Publications by authors named "Milan Milosevic"

129 Publications

Characteristics of work-related COVID-19 in Croatian healthcare workers: a preliminary report.

Arh Hig Rada Toksikol 2021 Mar 30;72(1):36-41. Epub 2021 Mar 30.

University of Zagreb School of Medicine, Andrija Štampar School of Public Health, Zagreb, Croatia.

Healthcare workers (HCWs) are considered to run a higher occupational risk of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and develop coronavirus disease (COVID-19) than the rest of the population. The aim of this study was to describe and analyse the characteristics of work-related COVID-19 in Croatian HCWs. Study participants were HCWs who contacted their occupational physician between 1 May 2020 and 12 November 2020 with a request for the registration of COVID-19 as an occupational disease. All participants filled out our online Occupational COVID-19 in Healthcare Workers Questionnaire. The study included 59 HCWs (median age 45.0, interquartile range 36.0-56.0 years). Most (78 %) were nurses or laboratory technicians, and almost all (94.9 %) worked in hospitals. Hierarchical cluster analysis revealed three clusters of COVID-19-related symptoms: 1) elevated body temperature with general weakness and fatigue, 2) diarrhoea, and 3) headache, muscle and joint pain, anosmia, ageusia, and respiratory symptoms (nasal symptoms, burning throat, cough, dyspnoea, tachypnoea). Almost half (44.6 %) reported comorbidities. Only those with chronic pulmonary conditions were more often hospitalised than those without respiratory disorders (57.1 % vs. 2.5 %, respectively; P=0.001). Our findings suggest that work-related COVID-19 among Croatian HCWs is most common in hospital nurses/laboratory technicians and takes a mild form, with symptoms clustering around three clinical phenotypes: general symptoms of acute infection, specific symptoms including neurological (anosmia, ageusia) and respiratory symptoms, and diarrhoea as a separate symptom. They also support evidence from other studies that persons with chronic pulmonary conditions are at higher risk for developing severe forms of COVID-19.
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http://dx.doi.org/10.2478/aiht-2021-72-3530DOI Listing
March 2021

Iron overload in aging mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss.

Int J Mol Med 2021 Apr 2;47(4):1-8. Epub 2021 Mar 2.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia.

The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6‑knockout () mouse model of hemochromatosis. The sera and pancreatic tissues of wild‑type (WT) and mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, F‑fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3‑month‑old mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α‑cell mass compared with those in the age‑matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging mice leading to iron‑induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.
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http://dx.doi.org/10.3892/ijmm.2021.4893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910010PMC
April 2021

Striatal Dopaminergic Deficit and Sleep in Idiopathic Rapid Eye Movement Behaviour Disorder: An Explorative Study.

Nat Sci Sleep 2021 6;13:1-9. Epub 2021 Jan 6.

Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, UK.

Introduction: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is increasingly recognised as an important precursor disease state of alpha-synucleinopathies. This parasomnia is characterized by a history of recurrent nocturnal dream enactment behaviour, loss of skeletal muscle atonia, and increased phasic muscle activity during REM sleep. Neuroimaging studies of striatal dopamine transporter uptake tracer signaling suggest increasing dopaminergic deficit across the continuum of the alpha-synucleinopathies, with early sleep dysfunction suggestive of early caudate dysfunction. Henceforth, we set out to investigate the relationship between early sleep changes and the striatal dopaminergic availability in iRBD.

Methods: Twelve patients with iRBD, who had undergone a video polysomnography and a neuroimaging assessment of striatal dopamine transporter (DaT) uptake tracer signaling, and 22 matched controls who had similarly undergone a video polysomnography were retrospectively identified. Data were statistically analyzed to identify altered sleep parameters and correlate them with striatal dopamine transporter uptake tracer signaling.

Results: The iRBD patients exhibited an increased number of periodic limb movements during sleep (=0.001), compared to 22 age-matched healthy subjects. In addition, several significant links were found between regional DaT-uptakes and sleep architecture. Correlational analyses suggested a strong positive association between sleep fragmentation and dopamine deficiency in left caudate (r=-0.630, =0.028), whilst an increased uptake in the whole striatum was strongly linked to the sleep efficiency, and to a lesser degree to the length of sleep duration.

Discussion: To the best of our knowledge, this is the first demonstration of a close relationship between dopaminergic availability in striatum and the quality of sleep in iRBD. Taken together, our exploratory findings suggest that subtle but functionally significant striatal changes in early stages of iRBD may contribute to the further shaping of sleep architecture.
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http://dx.doi.org/10.2147/NSS.S267037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802085PMC
January 2021

Brain MRI post-processing with MAP07 in the preoperative evaluation of patients with pharmacoresistant epilepsy - Croatian single centre experience.

Clin Neurol Neurosurg 2021 Feb 8;201:106426. Epub 2020 Dec 8.

School of Medicine, University of Zagreb, Zagreb, Croatia.

Objective: This study aimed to determine the role of brain MRI post-processing method MAP07 (Morphometric Analysis Program) in detecting epileptogenic brain lesions in patients with pharmacoresistant epilepsy (PE). MAP07 is a sophisticated diagnostic program that offers several morphometric maps and facilitates the detection and localization of hippocampal sclerosis (HS), focal cortical dysplasias (FCD), and other types of cortical malformations, which could be undetected by conventional visual MRI analysis (CVA).

Methods: 120 patients aged > 16 years with PE have been recruited. 3 T MRI was performed according to epilepsy imaging protocol followed by image postprocessing with a fully automated MATLAB script, MAP07, by applying SPM5 algorithms. Statistical analysis was performed in IBM SPSS Statistics, version 25.0.

Results: Analysis in our patients showed a high sensitivity of MAP07 with low specificity and with a high proportion of false-positive patients. After MRI analysis, out of 120 patients, 32 were found to have no structural abnormalities by conventional visual analysis in whom after MAP07 in 5 patients structural lesions were found (in one HS, in one FCD, in two perinatal vascular lesions, and in one hippocampal hyperintensity). There was a quite high overall coincidence of the findings of MAP07 and MRI for the detection of FCD, HS, perinatal ischemia/chronic vascular lesions, heterotopias, and polymicrogyria (kappa coefficient above 0.700).

