University Hospital Centre Zagreb

Background Intrasaccular devices are increasingly used in endovascular therapy of intracranial aneurysms, in particular wide-necked and ruptured aneurysms. The Trenza Embolization Device (TED) is an innovative intrasaccular device for medium- to large-sized aneurysms. Currently, literature about the TED is scarce. Methods In eight participating European centers, 25 aneurysms (3 ruptured) in 25 patients (18 females, mean age 62.4 years) treated with the TED outside the currently recruiting prospective, post-market, multicenter study were included in this retrospective, multicenter analysis. Primary endpoints for clinical safety were the absence of stroke and death. Primary endpoint for technical success was implantation of TED without necessity of adjunct stenting. Primary and secondary endpoints for efficacy were adequate angiographic occlusion according to the Modified Raymond–Roy Classification (MRRC) immediately after the procedure and at first follow-up (FU). Results Stent-assistance was required in two cases. Thus primary endpoint for technical success was reached in 23/25 (92%) cases. With one symptomatic thrombotic event, primary safety endpoint was reached in 24/25 (96%) cases. At the end of the procedure, complete occlusion (MRRC I) was achieved in 12/25 (48%), and a small residual neck (MRRC II) remained in 13/25 (52%) cases. In 19 cases FU (mean 6 months) was available, showing adequate occlusion in 17/19 (89.5%) cases (MRRC I in 8/19 and stable MRRC II in 9/19 cases) and relevant reperfusion MRRC IIIa with indication to retreatment in 2/19 (10.5%) cases. Conclusions The results of this first retrospective, multicenter experience with the TED appear promising. Further prospective, multicenter studies with larger patient cohorts, as well as long-term FU, are required.

Background Prevalence of potential drug-drug interactions (pDDIs) in adult patients with severe asthma on biological therapy and their clinical significance have not been fully addressed, thus the aim of this study was to investigate them. Methods In this retrospective observational study, patients who were diagnosed with severe asthma and to whom biological therapy was prescribed between September 2015 and December 2020, were enrolled. The study was conducted at the Department of Allergic and Obstructive Pulmonary Diseases, Clinic for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb. Data on demographic characteristics as well as concomitant medication were collected. The analysis of pDDIs was conducted via Lexicomp® online software. Interactions of significance levels A and B were only recorded, while those of levels C, D and X were further analysed. The collected data was processed via Microsoft Excel 365 software. Results 60 adult patients, 60% female and 40% male, with median age of 56.2 years, were enrolled. The incidence of pDDIs was 86.67%. Total number of pDDIs detected was 518, out of which 43.24%, 45%, 4.44% and 7.3% of clinical significance B, C, D and X. Interactions of level C, D and X were recorded in, as follows: 83.33%, 25% and 33.33% patients with an average of 4.66, 1.53 and 1.9 interactions per patient. Only 13.33% of the patients had none of the potential clinically significant DDI. Most drug pairs contained at least one antiasthmatic drug. Muscarinic receptor antagonists, oral corticosteroids, β2 agonists and methylxanthines showed potential of entering into clinically significant DDIs, while leukotriene antagonists and biologicals showed no potential for the above. Conclusion Prevalence of potential drug-drug interactions in patients with severe asthma on biological therapy is high. The majority of identified interactions have moderate to high level of clinical significance. Their identification, prevention and resolution could contribute to optimizing therapy, maximizing its therapeutic effect and avoiding undesirable adverse events.

