Publications by authors named "Ozren Polasek"

328 Publications

Does Each Menstrual Cycle Elicit a Distinct Effect on Olfactory and Gustatory Perception?

Nutrients 2021 Jul 22;13(8). Epub 2021 Jul 22.

Department of Public Health, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia.

The obesity pandemic has brought forth a scientific interest in food intake and sensory perception interactions. Olfactory perception and gustatory perception are very complex and under the influence of many factors, including the menstrual cycle. This study aims to clarify conflicting findings on the influence of the menstrual cycle on olfactory and gustatory perception. Women were assessed during four consecutive phases of one complete cycle (mid-follicular, ovulatory, mid-luteal, and late luteal phases ( = 21)), in contrast to women measured across the same phases belonging to two menstrual cycles ( = 29). Additional control groups were men ( = 17), postmenopausal women ( = 14), oral contraceptive users ( = 10), and women with an anovulatory cycle ( = 8). Olfactory threshold, odor discrimination, and identification were tested using the "Sniffin Sticks" test kit. Suprathreshold intensity and hedonic ratings for sweet, salty, sour, and bitter solutions were assessed. One-way ANOVA and ANOVA for repeated measurements was applied in the analysis, along with linear and trigonometric data fitting and linear mixed models. Linear increases in olfactory discrimination, identification, and overall olfactory performance were observed only in women followed across a complete menstrual cycle. Compared to other groups, these women displayed a cyclic pattern characterized by a predilection for sweet solution; reduced distaste for salty and sour solutions; and increased intensity perception of salty, sour, and bitter solutions towards the end of the cycle. These results suggest that a distinct hormonal milieu of a complete menstrual cycle may be affecting both olfactory and gustatory perception.
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http://dx.doi.org/10.3390/nu13082509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401541PMC
July 2021

Role of Lung Ultrasound in Predicting Clinical Severity and Fatality in COVID-19 Pneumonia.

J Pers Med 2021 Jul 30;11(8). Epub 2021 Jul 30.

Division of Rheumatology and Clinical Immunology, Centre of Excellence for Systemic Sclerosis in Croatia, University Hospital of Split, 21000 Split, Croatia.

Background: Lung ultrasound (LUS) is a useful imaging method for identifying COVID-19 pneumonia. The aim of this study was to explore the role of LUS in predicting the severity of the disease and fatality in patients with COVID-19.

Methods: This was a single-center, follow-up study, conducted from 1 November 2020, to 22 March 2021. The LUS protocol was based on the assessment of 14 lung zones with a total score up to 42, which was compared to the disease severity and fatality.

Results: A total of 133 patients with COVID-19 pneumonia confirmed by RT-PCR were enrolled, with a median time from hospital admission to lung ultrasound of one day. The LUS score was correlated with clinical severity at hospital admission (Spearman's rho 0.40, 95% CI 0.24 to 0.53, < 0.001). Patients with higher LUS scores were experiencing greater disease severity; a high flow nasal cannula had an odds ratio of 1.43 (5% CI 1.17-1.74) in patients with LUS score > 29; the same score also predicted the need for mechanical ventilation (1.25, [1.07-1.48]). An LUS score > 30 (1.41 [1.18-1.68]) and age over 68 (1.26 [1.11-1.43]) were significant predictors of fatality.

Conclusions: LUS at hospital admission is shown to have a high predictive power of the severity and fatality of COVID-19 pneumonia.
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http://dx.doi.org/10.3390/jpm11080757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399683PMC
July 2021

Rapid COVID-19 Antigen Testing in Croatia: Risk Perception Plays an Important Role in the Epidemic Control.

Front Public Health 2021;9:708907. Epub 2021 Jul 27.

Department of Public Health, University of Split School of Medicine, Split, Croatia.

