University Hospital Centre Zagreb
Recent publications
The knowledge on how gut microbes contribute to the inflammatory bowel disease (IBD) at the onset of disease is still scarce. We compared gut microbiota in newly diagnosed, treatment-naïve adult IBD (Crohn's disease (CD) and ulcerative colitis (UC)) to irritable bowel syndrome (IBS) patients and healthy group. Mucosal and fecal microbiota of 49 patients (13 UC, 10 CD, and 26 IBS) before treatment initiation, and fecal microbiota of 12 healthy subjects was characterized by 16S rRNA gene sequencing. Mucosa was sampled at six positions, from terminal ileum to rectum. We demonstrate that mucosal microbiota is spatially homogeneous, cannot be differentiated based on the local inflammation status and yet provides bacterial footprints superior to fecal in discriminating disease phenotypes. IBD groups showed decreased bacterial diversity in mucosa at all taxonomic levels compared to IBS. In CD and UC, Dialister was significantly increased, and expansion of Haemophilus and Propionibacterium characterized UC. Compared to healthy individuals, fecal microbiota of IBD and IBS patients had increased abundance of Proteobacteria, Enterobacteriaceae, in particular. Shift toward reduction of Adlercreutzia and butyrate-producing taxa was found in feces of IBD patients. Microbiota alterations detected in newly diagnosed treatment-naïve adult patients indicate that the microbiota changes are set and detectable at the disease onset and likely have a discerning role in IBD pathophysiology. Our results justify further investigation of the taxa discriminating between disease groups, such as H. parainfluenzae, R. gnavus, Turicibacteriaceae, Dialister, and Adlercreutzia as potential biomarkers of the disease.
Background Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by defects in genes coding for different lysosomal enzymes which degrade glycosaminoglycans. Impaired lysosomal degradation causes cell dysfunction leading to progressive multiorgan involvement, disabling consequences and poor life expectancy. Enzyme replacement therapy (ERT) is now available for most MPS types, offering beneficial effects on disease progression and improving quality of life of patients. The landscape of MPS in Europe is not completely described and studies on availability of treatment show that ERT is not adequately implemented, particularly in Southern and Eastern Europe. In this study we performed a survey analysis in main specialist centers in Southern and Eastern European countries, to outline the picture of disease management in the region and understand ERT implementation. Since the considerable number of MPS IVA patients in the region, particularly adults, the study mainly focused on MPS IVA management and treatment. Results 19 experts from 14 Southern and Eastern European countries in total responded to the survey. Results outlined a picture of MPS management in the region, with a high number of MPS patients managed in the centers and a high level of care. MPS II was the most prevalent followed by MPS IVA, with a particular high number of adult patients. The study particularly focused on management and treatment of MPS IVA patients. Adherence to current European Guidelines for follow-up of MPS IVA patients is generally adequate, although some important assessments are reported as difficult due to the lack of MPS skilled specialists. Availability of ERT in Southern and Eastern European countries is generally in line with other European regions, even though regulatory, organizational and reimbursement constrains are demanding. Conclusions The landscape of MPS in Southern and Eastern European countries is generally comparable to that of other European regions, regarding epidemiology, treatment accessibility and follow up difficulties. However, issues limiting ERT availability and reimbursement should be simplified, to start treatment as early as possible and make it available for more patients. Besides, educational programs dedicated to specialists should be implemented, particularly for pediatricians, clinical geneticists, surgeons, anesthesiologists and neurologists.
