1. Introduction
The activity of military personnel is associated with exposure to numerous harmful and stressful stimuli, such as noise, shock waves, physical injuries, and traumatic events. One of the most important problems in this group is the occurrence of traumatic brain injury (TBI), as experienced by 19% of veterans returning from Afghanistan and Iraq [1], which may further contribute to chronic traumatic encephalopathy. According to the report of the United States Armed Force Health Surveillance Center, there were 430,720 U.S. service members who sustained TBI between 2000 and the third quarter of 2020; the most frequent were mild (around 82%) [2]. Approximately 84% of TBIs are related to blast exposure and 63% are connected with loss of consciousness [3]. Regrettably, these statistics remain underestimated due to a large number of negligible subconcussive traumatic brain events, which are not reported to medical services, but their cumulative effect may also lead to chronic traumatic encephalopathy.
The development of various imaging techniques has enabled the notable broadening of knowledge regarding traumatic brain injury in military personnel. Of these techniques, the most effective are magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI), magnetic resonance spectroscopy (MRS), and susceptibility-weighted imaging (SWI) as well as positron emission tomography [4,5,6,7]. MRS, in particular its most common type—proton magnetic resonance spectroscopy (1HMRS), allows for a non-invasive examination of metabolites in brain tissue in vivo, namely N-acetyl aspartate (NAA), choline (Cho), creatine (Cr), myoinositol (mI), lipids (Lip), and lactate (Lac). The detected metabolites are markers of various cells and processes present in the brain tissue—N-acetyl aspartate is a marker of neuronal health, choline of cell membrane turnover, creatine of energy metabolism, and myoinositol of glial cells. These metabolites are found in the healthy brain. In states of pathology additional metabolites appear, such as lipids, which are markers of cell membranes and lactates that increase in such conditions as hypoxic or ischemic injury. Several studies focusing on the 1HMRS of soldiers’ brains [1,8,9,10,11,12,13,14] report contradictory results and different methods of measurement (as absolute units, a ratio to creatine, choline, or water). Thus, further research in this field is vital in order to investigate the potential health consequences of long-term military service, especially in terms of the presence of the first signs of chronic traumatic encephalopathy. The awareness of such sequelae will enable the provision of the highest standard of medical care for soldiers, tailored to their actual needs.
The aim of this study was to assess the most frequent anomalies in the MRI examination of the heads of soldiers. The second aim was to compare the relative concentrations of 1HMRS metabolites in the brain of soldiers and healthy age-matched controls.
2. Materials and Methods
2.1. Study Group
Overall, 54 professional soldiers, who continuingly served at least ten years and participated in international missions (such as in Iraq and Afghanistan), were included in the study group. The exclusion criteria were the presence of chronic diseases, neurological disorders, brain focal lesions, alcoholism, drug addiction, and contraindications to MRI examination. The mean age of the study group was 41.4 ± 4.0 years (range 32–52 years) and 100.0% of soldiers were male. In this group, 96.3% (n = 52) of soldiers preferred a right shooting position and only 3.7% (n = 2) a left shooting position. In this group, all soldiers were exposed to minor blasts, daily usage of long firearms, and intensive training, while 11.1% (n = 6) of soldiers had a history of blast exposure to improvised explosive devices.
2.2. Control Group
The control group consisted of 46 healthy males of the mean age of 40.2 ± 7.8 years (ranging between 25 and 53 years). The exclusion criteria in this group were: chronic diseases, neurological disorders, brain focal lesions, a history of head trauma, alcoholism, nicotinism, drug addiction, and contraindications to MRI examination.
A statistically significant difference in age was not detected between the study and the control group (p > 0.05).
2.3. MRI Examination Protocol
All MRI and single-voxel 1HMRS examinations of the head were performed with the use of 1.5 Tesla General Electric MRI system. Acquired MRI sequences were axial T1-weighted BRAVO, axial T2-weighted, and sagittal T2-weighted CUBE, which were further used for the positioning of 1HMRS volumes of interest. The 1HMRS volumes of interest (VOIs) were located symmetrically in the right and left frontal and occipital lobes. The spectra were obtained with the use of the point-resolved spectroscopy sequence (PRESS) with the echo time of 35 ms in which, apart from the analysis of N-acetyl aspartate, creatine, and choline peaks that are visible also in the long echo time, the detection of other metabolite peaks, such as myoinositol, is possible. The VOI dimensions were 2 × 2 × 2 cm. The detailed scan parameters are presented in Table 1.
2.4. Analysis of MRI and 1HMRS Data
Firstly, T1- and T2-weighted sequences were visually assessed for the presence of anatomical variations and abnormalities in the group of military personnel, both in the neurocranium and the visible part of the viscerocranium. All findings were categorized and the prevalence of particular anomalies was evaluated.