To explore the clinical presentation and epidemiological history of the subjects who underwent SARS-CoV-2 antigen testing. We included 1,000 consecutive subjects who presented themselves at the diagnostic clinic in Croatia and analyzed their symptoms and epidemiological history. All subjects were classified into three groups, according to their reason of arrival; symptomatic, contacts of confirmed patients, and those who were tested due to administrative reasons. On average, there were 24% of positive antigen results; the positivity rate was 51% among symptomatic, 16% in contacts, and 5% of administrative patients. The commonest symptoms of the disease included febrility and anosmia. We developed a clinical score to predict SARS-CoV-2 positivity, which had an area under the curve of 79.3 [95% confidence intervals (CI) 75.8-82.8]. Contact with the isolated person [odds ratio 0.54 (95% CI 0.31-0.94)] and international travel had a protective effect [0.20 (0.09-0.43)], suggesting that risk perception and mandatory pretravel measures had a key role in the determination of the infection risk. A combination of clinical symptoms can have reasonable predictive power for an antigen-positive test result. Risk perception seems to have a role in the epidemic spread, probably stricter adherence to personal preventative measures.
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http://dx.doi.org/10.3389/fpubh.2021.708907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353104PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611832PMC
August 2021

Using evidence, expert opinion and epidemiological model to understand pathways to survival and mortality: The Pathways to Survival (PATHS) Tool.

J Glob Health 2021 12;11:15001. Epub 2021 Jun 12.

Health Nutrition and Population, The World Bank, Washington, DC, USA.

Background: The reasons why episodes of illness can lead to fatal outcomes in affected persons in low resource settings are numerous and complex. A tool that allows policy makers to better understand those complexities could be useful to improve success of programmes that are implemented globally to reduce mortality.

Methods: We developed a "Pathways to Survival" (PATHS) tool: an epidemiological model using decision trees, available evidence and expert opinion. PATHS visualises the "architecture" of mortality in the population by following the entire population cohort over a certain period of time. It explains how initially healthy persons progress through health systems to lethal outcomes at the end of the specified time period. We developed an illustrative example based on the 136 million newborns and an estimated 907 000 deaths from newborn sepsis in the year 2008. This allowed us to develop an epidemiological model that described pathways to deaths from neonatal sepsis globally in 2010.

Results: The model described the "status quo' situation in 2010 with 907 000 deaths to allow an assessment of the potential impact and feasibility of different interventions and programmes at various level of health systems in reducing this cause of mortality. A useful model should incorporate both a 'horizontal' and a 'vertical' component. The 'horizontal' would track the progress of all neonates globally through time, ie, their first 28 days of life, and separate them into different 'pathways' every time a change in their risk of dying from neonatal infection occurs because of their specific contextual circumstances. The 'vertical' would track their position within the health systems of their countries and separate them into different categories based on the ability of health system to intervene and reduce their risk of dying. Based on those requirements, PATHS tool was developed which is based on decision trees where different "branches" of the trees are associated with varying case-fatality rates.

Conclusions: The application of the PATHS tool on the example of newborn sepsis revealed that novel diagnostic tests could save many lives, so we should continue to invest in them to improve their validity, deliverability and affordability. However, PATHS showed that investments in better diagnostics have limited impact unless they are coupled with improvements of the context. Programs for parental education improve compliance and care seeking. Promoting legislation change to empower community health workers (CHWs) to actively engage in prevention, diagnosis and care also makes a difference, as well as programs for training CHWs to use diagnostic tests and administer treatments correctly. Care-seeking behaviour can also be improved through programs of conditional cash transfers. Finally, PATHS demonstrated that improving access to primary and secondary health care for everyone is the most powerful contextual change.
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http://dx.doi.org/10.7189/jogh.11.15001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310575PMC
August 2021

The effect of food groups and nutrients on thyroid hormone levels in healthy individuals.

Nutrition 2021 Jun 20;91-92:111394. Epub 2021 Jun 20.

Department of Nuclear Medicine, University Hospital Split, Split, Croatia; Department of Medical Biology, School of Medicine, University of Split, Split, Croatia. Electronic address:

Objectives: The aim of the study was to analyze the association of dietary groups (groups of food items) with thyroid hormone levels in healthy individuals.