Conclusions: MAP07 analysis is a useful, additional, and automated method that may guide re-evaluation of MRI by highlighting suspicious cortical regions, as a complementary method to CVA, by enhancing the visualization of cortical malformations and lesions.
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http://dx.doi.org/10.1016/j.clineuro.2020.106426DOI Listing
February 2021

Autologous bone graft substitute containing rhBMP6 within autologous blood coagulum and synthetic ceramics of different particle size determines the quantity and structural pattern of bone formed in a rat subcutaneous assay.

Bone 2020 12 23;141:115654. Epub 2020 Sep 23.

Laboratory for Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia; Scientific Center of Excellence for Reproductive and Regenerative Medicine, Croatia. Electronic address:

Bone morphogenetic proteins (BMPs) are potent osteoinductive agents for bone tissue engineering. In order to define optimal properties of a novel autologous bone graft substitute (ABGS) containing rhBMP6 within the autologous blood coagulum (ABC) and ceramic particles as a compression resistant matrix (CRM), we explored the influence of their amount, chemical composition and particle size on the quantity and quality of bone formation in the rat subcutaneous assay. Tested ceramic particles included tricalcium phosphate (TCP), hydroxyapatite (HA) and biphasic calcium phosphate ceramic (BCP), containing TCP and HA in 80/20 ratio of different particle sizes (small 74-420 μm, medium 500-1700 μm and large 1000-4000 μm). RhBMP6 was either mixed with ABC or lyophilized on CRM prior to use with ABC. The experiments were terminated on day 21 and implants were analysed by microCT, histology and histomorphometry. Addition of CRM to ABGS containing rhBMP6 in ABC significantly increased the amount of newly formed bone and the optimal CRM/ABC ratio was found to be around 100 mg/500 μL. MicroCT analyses revealed that all tested ABGS formulations induced an extensive new bone formation and there were no differences between the two methods of rhBMP6 application as determined by the bone volume. However, the particle size played a significant role in the quantity and quality of newly formed bone. ABGS containing small particles induced new bone forming a dense trabecular network, cortical bone at the rim, bone and bone marrow in apposition to and in between ceramic particles. ABGS containing medium and large particles also resulted in new bone on the surface of particles as well as inside the pores. Histomorphometric analysis revealed that the ceramics particle size correlated with the quality of trabecular pattern of newly formed bone, bone/bone marrow ratio as observed in apposition and between particles, and the ratio between the cortical and trabecular bone. By employing rat subcutaneous implant assay, we showed for the first time that the size of synthetic ceramics particles affected the osteogenesis as defined by both the quantity and quality of ectopic bone.
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http://dx.doi.org/10.1016/j.bone.2020.115654DOI Listing
December 2020

A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures.

Bone 2020 11 27;140:115551. Epub 2020 Jul 27.

Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000 Zagreb, Croatia. Electronic address:

Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
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http://dx.doi.org/10.1016/j.bone.2020.115551DOI Listing
November 2020

Evaluation of synthetic ceramics as compression resistant matrix to promote osteogenesis of autologous blood coagulum containing recombinant human bone morphogenetic protein 6 in rabbit posterolateral lumbar fusion model.

Bone 2020 11 27;140:115544. Epub 2020 Jul 27.

Laboratory for Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia; Scientific Center of Excellence for Reproductive and Regenerative Medicine, Zagreb, Croatia. Electronic address:

Posterolateral lumbar fusion (PLF) is a commonly performed surgical procedure for the treatment of pathological conditions of the lumbosacral spine. In the present study, we evaluated an autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) and synthetic ceramics used as compression resistant matrix (CRM) in the rabbit PLF model. In the pilot PLF rabbit experiment, we tested four different CRMs (BCP 500-1700 μm, BCP 1700-2500 μm and two different TCP in the form of slabs) which were selected based on achieving uniform ABC distribution. Next, ABGS implants composed of 2.5 mL ABC with 0.5 g ceramic particles (TCP or BCP (TCP/HA 80/20) of particle size 500-1700 μm) and 125 μg rhBMP6 (added to blood or lyophilized on ceramics) were placed bilaterally between transverse processes of the lumbar vertebrae (L5-L6) following exposition and decortication in 12 New Zealand White Rabbits observed for 7 weeks following surgery. Spinal fusion outcome was analysed by μCT, palpatory segmental mobility testing and selected specimens were either tested biomechanically (three-point bending test) and/or processed histologically. The total fusion success rate was 90.9% by both μCT analyses and by palpatory segmental mobility testing. The volume of newly formed bone between experimental groups with TCP or BCP ceramics and the different method of rhBMP6 application was comparable. The newly formed bone and ceramic particles integrated with the transverse processes on histological sections resulting in superior biomechanical properties. The results were retrospectively found superior to allograft devitalized mineralized bone as a CRM as reported previously in rabbit PLF. Overall, this novel ABGS containing rhBMP6, ABC and the specific 500-1700 μm synthetic ceramic particles supported new bone formation for the first time and successfully promoted posterolateral lumbar fusion in rabbits.
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http://dx.doi.org/10.1016/j.bone.2020.115544DOI Listing
November 2020

Silicon erasable waveguides and directional couplers by germanium ion implantation for configurable photonic circuits.

Opt Express 2020 Jun;28(12):17630-17642

A novel technique for realization of configurable/one-time programmable (OTP) silicon photonic circuits is presented. Once the proposed photonic circuit is programmed, its signal routing is retained without the need for additional power consumption. This technology can potentially enable a multi-purpose design of photonic chips for a range of different applications and performance requirements, as it can be programmed for each specific application after chip fabrication. Therefore, the production costs per chip can be reduced because of the increase in production volume, and rapid prototyping of new photonic circuits is enabled. Essential building blocks for the configurable circuits in the form of erasable directional couplers (DCs) were designed and fabricated, using ion implanted waveguides. We demonstrate permanent switching of optical signals between the drop port and through the port of the DCs using a localized post-fabrication laser annealing process. Proof-of-principle demonstrators in the form of generic 1×4 and 2×2 programmable switching circuits were fabricated and subsequently programmed.
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http://dx.doi.org/10.1364/OE.394871DOI Listing
June 2020

The innate immune toll-like-receptor-2 modulates the depressogenic and anorexiolytic neuroinflammatory response in obstructive sleep apnoea.

Sci Rep 2020 07 10;10(1):11475. Epub 2020 Jul 10.