Fluctuation-related pain (FRP) affects more than one third of people with Parkinson’s disease (PwP, PD) and has a harmful effect on health-related quality of life (HRQoL), but often remains under-reported by patients and neglected by clinicians. The National Institute for Health and Care Excellence (NICE) recommends The Parkinson KinetiGraphTM (the PKGTM) for remote monitoring of motor symptoms. We investigated potential links between the PKGTM-obtained parameters and clinical rating scores for FRP in PwP in an exploratory, cross-sectional analysis of two prospective studies: “The Non-motor International Longitudinal, Real-Life Study in PD—NILS” and “An observational-based registry of baseline PKG™ in PD—PKGReg”. 63 PwP (41.3% female; age: 64.24±9.88 years; disease duration, DD: 6.83±5.63 years; Hoehn and Yahr Stage, H&Y: 2 (1–4); Levodopa Equivalent Daily Dose 535 (0–3230) mg) were included. PwP with FRP (n = 23) had longer DD (8.88 (1.29–19.05) vs. 3.16 (0.34–28.92), p = 0.001), higher severity of motor symptoms (H&Y 3 (1–4) vs. 2 (1–4), p = 0.015; SCOPA Motor total score 21.35±10.19 vs. 13.65±8.99, p = 0.003), more dyskinesia (SCOPA Motor Item 18 ≥1 60.9% vs. 7.5%, p<0.001), and worse HRQoL (PDQ-8 Total Score 10.74±5.98 vs. 6.78±5.13, p = 0.007) then PwP without FRP (n = 40). In the multivariate logistic regression, after the adjustment for DD, H&Y and SCOPA-Motor total score, the presence of FRP was significantly associated with the PKGTM-derived Fluctuation-dyskinesia score (Exp (B) = 1.305, 95% CI for Exp (B) 1.012–1.683, p = 0.040) and the Bradykinesia score (Exp (B) = 0.917, 95% CI for Exp (B) 0.842–0.999, p = 0.048). The PKGTM system may potentially advance the way we screen for, assess, and treat FRP in clinical practice.

Background Electroconvulsive therapy (ECT) is a safe and effective treatment for several major psychiatric conditions, including treatment-resistant depression, mania, and schizophrenia; nevertheless, its use remains controversial. Despite its availability in some European countries, ECT is still rarely used in others. This study aims to investigate the experiences and attitudes of early career psychiatrists (ECPs) across Europe towards ECT and to examine how their exposure to ECT influences their perceptions. Methods In Europe, a cross-sectional survey was conducted among ECPs, including psychiatric trainees and recently fully qualified psychiatrists. Results A total of 573 participants from 30 European countries were included in the study, of whom more than half ( N = 312; 54.5%) received ECT training. Overall, ECPs had a positive attitude towards ECT, with the vast majority agreeing or strongly agreeing that ECT is an effective ( N = 509; 88.8%) and safe ( N = 464; 81.0%) treatment and disagreeing or strongly disagreeing that ECT was used as a form of control or punishment ( N = 545; 95.1%). Those who had received ECT training during their psychiatry training were more likely to recommend ECT to their patients (p < 0.001, r = 0.34), and held more positive views on its safety (p < 0.001, r = 0.31) and effectiveness (p < 0.001, r = 0.33). Interest in further education about ECT was moderately high (modal rating on Likert scale: 4, agree), irrespective of prior training exposure. Conclusions ECT training is associated with more favorable perceptions of its safety and effectiveness among ECPs. There is a general willingness among ECPs to expand their knowledge and training on ECT, which could enhance patients’ access to this treatment.

Background The quality of life (QoL) in elderly post-stroke patients may deteriorate due to an interplay of physical and psychological impairments, compounded by social challenges stemming from these issues. Objective This study aimed to identify predictors of QoL in elderly post-stroke patients by evaluating their functional capabilities, depressive symptoms, and levels of social support. Methods A cohort of 122 individuals aged 65 and older, who had experienced a stroke, was assessed. Functional independence was gauged using the Functional Independence Measure (FIM), depressive states were evaluated with the Geriatric Depression Scale (GDS), and social support was quantified through the Social Support Scale (SSS). The WHOQOL-BREF questionnaire was employed to measure QoL. Results The FIM and GDS scores were significant predictors for WHOQOL-BREF domains 1 and 2 (adjusted R² = 0.522, p < 0.01; and adjusted R² = 0.586, p < 0.01, respectively). GDS alone was a significant predictor for domain 3 (adjusted R² = 0.236, p < 0.01), while all variables were significant predictors for domain 4 (adjusted R² = 0.315, p < 0.01). Conclusions Depression, motor function, and social support were identified as the primary predictors of QoL in elderly individuals after suffering a stroke.