Background Matrix metalloproteinase-9 protein (MMP-9) and cyclooxygenase-2 (COX-2) proteins may have a role in remodelling of atherosclerotic plaques. We analysed and compared the radiological, histological and immunohistochemical characteristics of carotid atherosclerotic plaques between symptomatic and asymptomatic patients who underwent carotid endarterectomy (CEA). Methods This prospective single-blinded study included 31 patients (70 [64-75] years, 58% males, 42% symptomatic) who underwent CEA and a total of 155 carotid plaque sections that were analysed. Preoperative assessment and multimodality diagnostic imaging with magnetic resonance imaging (MRI) or computed tomography angiography (CTA), histological and immunohistochemical analyses of carotid plaques including the expression of MMP-9 and COX-2 proteins were performed. Results Symptomatic and asymptomatic patients did not significantly differ in respect to preoperative characteristics. Unstable plaques were detected in 12/13 (92.3%, p = 0.020) symptomatic patients using MRI or CTA. There was no perioperative mortality and perioperative outcomes were comparable in both groups. A significantly higher expression of MMP-9 in macrophages was observed among symptomatic patients (p = 0.020). ROC curve analysis showed statistically significant associations of both the higher intensity of COX-2 staining in CD68 PG-M1 positive macrophages (area under the curve [AUC]=0.701, p = 0.014) and higher MVD (AUC=0.821, p < 0.001) within the plaque with cerebrovascular symptoms. The expression of COX-2 and the intensity of COX-2 staining in macrophages within the unstable carotid plaques detected by preoperative MRI or CTA were significantly higher (76.1% vs. 40.0%, p = 0.038; 76.2% vs. 30.0%, p = 0.01, respectively). Conclusions Advanced non-invasive multimodality diagnostic imaging including MRI or CTA is reliable in differentiating unstable from stable carotid plaques. High expression of MMP-9 and COX-2 in macrophages within the symptomatic plaque is associated with increased risk of cerebrovascular complications. Trial Registration This study has been registered at the ISRCTN registry (ID ISRCTN46536832), isrctn.org Identifier: https://www.isrctn.com/ISRCTN46536832
Introduction: Due to limitations in currently used methodologies, the widely acknowledged approach for quantifying M-protein (MP) is not available. If employed as a source of quantitative data, the immunosubtraction electropherogram (IS-EPG), a qualitative analysis of MP, has the potential to overcome known analytical issues. The aim of this study is to explore measured and derived variables obtained from immunosubtraction electropherogram as a tool for quantifying MP and to compare the derived results to currently available methods. Materials and methods: Measurands were amplitudes of MP and albumin fractions. Assessed derived variables included also immunoglobulin (Ig) G, IgA, IgM and total protein data. Capillary electrophoresis was used for determination of MP (in % of total protein concentration, or concentration of MP in g/L) by perpendicular drop and tangent skimming method. Results: Passing-Bablok analysis showed the most comparable results in D1Ig and D1nIg variables, and the largest discrepancies in AD1nIg and AD2nIg variables. The background presence had greater impact on D1nIg comparison results than did on D1Ig results. The contribution of albumin fraction data did not improve the comparability of the results. The coefficients of variation of derived variables were lower (maximum 3.1%) than those obtained by densitometric measurements, regardless of MP concentration, polyclonal background, or migration pattern (2.3-37.7%). Conclusion: The amplitude of MP spike in IS-EPG is an valuable measurand to compute derived variables for quantifying MP. The most comparable results were achieved with the D1Ig variable. Patients with monoclonal gammopathy can benefit from increased precision employing an objective and background independent measurand, especially during longitudinal follow-up.
Introduction: Laboratory plays important part in screening, diagnosis, and management of thyroid disorders. The aim of this study was to estimate current laboratory preanalytical, analytical and postanalytical practices and policies in Croatia. Materials and methods: Working Group for Laboratory Endocrinology of the Croatian Society of Medical Biochemistry and Laboratory Medicine designed a questionnaire with 27 questions and statements regarding practices and protocols in measuring thyroid function tests. The survey was sent to 111 medical biochemistry laboratories participating in external quality assurance scheme for thyroid hormones organized by Croatian Centre for Quality Assessment in Laboratory Medicine. Data is presented as absolute numbers and proportions. Results: Fifty-three participants returned the questionnaire. Response rate varied depending on question, yielding a total survey response rate of 46-48%. All respondents perform thyroid stimulating hormone (TSH). From all other thyroid tests, most performed is free thyroxine (37/53) and least TSH-stimulating immunoglobulin (1/53). Laboratories are using nine different immunoassay methods. One tenth of laboratories is verifying manufacturer's declared limit of quantification for TSH and one third is verifying implemented reference intervals for all performed tests. Most of laboratories (91%) adopt the manufacturer's reference interval for adult population. Reference intervals for TSH are reported with different percentiles (90, 95 or 99 percentiles). Conclusion: This survey showed current practices and policies in Croatian laboratories regarding thyroid testing. The results identified some critical spots and will serve as a foundation in creating national guidelines in order to harmonize laboratory procedures in thyroid testing in Croatia.