Methods: This cross-sectional study enrolled 4585 healthy individuals from the Dalmatian region of south Croatia with measurements of plasma free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) levels. Dietary intake was assessed according to data of the completed food frequency questionnaire, containing 58 food items. Principal component analysis was performed to reduce food items into dietary groups, followed by linear regression analyses to test the association between dietary groups and fT3, fT4, and TSH levels.

Results: Among the 4585 healthy individuals, we observed lower plasma fT3 and fT4 levels and higher TSH levels in women than in men. Smokers were found to have significantly lower TSH levels than non-smokers and ex-smokers, and participants with higher fasting glucose levels had higher fT4 levels. Different dietary groups (factors) showed association with fT3, fT4, and TSH levels. It was observed that dietary factors (with frequent consumption of fruit juices, Cedevita vitamin drink, and non-alcoholic drinks) that negatively affected TSH levels simultaneously had a positive effect on fT4, satisfying the expected pattern of effects.

Conclusions: In our study, frequent consumption of foods with a high glycemic index showed a positive association with fT3 and fT4 levels and a negative association with TSH levels, whereas foods rich in saturated fatty acids and with a high protein concentration showed a negative association with fT3 and fT4 levels.
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http://dx.doi.org/10.1016/j.nut.2021.111394DOI Listing
June 2021

N-glycosylation of immunoglobulin G predicts incident hypertension.

J Hypertens 2021 Jul 19. Epub 2021 Jul 19.

Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia Department of Twin Research, Kings College London, London, UK Genos Glycoscience Research Laboratory, Zagreb, Croatia Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health German Center for Diabetes Research (DZD) Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health LMU Munich, IBE-Chair of Epidemiology, Neuherberg, Germany Department of Public Health, University of Split, School of Medicine, Split, Croatia NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London Academic Rheumatology Clinical Sciences Building, Nottingham City Hospital, University of Nottingham, Nottingham University of Glasgow, Glasgow, Scotland, UK.

Objectives: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension.The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples.

Methods: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR < 0.1). Significant IgG-incident hypertension associations were replicated in the two independent cohorts by leveraging Cox regression mixed models in the 10 001 Dalmatians and logistic regression models in the KORA cohort.

Results: We identified and replicated four glycan traits, incidence of bisecting GlcNAc, GP4, GP9 and GP21, that are predictive of incident hypertension after adjusting for confoundes and multiple testing [hazard ratio (95% CI) ranging from 0.45 (0.24-0.84) for GP21 to 2.9 (1.5-5.68) for GP4]. We then linearly combined the four replicated glycans and found that the glycan score correlated with incident hypertension, SBP and DBP.

Conclusion: Our results suggest that the IgG glycome changes prior to the development of hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002963DOI Listing
July 2021

Sex Differences in Characteristics and Outcomes among Low-Risk Non-ST-Elevation Acute Coronary Syndrome Patients during Long Term Follow-Up.

J Clin Med 2021 Jun 25;10(13). Epub 2021 Jun 25.

