ABSTRACT Vaccination coverage in the Federation of Bosnia and Herzegovina, in Bosnia and Herzegovina, has been declining since 2014. This qualitative study aimed to identify barriers and drivers to childhood vaccination for parents. The COM-B (capability-opportunity-motivation-behavior) model was the underpinning theoretical framework. Face-to-face interviews with 22 parents of fully (n = 6), delayed/partially vaccinated (n = 9) and unvaccinated (n = 7) children were conducted. Interviews explored individual factors (capability–knowledge and skills; motivation–attitudes, confidence and trust) and context factors (physical opportunity–information, access, health systems; and social opportunity – social support, norms). Data were analyzed in NVivo using content analysis exploring differences in COM factors by vaccination status and location. Parents of fully vaccinated children typically reported individual and context drivers to vaccination. They accepted vaccination, trusted health workers, and were content with services. Parents of delayed/partially vaccinated children fell into two subgroups: (1) Those who accepted vaccination and attributed delays to their organizational skills or frustration with appointment times. (2) Those fitting the profile of “vaccine hesitant” – generally valuing vaccination and health worker advice, yet with concerns often triggered by media/social media. Parents of unvaccinated children mentioned individual and context barriers to vaccination, notably significant concerns about safety, some distrust of health workers and resentment of mandatory vaccination. Urban/rural differences included urban parents being more likely to report experiences with vaccine shortages and very few had received information leaflets. The study identified complex and inter-related barriers and drivers to parents’ childhood vaccination behaviors. These insights have informed the development of tailored interventions to improve coverage.

BACKGROUND Indoor air quality (IAQ) in classrooms affects children's health and academic perfor-mance. The aim of this pilot study was to determine IAQ in elementary schools different in their inter-nal and external characteristics, in settings of COVID-19 epidemics. METHODS IAQ parameters: fine particulate matter (PM2,5) mass concentration, CO2 concentration, tempera-ture and relative humidity were measured in parallel in four elementary schools/classrooms during October (non-heating season) and four months (including holiday in January) of heating season. IAQ parameters were measured in settings of anti-epidemic restrictions (≤13 students in classroom, frequent ventilation). RESULTS During October, except in one school, PM2,5 concentrations were below the upper recommended value (25 μg/m³), but started rising in all schools in the heating season. The highest concentrations of PM2,5 were registered in two schools with closed or shortly opened windows. CO2 concentrations were mostly in the recommended range (up to 1000ppm) except in the school with constantly closed windows and in three schools in February when concentrations were higher. Except in one, the same school, and in January, both temperature and relative humidity were out of the recommended range (24,0-27,0°C in non-heating; 20,0-24,0°C in heating season; and 45-55%), with temperature mainly above and relative humidity mainly below it in three schools. The largest deviation in temperature and relative humidity were registered in urban schools. Registered differ-ences may be explained by different internal and external characteristics. CONCLUSION Despite anti-epidemic restrictions, most of the measured IAQ parameters were out of the recom-mended values in heating season. In addition, further deterioration of IAQ could be expected if all students had been presented in the classroom. Finally, to assure a healthy school environment in heating season, further optimisation of both indoor and outdoor conditions is needed in both pandemic and non-pandemic settings.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

ABSTRACT Vaccination uptake in the Federation of Bosnia and Herzegovina (FBiH), in Bosnia and Herzegovina, is suboptimal. This study aimed to (1) assess vaccination coverage, timeliness and drop-out for children born in 2015 and 2016 and compare these with official administrative coverage estimates, (2) identify associations between characteristics of children/caregivers and vaccination uptake. This was a cross-sectional study based on patient files for children 12–23 months (n = 1800) and 24–35 months (n = 1800). Methods were adapted from the World Health Organization cluster survey methodology. A two-stage stratified sampling procedure was conducted in urban and rural strata. A structured paper-based form was completed by a pediatrician/nurse from randomly selected primary care centers and patient files. Estimates were based on weighted analysis with a 95% confidence interval to account for the survey sampling design. Vaccination coverage was consistent with administrative coverage levels for BCG, DTP and MMR, and lower for HepB; all considerably lower than regional targets. Children in urban areas had lower vaccination uptake. An assumption that anti-vaccination sentiment prevails among caregivers was not confirmed; only 2% of children were not vaccinated at all, instead challenges related to delays and drop-out. An assumption of caregiver concerns for the MMR vaccine was confirmed with low uptake and delays. The FBiH has experienced vaccination schedule changes due to supply issues; findings confirmed that sustainability in supply and schedule is high priority. These data are new and provide important information for developing strategies to increase uptake.

