Development of a model for predicting risk from breast interval cancer in the female population in the Republic of Croatia.

There are several risk prediction models for screen-detected breast cancer but to the best of our knowledge, none for predicting risk from the interval cancer in breast cancer screening. The challenge for developing such a model was that the risk factors for both cancers appear to be similar, but the effects of interval cancer on women's health are more severe due to its higher biological aggressiveness. Our model is based on risk factors identified in the female population in the Republic of Croatia. Anonymized data from 472,395 women who participated in the National Program for Early Detection of Breast Cancer during the first three cycles of the program (October 2006-May 2014) were used. Cancer data from the Breast Cancer Screening Registry were linked by the data linkage method with data from the Cancer Registry of the Republic of Croatia. A total of 789 women with interval cancer and 3,530 women with screen-detected cancer were identified. Multivariate logistic regression in R was used to model the difference between participants with screen-detected cancer and those with interval cancer, using the general linear model (glm) function. The variables used for the analysis were selected using the all subset regression analysis method. The criterion of the least complexity parameter, the Cp-Mallows index, was chosen. Three variables were found to be statistically significant in the model: breast tissue density (p=0.038), hormone replacement therapy (p=0.034), and a first-degree family history of breast cancer (p<0.001). The resulting model has a discriminant accuracy of 0.658 (95% CI 0.602-0.713). Although our model has poorer predictor reliability, its advantage is that it is based on real-world data and that the criteria for interval cancer were strictly followed. It is best suited for use in the Croatian population of women because we have identified the available risk factors for the development of interval cancer in our population, but with knowledge of a specific epidemiological environment, it can be more widely applied. The model can be used to make recommendations for individual screening participants. The variables of breast tissue density and first-degree family history of breast cancer increase the likelihood of interval cancer and indicate an increased risk of detecting interval cancer between mammograms. Consequently, individualized risk screening should be considered (modification of screening interval or additional screening by magnetic resonance or ultrasound). According to the model, hormone replacement therapy is positively related to screen-detected cancer, and participants who use hormone replacement therapy must be medically monitored due to the increased risk of screen-detected cancer. In addition, participants in the screening program who use hormone replacement therapy and have a higher density of breast tissue should be encouraged to have more frequent mammograms.

Vaccination attitudes, beliefs and behaviours among primary health care workers in northern Croatia.

Primary health care workers (HCWs) provide almost all vaccine services in Croatia, so they play an essential role in vaccine recommendations and uptake. The aim of this study was to determine the level of vaccine hesitancy among primary HCWs, to identify differences between nurses and physicians in attitudes, beliefs and behaviours towards vaccination, and to determine predictors of vaccine hesitancy among HCWs. We conducted a cross-sectional study from July to December in 2018 among physicians and nurses employed in the services of epidemiology, public health, school medicine, pediatrics and general practice/family medicine in Primorje-Gorski Kotar County, a primarily urban region with a population around 300 000 in the northern part of Croatia. The list of primary HCWs offices was obtained from the Croatian Health Insurance Fond website. We used a self-administered questionnaire on their attitudes, beliefs and behaviours relative to vaccination. Obtained response rate was 65.5% (324/495) of eligible primary HCWs; 64.1% (143/223) of physicians and 66.5% (181/272) of nurses. Seventeen percent of HCWs were identified as vaccine hesitant, and in univariate analysis, we observed an association between HCWs occupation and their own vaccination against flu (p = 0.001), measles (p = 0.016) and HPV (p = 0.025). Nurses and physicians differed (p < 0.001) in their general attitude, beliefs and behaviours towards vaccination, with a higher level of hesitancy among nurses. In multiple logistic regression, those more likely to be vaccine-hesitant were nurses (AOR = 5.73, 95%CI = 2.48-13.24), those who were uncertain or would never receive a vaccine against measles (AOR=11.13; 95%CI=5.37-23.10) and HPV (AOR=5.02; 95%CI=2.60-9.74), as well as those who had encountered a serious adverse event following immunization (AOR=7.55; 95%CI=3.13-19.18). As personal hesitancy may have a negative impact on vaccination education and recommendations, and therefore vaccine coverage, it is necessary to implement interventions to increase vaccination knowledge and confidence among primary health care workers, especially nurses.

OPPORTUNISTIC SCREENING FOR COLORECTAL CANCER IN HIGH-RISK PATIENTS IN FAMILY MEDICINE PRACTICES IN THE REPUBLIC OF CROATIA.

Colorectal cancer is a malignant neoplasm which has an increasing incidence and represents a global public health problem. The majority of patients are diagnosed after the age of 50, and the risk of developing it over lifetime is 5%. Development of preventive, diagnostic and treatment methods has resulted in a significant reduction in mortality and other negative clinical outcomes. Precisely because of the efficient method of prevention and early detection of this disease, numerous countries, including Croatia, have organized national colorectal cancer screening and monitoring programs. However, these programs are primarily organized for the population with the usual, i.e. average risk of developing colorectal cancer. High-risk groups include persons with endoscopically detected and removed colon polyps, persons surgically treated for colon cancer, persons with a positive family history of colorectal cancer, persons with inflammatory bowel diseases, individuals and families with hereditary disorders or genetic mutations that increase the risk of this disease several fold, persons with acromegaly, and patients who have undergone ureterosigmoidostomy. Recommendations for the detection and monitoring of high-risk groups are often not defined clearly, and some of the existing ones are based mostly on scarce scientific evidence. It is commonly accepted that screening in high-risk groups should start at an earlier age, with shorter intervals between follow-ups. The basic diagnostic method for screening and monitoring in these patient groups is endoscopic monitoring, or colonoscopy. The aim of this review paper is to present the characteristics of the abovementioned risk groups and provide clear screening recommendations.

