in the MYZAP gene in both affected sibs. MYZAP encodes for myocardial zonula adherens protein - a conserved cardiac protein in the intercalated disc structure of cardiomyocytes. Results: The effect of the variant was demonstrated by light and electron microscopy of the heart muscle and immunohistochemical and Western blot analysis of MYZAP protein in the heart tissue of the proband. Functional characterization using patient-derived induced pluripotent stem cell cardiomyocytes revealed significantly lower force and longer time to peak contraction and relaxation consistent with severe contractile dysfunction. Conclusion: We provide independent support for the role of biallelic loss-of-function MYZAP variants in dilated cardiomyopathy. This report extends the spectrum of cardiac disease associated with dysfunction of cardiac intercalated disc junction and sheds light on the mechanisms leading to DCM.
Background Remote access of trainees to training centers via video streaming (tele-observership, e‑fellowship) emerges as an alternative to acquire knowledge in endovascular interventions. Situational awareness is a summary term that is also used in surgical procedures for perceiving and understanding the situation and projecting what will happen next. A high situational awareness would serve as prerequisite for meaningful learning success during tele-observerships. We hypothesized that live perception of the angiographical procedures using streaming technology is feasible and sufficient to gain useful situational awareness of the procedure. Methods During a European tele-observership organized by the European Society of Minimally Invasive Neurological Therapy (ESMINT) and its trainee association (EYMINT), a total of six neurointerventional fellows in five countries observed live cases performed by experienced neurointerventionalists (mentors) in six different high-volume neurovascular centers across Europe equipped with live-streaming technology (Tegus Medical, Hamburg, Germany). Cases were prospectively evaluated during a 12-month period, followed by a final questionnaire after completion of the course. Results A total of 102/161 (63%) cases with a 1:1 allocation of fellow and mentor were evaluated during a 12-month period. Most frequent conditions were ischemic stroke (27.5%), followed by embolization of unruptured aneurysms (25.5%) and arteriovenous malformations (AVMs) (15.7%). A high level of situational awareness was reported by fellows in 75.5% of all cases. After finishing the program, the general improvement of neurointerventional knowledge was evaluated to be extensive (1/6 fellows), substantial (3/6), and moderate (2/6). The specific fields of improvement were procedural knowledge (6/6 fellows), technical knowledge (3/6) and complication management (2/6). Conclusion Online streaming technology facilitates location-independent training of complex neurointerventional procedures through high levels of situational awareness and can therefore supplement live hands-on-training. In addition, it leads to a training effect for fellows with a perceived improvement of their neurointerventional knowledge.
Purpose: To translate, adapt and validate the Endometriosis Health Profile-5 (EHP-5) in Croatian population. Methods: This validation study is a part of a prospective, observational study (EHP-5 CRO) with aim of implementation of EHP-5 and to provide better insight in quality of life consideration of women with endometriosis in Croatian clinical practice. A 150 consecutive patients with surgically proven endometriosis were enrolled. The translation to Croatian followed standardized procedure. Cronbach's Alpha was calculated to calculate internal consistency reliability of EHP-5. The test-retest reliability was calculated using intraclass correlation coefficient (ICC). The t test for independent samples was used to assess known-groups validity. Results: Both EHP-5 core and EHP-5 modular parts of the questionnaire had good internal consistency, assessed by the Cronbach's Alpha coefficient (α = 0.793 and α = 0.842, respectively). Obtained results indicate very good reliability for core as well as for modular part of EHP-5 questionnaire (ICC = 0.896 and 0.936, respectively). The independent t test showed that women who reported their pain with VAS scale 7 or more had significantly higher results (p < 0.001) on EHP-5 (M = 50.63) compared with women who reported their pain 6 or less (M = 26.91). Furthermore, we found statistically significant difference between women who are infertile with women who are fertile (p < 0.001), whereby infertile women had higher average result on EHP-5 (M = 49.55) compared with fertile women (M = 34.36). Conclusions: The Croatian version of the EHP-5 have very good psychometric characteristics and can be used as a reliable tool for assessing patients with endometriosis in everyday clinical practice.