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

Previous heterogenous studies show conflicting data about sex-based outcomes of non-ST-elevation acute coronary syndrome (NSTE-ACS) patients. This study evaluated 300 NSTE-ACS patients undergoing a coronary angiography between September 2012 and May 2015 that were managed with all-treatment strategies. The sample was stratified by sex and analyzed for the baseline characteristics and outcomes. The main outcome included major adverse cardiovascular and cerebrovascular events (MACCE), which were a composite of cardiac death, nonfatal myocardial infarction, ischemic stroke or urgent coronary revascularization. The female patients were older (median of 69.0 vs. 63.0 years, = 0.008) and had lower values of BMI (median of 26.3 vs. 28.2 kg/m, < 0.001) and eGFR (76.44 ± 22.43 vs. 94.04 ± 27.91 mL/min, < 0.001). There was no significant difference in the treatment strategies, angiographic characteristics and discharge therapy between the groups ( > 0.05). The female patients had significantly higher unadjusted rates of ischemic stroke (4.2% vs. 0.5%, = 0.023), cardiac mortality (11.3%, vs. 3.9%, = 0.022) and MACCE (33.8%, vs. 19.5%, = 0.014); female sex was a significant predictor of MACCE in the univariate analysis (HR 1.86, 95%CI 1.12-3.09, = 0.014); and the cumulative incidence of MACCE was higher in female patients ( = 0.014). After the adjustment, the predictive effect of female sex became non-significant (HR 1.60, 95%CI 0.94-2.73, = 0.083), while there was no difference in the cumulative incidence of MACCE among the propensity score matched cohort ( = 0.177). Female NSTE-ACS patients have worse long-term outcomes compared to their male counterparts. However, the differences disappear after adjustment and propensity score matching. Continuing efforts and health measures are required to alleviate any sex-based differences in the NSTE-ACS population.
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http://dx.doi.org/10.3390/jcm10132802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267884PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Fairer and healthier world for everyone - can lessons from the Dubrovnik Republic be applied to the COVID-19 pandemic?

Croat Med J 2021 04;62(2):107-109

Ozren Polašek, University of Split School of Medicine, Split, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107999PMC
April 2021

Validity of Appendicitis Inflammatory Response Score in Distinguishing Perforated from Non-Perforated Appendicitis in Children.

Children (Basel) 2021 Apr 19;8(4). Epub 2021 Apr 19.

Department of Public Health, School of Medicine, University of Split, 21 000 Split, Croatia.

Background: This prospective observational study aimed to evaluate the validity of appendicitis inflammatory response (AIR) score in differentiating advanced (perforated) from simple (non-perforated) appendicitis in pediatric patients.

Methods: A single-center prospective cross-sectional study was conducted between 1 January 2019 until 1 May 2020 including 184 pediatric patients who underwent appendectomy. Based on the intraoperative finding of advanced ( = 38) or simple ( = 146) appendicitis the patients were divided into two groups. Recipient-operator curve (ROC), with calculation of sensitivity and specificity of best cutoff and the area under the curve (AUC), were used to measure the diagnostic value and the potential for risk stratification of the AIR score, among the patients with simple or advanced acute appendicitis.

Results: The median value of the AIR score in the perforated and non-perforated groups was 10 (interquartile range, IQR 9, 11), and was 7 (IQR 6, 9), respectively ( < 0.001). Based on the calculated value of AIR score, the patients were classified with a high precision into low, indeterminate and high risk groups for acute appendicitis ( < 0.001). A cutoff value of ≥9 was demonstrated to serve as a reliable indicator of perforated appendicitis with a sensitivity and a specificity of 89.5% and 71.9%, respectively (AUC = 0.80; 95% CI: 0.719-0.871; < 0.001).

Conclusions: Acute appendicitis can be detected with a high level of sensitivity and specificity using the AIR score. Also, the AIR score may differentiate perforated from non-perforated appendicitis in pediatric patients with a high level of accuracy.
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http://dx.doi.org/10.3390/children8040309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073718PMC
April 2021

Mediterranean diet assessment challenges: Validation of the Croatian Version of the 14-item Mediterranean Diet Serving Score (MDSS) Questionnaire.

PLoS One 2021 1;16(3):e0247269. Epub 2021 Mar 1.

Department of Public Health, University of Split School of Medicine, Split, Croatia.