The European Clozapine Task Force is a group of psychiatrists and pharmacologists practicing in 18 countries under European Medicines Agency (EMA) regulation, who are deeply concerned about the underuse of clozapine in European countries. Although clozapine is the most effective antipsychotic for people with treatment-resistant schizophrenia, a large proportion of them do not have access to this treatment. Concerns about clozapine-induced agranulocytosis and stringent blood monitoring rules are major barriers to clozapine prescribing and use. There is a growing body of evidence that the incidence of clozapine-induced agranulocytosis is very low after the first year of treatment. Maintaining lifelong monthly blood monitoring after this period contributes to unjustified discontinuation of clozapine. We leverage recent and replicated evidence on the long-term safety of clozapine to call for the revision and updating of the EMA's blood monitoring rules, thus aiming to overcome this major barrier to clozapine prescribing and use. We believe the time has come for relaxing the rules without increasing the risks for people using clozapine in Europe.

The surveillance of mobile genetic elements facilitating the spread of antimicrobial resistance genes has been challenging. Here, we tracked both clonal and plasmid transmission in colistin- and carbapenem-resistant Klebsiella pneumoniae using short- and long-read sequencing technologies. We observed three clonal transmissions, all containing Incompatibility group (Inc) L plasmids and New Delhi metallo-beta-lactamase bla NDM-1 , although not co-located on the same plasmid. One IncL- bla NDM-1 plasmid had been transferred between sequence type (ST) 392 and ST15, and the promiscuous IncL- bla OXA-48 plasmid was likely shared between a singleton and a clonal transmission of ST392. Plasmids within clonal outbreaks and between clusters and STs had 0–2 single nucleotide polymorphism (SNP) differences, showing high stability upon transfer to same or different STs. The simplest explanation, without a comprehensive analysis with long-read sequencing, would be the spread of a single common IncL- bla NDM-1 plasmid. However, here, we report bla NDM-1 in five different plasmids, emphasizing the need to investigate plasmid-mediated transmission for effective containment of outbreaks. IMPORTANCE Antimicrobial resistance occupies a central stage in global public health emergencies. Recently, efforts to track the genetic elements that facilitate the spread of resistance genes in plasmids outbreaks, utilizing short-read sequencing technologies, have been described. However, incomplete plasmid reconstruction from short-read sequencing data hinders full knowledge about plasmid structure, which makes the exploration very challenging. In this study, we used both short- and long-read sequencing in clinical Klebsiella pneumoniae from University Hospital Centre Zagreb, Croatia, which was resistant to both last-resort antibiotics colistin and carbapenem. Our results show complex transmission networks and sharing of plasmids, emphasizing multiple transmissions of plasmids harboring carbapenem and/or colistin resistance genes between and within K. pneumoniae clones. Only full-length sequencing plus a novel way of determining plasmid clusters resulted in the complete picture, showing how future active monitoring of plasmids as a vital tool for infection prevention and control could be implemented.