The aim of our study was to investigate the influence of the degree of obesity on ambulatory blood pressure parameters in selected group of office normotensive obese children and adolescents. Our study involved 119 obese patients (55 males, 46.2%) aged 7–18 years divided into 3 groups based on their body mass index Z-score, who underwent ambulatory blood pressure monitoring. Our results show that obese patients, even when office normotensive, have alterations in blood pressure values obtained by ambulatory blood pressure monitoring. We found a positive correlation between systolic and diastolic blood pressure and body mass index in our patients (p≤\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\le$$\end{document} 0.001). Daytime blood pressure load correlated with rising body mass index and was higher in groups II and III compared to group I (p < 0.001). Body mass index category did not influence the dipping pattern in our subjects although most of our subjects (66.4%) showed non-dipping pattern for systolic blood pressure. The difference in blood pressure variability was confirmed only for daytime systolic and diastolic values between groups I and II (p = 0.019 and p = 0.002, respectively). In conclusion, our study showed that in office normotensive obese children and adolescents, systolic and diastolic blood pressure values obtained by ambulatory blood pressure monitoring are higher in subjects with higher body mass index. Patients with increased body mass index also have higher percentage of blood pressure readings above 95th percentile and increased daytime blood pressure variability. Obese patients show non-dipping pattern, independently of the rising body mass index category.
This is a brief communication stressing some critical points associated with cystic nodal metastasis (CNM) in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) and its implication on treatment protocols and outcomes.
Standard chemotherapy for early breast cancer consists generally of an anthracycline – taxane - based regimen, preferably in sequence. Anthracyclines are among the most active cytotoxic drugs against breast cancer. Nevertheless, benefits attained by the use of the more potent anthracycline schedules must be balanced against increased short – and long – term toxicity, and treatment options must be individualized for each patient. Authors review available data regarding anthracycline efficacy and toxicity in the early breast cancer setting and the potential directions for future research.
Shortcomings of oral donepezil administration in the treatment of Alzheimer’s disease have paved the way for ongoing investigations towards more efficient and safe donepezil nose-to-brain delivery. Herein we present the development of advantageous powder platform for donepezil nose-to-brain delivery, coupling careful design of chitosan and mannitol-based carrier matrix with spray-drying technology advantages and early consideration of adequate nasal administration mode, employing QbD approach. Unprecedentedly, ultrasonic nozzle was used to atomise the drying feed in response to size-related requirements for nasal aerosol particles. The optimised spray-drying process resulted in free-flowable dry powder with a great majority of particles larger than 10 µm, ensuring localised nasal deposition upon aerosolization, as evidenced by using 3D-printed nasal cavity model. QbD approach coupling formulation, process and administration parameters enabled optimisation of drug deposition profile reaching tremendously high 65.5% of the applied dose deposited in the olfactory region. The leading formulation exhibited favourable swelling, mucoadhesion, drug release and permeation-enhancing properties, suiting the needs for efficient brain-targeted delivery. Results of in vitro biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient donepezil nose-to-brain delivery. The obtained results encourage extending the study to an appropriate in vivo model needed for the final proof-of-concept.
Introduction : There has been a lot of talk lately about the importance of reduced serum vitamin D levels and their supplementation for patients with inflammatory skin diseases such as atopic dermatitis (AD) and other allergic diseases. Serum vitamin D values are associated with a number of factors such as limited sunlight exposure (modern lifestyle, extended indoor stay, enhanced sun protection, etc.) which can affect different diseases. Aim : To evaluate serum vitamin D values in patients with inflammatory skin diseases, comparing them on the basis of other parameters (age, gender/sex, residential areas, total serum IgE), and establishing whether vitamin D supplementation would affect the improvement of the clinical picture of the disease. Patients and methods : A total of 157 patients participated in this prospective study: 51 patients with AD, 55 with chronic urticaria (CU) and 51 with contact dermatitis (CD): 38 with irritant CD (ICD) and 13 with allergic CD (ACD). In all patients, the values of serum vitamin D were determined by chemiluminescence microparticle immunoassay (CMIA) and compared by diagnosis, age, sex, living environment, values of total IgE. In patients with reduced values of vitamin D, its supplementation for 3 months was recommended, after which the second evaluation of D vitamin values and disease status were determined and compared with an untreated/unsupplemented group with normal vitamin D values. Results : Vitamin D deficiency was often observed in patients with AD, CU and CD, most frequently in the ICD group, and least frequently in the ACD group. No significant differences were found in terms of age, gender or living environment, nor was any correlation with total IgE found. In the subjects supplemented with vitamin D, their levels increased significantly and, after its supplementation, improvement of the clinical condition was more common than in the untreated group; however, the differences were not statistically significant (69.8 vs. 58.1, p =0.428). Conclusions : Although serum vitamin D levels of the groups did not differ significantly, the supplementation of vitamin D in patients with prominent vitamin D deficiency may be useful and crucial for improving the prognosis of the disease.