Mediterranean diet (MD) is among the most commonly investigated diets and recognized as one of the healthiest dietary patterns. Due to its complexity, geographical and cultural variations, it also represents a challenge for quantification. The aim of this cross-sectional study was to assess reliability and validity of the Croatian version of the 14-item Mediterranean Diet Serving Score (MDSS), using the Mediterranean Diet Adherence Screener (MEDAS) as the referent test. We included the exploratory sample of 360 medical students, and a confirmatory sample of 299 health studies students from the University of Split, Croatia. Test-retest reliability and validity of the MDSS were tested using intra-class correlation coefficients (ICC), while Cohen's kappa statistic was used to test correct classification of subjects into MD adherent/non-adherent category. A very good reliability was shown for the overall MDSS score (ICC = 0.881 [95% CI 0.843-0.909]), and a moderate reliability for the binary adherence (κ = 0.584). Concurrent validity of the MDSS was also better when expressed as a total score (ICC = 0.544 [0.439-0.629]) as opposed to the adherence (κ = 0.223), with similar result in the confirmatory sample (ICC = 0.510 [0.384-0.610]; κ = 0.216). Disappointingly, only 13.6% of medical students were adherent to the MD according to MDSS, and 19.7% according to the MEDAS questionnaire. Nevertheless, MDSS score was positively correlated with age (ρ = 0.179: P = 0.003), self-assessed health perception (ρ = 0.123; P = 0.047), and mental well-being (ρ = 0.139: P = 0.022). MDSS questionnaire is a short, reliable and reasonably valid instrument, and thus useful for assessing the MD adherence, with better results when used as a numeric score, even in the population with low MD adherence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247269PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920370PMC
August 2021

ACEF performed better than other risk scores in non-ST-elevation acute coronary syndrome during long term follow-up.

BMC Cardiovasc Disord 2021 02 3;21(1):70. Epub 2021 Feb 3.

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

Background: Risk stratification of patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) is an important clinical method, but long-term studies on patients subjected to all-treatment strategies are lacking. Therefore, the aim was to compare several established risk scores in the all-treatment NSTE-ACS cohort during long-term follow-up.

Methods: Consecutive patients (n = 276) with NSTE-ACS undergoing coronary angiography were recruited between September 2012 and May 2015. Six risk scores for all patients were calculated, namely GRACE 2.0, ACEF, SYNTAX, Clinical SYNTAX, SYNTAX II PCI and SYNTAX II CABG. The primary end-point was Major Adverse Cardiovascular Events (MACE) which was a composite of cardiac death, nonfatal myocardial infarction, ischemic stroke or urgent coronary revascularization.

Results: During a median follow-up of 33 months, 64 MACE outcomes were recorded (23.2%). There was no difference between risk score categories, except in the highest risk group of ACEF and SYNTAX II PCI scores which exhibited significantly more MACE (51.6%, N = 33 and 45.3%, N = 29, P = 0.024, respectively). In the multivariate Cox regression analysis of individual variables, only age and atrial fibrillation were significant predictors for MACE (HR 1.03, 95% CI 1.00-1.05, P = 0.023 and HR 2.02, 95% CI 1.04-3.89, P = 0.037, respectively). Furthermore, multivariate analysis of the risk scores showed significant prediction of MACE only with ACEF score (HR 2.16, 95% CI 1.36-3.44, P = 0.001). The overall performance of GRACE, SYNTAX, Clinical SYNTAX and SYNTAX II CABG was poor with AUC values of 0.596, 0.507, 0.530 and 0.582, respectively, while ACEF and SYNTAX II PCI showed the best absolute AUC values for MACE (0.630 and 0.626, respectively).

Conclusions: ACEF risk score showed better discrimination than other risk scores in NSTE-ACS patients undergoing all-treatment strategies over long-term follow-up and it could represent a fast and user-friendly tool to stratify NSTE-ACS patients.
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http://dx.doi.org/10.1186/s12872-020-01841-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860189PMC
February 2021

Optimizing the diagnostic capacity for COVID-19 PCR testing for low resource and high demand settings: The development of information-dependent pooling protocol.

J Glob Health 2020 Dec 30;10(2):020515. Epub 2020 Dec 30.

Department of Public Health, University of Split School of Medicine, Split, Croatia.

Aim: To compare different pooling methods in an attempt to improve the COVID-19 PCR diagnostic capacities.