Objectives: Quizartinib is an oral, potent, selective, type II FLT3 inhibitor with prolonged OS as a single-agent in relapsed/refractory FLT3-ITD+ AML. We report results from the global, randomized, double-blind, phase 3 QuANTUM-First trial (NCT02668653), evaluating quizartinib plus standard induction and post-remission consolidation (including allogeneic hematopoietic cell transplant [allo-HCT] in first complete remission [CR1]) followed by single-agent continuation (up to 3 years) vs placebo plus chemotherapy in newly diagnosed FLT3-ITD+ AML. Methods: Patients 18-75 years with newly diagnosed FLT3-ITD+ AML received induction with cytarabine 100 or 200 mg/m2/day (days 1-7) and daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day (days 1-3). Patients were randomized to quizartinib (40 mg/day [days 8-21]) or placebo; stratified by region, age, and white blood cell count at diagnosis. Patients with CR or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus quizartinib (40 mg/day) or placebo and/or allo-HCT followed by continuation with quizartinib (30-60 mg/day) or placebo (up to 3 years). The primary endpoint was OS. Results: Between September 2016 and August 2019, 539 patients were randomized (quizartinib [n=268], placebo [n=271]). Median age was 56 years (range, 20-75 years). As of August 2021 (median follow-up, 39.2 months), 58 patients remained on continuation. Median OS was significantly longer with quizartinib vs placebo (31.9 vs 15.1 months; HR, 0.776; 95% CI, 0.615-0.979; 2-sided P=.0324). CR+CRi rates were 71.6% and 64.9%, respectively. Allo-HCT in CR1 was performed in 157 patients (quizartinib, 31%; placebo, 27%). When censored for allo-HCT, OS trended longer with quizartinib vs placebo (HR, 0.752; 95% CI, 0.562-1.008; 2-sided P=.055). Relapse-free survival was longer with quizartinib vs placebo (HR, 0.733; 95% CI, 0.554-0.969). Grade ≥3 adverse events (AEs) were similar across arms. Discontinuations due to AEs occurred in 20.4% (quizartinib) and 8.6% (placebo). Fifty-six patients died from treatment-emergent AEs (quizartinib, 11.3%; placebo, 9.7%); mostly infections. Grade 3/4 electrocardiographic QT prolongation occurred in 3.0% (quizartinib) and 1.1% (placebo). Conclusions: Quizartinib plus standard therapy, followed by continuation, including after allo-HCT, for up to 3 years was tolerable with statistically significant and clinically meaningful OS improvements in adults ≤75 years with newly diagnosed FLT3-ITD+ AML.
IntroductionOveractive bladder (OAB) is the most common urinary disorder and the leading cause of functional daytime intermittent urinary incontinence in children. The aim of this study was to determine whether urinary brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) concentrations, normalized to urine creatinine, could be used as biomarkers for diagnosis and treatment monitoring of OAB in children. Materials and methodsUrine samples of 48 pediatric patients with OAB were collected at the start of anticholinergic therapy (baseline), at follow-up visits (3 and 6 months), and from 48 healthy controls. Urinary BDNF and NGF concentrations were determined by ELISA method (Merck, Darmstadt, Germany) and Luminex method (Thermo Fisher Scientific, Waltham, USA). Differences of frequency between quantifiable analyte concentrations between subject groups were determined using Fisher’s exact test. ResultsThere was no statistically significant difference between quantifiable analyte concentrations between patients at baseline and the control group for BDNF and NGF by either the ELISA or Luminex method (P = 1.000, P = 0.170, P = 1.000, and P = N/A, respectively). There was a statistically significant difference between quantifiable BDNF by the ELISA method between patients at baseline and complete success follow-up (P = 0.027), while BDNF by Luminex method and NGF by both methods were not statistically significant (P = 0.078, P = 0.519, and P = N/A, respectively). Conclusions This study did not demonstrate that urinary BDNF and NGF concentrations, can be used as biomarkers for diagnosis and therapy monitoring of OAB in children.