Sleep and Brain Plasticity Centre, Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London (KCL), De Crespigny Park, Box 089, London, SE5 8AF, UK.

The increased awareness of obstructive sleep apnoea's (OSA) links to Alzheimer's disease and major psychiatric disorders has recently directed an intensified search for their potential shared mechanisms. We hypothesised that neuroinflammation and the microglial TLR2-system may act as a core process at the intersection of their pathophysiology. Moreover, we postulated that inflammatory-response might underlie development of key behavioural and neurostructural changes in OSA. Henceforth, we set out to investigate effects of 3 weeks' exposure to chronic intermittent hypoxia in mice with or without functional TRL2 (TLR2, C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj;TLR2,C57BL/6-Tlr2tm1Kir). By utilising multimodal imaging in this established model of OSA, a discernible neuroinflammatory response was demonstrated for the first time. The septal nuclei and forebrain were shown as the initial key seed-sites of the inflammatory cascade that led to wider structural changes in the associated neurocircuitry. Finally, the modulatory role for the functional TLR2-system was suggested in aetiology of depressive, anxious and anorexiolytic symptoms in OSA.
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http://dx.doi.org/10.1038/s41598-020-68299-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351955PMC
July 2020

Recombinant Human BMP6 Applied Within Autologous Blood Coagulum Accelerates Bone Healing: Randomized Controlled Trial in High Tibial Osteotomy Patients.

J Bone Miner Res 2020 10 2;35(10):1893-1903. Epub 2020 Jul 2.

Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.

Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689741PMC
October 2020

Autologous blood coagulum containing rhBMP6 induces new bone formation to promote anterior lumbar interbody fusion (ALIF) and posterolateral lumbar fusion (PLF) of spine in sheep.

Bone 2020 09 22;138:115448. Epub 2020 May 22.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia. Electronic address:

In the present study, we evaluated an autologous bone graft substitute (ABGS) composed of recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) used as a physiological carrier for new bone formation in spine fusion sheep models. The application of ABGS included cervical cage for use in the anterior lumbar interbody fusion (ALIF), while for the posterolateral lumbar fusion (PLF) sheep model allograft devitalized bone particles (ALLO) were applied with and without use of instrumentation. In the ALIF model, ABGS (rhBMP6/ABC/cage) implants fused significantly when placed in between the L4-L5 vertebrae as compared to control (ABC/cage) which appears to have a fibrocartilaginous gap, as examined by histology and micro CT analysis at 16 weeks following surgery. In the PLF model, ABGS implants with or without ALLO showed a complete fusion when placed ectopically in the gutter bilaterally between two decorticated L4-L5 transverse processes at a success rate of 88% without instrumentation and at 80% with instrumentation; however the bone volume was 50% lower in the instrumentation group than without, as examined by histology, radiographs, micro CT analyses and biomechanical testing at 27 weeks following surgery. The newly formed bone was uniform within ABGS implants resulting in a biomechanically competent and histologically qualified fusion with an optimum dose in the range of 100 μg rhBMP6 per mL ABC, while in the implants that contained ALLO, the mineralized bone particles were substituted by the newly formed remodeling bone via creeping substitution. These findings demonstrate for the first time that ABGS (rhBMP6/ABC) without and with ALLO particles induced a robust bone formation with a successful fusion in sheep models of ALIF and PLF, and that autologous blood coagulum (ABC) can serve as a preferred physiological native carrier to induce new bone at low doses of rhBMP6 and to achieve a successful spinal fusion.
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http://dx.doi.org/10.1016/j.bone.2020.115448DOI Listing
September 2020

Modelling the effect of a dedicated hip fracture unit on patient outcomes using segmented robust linear regression techniques.

Injury 2020 May 11. Epub 2020 May 11.

Trauma and Orthopaedics department, Medical University Hospital LKH Graz, Austria.

Introduction: Typically, a healthcare intervention is evaluated by comparing data before and after its implementation using statistical tests. Comparing group means can miss underlying trends and lead to erroneous conclusions. Segmented linear regression can be used to reveal secular trends but is susceptible to outliers. We described a novel method using segmented robust regression techniques to evaluate the effect of introducing a dedicated hip fracture unit (HFU).

Methods: We retrospectively analysed patient outcomes from a total of 2777 patients sustaining proximal femoral fragility fractures over a 6-year period at a Level 1 Major Trauma Centre. We compared time to surgical intervention and length of hospital stay before and after the implementation of the HFU using group comparison tests, segmented ordinary regression and robust regression techniques to evaluate the effect of the intervention.

Results: Group comparison tests did not identify a significant difference in time to surgery pre and post- HFU. Segmented regression revealed that there was a significant reduction in time to surgery but that this predated the introduction of the HFU. Group comparison tests did not identify a significant difference in length of stay pre and post-HFU. Ordinary segmented regression demonstrated that there was a constant reduction in length of stay, which accelerated after the introduction of the HFU. Robust regression identified that this change occurred prior to the HFU.

Discussion: There was a significant decrease in time to surgical intervention during the study period that occurred long before the introduction of the HFU, and that cannot be attributed to the HFU itself. Length of stay started dropping early in the study period and was unrelated to the HFU. However, with robust regression we concluded that the HFU was effective in reducing relatively long hospital stays (outliers). Several explanatory factors that may have affected the observed trends in time to surgery and length of stay were identified.

Conclusion: Robust regression is a useful adjunct to ordinary segmented linear regression techniques in modelling retrospective time-series and dealing with outliers. The changes observed in hip fracture patient outcomes over a 6-year period was likely multifactorial.
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http://dx.doi.org/10.1016/j.injury.2020.03.056DOI Listing
May 2020

Determination of Psychological Stress, Serum Immune Parameters, and Cortisol Levels in Patients With Human Papilloma Virus.

Clin Ther 2020 05 25;42(5):783-799. Epub 2020 Apr 25.

Clinical Department of Dermatovenerology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia. Electronic address:

Purpose: Because the results of studies investigating the relation between human papilloma virus (HPV) infection and the effects of psychological stress are inconsistent, this study was conducted to expand on previous research by analyzing patient stress levels, serum immune parameters, and cortisol levels in patients with clinical HPV manifestations. It also looked for differences in clinical manifestations of HPV depending on patient level of experienced stress.

