Faculty of Medicine

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Oscillation quenching induced by time-varying coupling functions
(AIP Publishing, 2025-12-01)
Stavrov, Dushko
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Koseska, Aneta
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The oscillatory dynamics of natural and man-made systems can be disrupted by their time-varying interactions, leading to oscillation quenching phenomena in which the oscillations are suppressed. We introduce a framework for analyzing, assessing, and controlling oscillation quenching using coupling functions. Specifically, by observing limit-cycle oscillators, we investigate the bifurcations and dynamical transitions induced by time-varying diffusive and periodic coupling functions. We studied the transitions between oscillation quenching states induced by the time-varying form of the coupling function while the coupling strength is kept invariant. The time-varying periodic coupling function allowed us to identify novel, non-trivial inhomogeneous states that have not been reported previously. Furthermore, by using dynamical Bayesian inference, we have also developed a Proportional Integral controller that maintains the oscillations and prevents oscillation quenching from occurring. In addition to the present implementation and its generalizations, the framework carries broader implications for identification and control of oscillation quenching in a wide range of systems subjected to time-varying interactions.
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Physiological Noise in Cardiorespiratory Time-Varying Interactions
(MDPI AG, 2026-01-19)
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Stavrov, Dushko
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The systems in nature are rarely isolated and there are different influences that can perturb their states. Dynamic noise in physiological systems can cause fluctuations and changes on different levels, often leading to qualitative transitions. In this study, we explore how to detect and extract the physiological noise, in terms of dynamic noise, from measurements of biological oscillatory systems. Moreover, because the biological systems can often have deterministic time-varying dynamics, we have considered how to detect the dynamic physiological noise while at the same time following the time-variability of the deterministic part. To achieve this, we use dynamical Bayesian inference for modeling stochastic differential equations that describe the phase dynamics of interacting oscillators. We apply this methodological framework on cardio-respiratory signals in which the breathing of the subjects varies in a predefined manner, including free spontaneous, sine, ramped and aperiodic breathing patterns. The statistical results showed significant difference in the physiological noise for the respiration dynamics in relation to different breathing patterns. The effect from the perturbed breathing was not translated through the interactions on the dynamic noise of the cardiac dynamics. The fruitful cardio-respiratory application demonstrated the potential of the methodological framework for applications to other physiological systems more generally.
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MECONIUM ILEUS AS INITIAL PRESENTATION OF CYSTIC FIBROSIS: A RETROSPECTIVE CASE SERIES FROM A MACEDONIAN PEDIATRIC CYSTIC FIBROSIS CENTER
(University Ss. Cyril and Methodius in Skopje, 2025-12-16)
Krsteska, Elena
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Spirevska, Lidija
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Andreevska Stepanovska, Andrijana
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Jordanova, Olivera
Introduction: Meconium ileus (MI) is often the earliest clinical sign of cystic fibrosis (CF), caused by intestinal obstruction due to thickened meconium from CFTR dysfunction. MI is commonly associated with severe CFTR mutations (classes I-III), which impair chloride and bicarbonate transport. Case report: We report a retrospective case series of six neonates with MI, diagnosed with CF at Pediatric CF Center at University Children’s Clinic, Skopje, over the last eight years. During this period, newborn bloodspot screening (NBS) program for CF was conducted, based on two sequential measurements of immunoreactive trypsinogen (IRT) and IRT-IRT protocol. All infants presented with early intestinal obstruction requiring surgical intervention, including enterotomy and ileostomy. Postoperative care included pancreatic enzyme therapy and nutritional support. CF diagnosis was confirmed via sweat chloride testing and genetic analysis, which showed a predominant presence of the F508del mutation in homozygous or compound heterozygous forms. Despite timely surgical intervention, three infants experienced severe complications and early mortality. It is noteworthy that one of these cases had false-negative NBS result, highlighting limitations of the IRT-IRT protocol in MI cases. The remaining patients showed varied recovery and nutritional outcomes. Conclusions: MI is a known cause of false-negative results in CF NBS, as IRT levels may be low in affected neonates. Therefore, any newborn presenting with MI should be presumed to have CF until proven otherwise. Confirmation requires sweat chloride testing and genetic analysis. These findings support the need for revised CF NBS protocols in all MI cases to ensure timely diagnosis and management.
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Current Status of Newborn Screening in Southeastern and Central Europe
(MDPI AG, 2026-03-02)
Požun, Nika
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Perko, Daša
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Barić, Ivo
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Baša, Mihail
Newborn screening (NBS) is a well-established public health program that enables early detection and treatment of rare disorders in newborns, preventing severe complications or death. Despite its recognized importance, the scope and implementation of NBS programs vary across Southeastern (SE) and Central Europe. This study aimed to evaluate the current status of NBS in 16 countries of SE and Central Europe and assess progress since the previous survey in 2021. A structured questionnaire was distributed to national experts between April and December 2025, collecting data on program organization, coverage, diseases included, laboratory methods, confirmatory testing, consent practices, and future expansion plans. All countries reported universal screening for congenital hypothyroidism, except Kosovo, where a national NBS is in the process of being established. Expanded NBS using tandem mass spectrometry was available in Austria, Bulgaria, Croatia, Cyprus, Greece, Hungary, North Macedonia, Romania, and Slovenia. Spinal muscular atrophy screening became universal in Austria, Croatia, Hungary, Serbia, and Slovenia. Most countries reported plans for further expansion, with congenital adrenal hyperplasia, severe combined immunodeficiency, spinal muscular atrophy, and cystic fibrosis being the most frequently targeted conditions. Although notable infrastructural progress has been achieved, financial constraints, lack of staff, and organizational barriers remain key challenges. The study’s assessment of program effectiveness was further limited by the absence of region-wide systems for capturing end-to-end performance indicators, such as the age of the infant at treatment initiation or missed cases. Regional collaboration and adoption of best practices are therefore vital to ensure equitable access and continuous advancement of NBS programs.