Furthermore, the analysis of the 1HMRS spectra of the soldiers and the control group was performed with the use of SAGE 7.0 software (Spectroscopy Analysis, GE). SAGE is an acronym for Spectroscopy Analysis by General Electric. SAGE provides file handling, display, processing, and analysis capability and is driven by a graphical user interface. The received signal was reconstructed and processed using the Gauss function with a line broadening of 8 Hz. The baseline present in the spectrum was not erased; however, the phase was manually corrected. The relative values of the concentration of N-acetylaspartate, choline, and myoinositol were calculated in relation to the creatine concentration. Statistically significant differences in the concentration of Cr between the soldiers and controls were not observed, for either the frontal (p = 0.099) or occipital lobes (p = 0.887). Following this, the relative concentrations of the particular substances obtained from symmetrical locations in the right and left frontal and occipital lobes were averaged to get the mean relative concentration of particular metabolites in the frontal and occipital lobes, respectively.
The mean relative concentrations of metabolites in the study and the control groups, were compared separately for the frontal and occipital lobes. Subsequently, the relative concentrations of metabolites in the frontal and occipital lobes were compared between the right and left hemispheres in the group of soldiers who preferred a right shooting position. A similar analysis within the group favoring a left shooting position could not be performed due to the small sample size. In the group of healthy controls, no significant differences in the concentration of metabolites between the hemispheres were detected (p > 0.05).
2.5. Statistical Analysis
The statistical analysis was performed with the use of IBM SPSS Statistics for Windows (IBM Corp.; Armonk, NY, USA), version 25.0. All measured values were presented as means ± standard deviation (SD), with 95% confidence intervals (CI). The level of statistical significance was set at p < 0.05. Initially, the normality of the data was assessed using the Shapiro–Wilk test. Subsequently, the mean relative concentrations of particular metabolites were compared between the study and the control group. If the obtained data did not have a normal distribution, the Mann–Whitney U test was applied. In cases where a normal distribution was observed, the equality of variances was evaluated with the use of Levene’s test. Student’s t-test was used for the analysis when the homogeneity of variance was observed, and Welch’s t-test was used when variances were heterogeneous. Furthermore, the relative concentrations of metabolites was compared between the hemispheres with the use of the Wilcoxon signed-rank test, as all data did not have a normal distribution.
3. Results
3.1. Findings from the MRI of the Heads of Soldiers
Overall, no anomaly was detected in 64.8% of the soldiers (n = 35)—one change in 33.3% (n = 18), two in 25.9% (n = 14), and three in 5.6% (n = 3) of the soldiers. In the neurocranium of soldiers the most frequently detected findings were the asymmetry of the lateral ventricles—11.1% (n = 6), dilated perivascular spaces—7.4% (n = 4), and enlargement of the subarachnoid spaces—7.4% (n = 4) as well as the presence of cavum septum pellucidum and cavum vergae—5.6% (n = 3). Additionally, a wide prevalence of sinusitis and paranasal sinus retention cysts was observed in the viscerocranium. A full summary of the most frequent findings from the head MRI examinations of the soldiers is presented in Table 2.
3.2. 1HMRS Spectroscopy–Soldiers vs. Control
The mean relative concentrations of particular metabolites were compared between the study and the control group for the frontal and occipital lobes separately. Means with standard deviations and 95% confidence intervals of the relative concentrations of particular metabolites within the frontal and occipital lobes of soldiers and healthy volunteers, as well as the p values obtained for the comparison of the mean relative concentrations of metabolites between these two groups, are shown in Table 3.
The results show that in the frontal lobes of the soldiers the mI/Cr (p = 0.005) ratio was significantly higher, while the NAA/Cr ratio was markedly lower (p = 0.001), than in the healthy group. However, the mean relative concentration of Cho/Cr was comparable for these two groups.
With regard to the occipital lobes, the NAA/Cr ratio was also significantly lower (p = 0.005) in military personnel compared to the control group. Furthermore, borderline statistical significance was observed for the mI/Cr ratio (p = 0.056), as there was a tendency to a higher mean relative concentration of mI in the soldiers’ occipital lobes, than within the control group. No notable difference in the mean relative concentration of choline was detected.
Exemplary spectra from VOIs in the brains of a healthy control and a soldier are shown on Figure 1.
3.3. 1HMRS Spectroscopy in Soldiers—The Comparison between the Brain Hemispheres
A comparison of the relative concentrations of metabolites between the hemispheres for the frontal and occipital lobes, separately, was only conducted in the group of soldiers who preferred a right shooting position (n = 52). The means with standard deviations and 95% confidence intervals of relative concentrations of particular metabolites within the right and left frontal and occipital lobes of soldiers preferring the right shooting position, as well as the p values obtained for their comparison, are presented in Table 4.
