University Medical Centre Ljubljana Research Articles

#2228 Hypocitraturia is the main factor associated with proteinuria in patients with kidney stones

Abstract Background and Aims Patients with kidney stones (KS) are at increased risk for chronic kidney disease. Research published so far has focused on factors associated with low glomerular filtration rate in KS patients, however, factors associated with proteinuria have not been fully described. The aim of this retrospective study was to assess the presence of proteinuria in our cohort of patients with known or presumed calcium KS and to analyze which common clinical and metabolic variables might be associated with proteinuria. Method We performed a retrospective cross-sectional study in patients (pts) treated at our stone clinic at the University Medical Centre Ljubljana in the ten-year period from January 1st 2010 to December 31st 2019. We excluded patients who did not have 24-hour proteinuria determined and patients with known urate, struvite or cystine stones. We noted the presence of arterial hypertension (AH), diabetes mellitus, a family history of kidney stones, age, sex, eGFR, body mass index, history of renal colic events and urological procedures for kidney stones, and 24-hour urine measurements (calcium, urate, oxalate, citrate, sodium, and proteinuria). Categorical variables were analyzed with Chi-Square test, normally distributed numerical values with Student's t-test and non-normally distributed with Mann-Whitney U test. P-values < 0.05 were considered statistically significant. Associations with p-values < 0.1 were included into a binary logistic regression analysis to determine the probability of predicting the presence of 24-hour proteinuria, defined as > 0.25 g/day in our laboratory. Results In the allocated time period 335 pts were examined. After exclusion, 251 pts were included into the analysis (mean age 49.5 ± 14.2 years, 116 (46.2%) males, 135 (53.8%) females). Complete 24-hour urine metabolic analysis was available for 238 pts. Proteinuria was present in 40 pts (15.9%) and was significantly more common in pts with AH compared to normotensive pts (18/77 (23.4%) vs. 22/174 (12.6%), p 0.027) and more common in males compared to females (23/116 (19.8%) vs. 17/135 (12.6%), p 0.083). Numerical variables with a p-value < 0.1 regarding the association with the presence of proteinuria are presented in Table 1. In regression analysis the model significantly predicted the presence of proteinuria (χ2 20.738, p 0.014, R2 0.343) and was able to predict the result overall in 85.2% of cases. Of all the variables included only citrate significantly predicted the presence of proteinuria (OR 1.732; 95% CI 1.009, 2.972; p 0.046). Proteinuria was significantly more common in pts with hypocitraturia (<1.67 mmol/day) compared to pts with normal urinary citrate (29/116 (25%) vs. 9/122 (7.4%), p < 0.001) and in pts with immeasurably low urinary citrate (<0.2 mmol/day) compared to higher citrate (15/27 (55.6%) vs. 23/211 (10.9%), p < 0.001). Conclusion Proteinuria was relatively common in our cohort. The main factor associated with proteinuria was urinary citrate. Proteinuria was significantly more common in pts with hypocitraturia compared to pts with normal urinary citrate and was present in the majority of pts with immeasurably low urinary citrate. Further studies are warranted to clarify the clinical relevance and implications of this findings.

#234 Clinical spectrum and genetic variants of Alport syndrome and thin basement membrane nephropathy—single center experience