Method: We developed a novel information-dependent pooling protocol (), based on transmission of less informative sequential pools on to the next pooling cycle to maximize savings. We then compared it to the , , and protocols in a simulation study, across variety of scenarios.

Results: All five methods yielded various amount of test savings, which mostly depended on the virus prevalence in the population. In situations of low prevalence (up to 5%), had the best performance, requiring on average 20% of tests needed for singular testing across scenarios that were analyzed. Nevertheless, this comes at the expense of speed, with the worst-case scenario of protocol requiring up to twice the time needed to test the same number of samples in comparison to the protocol. In order to offset this, we developed a faster version of the protocol (), which minimizes the number of terminal pools and manages to retain savings compared to other protocols, despite marginally longer processing times.

Conclusion: The increasing demand for more testing globally can benefit from application of pooling, especially in resource-restrained situations of the low- and middle-income countries or situations of high testing demand. Singular testing in situations of low prevalence should be systematically discouraged.
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http://dx.doi.org/10.7189/jogh.10.020515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774501PMC
December 2020

Coronavirus epidemic in Croatia: case fatality decline during summer?

Croat Med J 2020 Dec;61(6):501-507

Ozren Polašek, University of Split School of Medicine, Šoltanska 22, 21000 Split, Croatia,

Aim: To describe the SARS-CoV-2 epidemic pattern in Croatia during February-September 2020 and compare the case fatality ratio (CFR) between spring and summer.

Methods: National data were used to calculate the weekly and monthly CFRs, stratified by three age groups: 0-64, 65-79, and 80+ years. We also calculated the standardized mortality ratios (SMR) to offset the differences in age composition.

Results: The epidemic consisted of the initial wave, a trough in June, and two conjoined summer waves, yielding 17206 coronavirus disease 2019 cases and 290 deaths. While the number of confirmed cases nearly quadrupled during summer, case fatality estimates decreased; CFR in spring was 4.81 (95% confidence interval 3.91-5.71), compared with 1.24 (1.06-1.42) in summer. The SMR for summer was 0.45 (0.37-0.55), suggesting that the case fatality risk halved compared with spring. Cardiovascular comorbidity was an important risk factor for case fatality (SMR 2.63 [2.20-3.13] during spring and 1.28 [1.02-1.59] during summer). The risk of death in ventilated patients remained unchanged (SMR 0.98 [0.77-1.24]).

Conclusions: The epidemic dynamics suggests summer decline in case fatality, except in ventilated patients. While the effect of comorbidity also decreased, cardiovascular comorbidity remained an important risk factor for death even during summer. A plethora of possible confounders and an ever-changing landscape of SARS-CoV-2 epidemic in Croatia require constant monitoring and evaluation, with an aim to prevent the uncontrolled spread of the virus and a disruption of health care functioning.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821368PMC
December 2020

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 2021

Have Lifestyle Habits and Psychological Well-Being Changed among Adolescents and Medical Students Due to COVID-19 Lockdown in Croatia?

Nutrients 2020 Dec 30;13(1). Epub 2020 Dec 30.

Department of Public Health, University of Split School of Medicine, 21000 Split, Croatia.

Objective: To investigate dietary habits, sleep and psychological well-being of adolescents and medical students during COVID-19 lockdown in Split, Croatia.

Methods: We surveyed 1326 students during 2018 and 2019, and compared their responses with 531 students enrolled in May 2020. Perceived stress, quality of life (QoL), happiness, anxiety, and optimism were assessed as proxies of psychological well-being, using general linear modelling.

Results: We found no substantial differences in dietary pattern between pre-lockdown and lockdown periods, including the overall Mediterranean diet (MD) adherence. However, the MD pattern changed, showing increased adherence to the MD pyramid for fruit, legumes, fish, and sweets, while cereals, nuts, and dairy intake decreased during COVID-19 lockdown. A third of students reported weight loss during lockdown, 19% reported weight gain, while physical activity remained rather stable. The most prominent change was feeling refreshed after a night's sleep, reported by 31.5% of students during lockdown vs. 8.5% before; median length of sleep duration increased by 1.5 h. Lockdown significantly affected QoL, happiness, optimism (all < 0.001), and perceived stress in students ( = 0.005). MD adherence was positively correlated with QoL and study time, and negatively with TV and mobile phone use in pre-lockdown period (all < 0.001). Interestingly, higher MD adherence was correlated with less perceived hardship and greater happiness and QoL during lockdown.