The most severe form of male infertility is idiopathic non-obstructive azoospermia (NOA), a complete sperm absence in the ejaculate. We performed exome sequencing in the Croatian infertile brothers with NOA and found a variant in DMRT1 (Doublesex and mab-3 related transcription factor 1) gene that was further assessed by the EMSA assay and molecular dynamic simulations. We additionally screened for DMRT1 mutations in 1940 infertile men diagnosed with spermatogenic failure, 644 normozoospermic controls, and 105 females with primary ovarian insufficiency (POI) recruited to the GEnetics of Male INfertility Initiative (GEMINI) or Estonian Andrology (ESTAND) cohorts. DMRT1 p.Pro74Leu (chr9:g.842059C > T) variant was detected in infertile brothers in the highly conserved position within the DNA binding DM domain of the protein. EMSA assay showed reduced DNA binding of DMRT1P74L and molecular dynamic simulations showed differences in structural and dynamical properties between the wild type protein and DMRT1P74L. Plausible disease-causing DMRT1 variants were only identified in infertile men (13/1940; 0.67%), and none in 639 fertile controls. Burden testing showed an excess of rare deleterious DM domain mutations in the infertility cohort compared to gnomAD v.4.0 population-based controls (Fisher’s exact test, p = 1.44 x 10−5). Three rare deleterious variants in DMRT1 were found in 104 cases of POI. The findings of this study strengthen the evidence of DMRT1 variants being a causal factor for male infertility and provide the distribution of likely pathogenic variants across the gene. This is also the first study to suggest that DMRT1 variants may also be linked to POI.

Purpose Digital 3D exoscopes are promising tools for microneurosurgery. The results of exoscope-assisted resection of intracranial meningiomas have only been addressed in few case reports. We retrospectively compared the results of exoscope and microscope-assisted surgery of falx and parasagittal meningiomas. Methods We included all consecutive adult patients (n = 36) with falx or parasagittal meningioma who were operated with curative intention during an 8-year period by one senior neurosurgeon. The operations were performed either with a surgical microscope (n = 16; Zeiss Kinevo or Pentero 900) or a digital 3D exoscope (n = 20, Aesculap Aeos). We reviewed the pre- and postoperative radiological images, clinical examinations and surgical reports to assess clinical outcomes and complications. We also analyzed surgical videos. Results Gross-total resection (Simpson grade I-II) was achieved in approximately 90% of the patients in both groups (89% in exoscope and 92% in microscope group). The duration of the operation was slightly longer (117 vs. 88 min) in the exoscope group. Surgical outcomes were comparable, despite there being larger tumors (median diameter 53 vs. 38 mm) with higher grades (WHO Grade 2–3: 45% vs. 19%) in the exoscope group. Transient postoperative complications were more frequent in the exoscope group (40 vs. 25%) mainly related to the larger tumor size. Conclusion The digital 3D exoscope is an effective tool for performing surgery on falx and parasagittal meningiomas. The extent of removal, clinical results and complications seem to be comparable to surgical microscope even in large tumors. Larger prospective studies are required to confirm this result.

Symmetrical drug‐related intertriginous and flexural exanthema (SDRIFE) is a rare, symmetrical skin eruption triggered by various medications, predominantly beta‐lactam antibiotics. We report the case of a 69‐year‐old male with moderate‐to‐severe ulcerative colitis who developed SDRIFE following the seventh intravenous administration of infliximab. The patient presented with symmetrical, pruritic erythema in the cubital and popliteal fossae, groins, gluteal and retroauricular regions without systemic involvement. Skin biopsy showed mild exocytosis of T lymphocytes in the epidermis and dense superficial perivascular CD3+ and CD4+ infiltration, consistent with a type IVa hypersensitivity reaction. The patient responded well to a regimen of systemic antihistamines, topical corticosteroids and tacrolimus ointment, with complete regression of lesions within one week. Despite mild recurrences of SDRIFE after each infliximab administration, the therapy was not discontinued due to the mild nature of the reaction and favourable prognosis. The authors are not aware of previously published cases of type IVa SDRIFE induced by infliximab. Unlike previous reports of severe type IVc SDRIFE reactions requiring discontinuation of infliximab, our case highlights the predominance of CD4+ cells, which may explain the mild clinical course. Understanding the underlying immunologic mechanisms of infliximab‐induced SDRIFE could affect treatment decisions and prevent unnecessary discontinuation of effective therapies.