Abstract Background and aims Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are genetically heterogeneous kidney diseases that manifest with kidney involvement, AS also with hearing and visual impairment. Electron microscopic examination shows characteristic ultrastructural changes in the glomerular basement membrane (GBM) in AS and TBMN, but cannot reliably distinguish between the two entities. Therefore, molecular genetic studies and the identification of individual pathogenic variants in the target genes are crucial to confirm the diagnosis. The aim of our study is to determine the significance of the genetic variants associated with the ultrastructural changes of GBM found in the renal biopsy. Method We retrospectively analyzed records of patients from the University Medical Centre Ljubljana in which ultrastructural GBM changes characteristic for AS and TBMN were found in the renal biopsy, including their clinical, laboratory and histological features. Molecular genetic investigations were made using the new generation sequencing method (NGS) to determine germline pathogenic variants in genes directly related to AS and TBMN (COL4A3, COL4A4 and COL4A5) and in genes that are important in syndromes with a related clinical picture (COL4A6, CD151, LMX1B, MYH9, FN1 and MYO1E). The pathogenicity of variants was determined according to the Clinical Molecular Genetic Society best practice guidelines. Results The study included 73 patients with ultrastructurally confirmed thin GBM. Indications for kidney biopsy were chronic nephritis syndrome in 33 patients (45%), acute worsening of renal function in 16 (22%), nephrotic syndrome in 9 (12%), nephrotic proteinuria and chronic kidney disease in 6 (8%), isolated proteinuria in 5 (7%) and suspected vasculitis in 4 patients (6%). At the time of kidney biopsy average age was 50 ± 16 years, average creatinine 112 ± 70 µmol/L and average estimated glomerular filtration rate (eGFR) 65 ± 24 ml/min/1.73 m2, 7 patients had eGFR below 30 ml/min/1.73 m2. Average daily proteinuria was 2.4 ± 3.3 gr and 88% of patients had hematuria. 38% of them have hearing impairment and 43% had positive familiar history of kidney disease. We recorded 33 patients (45%) with genetic variants associated with AS or TBMN: 22 patients (67%) with pathogenic variants, 2 patients (6%) with likely pathogenic and 9 patients (27%) with variants of uncertain significance. The presence of a positive genetic analysis was associated with a higher level of hematuria (p = 0.003), a lower level of proteinuria (p = 0.004) and a positive family history of kidney disease (p < 0.001). It was also associated with hearing loss, but the association was not statistically significant (p = 0.099). Patients with genetic variants had similar eGFR to those with negative genetics (63.9 ml/min/1.73 m2 (58.3-69.4) vs 66.2 ml/min/1.73 m2 (60.0-72.3)), p = 0.698. We also found no differences in GBM thickness in patients without compared to those with identified gene variants (213 nm (160-315) vs. 209 nm (140-410)), p = 0.761. 32 patients (44%) had only focal chronic changes and ultrastructural changes of thin GBM present on kidney biopsy and 41 patients (56%) had also been diagnosed with other renal pathology. When comparing these two groups, patients without associated pathology had lower daily proteinuria (p = 0.048), higher level of hematuria (p = 0.021), frequent hearing impairment (p = 0.008) and also positive genetics analysis (p = 0.016). Conclusion We have shown that in patients with proven ultrastructural alterations in GBM, the presence of so far recognized genetic variants associated with AS and TBMN is 45%, and corresponds to the frequency of other phenotypic characteristics of AS, including hearing impairment and positive family history. In the future, additional clinical tools will be required to accurately determine the role of coexistent thin GBM on the prognosis of patients with other relevant kidney pathology and other genetic tools beyond NGS should be employed to explore other pathologic genetic variants associated with the AS spectrum.

#1250 Measurement of ionized calcium with a point-of-care ionometer during treatment with etelcalcetide

Abstract Background and Aims Etelcalcetide is an intravenous calcimimetic indicated for the treatment of mineral and bone disorders in hemodialysis patients by lowering parathyroid hormone (PTH), calcium and phosphorus. The assessment of ionized calcium versus total calcium has not yet been studied during treatment with etelcalcetide, and there are no real data on the occurrence of hypocalcemia as measured by ionized calcium in the pre- and post-hemodialysis period during treatment with etelcalcetide. The aim of this study was to describe the time course of ionized and total serum calcium levels during chronic treatment with etelcalcetide and to assess the occurrence of hypocalcemia in patients treated with etelcalcetide by measuring ionized calcium levels. Method This was an observational, non-interventional, prospective, single-arm phase IV study. A total of 20 chronic hemodialysis patients (15 men and 5 women) aged 55.9 ± 18.2 years undergoing dialysis for 5.5 ± 4.3 years in two hemodialysis centers of the University Medical Centre Ljubljana were enrolled in the study between January 2020 and March 2021. All patients received etelcalcetide as a bolus injection into the venous line of the dialysis circuit three times a week, immediately after each hemodialysis session. Ionized calcium levels were determined using a point-of-care ionometer (GEM Premier 3000) before starting treatment with etelcalcetide prior to dialysis, then during treatment in the first week before and after dialysis, then once a week until the maintenance phase was reached and at least once a month thereafter. Hypocalcemia was defined by a pre-dialysis ionized calcium concentration below 0.90 mmol/L. The corrected total calcium values was measured prior to dialysis at least once a month according to routine clinical practice. The data of all these patients were included in the analysis, except for one, who underwent a kidney transplantation after receiving only 4 doses of etelcalcetide. Results We demonstrated that both corrected total calcium and ionized calcium before dialysis decreased over time during treatment with etelcalcetide. Of 240 measurements of ionized calcium with a point-of-care ionometer at the bedside, the concentration of ionized calcium was below 0.90 mmol/L three times in two patients (0.81, 0.84, 0.85). In one patient, we increased a calcium level in the dialysate from 1.50 to 1.75 mmol/L and in the other from 1.25 to 1.50 mmol/L. In addition, we observed 2 further measurements of ionized calcium of 0.90 mmol/L and 18 measurements between 0.91 and 0.96 mmol/L. However, this corresponds to 1.25% of hypocalcemias with ionized calcium below 0.90 mmol/L and 8.3% of those with calcium between 0.90 and 0.96 mmol/L. As calcium concentration in the bath increased, the pre-dialysis calcium concentrations also appeared to increase. At the beginning of the study, the calcium concentration in the dialysate was 1.5 mmol/L in 16 of 20 patients. 2 patients were treated with a calcium concentration in the dialysate of 1.75 mmol/L and 2 others with 1.25 mmol/L. The proportion of patients using higher dialysate calcium concentration was higher at the end of the study, as two patients switched to 1.75 mmol/L, and one from 1.25 to 1.50 mmol/L. This probably indicates a co-intervention triggered by a reduction in serum calcium levels prior to dialysis during treatment with etelcalcetide. Visual comparisons of the time course of ionized and corrected calcium concentrations before dialysis during chronic treatment with etelcalcetide in 19 patients showed a good correlation between point-of-care ionized calcium and routinely measured total calcium. Conclusion A point-of-care ionometer for the determination of ionized calcium at the bedside has the potential to guide etelcalcetide therapy by optimizing serum calcium levels and also to prevent potentially threatening hypocalcemia.