Methods: This cross-sectional study included 213 subjects (94 women and 119 men aged ≥18 years; average age, 41 years) with clinical manifestations of HPV infection (165 subjects with extragenital manifestations and 48 with genital manifestations) who were treated at the Department of Dermatovenerology, Karlovac General Hospital, from January 1, 2012, to December 31, 2015. Psychological, neurohormonal and immune parameters (serum values of leukocytes, alpha-globulins, beta-globulins, albumins, and proteins), and serum cortisol levels were analyzed. Questionnaires were used to determine patients' perception of stress: the Recent Life Changes Questionnaire, the Perceived Stress Scale, and the Brief Cope Test. One group of subjects had confirmed stressful experiences, defined by the Recent Life Changes Questionnaire as a period of 1 year with at least 500 life change units; the control group included patients with no significant stressful experiences.

Findings: Patients with confirmed significant stress experience had a statistically significant higher degree of perception of stress. There were no statistically significant differences in terms of the impact of stress on clinical HPV manifestations (genital and extragenital), sex, lesional duration, or recurrence. In patients with significant stress experience, significantly higher values of leukocytes (6.68 × 10/L), alpha-globulins (6.85 g/L), and beta-globulins (7.33 g/L) were observed. Adaptive coping and a lower perception of stress significantly reduced the chances of having extragenital manifestations by 2.63 times. A higher perception of stress significantly increased the likelihood of genital manifestations.

Implications: Although this study found that stress increased the values of leukocytes, alpha-globulins, and beta-globulins, no evidence was found that it affected clinical manifestations of HPV infection. The redundancy of the immune system could account for this finding. This study is among the first to investigate the correlation between psychological, neurohormonal, and immune indicators of stress.
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http://dx.doi.org/10.1016/j.clinthera.2020.03.017DOI Listing
May 2020

Association of Triiodothyronine Levels With Prostate Cancer Histopathological Differentiation and Tumor Stage.

Anticancer Res 2020 Apr;40(4):2323-2329

Department of Oncology and Nuclear Medicine, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia.

Background/aim: The aim of this study was to determine the association between total triiodothyronine (T3), free fraction of thyroxin (FT4), and thyrotropin (TSH) levels with prostate cancer histopathological features.

Patients And Methods: Blood samples from 140 patients with prostate cancer were analyzed preoperatively and stratified according to postoperative histopathological differentiation. The first group (N=62) included patients with prostate cancer Grade Groups (GG) 1-2, while the second group (N=63) included patients with prostate cancer GG 3-5.

Results: T3 levels were significantly higher in patients with prostate cancer GG 3-5 (p=0.047). There was no significant difference in the FT4 and TSH levels between the two groups (p=0.680 and 0.801, respectively). T3 levels were positively correlated with tumor percentage involvement (TPI) (p=0.002), and pT stage (p=0.047) on definitive pathology.

Conclusion: Higher T3 levels are associated with several indicators of prostate cancer histopathological aggressiveness.
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http://dx.doi.org/10.21873/anticanres.14199DOI Listing
April 2020

Gender Differences in Relationship between Body Mass Index and Asthma.

Psychiatr Danub 2019 Dec;31(Suppl 5):786-791

University Hospital Centre Zagreb, Clinic of Lung Diseases Jordanovac, Department of Allergic and Inflamatory Lung Diseases, Zagreb, Croatia.

Background: Asthma is one of the most common chronic diseases in the world. Obesity is the most common comorbidity of asthma and is connected to incidence and course of the disease. Obesity is associated with non-allergic asthma phenotype, but this relation could be influenced by gender. The aim of our study was to determine the relationship between BMI and asthma and to explore possible gender differences.

Subjects And Methods: Study included 149 patients with asthma (examined group) and 153 healthy blood donors (control group). Data from the medical records of patients with asthma were used, and all included subjects had their BMI calculated using standard formula. Data were analyzed using descriptive statistics methods. Data with non-parametric distribution were analysed with Mann-Whitney U test and showed through medians with corresponding interquartile ranges. Statistical significance of BMI differences between non-allergic asthma, allergic asthma and control groups were analyzed by one-way analysis of variance - ANOVA. The results were interpreted at a significance level of P<0.05.

Results: The comparison between median BMI values of two groups shows that examined group of patients with astma has significantly higher median BMI value in comparison with control group (P=0.035). Correlation was stronger for women than men (P=0.002 vs P=0.898). Incresed BMI of the examined group of patients with asthma was not asociated with non-allergic asthma (P=0.085). However, when stratified according to gender, there was a strong association of increased BMI with non-allergic asthma in women (P<0.001).

Conclusion: Patients with asthma in our study have higher BMI in comparison to healthy individuals, which contributes to hypothesis that BMI is a risk factor for development of asthma. We found that possible effect that BMI has on asthma is stronger in women, since there was a strong association between increased BMI and non-allergic asthma only in women.
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December 2019

Operative versus non-operative management of blunt pancreatic trauma in children: Systematic review and meta-analysis.

Injury 2020 Feb 12. Epub 2020 Feb 12.

Institute for Anthropological Research, Zagreb, Croatia.

Aim: Blunt abdominal trauma is the major cause of abdominal injury in children. No clear guidelines exist for the initial management of blunt pancreatic trauma in children. The aim of this study was to perform a systematic review and meta-analysis of initially non-operative versus initially operative treatment in children with blunt pancreatic injury.

Methods: Studies including children (<18 years) with blunt pancreatic injuries published in any language after year 1990 were included. Total of 849 studies were identified by searching PubMed, Scopus, CINAHL and Cochrane Database. After review, 42 studies met inclusion criteria and were included in this systematic review. There were 1754 patients, of whom 1095 were initially managed non-operatively (NOM), and 659 operatively (OM). Primary outcome was non-operative management success rate, and secondary outcomes were mortality, complications (including specifically pseudocysts and pancreatic fistulas), percent of patients and days on total parenteral nutrition (TPN), length of hospital stay and readmissions.

Results: There was no difference in mortality between NOM and OM groups. The incidence of pseudocysts was significantly higher in NOM group compared to OM (P<0.001), especially for AAST grade III or higher (P<0.00001). Overall incidence of pancreatic fistulas was significantly lower for NOM group (p = 0.02) but no difference was observed for AAST grades III or higher (p = 0.49). There was no difference in the length of hospital stay (P = 0.31). Duration of total parenteral nutrition was not different for all AAST grades (P = 0.35), but was significantly shorter for OM group for AAST grades III and higher (p = 0.0001). There was no overall difference in readmissions (P = 0.94). Overall success rate of initial non-operative treatment was 87%.