Background Current guidelines discourage prophylactic plasma use in non‐bleeding patients. This study assesses global plasma transfusion practices in the intensive care unit (ICU) and their alignment with current guidelines. Study Design and Methods This was a sub‐study of an international, prospective, observational cohort. Primary outcomes were in‐ICU occurrence rate of plasma transfusion, proportion of plasma events of total blood products events, and number of plasma units per event. Secondary outcomes included transfusion indications, INR/PT, and proportion of events for non‐bleeding indications. Results Of 3643 patients included, 356 patients (10%) experienced 547 plasma transfusion events, accounting for 18% of total transfusion events. A median of 2 (IQR 1, 2) units was given per event excluding massive transfusion protocol (MTP) and 3 (IQR 2, 6) when MTP was activated. MTP accounted for 39 (7%) of events. Indications of non‐MTP events included active bleeding (54%), prophylactic (25%), and pre‐procedure (12%). Target INR/PT was stated for 43% of transfusion events; pre‐transfusion INR/PT or visco‐elastic hemostatic assays (VHA) were reported for 73%. Thirty‐seven percent of events were administered for non‐bleeding indications, 54% with a pre‐transfusion INR < 3.0 and 30% with an INR < 1.5. Discussion Plasma transfusions occurred in 10% of ICU patients. Over a third were given for non‐bleeding indications and might have been avoidable. Target INR/PT was not stated in more than half of transfusions, and pre‐transfusion INR/PT or VHA was not reported for 27%. Further research and education is needed to optimize guideline implementation and to identify appropriate indications for plasma transfusion.

Background The second victim (SV) experience limits the performance of health and care workers and places patients at risk. Peer support is recognised as the most effective, feasible and acceptable intervention to mitigate its impact. Objective To define a set of success factors when designing interventions to support SVs in health and care facilities based on expertise in different European countries. Setting International collaboration involving countries with diverse cultures, structures and legal frameworks. Design Qualitative research. Method Focus groups involving a total of 43 participants were conducted in five countries. Prominent professionals in European peer support interventions were engaged. Analysis of common elements considered key to the success of these programmes was underscored. Results Critical success factors for designing effective SV support interventions included the need for an occupational health approach, the establishment of a strong organisational safety culture, immediate psychological first aid, long-term resilience building, the engagement and training of peer supporters, the provision of adequate resources and ongoing support, the importance of leadership commitment and the necessity of tailoring interventions to the specific context and needs of each institution and country considering their diverse sociocultural and legal framework. The expected benefits included ensuring optimal patient care and reducing associated costs such as staff turnover and litigation. Conclusion Effective SV support interventions are essential for enhancing the resilience and performance of health and care workers, ultimately improving patient safety. By implementing tailored and well-resourced interventions, healthcare institutions can mitigate the negative impact of the SV phenomenon, promoting optimal care.

Thyroid dysfunctions are common in type 1 diabetes mellitus (T1DM) pregnancies, impacting embryogenesis and fetal neurodevelopment. This study investigates the effects of subclinical hypothyroidism and BDNF (Brain-derived neurotrophic factor) telomere length in T1DM mothers and their newborns. In a recent study, researchers found an inverse relationship between TSH (thyroid-stimulating hormone) levels and telomere length in the cord blood of newborns. This was prospective cohort analysis of 70 mothers and their newborns with T1DM. The study measured leukocyte telomere length (LTL) in maternal and neonatal samples. Subclinical hypothyroidism during the first trimester was characterized by TSH levels ranging from 2.5 to 5.0 mIU/L alongside normal free thyroxine (FT4) concentrations. In this study, we proved that maternal telomere length predicts telomere length in the newborn. Furthermore, we investigated the influence of maternal hypothyroidism on telomere length in the newborn. Maternal hypothyroidism in the first trimester of pregnancy has a strong influence on the shortening of newborn telomeres. BDNF has a positive effect on maternal and newborn telomere length. These results can have an important impact on the subsequent development of a child born to a diabetic mother. Health and disease associated with telomere length later in life may be programmed at birth.