SMAD7 variant rs4939827 is associated with colorectal cancer risk in Croatian population.

BACKGROUND: Twenty common genetic variants have been associated with risk of developing colorectal cancer (CRC) in genome wide association studies to date. Since large differences between populations exist, generalisability of findings to any specific population needs to be confirmed. AIM: The aim of this study was to perform an association study between risk variants: rs10795668, rs16892766, rs3802842 and rs4939827 and CRC risk in Croatian population. METHODS: An association study was performed on 320 colorectal cancer cases and 594 controls recruited in Croatia. We genotyped four variants previously associated with CRC: rs10795668, rs16892766, rs3802842 and rs4939827. RESULTS: SMAD7 variant rs4939827 (18q21.1) was significantly associated with CRC risk in Croatian population. C allele was associated with a decreased risk, odds ratio (OR): 0.70 (95% CI: 0.57-0.85, P=3.5E-04). Compared to TT homozygotes, risk was reduced by 34% in heterozygotes (OR=0.66, 95% CI: 0.47-0.92) and by 52% in CC homozygotes (OR=0.48, 95% CI: 0.33-0.72). CONCLUSION: Our results show association of rs4939827 with colorectal cancer risk in Croatian population. The higher strength of the association in comparison to other studies suggests population-specific environmental or genetic factors may be modifying the association. More studies are needed to further describe role of rs4939827 in CRC. Likely reason for failure of replication for other 3 loci is inadequate study power.

Results of National Colorectal Cancer Screening Program in Croatia (2007-2011).

AIM: To study the epidemiologic indicators of uptake and characteristic colonoscopic findings in the Croatian National Colorectal Cancer Screening Program. METHODS: Colorectal cancer (CRC) was the second leading cause of cancer mortality in men (n = 1063, 49.77/100,000), as well as women (n = 803, 34.89/100,000) in Croatia in 2009. The Croatian National CRC Screening Program was established by the Ministry of Health and Social Welfare, and its implementation started in September, 2007. The coordinators were recruited in each county institute of public health with an obligation to provide fecal occult blood testing (FOBT) to the participants, followed by colonoscopy in all positive cases. The FOBT was performed by hypersensitive guaiac-based Hemognost card test (Biognost, Zagreb). The test and short questionnaire were delivered to the home addresses of all citizens aged 50-74 years consecutively during a 3-year period. Each participant was required to complete the questionnaire and send it together with the stool specimen on three test cards back to the institute for further analysis. About 4% FOBT positive cases are expected in normal risk populations. A descriptive analysis was performed. RESULTS: A total of 1,056,694 individuals (born between 1933-1945 and 1952-1957) were invited to screening by the end of September 2011. In total, 210,239 (19.9%) persons returned the envelope with a completed questionnaire, and 181,102 of them returned it with a correctly placed stool specimen on FOBT cards. Until now, 12,477 (6.9%), FOBT-positive patients have been found, which is at the upper limit of the expected values in European Guidelines for Quality Assurance in CRC Screening and Diagnosis [European Union (EU) Guidelines]. Colonoscopy was performed in 8541 cases (uptake 66%). Screening has identified CRC in 472 patients (5.5% of colonoscopied, 3.8% of FOBT-positive, and 0.26% of all screened individuals). This is also in the expected range according to EU Guidelines. Polyps were found and removed in 3329 (39% of colonoscopied) patients. The largest number of polyps were found in the left half of the colon: 64% (19%, 37% and 8% in the rectum, sigma, and descendens, respectively). The other 36% were detected in the proximal part (17% in the transverse colon and 19% in ceco-ascending colon). Small polyps in the rectum (5-10 mm in diameter), sigmoid and descending colon were histologically found to be tubular adenomas in 60% of cases, with a low degree of dysplasia, and 40% were classified as hyperplastic. Polyps of this size in the transverse or ceco-ascending colon in almost 20% had a histologically villous component, but still had a low degree of dysplasia. Polyps sized 10-20 mm in diameter were in 43% cases tubulovillous, and among them, 32% had areas with a high degree of dysplasia, especially those polyps in the ceco-ascending or transverse part. The characteristics of the Croatian CRC Screening National Program in the first 3 years were as follows: relatively low percentage of returned FOBT, higher number of FOBT-positive persons but still in the range for population-based programs, and higher number of pathologic findings (polyps and cancers). CONCLUSION: These results suggest a need for intervention strategies that include organizational changes and educational activities to improve awareness of CRC screening usefulness and increase participation rates.