Conclusions: Most patients with pancreatic trauma can initially be treated non-operatively, while early surgical treatment may benefit patients with lesions of the main pancreatic duct. ERCP offers both highly accurate diagnosis and potential treatment of ductal injuries.
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http://dx.doi.org/10.1016/j.injury.2020.02.035DOI Listing
February 2020

Experimental shortening of the radius in the treatment of Kienböck's disease.

Injury 2020 Feb 13. Epub 2020 Feb 13.

Institute for Anthropological Research, Zagreb, Croatia.

Aim: The aim of the research was to determine the smallest amount of loading on the lunate bone obtained by gradually shortening the radius in different ulnar variants as the potential treatment of Kienböck's disease.

Methods: The research was conducted on anatomic preparations of 20 upper extremities using only the distal part of the forearm and hand, placing them in exactly defined positions. A Fuji Prescale film was inserted in the open radiocarpal joint to measure pressure after compressing axially by changing the length of forearm in four stages by the gradual shortening of the radius.

Results: The greatest reduction of average pressure on the lunatum achieved by shortening the radius depended on ulnar variant. In ulnar variant 0, the greatest reduction of average pressure on lunatum was achieved by shortening the radius for 3 mm (24% reduction). For ulnar variant -1, the greatest reduction of average pressure on lunatum was achieved by shortening the radius for 2 mm (37% reduction). For ulnar variants -2, -3 and +1, the greatest reduction of average pressure on lunatum was achieved by shortening the radius for 3 mm (5%, 75% and 9% respectively).

Conclusions: The pressure distribution in the distal radiocarpal joint is vital for healing, and shortening of the radius relieves the pressure on the lunate bone. The exact type of surgery and the amount of radial osteotomy depends on preoperative ulnar variant.
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http://dx.doi.org/10.1016/j.injury.2020.02.036DOI Listing
February 2020

Hyperuniform disordered waveguides and devices for near infrared silicon photonics.

Sci Rep 2019 Dec 30;9(1):20338. Epub 2019 Dec 30.

Department of Physics and the Advanced Technology Institute, University of Surrey, Guildford, GU2 7XH, UK.

We introduce a hyperuniform-disordered platform for the realization of near-infrared photonic devices on a silicon-on-insulator platform, demonstrating the functionality of these structures in a flexible silicon photonics integrated circuit platform unconstrained by crystalline symmetries. The designs proposed advantageously leverage the large, complete, and isotropic photonic band gaps provided by hyperuniform disordered structures. An integrated design for a compact, sub-volt, sub-fJ/bit, hyperuniform-clad, electrically controlled resonant optical modulator suitable for fabrication in the silicon photonics ecosystem is presented along with simulation results. We also report results for passive device elements, including waveguides and resonators, which are seamlessly integrated with conventional silicon-on-insulator strip waveguides and vertical couplers. We show that the hyperuniform-disordered platform enables improved compactness, enhanced energy efficiency, and better temperature stability compared to the silicon photonics devices based on rib and strip waveguides.
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http://dx.doi.org/10.1038/s41598-019-56692-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937303PMC
December 2019

CHOLESTEROL AND CHLORIDE IN ACUTE HEART FAILURE.

Acta Clin Croat 2019 Jun;58(2):195-201

1Zagreb University Hospital Centre, Zagreb, Croatia; 2Sestre milosrdnice University Hospital Centre, Zagreb, Croatia; 3University of Zagreb School of Medicine, Zagreb, Croatia; 4University of Zagreb Faculty of Pharmacy and Biochemistry, Zagreb, Croatia; 5Occupational Medicine Office, Zagreb, Croatia; 6Sveti Duh University Hospital, Zagreb, Croatia; 7Andrija Štampar School of Public Health, University of Zagreb School of Medicine, Zagreb, Croatia; 8Institute of Molecular Biology and Biochemistry, Centre of Molecular Medicine, Medical University of Graz, Graz, Austria.

Detecting predictors of poor outcome is crucial for understanding the underlying pathophysiology of heart failure (HF) and thus creating new therapeutic concepts. It is well established that low serum lipid levels are associated with unfavorable outcomes in HF patients. Several studies examined the association between serum lipids and established predictors of mortality in HF patients. The aim of the present study was to examine the association of serum lipid and chloride concentrations, as well as their impact on survival in acute heart failure (AHF). The present study was performed as a prospective, single-centre, observational research. The study included 152 patients with AHF. Spearman's correlation coefficient revealed a significant positive correlation of serum chloride levels with serum levels of total cholesterol (ρ 0.221, p=0.006), low-density lipoprotein cholesterol (LDL-c) (ρ 0.187, p=0.015) and high-density lipoprotein-cholesterol (HDL-c) (ρ 0.169, p=0.038). Binary logistic regression revealed a significant association of chloride, total cholesterol and LDL-c serum levels measured at admission with hospital survival (OR 1.077, CI 1.01-1.154, p=0.034), (OR 1.731, CI 1.090-2.748, p=0.020) and (OR 1.839, CI 1.033-3.274, p=0.038), respectively, as well as with 3-month survival (OR 1.065, CI 1.002-1.131, p=0.042), (OR 1.625, CI 1.147-2.303, p=0.006) and (OR 1.711, CI 1.117-2.622, p=0.014), respectively. In conclusion, positive statistical association between serum cholesterol (total cholesterol, LDL-c and HDL-c) and chloride levels may suggest their similar modulation by AHF pathophysiology. Serum levels of total cholesterol, LDL-c and chloride contribute to patient survival.
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http://dx.doi.org/10.20471/acc.2019.58.02.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884370PMC
June 2019

Culture of Blame-An Ongoing Burden for Doctors and Patient Safety.

Int J Environ Res Public Health 2019 12 1;16(23). Epub 2019 Dec 1.

University of Zagreb, School of Medicine, Andrija Štampar School of Public Health, Department of Environmental and Occupational Health and Sports Medicine, WHO CC for Occupational Health, Zagreb 10 000, Croatia.