Results of Surgical Treatment of Occult Spinal Dysraphisms-A Single Centre Experience.

Occult spinal dysraphisms (OSDs) are caused by various defects in the embryogenesis of the spinal cord and represent an obstacle to the ascent of the conus, which allows the conus to pass from the lower levels of the spinal canal to the final position between L1 and L2 during normal foetal life. When an OSD tethers the spinal cord at the lower levels, it can lead to neurological symptoms, better known as tethered cord syndrome. Surgical treatment of OSD is primarily aimed at untethering the spinal cord. In asymptomatic patients, this can protect against the long-term development of neurological deficits. In symptomatic patients, this can halt or limit the progression of existing symptoms. The aim of this study is to examine all paediatric and adult patients diagnosed with OSD and treated in the Department of Neurosurgery at the University Medical Centre Ljubljana during the 5-year period of 2016-2021. All patients diagnosed with OSD during this period were included in the study. Patient characteristics, treatment modalities and outcomes were studied with the aim of describing the differences between the paediatric and adult population and defining the rationality of treating these pathological conditions. We included in the study 52 patients with 64 occult dysraphic lesions. Adults (>18 years old) represented 15/52 (28.8%) of all patients, while 37/52 (71.8%) were children. The most common OSDs were conus lipomas, followed by dermal sinus tracts, filum terminale lipomas and split cord malformations. Surgical treatment was performed in 35/52 (67.3%) cases, while conservative management was chosen in 17/52 (32.6%) cases. The preoperative presence of symptoms was statistically higher in adults than in children (p = 0.0098). Surgery on complex spinal cord lipomas was statistically related to a higher rate of postoperative neurological complications (p = 0.0002). The treatment of OSD is complex and must be based on knowledge of the developmental anomalies of the spine and spinal cord. Successful surgical treatment relies on microsurgical techniques and the use of neuromonitoring. Successful treatment can prevent or limit the occurrence of neurological problems.

Relationship between labour analgesia modalities and types of anaesthetic techniques in categories 2 and 3 intrapartum caesarean deliveries.

General anaesthesia is typically recommended for category 1 emergency caesarean delivery (CD). For categories 2-4 emergencies, either regional and general anaesthesia could be used. However, the factors influencing the choice of anaesthetic technique in these categories remain poorly understood. We analysed the association between the type of labour analgesia and subsequent anaesthetic techniques employed for intrapartum categories 2 and 3 CD. A prospective longitudinal cohort study was conducted at the University Medical Centre Ljubljana. A total of 300 women who underwent emergency CD between March and October 2021 were consecutively enrolled and categorised according to Lucas's classification of CD urgency. Parturients with category 1 and category 4 emergency CD were excluded from the analysis. Demographic, obstetric, and anaesthetic data were recorded. The techniques of anaesthesia (general, spinal, and epidural anaesthesia) employed for CD were analysed with respect to labour analgesia methods (remifentanil patient-controlled analgesia [remifentanil-PCA], epidural analgesia, and nitrous oxide). Of the participants, 124 (41.3%) had category 2, and 96 (32%) had category 3 emergency CD. Epidural analgesia was the most frequent analgesic option (43.8%), followed by remifentanil-PCA (20.7%) anditrous oxide (5.1%), while 30.4% of parturient women received no analgesia. All anaesthetic methods showed a significant relationship with analgesic modalities (P < 0.001). Remifentanil-PCA was associated with a higher incidence of general anaesthesia. Contraindication to epidural analgesia was the primary factor related to the transition from remifentanil-PCA to general anaesthesia. Most parturients who received epidural analgesia were successfully converted to epidural anaesthesia. Spinal anaesthesia was the most common technique in women using N2O and those without labour analgesia. General anaesthesia was associated with lower 5 min Apgar scores. The method of labour analgesia was associated with the anaesthesia technique employed for categories 2 and 3 CD. This finding may guide patient counselling and intrapartum anaesthetic planning. However, the analysis should be cautiously interpreted as the selection of anaesthesia is a complex decision influenced by several clinical considerations.

The Impact of COVID-19 on Multidrug-Resistant Bacteria at a Slovenian Tertiary Medical Center.