The aim of this paper is to introduce the digitalization process and its effects on better reach of the target population. Progress in the digitalization and e-health tools worldwide enables new opportunities in prevention, diagnostics and treatment for people living with HIV (PLHIV) and people in the risk of HIV infection, hepatitis C (HCV) and other sexually transmitted infections (STIs), especially in the context of the COVID-19 pandemic. The system already used for voluntary counselling and testing (VCT) at the CheckPoint Centre Zagreb run by the non-governmental organization (NGO) Croatian Association for HIV and Viral Hepatitis (CAHIV) was upgraded and adapted (due to the COVID-19 prevention epidemiological measures) and developed for implementation of the pilot project of feasibility and acceptability of home HIV self-testing (HIVST) among men who have sex with men (MSM) in Zagreb. A special feature of the HIVST mobile application enables an innovative approach in collecting clients' test result feedback. This paper presents the method of use digitalization of the VCT and HIVST activities to support and increase availability of screening testing. Described procedures of new technologies application in VCT services and preliminary results of the HIVST pilot project indicate that technology-delivered interventions can contribute and improve access and utilisation of HIV/STI prevention and care services.
Objectives: This study aims to evaluate the diagnostic accuracy of preoperative computed tomography (CT) and intraoperative endoscopic tumor staging with regard to histopathologic staging in patients with early laryngeal cancer. Study design: A retrospective nonrandomized single-institution comparative cohort study including 109 patients. Setting: A tertiary surgical center. Methods: Patients were treated for T1a, T1b, and T2a laryngeal squamous cell carcinoma by endoscopic laser surgery. The outcome measures were the presence of under- or overstaging in endoscopic and CT findings and positive postoperative margins. Results: Endoscopic overstaging as compared with histopathologic T category correlated with rising tumor category (P = .001; odds ratio [OR], 69.1) and CT findings showing anterior commissure involvement (P = .002; OR, 9.54), while endoscopic understaging correlated with rising tumor histologic grade (P = .039; OR, 4.28) and smaller tumor size (P = .011; OR, 6.39). CT overstaging vs histopathologic T category correlated with CT findings showing anterior commissure involvement (P = .001; OR, 21.76), supraglottic involvement (P = .001; OR, 59.98), subglottic involvement (P = .001; OR, 39.94), rising clinical T category (P = .01; OR, 9.11), and rising tumor histologic grade (P = .004; OR, 10.95). CT understaging as compared with histopathologic T category correlated with smaller clinical T categories (P = .002; OR, 12.72) and smaller tumor histologic grade (P = .030; OR, 7.02). Rising age, rising tumor size, anterior commissure involvement on CT, and tumor extension into the supraglottis were risk factors for positive margins. Conclusion: Our results indicate that CT adds little valuable information in differentiating small superficial lesions in the glottis, while systematically overstaging cases of early laryngeal cancer. In T1a and T1b glottic tumors, endoscopy should be the preferred diagnostic method.