Pancreatic cancer is one of the most lethal malignancies with a rise in mortality rates. FOLFIRINOX and nab-paclitaxel plus gemcitabine demonstrated a survival benefit compared to gemcitabine alone. Both protocols are now considered the standard of first-line treatment with no significant difference between them, primarily based on observational studies. Although new therapeutic options have emerged recently, the prognosis remains poor. We conducted a retrospective single-center study on 139 patients treated for metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine monotherapy (Gem) or nab-paclitaxel + gemcitabine (Nab-P/Gem) in the first line. The aim of our study was to evaluate the effectiveness in terms of overall survival (OS) and progression-free survival (PFS) as well as the influence of patient and disease characteristics on outcomes. Nab-P/Gem resulted in OS of 13.87 months compared to 8.5 months in patients receiving Gem. The same trend was achieved in PFS, 5.37 versus 2.80 months, respectively, but without reaching statistical significance. Furthermore, the 6-month survival in the Nab-P/Gem group was also higher, 78.1% versus 47.8%. In terms of survival, the group of elderly patients, patients of poorer performance, with higher metastatic burden and liver involvement, benefited the most from combination therapy. In our analysis ECOG performance status (p.s.), previous primary tumor surgery, and liver involvement were found to be independent prognostic factors. The addition of nab-paclitaxel to gemcitabine resulted in a significant improvement in the OS of patients with mPDAC. Subgroup analysis demonstrated that patients with some unfavorable prognostic factors benefited the most.
Purpose To report a unique case of a delayed diagnosis of stronglyoidasis hyperinfection in a patient with systemic lupus erythematotus (SLE), lymphoplasmatic lymphoma and proteinuria with microhaematuria. Stronglyoidasis stercoralis is a rare nematode endemic to the tropical and sutbtropic regions and immunocompromised patients are at risk of infection. Stronglyoidasis hyperinfection has been described in SLE cases previously, yet not also co-occurring with lymphoplasmacytic lymphoma. Methods A 67-year-old female with a fifteen year history of SLE was referred to the immunology outpatient clinic due to malaise and ataxia progressing over several months. Before the referral, neurological, radiological, and hematological workup was performed, which objectified the clinical symptoms, showed CNS affection, and confirmed remission of a lymphoplasmacytic lymphoma treated using an B-R protocol over the previous year. Physical examination findings were consistent with previous chronic SLE sequelae, yet a decrease in body weight was noted, as well as a mild anemia, proteinuria (175 mg/dU) with microhaematuria, and increased eosinophile count. Workup was broadened, including kidney biopsy, bone marrow biopsy, parasite serology, and stool ova and parasite test. Results Follow-up laboratory showed a further increase in eosinophile count (25%), positive Stronglyoides stercoralis serology (immunoglobulin G ELISA), and strongyloides larvae in stool samples. Bone marrow biopsy showed no abnormalities and kidney biopsy analysis ruled out lupus nephritis as a cause of proteinuria and haematuria. Single oral dose of ivermectin (200 µg/kg) was administered. One month after treatment the eosinophile count normalized and follow-up stool sample was free of larvae. Proteinuria and haematuria had resolved and other chronic morbidity remains under remission. Conclusion Stronglyoidasis stercoralis hyperinfection should be considered when differentiating between possible causes of general deterioration in multi-morbid SLE cases, presenting even in areas not considered endemic. Paraneoplastic syndrome remains a possible etiology of the observed kidney injury.