BACKGROUND Energy drinks (EDs) are non-alcoholic beverages that contain caffeine and other ingredients, marketed for their actual or perceived effects as stimulants, energizers and performance enhancers. The aim of this pilot study was to evaluate patterns of EDs consumption in leisure, sports, and academic activities over the last year among a group of pregraduate students of the University of Sarajevo, Bosnia and Herzegovina. STUDY DESIGN A cross-sectional study conducted by an online questionnaire-based survey. METHODS An anonymous questionnaire was mainly based on a Consortium Nomisma-Areté questionnaire [background information and consumer profile, general EDs consumption practices and reasons; alcohol mixed with EDs (AmEDs) consumption, EDs consumption in sports, consumption of other caffeinated beverages], and an additional part to evaluate EDs consumption during academic activities. RESULTS Out of 812 respondents from 22 faculties (participation rate of 23%), mean age 21.37 ± 1.98 years, 498 (61.7%) reported EDs consumption over the last year. Three main reasons for EDs consumption were to stay awake (58.2%), to enjoy the taste (46.8%), and to boost energy (38.0%). Energy drinks were mainly consumed less than once a month (70.5%), most frequently during academic activity (50.4%), less frequently mixed with alcohol for relaxation (21.5%), and only rarely in association with sports or other physical activity (10%). Drinking coffee (OR = 2.022; 95% CI 1.416-2.830; p < 0.001) and being a higher year student (OR = 0.723; 95% CI 0.639-0.819; p < 0.001) were independent predictors for EDs consumption; being single and living with parents (OR = 17.138; 95% CI 1.328-221.528; p = 0.030) for consumption of AmEDs; and being a man (OR = 2.251; 95% CI 1.493-3.392; p < 0.001) and living in urban environment (OR = 1.193; 95% CI 1.125-3.251; p = 0.017) for consuming EDs in association with sports or other physical activity. CONCLUSION Based on these preliminary data and taking low participation rate into account, EDs consumption seems not to be alarming among university students in our region. EDs are most frequently consumed during academic activity, less frequently mixed with alcohol for relaxation, and only rarely in association with sports or other physical activity. However, as EDs are increasingly aggressively promoted and easily accessible, the larger study is warranted to provide more reliable and up to date conclusions, and if necessary, to inform measures preventing health risks associated with EDs consumption.

Diabetes mellitus (DM) as a chronic condition is a growing global problem. Its numerous complications, including ocular diseases, affect patients’ quality and length of life. Metformin is an effective, safe, and inexpensive first-line pharma-cotherapy for type 2 diabetes (T2D). The current evidence indicates metformin’s multiple sites of action and multiple molecular mechanisms leading to its beneficial impact on metabolism, inflammation, oxidative stress, aging, as well as to its cardiovascular, neurological, bone, and antiproliferative properties. These impacts are the result of its acting on adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Limited data suggest the protective role of metformin on microvascular ocular complications, including retinopathy, glaucoma, and age-related macular degeneration in patients with T2D. However, to confirm its mentioned protective and therapeutic effects, more large, randomized, double-blind, and placebo-controlled clinical studies are needed.