Background Diabetic patients tend to have increased platelet reactivity after coronary artery bypass grafting (CABG). The aim of this study was to determine the association between hemoglobin A1c (HbA1c) values and platelet reactivity and to evaluate the consequent impact on clinical outcomes in patients undergoing CABG. Methods This prospective observational trial consecutively enrolled 225 diabetic patients undergoing CABG, between February 2014 and October 2018. HbA1c levels and platelet function (multiple electrode aggregometry [MEA]) were analyzed the day before surgery and on postoperative day 4 (POD 4). Patients were divided into two groups according to the HbA1c value: HBA1c < 7% and HbA1c ≥ 7%. Results Significantly higher postoperative ASPI (platelet function test based on arachidonic acid) and ADP (platelet function test based on adenosine diphosphate) test values were observed at POD 4 compared with preoperative values (ASPI test: p < 0.001; ADP test: p < 0.001). The prevalence of preoperative aspirin resistance (AR) was 46.4% relative to 57.2% after surgery showing consistent increase in postoperative AR by approximately 10%. In addition, the prevalence of AR in the HbA1c < 7% group was higher by 10% compared with the HbA1c ≥ 7% group, both before and after surgery. We did not demonstrate differences in clinical outcomes between the HbA1c groups. Conclusion Perioperative assessment of platelet reactivity in diabetic patients detects those with AR who may be at increased risk of adverse ischemic events. A personalized approach guided by MEA and administration of early and more potent antiaggregation therapy after CABG can be beneficial in this group of patients.
Cerebral and retinal ischemia share similar pathogenesis and epidemiology, each carrying both acute and prolonged risk of the other and often co-occurring. The most used preclinical stroke models, the Koizumi and Longa middle cerebral artery occlusion (MCAO) methods, have reported retinal damage with great variability, leaving the disruption of retinal blood supply via MCAO poorly investigated, even providing conflicting assumptions on the origin of the ophthalmic artery in rodents. The aim of our study was to use longitudinal in vivo magnetic resonance assessment of cerebral and retinal vascular perfusion after the ischemic injury to clarify whether and how the Koizumi and Longa methods induce retinal ischemia and how they differ in terms of cerebral and retinal lesion evolution. We provided anatomical evidence of the origin of the ophthalmic artery in mice from the pterygopalatine artery. Following the Koizumi surgery, retinal responses to ischemia overlapped with those in the brain, resulting in permanent damage. In contrast, the Longa method produced only extensive cerebral lesions, with greater tissue loss than in the Koizumi method. Additionally, our data suggests the Koizumi method should be redefined as a model of ischemia with chronic hypoperfusion rather than of ischemia and reperfusion.
In this study, we developed a high-resolution tandem mass spectrometry (HR MS) approach to assess presumed changes in gangliosidome of a human hippocampus affected by temporal lobe epilepsy (TLE) in comparison with a normal hippocampus. Gangliosides, membrane glycolipids, are particularly diverse and abundant in the human brain, and participate in ion transport and modulation of neuronal excitability. Changes in structural ganglioside pattern potentially linked to TLE molecular pathogenesis have not been explored in detail. Aiming to characterize TLE-specific gangliosidome, we analyzed the native gangliosides purified from a human hippocampal tissue sample affected by TLE and a control hippocampus using HR MS. Marked differences of ganglioside expression were shown in TLE vs. control, particularly with respect to the sialylation degree of components, discovered as a characteristic feature of TLE. Another major finding is the occurrence of tetrasialofucogangliosides in TLE and species modified by either O-acetylation or CH3COO−. Structural analysis by higher-energy collisional dissociation (HCD) MS/MS gave rise to fragmentation patterns implying that the GQ1b (d18:1/18:0) isomer is specifically associated with TLE. Further investigation in a larger sample is needed in order to confirm the discovery of ganglioside structures specifically expressed in human TLE and to provide information on the probable role of gangliosides in the molecular events underlying seizures.
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292 members
Irena Martinić Popović
  • University Department of Neurology
Miroslav Harjacek
  • Department of Pediatrics
Damir Danolic
  • University Hospital for Tumors
Snjezana Ramic
  • Dept. of Oncological Pathology, University Hospital for Tumors
Marko Boban
  • Department of cardiology
Vinogradska cesta 29, 10000, Zagreb, Croatia