The COVID-19 pandemic has strained healthcare systems globally. Shortages of hospital beds, reassignment of healthcare workers to COVID-19-dedicated wards, an increased workload, and evolving infection prevention and control measures have potentially contributed to the spread of multidrug-resistant bacteria (MDRB). To determine the impact of the COVID-19 pandemic at the University Medical Center Ljubljana, a tertiary teaching hospital, we analyzed the monthly incidence of select bacterial species per patient from 2018 to 2022. The analysis was performed for all isolates and for MDRB isolates. The data were analyzed separately for isolates from all clinical samples, from blood culture only, and from clinical and surveillance samples. Our findings revealed an increased incidence density of patients with Enterococcus faecium, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa isolates from clinical samples during the COVID-19 period in the studied hospital. Notably, the incidence density of MDRB isolates-vancomycin-resistant E. faecium, extended-spectrum betalactamase-producing K. pneumoniae, and betalactam-resistant P. aeruginosa-from clinical samples increased during the COVID-19 period. There were no statistically significant differences in the incidence density of patients with blood culture MDRB isolates. We observed an increase in the overall MDRB burden (patients with MDRB isolates from both clinical and surveillance samples per 1000 patient days) in the COVID-19 period in the studied hospital for vancomycin-resistant E. faecium, carbapenem-resistant K. pneumoniae, and betalactam-resistant P. aeruginosa and a decrease in the methicillin-resistant S. aureus burden.

P784 Efficacy of ustekinumab in biologically naïve patients with Inflammatory Bowel Disease

Abstract Background In recent years, there are several new treatment options for inflammatory bowel disease (IBD). Tumour necrosis factor α inhibitors have been joined by novel advanced therapies (vedolizumab, ustekinumab (UST) and Janus kinase inhibitors). These drugs are mostly used as second-line treatments after tumor necrosis factor α inhibitors, with subsequent poorer efficacy. There are few data available on the efficacy of first-line treatment with UST. The aim of our study was to assess efficacy of UST in biologically naïve patients with IBD. Methods All patients older than 18 years who had a confirmed diagnosis of IBD, treated in a tertiary IBD centre (University Medical Centre Ljubljana, Slovenia), who started first-line treatment with UST, were included in this retrospective cross-sectional cohort study. Demographics, clinical characteristics of patients, treatment persistence of UST, clinical disease activity scores, C-reactive protein (CRP), faecal calprotectin (FC), UST concentrations, and endoscopic scores were collected retrospectively in medical files. We determined a Kaplan-Meier curve of treatment persistence. Results We included 71 patients, 11 of which had ulcerative colitis and 60 had Crohn’s disease. Persistence of treatment with UST in biologically naïve patients is 88% at one year (Figure 1). Clinical remission was achieved in 57.7% of patients. Biochemical remission was achieved in 77.6% (CRP&amp;lt;5mg/ml) and 71.1% (FC&amp;lt;100mg/kg) of patients. Endoscopic remission (Mayo endoscopic score &amp;lt;2 in ulcerative colitis or absence of ulcers in Crohn’s disease) was achieved in 50.0% of patients. There was no significant difference (P&amp;gt;0.05) between the median serum concentrations of UST in the group of patients who achieved remission (clinical (5.86μg/ml), biochemical (5.93μg/ml based on CRP, 5.63μg/ml based on FC) and endoscopic (7.14μg/ml)) and who did not achieve remission (5.31μg/ml, 3.25μg/ml, 4.47μg/ml and 4.64μg/ml, respectively). Conclusion Treatment of UST in biologically naïve IBD patients shows high treatment persistence with high biochemical and endoscopic remission rates. It appears that UST is more efficacious if used as first-line therapy compared to the use after other advanced therapies. Further prospective data are needed to confirm our findings.

Management of severe delirium with dexmedetomidine in a palliative care patient—a case report

Dexmedetomidine is used as an adjunct to anaesthesia or as a stand-alone agent for conscious sedation. It is a potent α2-adrenergic receptor agonist, with a fast onset of action and peak effects in 30 minutes to 1 hour after application, depending on the route of administration. It is metabolized in the liver and excreted in urine as a glucuronide. It potentiates analgesia and is effective in opioid sparing. Clinical trials show its efficacy in the treatment of Intensive Care Unit (ICU) delirium with an effect comparable to antipsychotics and benzodiazepines. It has also been used at the Eye Clinic of the University Medical Centre Ljubljana to sedate patients undergoing intraocular surgery. It proved to be an excellent alternative to other sedatives and analgesics, such as midazolam and remifentanil. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine and to investigate its potential use in the palliative care population, particularly in the management of delirium. This area of application is still largely unexplored and opens up a new field of application. At the Institute of Oncology (IO) Ljubljana, we have used it with success in several palliative patients with delirium, when all other modalities were failing. At the IO Ljubljana, anaesthesiologists are involved in the palliative management of patients, especially in pain management, but also in sedation and delirium treatment. Given its favourable pharmacokinetic and pharmacodynamic effects, dexmedetomidine could be used more frequently and perhaps alternative and less complex routes of administration, such as intranasal administration, could be explored. In this paper, we present a case of a palliative care patient in whom dexmedetomidine was used successfully.