Purpose Complement activation is an important step in the mechanism of tissue damage in lupus nephritis (LN). Complement deposition in kidney tissue might reflect different immunologic processes and higher disease severity and result in adverse outcomes, but very few studies explored these potentially important associations. Given these immunologic consequences, we have postulated that complement deposition in the kidney might be associated with higher risk for serious infections in LN. Methods We have conducted a retrospective cohort study to evaluate the prognostic significance of C1q and C3 complement factors in renal tissue compartments for the occurrence of serious infections. We have collected data on demographics, clinical and laboratory parameters and histopathology (light, immunofluorescent and electron microscopy) at the time of biopsy and after long-term follow-up. Serious infections were defined as those that: 1. require intravenous therapy OR 2. lead to hospitalization OR 3. have resulted in death in 30 days from diagnosis. C1q and C3 expression graded in different kidney compartments (mesangium, glomerular basement membrane (GBM), tubular basement membrane (TBM) and peripheral capillary wall) as 0 to 3+ and another analysis was performed with dichotomized grading as 0 (absent) and 1+ to 3+ (present). SLE was diagnosed using the American College of Rheumatology criteria. Results A total of 51 patients with biopsy-proven LN were followed up for 4.5±2.9 years (80% women, mean age at biopsy 38±14). Of these, 22 (43%) had at least one episode of serious infection with 4 patients having 2 episodes. Complement expression in different kidney compartments was as follows: mesangium (C1q 54%, C3 59%), GBM (C1q 34%, C3 41%), TBM (C1q 5%, C3 5%) and blood vessel wall (C1q 0%, C3 5%). There was no difference in the distributions of mesangial (present vs. absent, 80% vs. 78%, p>0.99), GBM (53% vs. 38%, p=0.53), TBM (20% vs. 5%, p=0.17) and peripheral capillary wall C3 deposition (25% vs. 35%, p=0.53) or mesangial (75% vs. 65%, p=0.53), GBM (47% vs. 33%, p=0.52), TBM (5% vs. 5%, p>0.99) and peripheral capillary wall C1q deposition (25% vs. 30%, p=0.75). Conclusions Complement deposition in kidney tissue, while an underexplored and potentially important process, was not associated with serious infections in LN.
Purpose Systematic lupus erythematosus (SLE) and lupus nephritis (LN) are associated with a higher frequency of serious infections compared to the general population which are in turn associated with adverse outcomes, morbidity and mortality. Very few studies have explored risk factors for infections in these patients and, to the best of our knowledge, there are no studies examining the association with disease activity and serious infections. Methods We have conducted a retrospective cohort study to evaluate the prognostic significance of disease activity for serious infections in LN. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). Serious infections were defined as those that: 1. require intravenous therapy OR 2. lead to hospitalization OR 3. have resulted in death in 30 days from diagnosis. SLE was diagnosed using the American College of Rheumatology criteria. Results A total of 51 patients with biopsy-proven LN were followed up for 4.5±2.9 years (80% women, mean age at biopsy 38±14). Of these, 22 (43%) had at least one episode of serious infection with 4 patients having 2 episodes for an incidence of 5.7 infections per year of follow-up. Most common sites of infection were pneumonia (N=6), urinary tract infections (N=5), gastrointestinal infections (N=4) and skin infections (N=2). Five patients had sepsis with one progressing to septic shock and two patients died. Disease activity was higher at the time of biopsy compared to at the time of infection/up to one month prior to infection (15.4±6.3 vs. 11.3±5.5, p=0.001). There was no difference between either disease activity at the time of biopsy (18.0±1.0 vs. 15.5±6.5, p=0.36) or at the time of infection/preceding infection (12.0 vs. 11.25, p=0.90). SLEDAI-2K damage index at the time of biopsy was not an independent predictor of serious infection (OR 0.88 [0.72, 1.08]). Conclusions Serious infections are common in LN with nearly half of the patients having at least one episode. While high disease activity indices are important markers of immune-mediated damage, more serious disease and adverse outcomes, SLEDAI-2K at the time of biopsy was not an independent predictor of serious infections in our cohort of patients with LN.