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MISMATCH REPAIR STATUS IN COLON CANCER: A SINGLE-CENTRE EXPERIENCE FROM NORTH MACEDONIA
(2025-10-01)
Bajdevska Dukovska D
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Diet and sex inequities in ischemic heart disease mortality across Europe: findings from the global burden of disease study
(Oxford University Press (OUP), 2025-11)
Bugiardini, Raffaele
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Rahaman, Tania
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Manfrini, Olivia
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Maas, Angela
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Bergami, Maria
Aims Sex differences in ischemic heart disease (IHD) mortality remain underexplored from a population-level case fatality perspective. This study evaluates sex-specific disparities in IHD mortality and risk-attributable causes across 27 European Union (EU) countries using Global Burden of Disease (GBD) 2021 data. Methods and results We calculated age-standardized mortality rates (ASMRs), prevalence rates (ASPRs), and mortality-to-prevalence ratios (MPRs) as a proxy for population-level case fatality. To quantify mortality attributable to specific exposures among individuals with IHD, we derived a case fatality index (CFI) by normalizing risk-attributable ASMRs to ASPRs. Z-scores quantified the magnitude and statistical significance of sex differences in MPRs and CFIs (|Z| ≥ 1.96 = P < 0.05; |Z| ≥ 2.58 = P < 0.01). From 2011 to 2021, IHD ASMRs declined by 24.0% in men and 19.1% in women. In 2011, 12 countries showed significantly higher MPRs in women than men. By 2021, Austria (MPR 6.0% vs. 3.6%), Greece (9.4% vs. 5.3%), and Malta (9.3% vs. 4.2%) remained outliers, with Z-scores >2.58 (P < 0.01). CFIs showed that women in these countries faced 40 to 60% higher mortality burdens from hypertension, hyperglycemia, and poor dietary intake. Low intake of omega-3 fatty acids, fibers, vegetables, and nuts/seeds accounted for the largest dietary disparities. Conclusion Despite declining IHD mortality rates, Austria, Greece, and Malta continue to exhibit significant sex disparities, with women experiencing disproportionately higher case fatality. These disparities are largely driven by modifiable cardiometabolic and dietary risks, underscoring the need for sex-specific, regionally tailored prevention strategies.
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A challenging "silent depth" clinical scenario in North Macedonia: Unmasking a rare case of amelanotic melanoma with trapezius muscle invasion and metastatic disease
(Centre for Evaluation in Education and Science (CEON/CEES), 2025)
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Gjorgjeska, Andrijana
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Ivanova, Maja
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Aleksovski, Darko
Introduction: Amelanotic melanoma is a subtype of melanoma that exhibits little or no pigment on visual or histological examination. Approximately 1-8% of all melanomas are amelanotic. It can mimic various benign or malignant melanocytic and non-melanocytic skin tumors, thereby presenting a significant diagnostic challenge. Primary amelanotic melanoma with muscle involvement is an extremely rare entity. A review of the literature revealed no series or case reports. Case Report: We present the case of a 62-yearold female patient with primary amelanotic melanoma infiltrating the trapezius muscle. The tumor was excised together with a clinically positive lymph node on the right side of the neck. Computed tomography (CT) angiography of the lungs, abdomen, and pelvis demonstrated bilateral diffuse nodular changes, a mediastinal pretracheal lymph node, and multiple diffuse liver lesions, consistent with secondary deposits. Molecular pathology revealed positivity for the BRAF V600E2/K/R/D mutation, and the patient began firstline targeted therapy with BRAF/MEK inhibition in accordance with protocols for BRAF-positive metastatic melanoma. Three months later, a follow-up CT scan demonstrated complete remission of the previously observed metastatic changes. Conclusion: Primary amelanotic melanoma with muscle involvement is exceptionally rare, with no published series or case reports identified. This case highlights the importance of early detection and treatment in suspected melanoma and underscores the need to consider melanoma in all clinically unclear cases.
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Status of Sepsis Care in European Hospitals: Results from an International Cross-Sectional Survey
(Oxford University Press (OUP), 2025-04-01)
Scheer, Christian S.
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Giamarellos-Bourboulis, Evangelos J.
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Ferrer, Ricard
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Idelevich, Evgeny A.