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery—A Randomized, Controlled Clinical Trial

ObjectivesCardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role, whose activity is decreased in systemic inflammation, and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by up-regulating PON1 gene expression. We aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DesignProspective, randomized, controlled clinical trial. SettingThe study was conducted at the University Medical Centre Ljubljana, Slovenia. Participants40 adult patients, who underwent complex cardiac surgery on CPB between February 2016 and December 2017, were randomized into methylprednisolone and control group (n=20 each). InterventionsPatients in the methylprednisolone group received 1g of methylprednisolone in the CPB priming solution, while patients in the control group were not given methylprednisolone during CPB. Measurements and Main ResultsWe compared the effect of methylprednisolone from CPB priming solution with standard care during CPB on PON1 activity until the 5. postoperative day. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed as well. No significant differences existed between study groups for PON1 activity, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in any of the measurement intervals (p>0.016). Methylprednisolone group had significantly lower TNF-a (p<0.001), IL-6 (p<0.001), as well as CRP and procalcitonin (p<0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and TNF-a, IL-6, as well as CPB duration. ConclusionsMethylprednisolone doesn't influence PON1 activity during cardiac surgery on CPB.

High expression of Alzheimer’s disease‐related metabolic brain pattern is predictive of conversion to mild cognitive impairment or dementia and faster cognitive decline

AbstractBackgroundAlzheimer’s disease‐related pattern (ADRP) is a metabolic brain biomarker of Alzheimer’s disease (AD), which was previously identified and validated. Its utility for differential diagnosis is known. Here, we aimed to explore its predictive value for conversion from cognitively normal (CN) to mild cognitive impairment (MCI), from MCI to dementia and for the rate of cognitive decline.MethodsWe analysed 609 participants followed for up to 15 years and their FDG PET scans from ADNI database (CN = 133, MCI = 352, dementia due to AD = 124) and 56 participants from University Medical centre Ljubljana (MCI = 22, AD = 34). ADRP expression was calculated from pre‐processed FDG PET scans. CN and MCI participants were stratified according to their conversion status and cerebrospinal fluid biomarkers. Amyloid positivity (A+) was defined as Aβ42 &lt; 880 pg/mL and tau positivity (T+) as pTau &gt; 21.8 pg/mL. AD patients were stratified into slow (&lt; 2 points/per year decline on mini mental state examination (MMSE)) and fast (&gt; 2 points/per year decline on MMSE) progressors.ResultsA+T+ cCN had higher baseline ADRP expression than A–T– (p&lt;0.001), A+T– (p = 0.003) and A+T+ (p = 0.01) stable CN corrected for age, while the groups did not differ in gender, education or baseline MMSE scores. A+T+ cMCI had higher baseline ADRP expression than A–T– (p&lt;0.001), A+T– (p = 0.001) and A+T+ (p&lt;0.001) stable MCI, corrected for baseline age and MMSE. A+T– stable MCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.02). ADRP was a predictor of conversion to dementia in survival analysis (HR = 4.5[2.4‐8.7]). Similarly, in the UMCL dataset A+T+ cMCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.03). Fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p&lt;0.001). Similarly, in the UMCL dataset fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p = 0.02). In neither dataset, AD groups differed in age, sex or baseline MMSE scores.ConclusionADRP expression levels can be used to predict conversion from CN to MCI and from MCI to dementia in A+T+ individuals. AD patients with high ADRP expression are at an elevated risk for faster progression of cognitive decline.

High expression of Alzheimer’s disease‐related metabolic brain pattern is predictive of conversion to mild cognitive impairment or dementia and faster cognitive decline