Every procedure in healthcare carries a certain degree of inherent unsafety resulting from problems in practice, which might lead to a healthcare adverse event (HAE). It is very important, and even mandatory, to report HAE. The point of HAE reporting is not to blame the person, but to learn from the HAE in order to prevent future HAEs. Our aim was to examine the prevalence and the impact of culture of blame on health workers' health. A cross-sectional study on healthcare workers at two Croatian hospitals was conducted using the Hospital Survey on Patient Safety Culture (PSC). : The majority of PSC dimensions in both hospitals were high. Among the dimensions, Hospital Handoffs and Transitions and Overall Perceptions of Safety had the highest values. The Nonpunitive Response to Error dimension had low values, indicating the ongoing culture of blame. The Staffing dimension had low values, indicating the ongoing shortage of doctors and nurses. : We found inconsistencies between a single-item measure and PSC dimensions. It was expected that Frequency of Events Reported (PSC dimension) relates to Number of Events Reported (single-item measure). However, in our study, the relations between these pairs of measures were different between hospitals. Our results indicate the ongoing culture of blame. Healthcare workers do not report HAE because they fear they will be punished by management or by law.
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http://dx.doi.org/10.3390/ijerph16234826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926580PMC
December 2019

The Usefulness of Spectroscopic Simulations.

Appl Spectrosc 2020 Mar;74(3):305-313

Department of Chemistry and Biochemistry, Samford University, Birmingham, AL, USA.

This article presents a method for extracting the optical constants of homogeneous isotropic materials using the infrared spectra of that material. The method is based on using the harmonic oscillator model of molecular polarizability to obtain optical constants, then calculating the spectrum, comparing the calculated spectrum to an experimental spectrum of the material, and adjusting the model parameters until a close fit between the spectra is obtained. Corrections that need to be made to the experimental spectra in order to remove instrumental distortions are also briefly described. The remainder of the article centers on describing how the optical constants can be used to simulate spectra of that material in different experimental arrangements and the benefits that spectral simulations afford to experimentalists.
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http://dx.doi.org/10.1177/0003702819893689DOI Listing
March 2020

Changes in total body surface area and the distribution of skin surfaces in relation to body mass index.

Burns 2020 06 15;46(4):868-875. Epub 2019 Nov 15.

University Hospital Rebro, Department of Plastic, Reconstructive and Aesthetic Surgery, Kispaticeva 12, 10000 Zagreb, Croatia.

Background: A correct estimation of total burn surface area is important since it is used for determining fluid resuscitation volumes, nutritional estimates and hospital admission criteria. Wallace's rule of nines is the most commonly used methods for this purpose. However, fat distribution is non-uniform and the total body surface area changes with obesity. The aim of this study was to determine if the rule of nines applies to all body mass index groups.

Methods: A total of 217 individuals were included in the study. The patients were divided into 4 groups according to their BMI (18.5-25kg/m (60 persons)), 25-29.9kg/m (61 individuals)), 30-34.9kg/m (55 persons)), >35kg/m (41 persons)). Each patient underwent a complete duel-energy X-ray absorptiometry body scan to determine the surface area (cm) of the various regions of the body.

Results: We found no statistically significant variations between the Wallace body percentage distributions and our results in the men for all BMI ranges (head p=0.331, arms p=0.861, legs p=0.282, trunk p=0.696). In contrast, among women we found a statistically significant change in body surface area percentage distribution between the BMI groups and specific body regions (head p=0.000, legs p=0.000 and trunk p=0.001).

Conclusion: The Wallace rule of nines is a quick and acceptable method for estimating the total burn surface area percentage in men of all BMI ranges. However, for women, a more accurate method of burn area estimation is required as proposed by our BMI adjusted charts.
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http://dx.doi.org/10.1016/j.burns.2019.10.015DOI Listing
June 2020

The influence of size, depth and histologic characteristics of invasive ductal breast carcinoma on thermographic properties of the breast.

EXCLI J 2019 22;18:549-557. Epub 2019 Jul 22.

University of Zagreb, School of Medicine. Mirogojska cesta 16, 10000, Zagreb.

Invasive breast carcinoma is the most common oncologic disease worldwide. The existing diagnostic methods use morphologic changes in the breast to diagnose a carcinoma when it has reached a certain size. Therefore, it is important to augment the morphologic diagnostic examinations with a new method that focuses on characteristics other than morphology such as electromagnetic changes produced by cancer. 50 adult female patients with confirmed ductal carcinoma following a core biopsy due to a suspicious breast mass were included in the study. They underwent breast thermography using a specially designed infrared camera. The data collected was statistically analyzed to determine how the presence of a tumor and its histologic characteristics influence breast thermographic properties. Twenty eight [56 %] patients in the study had an abnormal thermogram. Following statistical analysis, it was found that temperature of the diseased breast was directly correlated to tumor volume [=0.009] and negatively correlated to depth of tumor [=0.042]. Tumors that were ER+ and PR+ tumors produced warmer temperatures [=0.017 and =0.038 respectively] than tumors without these receptors. HER2 status and Ki-67 index had no statistical correlation with breast temperature. Tumor size, distance from the skin surface and receptor status cause changes in breast thermographic properties. Despite technical advances in the field of thermography, there are still contradictory results associated with thermography. Its diagnostic abilities are generally poorer than conventional methods and its use in breast cancer screening or as an adjunctive tool for diagnostic purposes is not recommended.
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http://dx.doi.org/10.17179/excli2019-1600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785770PMC
July 2019

Chromosomal Heterogeneity of the G-401 Rhabdoid Tumor Cell Line: Unusual Partial 7p Trisomy.

Front Med (Lausanne) 2019 30;6:187. Epub 2019 Aug 30.

Department of Pediatric Surgery, Children's Hospital, Inselspital, University of Bern, Bern, Switzerland.