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Annane, Djillali
Rationale Early detection, standardized therapy, adequate infrastructure, and strategies for quality improvement should constitute essential components of every hospital’s sepsis plan. Objectives To investigate the extent to which recommendations from the sepsis guidelines are implemented and the availability of infrastructure for the care of patients with sepsis in acute-care hospitals. Methods A multidisciplinary cross-sectional questionnaire was used to investigate sepsis care in hospitals. This included the use of sepsis definitions, the implementation of sepsis guideline recommendations, diagnostic and therapeutic infrastructure, antibiotic stewardship, and quality improvement initiatives (QIIs) in hospitals. Measurements and Main Results A total of 1,023 hospitals in 69 countries were included. Most of them, 835 (81.6%), were in Europe. Sepsis screening was used in 54.2% of emergency departments (EDs), 47.9% of wards, and 61.7% of ICUs. Sepsis management was standardized in 57.3% of EDs, 45.2% of wards, and 70.7% of ICUs. The implementation of comprehensive QIIs was associated with increased screening (EDs, +33.3%; wards, +44.4%; ICUs, +23.8% absolute difference) and increased standardized sepsis management (EDs, +33.6%; wards, +40.0%; ICUs, +17.7% absolute difference) compared with hospitals without QIIs. A total of 9.8% of hospitals had implemented ongoing QIIs, and 4.6% had invested in sepsis programs. Conclusions The findings indicate that there is considerable room for improvement in a large number of mainly European hospitals, particularly with regard to early identification and standardized management of sepsis, the availability of guidelines, diagnostic and therapeutic infrastructure, and the implementation of QIIs. Further efforts are required to implement a more comprehensive and appropriate quality of care.
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Safe pediatric one-lung ventilation in a resource-limited setting: an age- and weight-guided approach
(Springer Science and Business Media LLC, 2025-12-10)
Sulejmani, Haris
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Golubic, Sanja
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Background One-lung ventilation (OLV) in children is technically demanding due to small airway calibers, variable bronchial anatomy, and limited pediatric-specific devices. Challenges are greater in resource-limited settings where double-lumen tubes (DLTs) and fiberoptic bronchoscopes are not consistently available. Methods We retrospectively reviewed five consecutive pediatric patients (ages 4–13 years) who underwent thoracic surgery with OLV between 2022 and 2024. Case summaries highlighted device choice, confirmation method, and perioperative challenges. Variables included demographics, diagnosis, surgical side, isolation technique, OLV duration, ventilatory parameters, arterial blood gases, and defined outcomes (desaturation, hypercarbia, hemodynamic instability, device dislodgement, and postoperative complications). Results Lung isolation was achieved with DLTs in two older patients and bronchial blockers in three younger ones, guided by age and weight. OLV lasted 105–150 min. Two children developed transient desaturation (nadir SpO₂ 75%), one experienced hypercarbia (PaCO₂ >50 mmHg), and two had hemodynamic instability. No tube dislodgement occurred. Median ICU stay was 17 h (IQR 8–19), and hospital stay 21 days (IQR 15–21). All patients were discharged in stable condition. Conclusion An age- and weight-based algorithm bronchial blockers for children < 8 years or < 30 kg, DLTs for older/heavier patients enabled safe OLV and preserved oxygenation, even without routine fiberoptic bronchoscopy. Vigilant ETCO₂ monitoring, careful device fixation, and close intraoperative assessment compensated for equipment limitations. This pragmatic workflow demonstrates feasibility in resource-constrained environments, provides practical guidance for clinicians, and is hypothesis-generating for future multicenter studies.
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Early airway management in patients with severe traumatic brain injury
(Hrvatski Prirodoslovno Drustvo (Croatian Society for Natural Sciences), 2025-09-11)
Nastasović, Tijana
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Ivošević, Tjaša
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Bojić, Suzana
Background and purpose: Traumatic brain injury (TBI) is the main cause of death and disability in injured patients. Airway management in these patients is challenging because unsuccessful endotracheal intubation (ETI) can lead to hypoxemia, hypercapnia, and consecutive secondary brain damage. The aim of this review is to answer the questions about appropriate airway management in patients with severe TBI. Materials and methods: We searched the PubMed database using keywords of our paper: „airway management“, „traumatic brain injury“ and „intubation”. During the period from January 2010 to January 2025, 213 articles were published, relevant for this review. Discussion: The difficulty of obtaining an airway in patients with TBI is a consequence of presence of airway reflexes and muscular tone, the necessity to maintain cervical spine stabilization, and presence of blood and secretions in the upper airway. Influence of ETI on intracranial pressure and cerebral blood flow can also determine outcome. An alternative way for airway management is the use of supraglottic airway devices. Rapid sequence intubation (RSI) as a form of ETI for patients with severe TBI is an appropriate choice with the use of sedatives, hypnotics, opioid analgesics, and muscle relaxants to prevent an increase in intracranial pressure. ETI in patients with cervical spine injury should be done using manual in-line stabilization and video laryngoscope. Conclusions: Airway management in patients with severe TBI is essential because it can influence mortality. TBI patients with airway compromise must be identified, and airway must be secured early to ensure ventilation and oxygenation.

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