AbstractBackgroundAlzheimer’s disease‐related pattern (ADRP) is a metabolic brain biomarker of Alzheimer’s disease (AD), which was previously identified and validated. Its utility for differential diagnosis is known. Here, we aimed to explore its predictive value for conversion from cognitively normal (CN) to mild cognitive impairment (MCI), from MCI to dementia and for the rate of cognitive decline.MethodWe analysed 609 participants followed for up to 15 years and their FDG PET scans from ADNI database (CN = 133, MCI = 352, dementia due to AD = 124) and 56 participants from University Medical centre Ljubljana (MCI = 22, AD = 34). ADRP expression was calculated from pre‐processed FDG PET scans. CN and MCI participants were stratified according to their conversion status and cerebrospinal fluid biomarkers. Amyloid positivity (A+) was defined as Aß42 &lt; 880 pg/mL and tau positivity (T+) as pTau &gt; 21.8 pg/mL. AD patients were stratified into slow (&lt; 2 points/per year decline on mini mental state examination (MMSE)) and fast (&gt; 2 points/per year decline on MMSE) progressors.ResultA+T+ cCN had higher baseline ADRP expression than A–T– (p&lt;0.001), A+T– (p = 0.003) and A+T+ (p = 0.01) stable CN corrected for age, while the groups did not differ in gender, education or baseline MMSE scores. A+T+ cMCI had higher baseline ADRP expression than A–T– (p&lt;0.001), A+T– (p = 0.001) and A+T+ (p&lt;0.001) stable MCI, corrected for baseline age and MMSE. A+T– stable MCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.02). ADRP was a predictor of conversion to dementia in survival analysis (HR = 4.5[2.4‐8.7]). Similarly, in the UMCL dataset A+T+ cMCI had higher baseline ADRP expression than A–T– stable MCI (p = 0.03). Fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p&lt;0.001). Similarly, in the UMCL dataset fast progressing AD patients had higher baseline ADRP expression than slowly progressing AD patients (p = 0.02). In neither dataset, AD groups differed in age, sex or baseline MMSE scores.ConclusionADRP expression levels can be used to predict conversion from CN to MCI and from MCI to dementia in A+T+ individuals. AD patients with high ADRP expression are at an elevated risk for faster progression of cognitive decline.

Insights into the immunological description of cryoglobulins with regard to detection and characterization in Slovenian rheumatological patients

The detection of cryoglobulins (CG) used to diagnose cryoglobulinemic vasculitis requires strict adherence to protocol, with emphasis on the preanalytical part. Our main objectives were to introduce a more sensitive and specific protocol for the detection of CG and to characterize CG in Slovenian patients diagnosed with cryoglobulinemic vasculitis, other vasculitides, connective tissue diseases or non-rheumatic diseases examined at the Department of Rheumatology (University Medical Centre Ljubljana). Samples were routinely analyzed for the presence of CG with the protocol using the Folin-Ciocalteu reagent. In the newly introduced protocol, the type of CG was determined by immunofixation on visually observed positive samples and the concentration of CG in the cryoprecipitate and rheumatoid factor (RF) activity were measured by nephelometry. RF, C3c and C4 were measured in patients` serum and a decision tree analysis was performed using all results. The agreement between negative and positive results between the two protocols was 86%. Of the 258 patient samples tested, we found 56 patients (21.7%) with positive CG (37.5% - type II, 62.5% - type III). The RF activity was observed in 21.4% of CG positive subjects. The median concentration of type II CG was significantly higher than that of type III CG (67.4 mg/L vs. 45.0 mg/L, p = 0.037). Patients with type II had lower C4 concentrations and higher RF compared to patients with type III CG. In the decision tree, C4 was the strongest predictor of cryoglobulinemia in patients. With the newly implemented protocol, we were able to improve the detection and quantification of CG in the samples of our rheumatology patients and report the results to adequately support clinicians.

Management and Outcomes of Invasive Procedures in Individuals with Hemophilia A on Emicizumab Prophylaxis: A Single Center Experience.

Prophylactic treatment with emicizumab has become an important and effective bleeding prevention for people with hemophilia A (PwHA). Perioperative management of PwHA using emicizumab prophylaxis is still challenging due to a lack of experience. Medical records of perioperative management and outcomes were reviewed, and data were collected for adult PwHA receiving emicizumab and undergoing surgical procedures between August 2019 and July 2022 at the University Medical Center Ljubljana. Twelve surgical procedures were performed in eight PwHA (one with FVIII inhibitors) while on emicizumab prophylaxis. Three minor procedures included cataract surgery, cystoscopic lithotripsy, and percutaneous coronary intervention. Nine major surgeries included four osteosyntheses, necrectomy of chronic osteomyelitis with new ankle arthrodesis, two below-knee amputations, total knee replacement, and placement of ventriculostomy after a spontaneous intraventricular hemorrhage. No major bleeds, thrombotic events or deaths, or new inhibitors appeared. Our real-world experience demonstrates that minor and major surgeries can be performed safely in PwHA on emicizumab prophylaxis. Additional data are needed to optimize dosing/duration of additional hemostatic agents in diverse invasive procedures and complex clinical situations.

A Higher Amount of Nutritional Intake as a Possible Cause of Hyperglycemia in Extremely Premature Infants in Parenteral and Enteral Nutrition at the Tertiary Neonatal Intensive Care Unit.