The aim of this study was to test the sexual dimorphism of orbital measurements in the Croatian population using multi-slice computed tomography (MSCT) images. We have retrospectively taken 414 head CT scans of adults from Croatian clinical hospitals in Split and Zagreb (214 males and 200 females) with slice thickness < 1 mm and no pathological or traumatic changes that could affect the measurements. DICOM files were imported into Stratovan Checkpoint Software and viewed in 2D and 3D using semi-transparent 3D volume rendering. Eight standard measurements were calculated based on twelve orbital landmarks (six paired). Principal component analysis (PCA) was used to explore sexual and regional differences, and linear discriminant analysis was used to develop sex classification models. The PCA showed separation based on sex and region, and additional analysis demonstrated that females and males in Split and Zagreb differed in four orbital measurements (P ≤ 0.001). Only those measurements that did not show regional differences were further analyzed, and all showed statistically significant sexual dimorphism. The accuracy of univariate functions for sex estimation ranged from 53.43 to 71.88%, and for multivariate function, the accuracy was 73.45%. The orbital measurements of the Croatian population showed restricted forensic significance for sex classification. On the other hand, we have shown that they can have a potential for exploring the inter- and intra-population differences.
Iconodiagnosis is the discipline that combines a medical and humanistic approach to provide a heuristic insight into the historical moment represented in the work of art by overlaying a presumable pathophysiological context. The concept of iconodiagnosis, first introduced in 1983 by a Harvard psychiatrist Anneliese Alma Pontius [Pontius, 1983] was later embraced by many medical doctors (e.g. [Bianucci et al., 2016; Benedicenti et al., 2017; Charlier, 2007; Als et al., 2002; Ashrafian, 2018; Kluger, 2019; Bukvic and Elling, 2015; Emery, 1996]) who recognized it as „an enjoyable exercise“ of clinical reasoning [Kluger, 2020] and an invaluable tool in medical education [Ferrara, 2021]. Here we use the iconodiagnostic approach to analyze two portraits of the Italian cleric and diplomat Cesare Alessandro Scaglia di Verrua made by Flemish Baroque artist Sir Anthony van Dyck exhibited at the National Gallery in London.
Background: Nickel allergy is the most common contact allergy, and a nickel salt is, therefore, included in most baseline patch test series. In the baseline series of the International Contact Dermatitis Research Group and the American Contact Dermatitis Society, nickel sulfate hexahydrate (NSH) in petrolatum at 2.5% is included, whereas NSH at 5.0% is included in many other baseline series, such as the European and Swedish ones. Objective: The aim of the study is to investigate whether NSH at 5.0% detects significantly more contact allergy than NSH 2.5% when both preparations are tested simultaneously in consecutive dermatitis patients. Patients and methods: Two thousand two hundred eighty-seven consecutive dermatitis patients were patch tested simultaneously with NSH in petrolatum at 2.5% and 5.0%. The allergy rates were compared for all clinics individually and combined using McNemar test, 2-sided. Results: Contact allergy to NSH 5.0% and 2.5% was found in 20.3% and 16.8%, respectively (P < 0.0001). In 6 of 11 clinics, significantly more patients tested positive to the higher NSH concentration. For the 2 clinics in North America combined, significantly more patients tested positive to NSH 5.0%. Conclusions: The NSH preparation in the International Contact Dermatitis Research Group baseline patch test series should be considered to be changed from NSH 2.5% (1 mg NSH/cm2) to 5.0% (2 mg NSH/cm2).