Conclusion: These insights provide valuable information for tailored interventions aimed at maintaining healthy lifestyle in young population. Given the numerous beneficial effects associated with MD adherence, modification of lifestyle through application of lifestyle medicine deserves a priority approach.
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http://dx.doi.org/10.3390/nu13010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830522PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Hyponatremia as a predictor of perforated acute appendicitis in pediatric population: A prospective study.

J Pediatr Surg 2021 Oct 8;56(10):1816-1821. Epub 2020 Oct 8.

Department of Public Health, University of Split, School of Medicine, Šoltanska 2, 21 000 Split, Croatia.

Background: The aim of this study was to investigate hyponatremia as a new biochemical marker associated with complicated appendicitis in the pediatric population.

Methods: Pediatric patients (n = 184) with acute appendicitis confirmed by histopathology were enrolled in a prospective cohort study from January 2019 to May 2020. Medical history, demographic and clinical data were recorded in the study protocol. Blood samples for biochemical analysis, electrolytes and acute inflammatory markers were taken before surgery. Patients were further divided in two groups, those with non-perforated (n = 148; 79%) and perforated appendicitis (n = 38; 21%).

Results: The mean serum sodium level in patients with complicated appendicitis was significantly lower compared to patients with non-complicated appendicitis (132.2 mmol/L vs. 139.2 mmol/L, p < 0.001). The receiver operating characteristic curve of plasma sodium concentration in patients who were diagnosed with perforated acute appendicitis showed an area under the curve of 0.983 (95% CI, 0.963-1.00). A cut-off-value of plasma sodium concentration of ≤135 mmol/L was shown to give the best possible sensitivity and specificity, 94.7% (95% CI: 82.2-99.3) and 88.5% (95% CI: 88.2-93.2) respectively (p < 0.001). Patients with complicated appendicitis were more likely to be younger than five years of age (10.5% vs. 1.4%, p = 0.005), have a duration of symptoms for >24 h (97.4% vs. 59.6%, p < 0.001), sodium serum concentration ≤135 mmol/L (89.5% vs. 5.5%, p < 0.001), body temperature >38.5 °C (47.4% vs. 11.0%, p < 0.001) and CRP serum concentration >62 mg/L (26% vs. 2%, p < 0.001).

Conclusion: Hyponatremia is a novel and very discriminative marker of complicated appendicitis in the pediatric population, and is therefore recommended in appendicitis diagnostic and treatment planning.

Type Of Study: Prospective comparative study LEVEL OF EVIDENCE: II.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.066DOI Listing
October 2021

Informing epidemic (research) responses in a timely fashion by knowledge management - a Zika virus use case.

Biol Open 2020 12 2;9(12). Epub 2020 Dec 2.

Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.