This study aimed to find an association between infants who had hyperglycemia and those who did not, those treated with insulin or not and several prenatal and postnatal variables or the suboptimal prescription of parenteral nutrition. We conducted a retrospective study, which included extremely premature infants (<28 weeks of gestation) admitted to the tertiary NICU, University Medical Centre Ljubljana, between 1 January 2021 and 31 December 2021. Blood glucose measurements, insulin treatment, general characteristics, nutritional data and complications of prematurity were obtained retrospectively from hospital data. There were 21 infants included in the study who did not receive insulin and 17 who were treated with insulin. Infants receiving insulin were younger and lighter compared to the non-insulin treatment group (mean gestational age 178 vs. 188 days; median birth weight 680 g vs. 990 g). The younger insulin group of infants received the same daily number of total macronutrients per kg per day compared to the older non-insulin group, i.e., glucose, lipids and amino acids, as recommended for the gestational age and birth weight. After adjusting for gestational age, no significant association with complications of prematurity was found. The postulated explanation (with the prescription of a higher amount of macronutrients during the first seven days) for hyperglycemia and treatment with insulin in the less mature and lighter infants cannot be supported by the data given.

An open dataset with electrohysterogram records of pregnancies ending in induced and cesarean section delivery

The existing non-invasive automated preterm birth prediction methods rely on the use of uterine electrohysterogram (EHG) records coming from spontaneous preterm and term deliveries, and are indifferent to term induced and cesarean section deliveries. In order to enhance current publicly available pool of term EHG records, we developed a new EHG dataset, Induced Cesarean EHG DataSet (ICEHG DS), containing 126 30-minute EHG records, recorded early (23rd week), and/or later (31st week) during pregnancy, of those pregnancies that were expected to end in spontaneous term delivery, but ended in induced or cesarean section delivery. The records were collected at the University Medical Center Ljubljana, Ljubljana, Slovenia. The dataset includes 38 and 43, early and later, induced; 11 and 8, early and later, cesarean; and 13 and 13, early and later, induced and cesarean EHG records. This dataset enables better understanding of the underlying physiological mechanisms involved during pregnancies ending in induced and cesarean deliveries, and provides a robust and more realistic assessment of the performance of automated preterm birth prediction methods.

Predictive value of preoperative albumin-bilirubin score and other risk factors for short-term outcomes after open pancreatoduodenectomy.

Pancreatoduodenectomy represents a complex procedure involving extensive organ resection and multiple alimentary reconstructions. It is still associated with high morbidity, even in high-volume centres. Prediction tools including preoperative patient-related factors to preoperatively identify patients at high risk for postoperative complications could enable tailored perioperative management and improve patient outcomes. To evaluate the clinical significance of preoperative albumin-bilirubin score and other risk factors in relation to short-term postoperative outcomes in patients after open pancreatoduodenectomy. This retrospective study included all patients who underwent open pancreatic head resection (pylorus-preserving pancreatoduodenectomy or Whipple resection) for various pathologies during a five-year period (2017-2021) in a tertiary care setting at University Medical Centre Ljubljana, Slovenia and Cattinara Hospital, Trieste, Italy. Short-term postoperative outcomes, namely, postoperative complications, postoperative pancreatic fistula, reoperation, and mortality, were evaluated in association with albumin-bilirubin score and other risk factors. Multiple logistic regression models were built to identify risk factors associated with these short-term postoperative outcomes. Data from 347 patients were collected. Postoperative complications, major postoperative complications, postoperative pancreatic fistula, reoperation, and mortality were observed in 52.7%, 22.2%, 23.9%, 21.3%, and 5.2% of patients, respectively. There was no statistically significant association between the albumin-bilirubin score and any of these short-term postoperative complications based on univariate analysis. When controlling for other predictor variables in a logistic regression model, soft pancreatic texture was statistically significantly associated with postoperative complications [odds ratio (OR): 2.09; 95% confidence interval (95%CI): 1.19-3.67]; male gender (OR: 2.12; 95%CI: 1.15-3.93), soft pancreatic texture (OR: 3.06; 95%CI: 1.56-5.97), and blood loss (OR: 1.07; 95%CI: 1.00-1.14) were statistically significantly associated with major postoperative complications; soft pancreatic texture was statistically significantly associated with the development of postoperative pancreatic fistula (OR: 5.11; 95%CI: 2.38-10.95); male gender (OR: 1.97; 95%CI: 1.01-3.83), soft pancreatic texture (OR: 2.95; 95%CI: 1.42-6.11), blood loss (OR: 1.08; 95%CI: 1.01-1.16), and resection due to duodenal carcinoma (OR: 6.58; 95%CI: 1.20-36.15) were statistically significantly associated with reoperation. The albumin-bilirubin score failed to predict short-term postoperative outcomes in patients undergoing pancreatoduodenectomy. However, other risk factors seem to influence postoperative outcomes, including male sex, soft pancreatic texture, blood loss, and resection due to duodenal carcinoma.

Rare neurological indications for Deep Brain Stimulation treatment: experience at the University Medical Center Ljubljana

Rare neurological indications for Deep Brain Stimulation treatment: experience at the University Medical Center Ljubljana

Relative Importance of Glaucoma-Referral Indicators in Retinal Images in a Diabetic Retinopathy Screening Programme in Slovenia: A Cross-Sectional Study.