OBJECTIVE The aim of this study was to assess the relationship between the use of neuroenhancing substances, exam anxiety and academic performance among first-year Bosnian-Herzegovinian (BH) university students. METHODS In a cross-sectional study, an ad hoc questionnaire was delivered to a sample of BH first-year university students. The following data were collected: socio-demographic features, consumption of neuroenchancing substances, the Westside Test Anxiety Scale (WTAS) and academic performance. RESULTS A total of 214 students were included. Consumption of lifestyle substances, coffee, energy drinks, nicotine, alcohol, and marijuana, for the purpose of neuroenhancement increased during the week before the exams. OTC cognitive enhancer use was reported by 31.0%, and of benzodiazepines by 1.5% of students. No psycostimulants were used. A high to extremely high exam WTAS score was reported in 38.3% students. The exam WTAS score was positively correlated with consumption of coffee (rho=0.31; P<0.001), energy drinks (rho=0.18; P=0.009), and nicotine (rho=0.22; P=0.001), and negatively correlated with last exam grade (rho=-0.33; P<0.001). The exam WTAS score was a significant independent predictor (OR=0.55; 95% CI 0.31 to 0.97, P=0.039) for self-assessed academic performance. Self-assessed academic performance was positively correlated with last exam grade (rho=0.15; P=0.043). CONCLUSIONS Although first-year BH university students do not seem to use either prescription or illicit psycostimulants, the consumption of nicotine, alcohol, and marijuana is worrying. However, the consumption of these neuroenhancing substances seems not to be related to better self-assessed academic performance. Finally, exam anxiety seems to be a significant problem among BH first-year university students.

OBJECTIVE The aim was to study the association of the use of an oral antihyperglycemic agent metformin with the presence of ocular complications in patients with type 2 diabetes (T2D). METHODS Medical records were reviewed for 234 patients with diagnosed T2D. 81.2% (n=190) patients were using metformin and 18.8% (n=44) using other oral antihyperglycemic agents. Plasma glucose concentration, glycated haemoglobin, and the presence of ocular complications in patients treated with metformin were compared to those in patients treated with other oral antihyperglycemic agents. RESULTS Ocular complications occurred in 65 patients (27.8%). Patients treated with metformin had fewer ocular complications compared to patients treated with other oral antihyperglycemic agents (χ2=19.985; p<0.0001). After adjustment for gender, age, duration of T2D, serum concentration of cholesterol, smoking, body mass index and presence of other diseases, treatment with metformin decreased the odds of both glaucoma (OR=0.14, 95% CI: 0.03-0.57, p=0.006) and diabetic retinopathy (OR=0.33, 95% CI: 0.14-0.82, p=0.017) compared with other oral antihyperglycemic agents. CONCLUSION Our results suggest that metformin may have a protective effect on ocular complications, especially glaucoma, in patients with T2D. The effects of metformin either regarding prevention of ocular complications or ocular complications already developed in patients with T2D, should be further investigated.

ABSTRACT Aminoglycoside pharmacokinetics (PK) is expected to change in neonates with perinatal asphyxia treated with therapeutic hypothermia (PATH). Several amikacin dosing guidelines have been proposed for treating neonates with (suspected) septicemia; however, none provide adjustments for cases of PATH. Therefore, we aimed to quantify the differences in amikacin PK between neonates with and without PATH to propose suitable dosing recommendations. Based on amikacin therapeutic drug monitoring data collected retrospectively from neonates with PATH, combined with a published data set, we assessed the impact of PATH on amikacin PK by using population modeling. Monte Carlo and stochastic simulations were performed to establish amikacin exposures in neonates with PATH after dosing according to the current guidelines and according to proposed model-derived dosing guidelines. Amikacin clearance was decreased 40.6% in neonates with PATH, with no changes in volume of distribution. Simulations showed that increasing the dosing interval by 12 h results in a decrease in the percentage of neonates reaching toxic trough levels (>5 mg/liter), from 40 to 76% to 14 to 25%, while still reaching efficacy targets compared to the results of current dosing regimens. Based on this study, a 12-h increase in the amikacin dosing interval in neonates with PATH is proposed to correct for the reduced clearance, yielding safe and effective exposures. As amikacin is renally excreted, further studies into other renally excreted drugs may be required, as their clearance may also be impaired.