The present study aimed to clarify unusual total antibody kinetics in three female individuals observed during longitudinal monitoring of antibody response to BNT162b2 COVID-19 vaccine in 54 healthy volunteers. Total and IgG antibodies against the SARS-CoV-2 spike glycoprotein were measured using Roche and Abbott quantitative assays, respectively, a day before and 8, 71, 135 and 217 days after the second dose. Samples showing unusual kinetics were additionally tested with Beckman Coulter and Euroimmun IgG assays, as well as IgA assay. Antibody levels peaked 8 days after the second dose (total:2769 U/mL; IgG:20022 AU/mL) and declined to 611 U/mL (total) and 783 AU/mL (IgG), after 217 days. A delayed increase of total but not IgG antibodies evidenced in three females, was in two cases coupled with an increase in IgA antibodies. This study identified a previously unknown contribution of anti-SARS-CoV-2 IgA antibodies to a delayed total antibody increase in a subgroup of vaccinated individuals. It also emphasizes that different commercially available serological assays do not provide uniform information about the post-vaccination immune status and that thorough understanding the assays' features is crucial for the proper interpretation of antibody response monitoring.
Posttraumatic stress disorder (PTSD) is a heritable (h² = 24–71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10⁻⁸). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.
Limited data have been published on the epidemiology and outcomes of breakthrough COVID-19 in patients with hematological malignancy (HM) after anti-SARS-CoV-2 vaccination. Adult HM who received at least one dose of anti-SARS-CoV-2 vaccine and diagnosed with breakthrough COVID-19 between January 2021 and March 2022 and registered in EPICOVIDEHA were included in this analysis. A total of 1548 cases were included, mainly with lymphoid malignancies (1181 cases, 76%). After viral genome sequencing in 753 cases (49%), Omicron variant was prevalent (517, 68.7%). Most of the patients received at least two vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received specific treatment for COVID-19. After 30-days follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with Omicron variant was of 7.9%, comparable to that reported for the other variants. The 30-day mortality rate was significantly lower than in the pre-vaccine era (31%). In the univariable analysis, older age (p<0.001), active HM (p<0.001), severe and critical COVID-19 (p=0.007 and p<0.001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (p<0.001). In the multivariable model, older age, active disease, critical COVID-19 and at least 2-3 comorbidities were correlated with a higher mortality, whereas the administration of monoclonal antibodies, alone (p<0.001) or combined with antivirals (p=0.009), was observed protective. While mortality is significantly lower than in the pre-vaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals. EPICOVIDEHA (www.clinicaltrials.gov; National Clinical Trials identifier NCT04733729) is an international open web-based registry for patients with HMs infected with SARS-CoV-2.
Parkinson’s disease (PD) is a progressive neurodegenerative disease predominantly characterized by tremor, bradykinesia, and rigor. In addition to motor and non-motor manifestations of Parkinson’s disease, there are a number of symptoms, including speech disorders and other cognitive impairments. The most common speech symptoms are bradylalia, dysarthria, hypophonia and impaired prosody. Cognitive changes that occur in the prodromal phase of PD include impairment in executive functions and working memory, followed by impairment in attention and verbal fluency, and that is before the motor characteristics of PD become visible. The aim of the study is to present the case of a 74-year-old patient with Parkinson’s disease who has speech and language difficulties and atypical speech disfluency. Diagnostic processing was performed using a clinical battery of tests for speech – language assessment and neuropsychological assessment. The results of the speech – language assessment indicate significantly reduced intelligence due to non-specific speech disfluency and inaccurate articulation, difficulty in organizing spontaneous expression and understanding grammatical structures, impaired phonemic verbal fluency and difficulties in receptive vocabulary. Neuropsychological processing indicated diffuse deterioration of the examined cognitive functioning to be larger than expected when taking ito consideration the age and probably good premorbid abilities of this person.
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726 members
Diana Muacevic-katanec
  • Department of Internal Medicine
Zoran Rakusic
  • Department of Oncology
Nikica Darabos
  • Department of traumatology, bone and joint surgery, Clinic of surgery
Davor Mijatovic
  • Department of Surgery
Nikola Radovic
  • Department of Urology
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