Rhabdoid tumor is a very aggressive and hardly curable pediatric malignancy. It commonly starts in the kidneys but also can occur in the brain, liver, and other organs. The treatment of this tumor usually involves a combination of surgery, radiation, and chemotherapy. Because this tumor is rare, there is still limited experience with a defined standard of care. Cytogenetic analysis is an important routine method to monitor chromosomal aberrations. We have analyzed metaphases of the G-401 rhabdoid tumor cell line. In these cells we have observed metaphases with derivative chromosome 12 arising from partial trisomy 7p. With increasing passage number the numbers of metaphases having this derivative chromosome 12 were found to be higher. In passage number 2 only one metaphase had this pathological chromosome 12. By passage number 10 and passage number 15 about 25 and 95% of this derivative chromosome 12 were found, respectively. We were able to subclone G-401 cells by limiting dilutions and successfully separated cells having apparently normal karyotypes from cells having derivative chromosome 12. Using the cell proliferation assay we showed that clones possessing the derivative chromosome 12 grew more rapidly than clones with normal chromosomes. The cell cycle analysis confirmed this observation. Overall, in this study we describe for the first time a 7p triplication in a rare rhabdoid tumor of kidney. Both types of clones described in this study could be used as a preclinical model to study the involvement of partial chromosome 7 alterations in the development of rhabdoid tumors.
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http://dx.doi.org/10.3389/fmed.2019.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729120PMC
August 2019

Association among Clopidogrel Cessation, Platelet Function, and Bleeding in Coronary Bypass Surgery: An Observational Trial.

Thorac Cardiovasc Surg 2019 Jul 30. Epub 2019 Jul 30.

Klinik fur Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Universität Duisburg-Essen, and TEM International GmbH, Munich, Germany.

Objectives:  This study sought to determine (1) the association between the length of preoperative clopidogrel discontinuation, blood loss, and transfusion requirements and (2) whether preoperative platelet function testing predicts excessive postoperative bleeding in patients undergoing coronary artery bypass grafting (CABG) surgery.

Methods:  In this retrospective analysis, patients undergoing CABG were divided into three groups with regard to the period between preoperative clopidogrel cessation and surgery: group 1 ( = 94, ≤3 days), group 2 ( = 100, 4-5 days), and group 3 ( = 83, 6-7 days), respectively. Impedance aggregometry (Multiplate) with arachidonic acid (ASPI) test assay (used for platelets stimulation) and adenosine diphosphate (ADP) test (used for platelets stimulation) was performed before the surgery. Primary outcome was 24 hours chest tube output (CTO) and transfusion requirements (red blood cell concentrate [RBCC], platelet concentrate [PC], fibrinogen concentrate [FC], and fresh-frozen plasma [FFP]) were considered as secondary outcomes.

Results:  CTO during 24 hours was significantly higher in group 1 as compared with groups 2 and 3, respectively ( = 0.003). Considering secondary outcomes, RBCC ( = 0.043), PC ( = 0.001), FC ( = 0.003), and FFP ( = 0.010) were more frequently transfused in group 1 as compared with groups 2 and 3, respectively. Multiple electrode aggregometry ASPI and ADP tests were significantly correlated with the 24-hour CTO (ASPI test-rho = -0.258,  < 0.001; ADP test-rho = -0.164,  = 0.007). A significant correlation was observed between clopidogrel-free interval and 24-hour CTO (rho = -0.200,  < 0.001). Receiver-operating characteristics (ROC) curve analysis revealed cutoff values to delineate bleeding tendency (ASPI test ≤ 25 area under the aggregation curve [AUC], ADP test ≤63 AUC, and clopidogrel-free interval ≤3 days).

Conclusion:  Excessive postoperative bleeding occurred less frequently if the period between clopidogrel discontinuation and surgery was longer than 3 days, as compared with shorter waiting time. Inadequate recovery of the platelets function following clopidogrel cessation in preoperative period was associated with increased bleeding risk. Platelet function testing was found to be a useful tool for postoperative bleeding management in our hands.
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http://dx.doi.org/10.1055/s-0039-1693122DOI Listing
July 2019

Influence of human embryo cultivation in a classic CO2 incubator with 20% oxygen versus benchtop incubator with 5% oxygen on live births: the randomized prospective trial.

Zygote 2019 Jun 10;27(3):131-136. Epub 2019 May 10.

3Polyclinic Repromed,Gradiščanska 36,10 000 Zagreb,Croatia.

SummaryOur objective was to assess the effect of benchtop incubators with low oxygen concentrations on the clinical and embryological parameters of our patients. We conducted a prospective, randomized, opened controlled trial on infertile patients in stimulated cycles. In total, 738 infertile patients were assessed for eligibility and, after final exclusions, 230 patients were allocated either to a 5% O2 group (benchtop incubator) or a 20% O2 group (classic incubator). Finally, 198 patients in the 5% O2 group and 195 in the 20% O2 group were analysed. The outcomes measured were fertilization rate, clinical pregnancy rate, and live birth rate. The primary outcome - live birth rate per all transfers - did not show any improvement in the 5% oxygen group over the 20% oxygen group (25.3% versus 22.6%, P=0.531), but the number of day 5 blastocysts was significantly higher (P=0.009). Fertilization rate did not show any beneficial effect of reduced oxygen (5%) (73.4%±22.4% versus 74.6%±24.0%, P=0.606) per all transfers but there was statistically significant difference in the day 5 SET subgroup (85.3±15.1 versus 75.1±17.5; P=0.004). Clinical pregnancy rate showed results in favour of the 5% oxygen group for all subgroups (day 3: 23.7% versus 21.1%, P=0.701; day 5 SET: 35.0% versus 30.6%. P=0.569) but showed statistical significance only in the day 5 SET subgroup (51.1% versus 29.8%; P=0.038). Culturing of embryos in benchtop incubators under low oxygen produced more blastocysts and therefore was a better alternative for embryo selection, which resulted in higher pregnancy rates. To achieve higher live birth rates, embryo quality is not the only factor.
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http://dx.doi.org/10.1017/S0967199418000618DOI Listing
June 2019

E-cadherin and NEDD9 expression in primary colorectal cancer, metastatic lymph nodes and liver metastases.

Oncol Lett 2019 Mar 10;17(3):2881-2889. Epub 2019 Jan 10.

Ljudevit Jurak Department of Pathology and Cytology, University Hospital for Tumors, Clinical Hospital Center Sestre Milosrdnice, Zagreb 10000, Croatia.