AIMS Although ketorolac analgesia is linked only to the S-enantiomer, there is limited information on the stereo-selective pharmacokinetics of this agent. We studied the stereo-selective pharmacokinetics of ketorolac in a pooled dataset of two studies, with women at delivery and 4-5 months postpartum, and males and nonpregnant females. METHODS Nonlinear mixed-effect modelling was used to evaluate the stereo-selective pharmacokinetics of ketorolac tromethamine after a single intravenous injection immediately after delivery (n = 41), 4-5 months postpartum (n = 8, paired), and in male (n = 12) and nonpregnant female (n = 14) subjects. All of the males and six of the nonpregnant females were recruited from another study, in which they were undergoing blood sampling for 24 h. All remaining cases underwent blood sampling for 8 h. RESULTS For both the R- and S-enantiomers, body weight affected ketorolac clearance. In addition, clearance for both enantiomers was 36% [95% confidence interval (CI) 15%, 58%] higher in male than in female subjects of the same body weight, and 55% (95% CI 33%, 78%) higher in women at delivery than in nonpregnant women of the same body weight. Women at delivery also had a 27% (95% CI 8%, 46%) higher distribution volume than nonpregnant women. The proportional effects of the covariates were not significantly different for the two ketorolac enantiomers. CONCLUSIONS Besides the anticipated impact of body weight on clearance, R- and S-ketorolac clearance is increased in male subjects and in women at delivery. To reach an exposure equivalent to that in nonpregnant women, males should receive a 36% increased ketorolac dose and pregnant women a 55% increased dose, in addition to a dose adjustment by body weight.

ABSTRACT Introduction: For safe and effective use of antibacterial agents in neonates, specific knowledge on the pharmacokinetics (PK) and its covariates is needed. This necessitates a stepwise approach, including prospective validation. Areas covered: We describe our approach throughout almost two decades to improve amikacin exposure in neonates. A dosing regimen has been developed and validated using pharmacometrics, considering current weight, postnatal age, perinatal asphyxia, and ibuprofen use. This regimen has been developed based on clinical and therapeutic drug monitoring (TDM) data collected during routine care, and subsequently underwent prospective validation. A similar approach has been scheduled to quantify the impact of hypothermia. Besides plasma observations, datasets on deep compartment PK were also collected. Finally, the available literature on developmental toxicology (hearing, renal) of amikacin is summarized. Expert opinion: The amikacin model reflects a semi-physiological function for glomerular filtration. Consequently, this model can be used to develop dosing regimens for other aminoglycosides or to validate physiology-based pharmacokinetic models. Future studies should explore safety with incorporation of covariates like pharmacogenetics, biomarkers, and long-term outcomes. This includes a search for mechanisms of developmental toxicity. Following knowledge generation and grading the level of evidence in support of data, dissemination and implementation initiatives are needed.

Racemic ketorolac clearance (CL) is significantly higher at delivery, but S-ketorolac disposition determines the analgesic effects. The aim of this study was to investigate the effect of pregnancy and postpartum period on enantiomer-specific (S and R) intravenous (IV) ketorolac pharmacokinetics (PKs). Data in women shortly following cesarean delivery (n=39) were pooled with data in a subgroup of these women that was reevaluated in the later postpartum period (postpartum group, n=8/39) and with eight healthy female volunteers. All women received single IV bolus of 30 mg ketorolac tromethamine. Five plasma samples were collected at 1, 2, 4, 6, and 8 hours and plasma concentrations were determined using high performance liquid chromatography. Enantiomer-specific PKs were calculated using PKSolver. Unpaired analysis showed that distribution volume at steady state (Vss, L/kg) for S- and R-ketorolac was significantly higher in women shortly following cesarean delivery (n=31) compared to postpartum group (n=8) or to healthy female volunteers (n=8). CL, CL to body weight, and CL to body surface area (CL/BSA) for S- and R-ketorolac were also significantly higher in women following delivery. In addition, S/R-ketorolac CL/BSA ratio was significantly higher at delivery. Paired PK analysis in eight women shortly following delivery and in postpartum group showed the same pattern. Finally, the simultaneous increase in CL and Vss resulted in similar estimates for elimination half-life in both unpaired and paired analysis. In conclusion, pregnancy affects S-, R-, and S/R-ketorolac disposition. This is of clinical relevance since S-ketorolac (analgesia) CL is even more increased compared to R-ketorolac CL, and S/R-ketorolac CL ratio is higher following delivery compared to postpartum period or to healthy female volunteers.