Plasma interleukin-8 as a potential predictor of mortality in adult patients with severe traumatic brain injury.

Because of complex pathophysiology and severe consequences, traumatic brain injuries (TBI) are an important medical problem. Pathophysiology of TBI includes local and systemic stress response, in which interleukin-8 (IL-8) is considered as a key mediator of neuroinflammation. However, prognostic relevance of IL-8 measurement in adult patients with severe TBI is not certain. Therefore, IL-8 was determined in blood samples from central venous and jugular bulb catheter and in cerebrospinal fluid of twenty patients with isolated TBI at admission to Intensive Care Unit. None of the patients had history of stroke, dementia, autoimmune diseases, acute infection or medication with anti-inflammatory drugs. Ten patients died due to traumatic brain injury, while the other ten recovered well. While there was no significant difference of IL-8 levels in cerebrospinal fluid between survivors and nonsurvivors, central venous plasma level of IL-8 was significantly lower in survivors (71.00 +/- 14.17 pg/ml), than in nonsurvivors (111.26 +/- 16.9 pg/ml). Receiver Operating Characteristic (ROC) analysis revealed significant prognostic value for IL-8 in the blood as well as for the age of patients, Glasgow Coma Scale (GCS) and Acute Physiologic and Chronic Health Evaluation (APACHE II). These findings suggest that the central venous plasma values of IL-8 at admission might be an early predictive marker in patients with severe TBI, comparative to standard clinical prognostic markers such as APACHE II and GCS.

Association of methylenetetrahydrofolate (MTHFR) and apolipoprotein E (apo E) genotypes with homocysteine, vitamin and lipid levels in carotid stenosis.

The aim of the study was to investigate the association between methylenetetrahydrofolate (MTHFR) genotypes and levels of homocysteine (Hcy), folate, vitamin B12 and lipids as well as the association between apolipoprotein E (apo E) genotypes and levels of lipids in a Croatian healthy control group and a group of patients with > 70% carotid stenosis (CS). The study included 98 Croats, 38 patients with > 70% carotid stenosis and 60 age- and sex-matched controls. The MTHFR and apo E genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), Hcy by enzyme immunoassay, vitamins by immunochemiluminiscence, and lipids by spectrophotometric method. There was no difference between control subjects and CS patients in the distribution of C677T MTHFR genotypes (p=0. 786) and alleles (p=0.904), however, differences in the frequencies of apo E genotypes (p=0.012) and alleles (p=0.029) were statistically significant. The odds ratio for apo E 3/4 genotype was 3.93 (95% CI 1.23-12.61). Hyperhomocysteinemia (> or =15 micromol/L) was found in 11% of CS patients and 5% of control subjects. Total cholesterol, triglycerides, vitamin B12 and folate were statistically different in "all MTHFR genotypes" (p<0.001, p<0.01, p=0.044 and p=0.036, respectively), and in TC/TT (p<0.001, p=0.003, p=0.030 and p=0.032, respectively) groups. The levels of total cholesterol, LDL cholesterol and triglycerides in the apo E 3/3, and total cholesterol in the apo E 3/4 group yielded statistical difference. An association was found of apo E 3/4 genotype but not of MTHFR genotypes with the risk of CS. MTHFR and apo E affect blood lipid levels, which was statistically confirmed. An association was also recorded between hyperhomocysteinemia and patients with CS. Vitamin status in CS showed a statistically verified association with TC/TT MTHFR genotype. In the group of patients with TC/TT MTHFR genotype, lower vitamin B12 and higher folate values were recorded. The results of multiple logistic analysis showed that there was no statistical significance of Hcy levels (OR 2.403, p=0.334) or conventional vascular risk factors such as smoking habit (OR 0.505, p=0.149), age (OR 1.048, p=0.087) or sex (OR 2.037, p=0.112) in predicting CS.

Croatian population data for the C677T polymorphism in methylenetetrahydrofolate reductase: frequencies in healthy and atherosclerotic study groups.

BACKGROUND: The aim of this study was to investigate the frequency of C677T methylenetetrahydrofolate reductase (MTHFR) mutation in healthy Croatian volunteers and in patients with atherosclerosis. METHODS: The C677T MTHFR gene mutation was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 640 subjects, residents of the Zagreb city or Zagreb surroundings. Control group (n=298) was healthy blood donors. Patients (n=342) were divided into two groups of those with coronary heart disease, CAD (n=247) and those with >60% carotid stenosis, CS (n=95). RESULTS: CC genotype was recorded in 45% of healthy volunteers and 46% of patients (46.3% with CS and 46.2% with CAD). TC genotype was found in 49% of healthy volunteers and 45% of patients (46.3% with CS and 44.9% with CAD). There was no significant difference (p>0.05) from the control group in the genotype or allele frequency either for the overall group of patients with atherosclerosis or for the patient subgroups. CONCLUSION: The preliminary study of MTHFR polymorphism in control subjects and cardiovascular disease/carotid stenosis patients revealed that in Croats there was a low frequency of TT genotype (6% in controls vs. 9% in patients) and T allele (31% for cases and controls). Additionally, our results did not show significantly higher frequency of MTHFR mutation in CAD and CS studied groups.