In Croatia, colorectal cancer mortality rates in males are the third highest in Europe, after Hungary and Slovakia. The results for females rank Croatia in second place after Hungary. According to previous studies, the loss of E-cadherin expression and the higher expression of neural precursor cell-expressed developmentally downregulated 9 (NEDD9) are associated with a worse prognosis. The aim of the present study was to analyze the immunohistochemical expression of NEDD9 and E-cadherin as markers of metastatic potential using a tissue microarray. This retrospective study included 40 previously untreated patients, including 23 males and 17 females with a median age of 64.5 years (range 38-84), with colorectal cancer and synchronous liver metastases that underwent simultaneous colorectal and hepatic resection between January 1st 2006 and December 31st 2013, in the Clinical Hospital Center Sestre Milosrdnice (Zagreb, Croatia). The most frequent tumor stage was T3, while the most frequent nodal stage was N1. Microvascular invasion was present in 37.5% of patients, while perineural invasion was observed in 30% of patients. The immunohistochemical staining index of E-cadherin was highly positive in 87.5% samples of colorectal cancer, 67.7% of lymph nodes and 77.5% of liver metastases. In the primary tumor, highly positive NEDD9 expression was identified in 22.5% of patients. In lymph nodes, it was identified in 35.5% of patients, while in the liver, it was identified in 30% of patients. Significant positive correlations were observed between the percentage of positive lymph nodes and the immunohistochemical staining index of E-cadherin (ρ=0.372; P=0.039) and NEDD9 (ρ=0.451; P=0.011) in lymph nodes. After the conclusion of the study, 55% of the patients succumbed. No significant differences in survival rates were identified regarding the expression of E-cadherin and NEDD9 in the primary tumor, metastatic lymph nodes and liver metastases. Due to the small sample size and the negative results obtained, further research is required to implement these parameters as prognostic factors.
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http://dx.doi.org/10.3892/ol.2019.9917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365943PMC
March 2019

Effect of clonidine on the cutaneous silent period during spinal anesthesia.

World J Clin Cases 2018 Dec;6(16):1136-1145

Center for Clinical Research, Winston Salem, NC 27103, United States.

Aim: To investigate the effect of clonidine on the cutaneous silent period (CSP) during spinal anesthesia.

Methods: A total of 67 adult patients were included in this randomized, prospective, single-center, double-blind trial. They did not have neurological disorders and were scheduled for inguinal hernia repair surgery. This trial was registered on ClinicalTrials.gov (NTC03121261). The patients were randomized into two groups with regards to the intrathecally administered solution: (1) 15 mg of 0.5% levobupivacaine with 50 µg of 0.015% clonidine, or (2) 15 mg of 0.5% levobupivacaine alone. There were 34 patients in the levobupivacaine-clonidine (LC) group and 33 patients in the levobupivacaine (L) group. CSP and its latency were measured four times: prior to the subarachnoid block (SAB), after motor block regression to the 0 level of the Bromage scale, with ongoing sensory blockade, and both 6 and 24 h after SAB.

Results: Only data from 30 patients in each group were analyzed. There were no significant differences between the groups investigated preoperatively and after 24 h. The CSP of the L group at the time point when the Bromage scale was 0 was 44.8 ± 8.1 ms, while in the LC group it measured 40.2 ± 3.8 ms ( = 0.007). The latency in the L group at the time point when the Bromage scale was 0 was 130.3 ± 10.2 ms, and in the LC group it was 144.7 ± 8.3 ms ( < 0.001). The CSP of the L group after 6 h was 59.6 ± 9.8 ms, while in the LC group it was 44.5 ± 5.0 ms ( < 0.001). The latency in the L group after 6 h was 110.4 ± 10.6 ms, while in LC group it was 132.3 ± 9.7 ms ( < 0.001).

Conclusion: Intrathecal addition of clonidine to levobupivacaine for SAB in comparison with levobupivacaine alone results in a diminished inhibitory tonus and shortened CSP.
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http://dx.doi.org/10.12998/wjcc.v6.i16.1136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306629PMC
December 2018

Real-time monitoring and gradient feedback enable accurate trimming of ion-implanted silicon photonic devices.

Opt Express 2018 Sep;26(19):24953-24963

Fabrication errors pose significant challenges on silicon photonics, promoting post-fabrication trimming technologies to ensure device performance. Conventional approaches involve multiple trimming and characterization steps, impacting overall fabrication complexity. Here we demonstrate a highly accurate trimming method combining laser annealing of germanium implanted silicon waveguide and real-time monitoring of device performance. Direct feedback of the trimming process is facilitated by a differential spectroscopic technique based on photomodulation. The resonant wavelength trimming accuracy is better than 0.15 nm for ring resonators with 20-µm radius. We also realize operating point trimming of Mach-Zehnder interferometers with germanium implanted arms. A phase shift of 1.2π is achieved by annealing a 7-μm implanted segment.
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http://dx.doi.org/10.1364/OE.26.024953DOI Listing
September 2018

Plasminogen activator inhibitor-1 activity and long-term outcome in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: a prospective cohort study.

Croat Med J 2018 Jun;59(3):108-117

Marin Pavlov, Department of Cardiology, Sestre Milosrdnice University Hospital Center, Vinogradska cesta 29, 10000 Zagreb, Croatia,

Aim: To determine the relationship between plasminogen activator inhibitor-1 (PAI-1) activity rise during the first 24 hours of ST-elevation myocardial infarction (STEMI) treatment and death after 5 years.

Methods: From May 1, 2009 to March 23, 2010, 87 STEMI patients treated with primary percutaneous coronary intervention (PCI) at the Sestre Milosrdnice University Hospital Center were consecutively enrolled in prospective single-center cohort study. PAI-1 activity was determined on admission and 24 hours later. The primary end-point was death after 5 years. The predictive value of PAI-1 activity variables as biomarkers of death was assessed using receiver operating characteristic (ROC) curve, independent predictors of death were assessed using multivariate Cox regression, and covariates independently related to higher PAI-1 activity rise were assessed using linear regression.

Results: Two patients died during the hospital treatment and 11 during the follow-up. PAI-1 activity rise had the largest area under curve (0.748) for predicting death rate (optimal cut-off point 3.7 U/mL, sensitivity 53.8%, specificity 90.5%). Patients with PAI-1 activity rise higher than 3.7 U/mL had significantly higher mortality (P<0.001). Kaplan-Meier survival curve diverged within the first year after STEMI. Independent predictors of death were PAI-1 rise and final Thrombolysis in Myocardial Infarction flow. PAI-1 activity rise was independently related to heart failure, thrombus aspiration, and body weight.

Conclusion: PAI-1 activity rise higher than 3.7 U/mL is associated with higher 5-year death rate in STEMI patients treated with primary PCI.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045897PMC
http://dx.doi.org/10.3325/cmj.2018.59.108DOI Listing
June 2018