Background and Objectives: Glaucoma is a major cause of irreversible visual impairment and blindness, so its timely detection is crucial. Retinal images from diabetic retinopathy screening programmes (DRSP) provide an opportunity to detect undiagnosed glaucoma. Our aim was to find out which retinal image indicators are most suitable for referring DRSP patients for glaucoma assessment and to determine the glaucoma detection potential of Slovenian DRSP. Materials and Methods: We reviewed retinal images of patients from the DRSP at the University Medical Centre Ljubljana (November 2019-January 2020, May-August 2020). Patients with at least one indicator and some randomly selected patients without indicators were invited for an eye examination. Suspect glaucoma and glaucoma patients were considered accurately referred. Logistic regression (LOGIT) with patients as statistical units and generalised estimating equation with logistic regression (GEE) with eyes as statistical units were used to determine the referral accuracy of indicators. Results: Of the 2230 patients reviewed, 209 patients (10.1%) had at least one indicator on a retinal image of either one eye or both eyes. A total of 149 (129 with at least one indicator and 20 without) attended the eye exam. Seventy-nine (53.0%) were glaucoma negative, 54 (36.2%) suspect glaucoma, and 16 (10.7%) glaucoma positive. Seven glaucoma patients were newly detected. Neuroretinal rim notch predicted glaucoma in all cases. The cup-to-disc ratio was the most important indicator for accurate referral (odds ratio 7.59 (95% CI 3.98-14.47; p < 0.001) and remained statistically significant multivariably. Family history of glaucoma also showed an impact (odds ratio 3.06 (95% CI 1.02-9.19; p = 0.046) but remained statistically significant only in the LOGIT multivariable model. Other indicators and confounders were not statistically significant in the multivariable models. Conclusions: Our results suggest that the neuroretinal rim notch and cup-to-disc ratio are the most important for accurate glaucoma referral from retinal images in DRSP. Approximately half of the glaucoma cases in DRSPs may be undiagnosed.

Does tumor rupture during robot-assisted partial nephrectomy have an impact on mid-term tumor recurrences?

Intraoperative kidney tumor rupture (TR) can occur during robot-assisted partial nephrectomy (RAPN) in daily clinical practice, but there are no solid guidelines on the management and implications of it. The purpose of the study was to investigate the impact of TR on tumor recurrences, what a surgeon should do if this adverse event occurs, and how to avoid it. We retrospectively analyzed the first 100 patients who underwent RAPN at University Medical Centre Ljubljana, between 2018 and 2021. Patients were stratified into 2 groups (TR and no-TR) and were compared according to patient, tumor, pathologic, perioperative and postoperative characteristics and tumor recurrences, using the Mann-Whitney U test and chi-squared test. Of the 100 patients, 14 had TR (14%); this occurred in tumors with higher RENAL nephrometry scores (P = 0.028) and mostly with papillary renal cell carcinomas (P = 0.043). Median warm ischemia time was longer for the TR group (22 vs. 15 min, P = 0.026). In terms of studied outcomes, there were no cases of local or distant recurrence after a median observation time of 39 months (interquartile range, 31-47 months) in both groups. We observed positive surgical margins on the final oncologic report in one case in the no-TR group. Tumor rupture during RAPN seems to be of no mid-term oncologic importance. According to presented results, we would recommend surgeons to proceed with tumor resection if this event occurs and abstain from conversion to radical nephrectomy or open partial nephrectomy. However, more similar cases should be studied to make more solid conclusions.

Twenty years of intrathecal baclofen therapy in Slovenia: a retrospective single-center analysis of complications.

Since the first implantation in July 2001, the intrathecal baclofen (ITB) therapy for patients with generalized spasticity has been used in Slovenia for 20 years. The aim of this retrospective study was to evaluate the rates of different complications, especially if catheter-related complications were less frequent after the introduction of the coated catheter type in February 2013, and the potential correlation between higher baclofen doses and the incidence of complications. We retrospectively collected data from all patients in the registry during the period from 3 July 2001 to 31 December 2021. Among 138 patients (48 females), 120 patients had the first ITB system implanted at the University Medical Centre Ljubljana. Forty-three complications were reported in 38 patients (27%), with a total complication rate of 0.203/1000 days or 0.074/pump year. The most frequent was catheter-related (0.083/1000 days or 0.030/pump year), followed by skin-related (0.063/1000 days or 0.023/pump year) and pump-related complication (0.026/1000 days or 0.009/pump year). The incidence of catheter-related complications decreased significantly since the use of Ascenda type catheter: 14/7 complications per 88/147 implantations ( P = 0.008). Patients with complications had a statistically significantly higher dose of baclofen: median 400 µg/24h vs. median 300 µg/24h ( P = 0.016). Our retrospective analysis confirmed a significant decrease of catheter-related complications after the implementation of Ascenda type catheter in February 2013. Patients with a higher ITB dose had a statistically significantly higher incidence of complications. The total complication rate was a bit higher as previously reported in other studies, which is consistent with a long follow-up time.