In the frontal lobes, the relative mean concentration of the mI/Cr (p < 0.001) ratio was significantly higher on the right side than on the left side—in this case the difference was particularly pronounced (2.446 ± 1.277 on the right side, 0.845 ± 0.251 on the left side). Furthermore, in the occipital lobes, the NAA/Cr (p = 0.003) ratio was markedly lower on the right side, in comparison to the left side. There was no statistically significant difference in the relative concentrations of the remaining metabolites, either in the frontal or occipital lobes.
4. Discussion
The principal purpose of the study was to assess the differences in the relative concentrations of brain metabolites between veterans and healthy, age-matched controls, as well as to compare the same between the brain hemispheres of the military personnel. Our paper provides evidence of significant differences in brain chemical composition between the two groups and between brain hemispheres, which has further implications on the health outcomes of former soldiers. To date, this is the first study on European soldiers with the use of 1HMRS of the brain.
The first important results of this study are the presence of a notably increased mI/Cr ratio in the frontal lobes, and to the lesser extent in the occipital lobes, as well as a decreased NAA/Cr ratio in the frontal and occipital lobes of soldiers, in comparison to healthy, age-matched controls. The comparison of our results with other studies is hindered by the inconsistency in their methods of results’ presentation—as a ratio to water [8], choline [1], or as absolute units [10]. Moreover, the majority of studies focus on the comparison of brain metabolites between veterans with and without post-traumatic stress disorder diagnoses [10,11,12,13,14] or the history of mild TBI [8,9,10], without the comparison to healthy controls. Nonetheless, some tendencies are visible and they are consistent with the results of our study. Sheth et al. discovered an increased mI/H2O ratio in veterans with a history of mild traumatic brain injury, especially in the group with suicidal thoughts and attempts [8]. Similar results regarding an increased mI/H2O ratio were also observed in other groups with frequent exposure to brain trauma, such as ice hockey players or American football players [15]. Myoinositol is an osmolyte and an astrocyte marker and its elevated concentration is linked with glial proliferation, secondary to microglial activation and astrocytosis [16]. Such a phenomenon was also discovered histologically in the frontal cortex of rats exposed to repetitive blast overpressure injury, where an increase in gliosis marker GFAP and microglia activation marker Iba-1 immunoreactivity was observed, together with signs of astrocyte and microglia hypertrophy [17]. In turn, a decrease in the relative concentration of NAA, similar to that observed in our study, was previously detected in veterans’ hippocampi [1,9,13,14], especially in groups with PTSD [13,14] and with a history of mild traumatic brain injury [9]. NAA is known as a marker of neuronal viability and its decline is associated with neuronal loss [15]. Interestingly, the long-term decrease of the NAA/Cr ratio was observed only in groups with chronic exposure to brain trauma, after a single brain trauma the NAA/Cr ratio recovers to the initial level after a few days [16]. Unfortunately, these molecular changes have their health implications. A reduction in the relative concentration of NAA correlates with poor long-term cognitive outcomes, lower neuropsychological measures of psychomotor speed, motor scanning and attention, impaired long-term memory, and attention deficits [16]. Moreover, lower NAA/Cr and NAA/mI ratios predict a higher hyperphosphorylated tau (p-tau) burden, which is a pathognomonic lesion of chronic traumatic encephalopathy [15]. Therefore, 1HMRS examination in the population of military workers may become a useful tool for the monitoring of the probability of chronic traumatic encephalopathy and its cognitive consequences. This may help to undertake adequate measures such as regular neurorehabiliation and neuropsychological care before irreversible changes in the brain occur.
Regarding variations in brain metabolites between sides in military personnel, statistically significant differences were observed for both the mI/Cr and NAA/Cr ratios. In soldiers preferring a right shooting position, the mI/Cr ratio was higher and the NAA/Cr ratio was lower in the right hemisphere compared to the left. Discrepancies in the mI/Cr ratio were observed only in the frontal lobes, while for the NAA/Cr ratio they were observed in the occipital lobes. Hence, the preferred shooting position may have an influence on the localization of more prominent brain damage. A markedly increased mI/Cr ratio in the right frontal lobe may be the consequence of vivid glial proliferation associated with neuroinflammation related to chronic traumatic encephalopathy [18]. Neuronal loss, reflected as a decrease in the NAA/Cr ratio, is more uniform in the frontal lobes as the difference between the sides was not detected, and may be a result of generalized atrophy of frontal and temporal lobes characteristic of chronic traumatic encephalopathy [18]. Meanwhile, a significantly lower NAA/Cr ratio in the right occipital lobe in comparison to left side might be caused by a neuronal loss due to repetitive brain countercoup injury secondary to a blast wave generated from shooting. The cumulative peak overpressure affecting the head of a trainee equipped with a 0.50 caliber sniper rifle with 20″ long barrel during three days of training ranged from 160–300 psi. Furthermore, the average peak overpressure for the head generated by the same type of rifle was approximately 6 psi [19]. The maximum wind speed associated with a blast overpressure at the level of 5 psi is equivalent to around 260 km per hour [20]. Hence, a more prominent exposure to blast overpressure on the one side may result in significant brain damage, and frequent switching of the shooting position should be recommended as a potential factor which may decrease the risk of chronic traumatic encephalopathy. Nonetheless, further research which also includes the analysis of brain metabolites in the group of soldiers preferring a left shooting position is necessary to confirm this hypothesis.