The response of pathophysiological research to emerging epidemics often occurs after the epidemic and, as a consequence, has little to no impact on improving patient outcomes or on developing high-quality evidence to inform clinical management strategies during the epidemic. Rapid and informed guidance of epidemic (research) responses to severe infectious disease outbreaks requires quick compilation and integration of existing pathophysiological knowledge. As a case study we chose the Zika virus (ZIKV) outbreak that started in 2015 to develop a proof-of-concept knowledge repository. To extract data from available sources and build a computationally tractable and comprehensive molecular interaction map we applied generic knowledge management software for literature mining, expert knowledge curation, data integration, reporting and visualization. A multi-disciplinary team of experts, including clinicians, virologists, bioinformaticians and knowledge management specialists, followed a pre-defined workflow for rapid integration and evaluation of available evidence. While conventional approaches usually require months to comb through the existing literature, the initial ZIKV KnowledgeBase (ZIKA KB) was completed within a few weeks. Recently we updated the ZIKA KB with additional curated data from the large amount of literature published since 2016 and made it publicly available through a web interface together with a step-by-step guide to ensure reproducibility of the described use case. In addition, a detailed online user manual is provided to enable the ZIKV research community to generate hypotheses, share knowledge, identify knowledge gaps, and interactively explore and interpret data. A workflow for rapid response during outbreaks was generated, validated and refined and is also made available. The process described here can be used for timely structuring of pathophysiological knowledge for future threats. The resulting structured biological knowledge is a helpful tool for computational data analysis and generation of predictive models and opens new avenues for infectious disease research. ZIKV Knowledgebase is available at www.zikaknowledgebase.eu.
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http://dx.doi.org/10.1242/bio.053934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725600PMC
December 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611474PMC
October 2020

A strategy to incorporate prior knowledge into correlation network cutoff selection.

Nat Commun 2020 10 14;11(1):5153. Epub 2020 Oct 14.

Institute of Computational Biology, Helmholtz Center Munich - German Research Center for Environmental Health, 85764, Neuherberg, Germany.

Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization.
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http://dx.doi.org/10.1038/s41467-020-18675-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560866PMC
October 2020

Genome-wide association study identifies 48 common genetic variants associated with handedness.

Nat Hum Behav 2021 01 28;5(1):59-70. Epub 2020 Sep 28.

Institute of Biological Psychiatry, Mental Health Services of Copenhagen, Copenhagen, Denmark.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (r = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.
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http://dx.doi.org/10.1038/s41562-020-00956-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116623PMC
January 2021

Global variability of the human IgG glycome.

Aging (Albany NY) 2020 08 12;12(15):15222-15259. Epub 2020 Aug 12.

Institute of Clinical Biochemistry, Priština, Kosovo.

Immunoglobulin G (IgG) is the most abundant serum antibody which structural characteristics and effector functions are modulated through the attachment of various sugar moieties called glycans. Composition of the IgG N-glycome changes with age of an individual and in different diseases. Variability of IgG glycosylation within a population is well studied and is known to be affected by both genetic and environmental factors. However, global inter-population differences in IgG glycosylation have never been properly addressed. Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG's fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability. IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing. Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.
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http://dx.doi.org/10.18632/aging.103884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467356PMC
August 2020

Thyroid hormone levels are associated with metabolic components: a cross-sectional study.

Croat Med J 2020 Jul;61(3):230-238

Tatijana Zemunik, Department of Medical Biology, University of Split School of Medicine,Šoltanska 2, 21000 Split, Croatia,

Aim: To analyze the association of thyroid function and hormone levels with metabolic syndrome (MetS) and its components.

Methods: This cross-sectional population-based study involved 2183 Croatian individuals with no history of thyroid disease, hypertension, diabetes, and hyperlipidemia. MetS was diagnosed according to the National Cholesterol Education Program's Adult Treatment Panel III criteria.

Results: We found no association between thyroid function groups and the prevalence of MetS and its components. Clinically hypothyroid participants showed significantly higher triceps skinfold measurements than subclinically hypothyroid and euthyroid participants. Furthermore, clinically hypothyroid participants had higher abdominal skinfold thickness than subclinically hypothyroid participants. Otherwise, suprailiac and abdominal skinfold measurements were higher in the subclinically and clinically hyperthyroid group of participants compared with euthyroid and subclinically hypothyroid participants. A strong positive association of thyroid-stimulating hormone (TSH) and strong negative association of free triiodothyronine (fT3) and free thyroxine (fT4) levels with HOMA-IR and cholesterol levels were found. Furthermore, the fT4 level also showed a strong negative association with HDL and triceps skinfold thickness.

Conclusions: This study supports the standing that TSH, fT3, and fT4 levels are important variables to determine the association of thyroid function with MetS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358678PMC
July 2020
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