The most frequent findings In the neurocranium were asymmetry of the lateral ventricles (11.1%), dilated Virchow–Robin spaces (7.4%), and the enlargement of the subarachnoid spaces (7.4%) as well as the presence of cavum septum pellucidum and cavum vergae (5.6%). The prevalence of the lateral ventricles’ asymmetry in the population is approximately 6% [21], while for cavum septum pellucidum and cavum vergae it is about 1–2% [22,23]. The elevated frequency of these anomalies in military personnel in comparison to the general population was also observed by Riedy et al.—asymmetric ventricles were observed in 25.4% of cases, while the cavum septum pellucidum was present in 46.4% of cases [3]. The higher incidence of the lateral ventricles’ asymmetry and the enlargement of the subarachnoid spaces may be associated with the neuronal loss secondary to brain injury. The neuronal loss may be asymmetric, as our results regarding the differences in the NAA/Cr ratio between sides indicate, leading to the different sizes of the lateral ventricles. In turn, the presence of the cavum septum pellucidum and cavum vergae (fluid-filled spaces between the laminae of the septum pellucidum, located in its anterior and posterior part, respectively), generally regarded as anatomical variants, are characteristic findings in subjects with chronic traumatic encephalopathy. The postulated mechanism of their formation is the presence of shearing forces acting on the septum pellucidum due to blast wave propagation in the lateral ventricles causing its fenestration [24]. Their frequent occurrence were also observed among such sport professionals as football players or boxers. The size of the cavum septum pellucidum correlates with decreased performance on a list learning task and worse scores on tests of estimated verbal intelligence [25]. In addition, the prevalence of dilated perivascular spaces is between 2% and 3% of healthy population and it generally increases with advancing age [26]. However, it is also associated with mild traumatic brain injury as the probable reflection of early and permanent brain alterations [27]. The increased incidence of dilated Virchow–Robin spaces in veterans was found in the Riedy et al. study—nonetheless, it was as high as 64.3% [3]. Importantly, dilated perivascular spaces in the basal ganglia or centrum semiovale are associated with compromised nonverbal reasoning and visuospatial cognitive abilities [26]. Fortunately, brain ischemic lesions in our cohort were observed in only 5.6%. In other studies concentrating on military personnel, the frequency of such changes was notably higher—encephalomalacia was detected in 5.0% of cases and white matter hyperintensities in 29% to 51.8% of cases [3,28]. Overall, the prevalence of the previously mentioned anomalies was lower in our cohort in comparison to other similar studies, even though the mean age of our study group was higher, probably due to smaller exposure to brain injury events [3,28].
Another finding attracting attention is a high prevalence of sinus pathologies among soldiers—sinusitis was observed in 38.9% of the study group, sinus retention cysts in 14.8%, and sinonasal polyps in 3.7%. A similar observation was made by Riedy et al., as sinus disease was visible in the MRI examination of 48.3% soldiers [3]. These findings have clinical confirmation as well, since the symptoms related to the upper respiratory tract, especially the paranasal sinuses, are among the most frequent complaints of soldiers deployed in the Middle East [29]. Overall, deployed veterans are at a 29% increased risk for sinusitis, in comparison to non-deployed veterans [30]. There is an abundance of possible causes of an elevated incidence of sinus disease—such as exposure to particulate matter, smoke, toxic chemical substances, aeroallergens, an unfavorable climate, and air-conditioning as well as chronic stress and close living quarters [29]. Nonetheless, further research on the etiology of deployment-related sinus disease is vital. It is crucial for active-duty service members to have access to proper otorhinolaryngological and allergological care during and after their missions.
This study also has certain limitations. Firstly, the size of the study group is moderate. However, the number of our National Army soldiers participating in the international missions is incomparably smaller than for the U.S. Army, on which all previous studies utilizing 1HMRS were conducted, and therefore a larger sample was unavailable. Secondly, the use of Cr as a reference to the calculation of metabolite ratio is controversial, as its absolute concentration changes with age and in subjects who have undergone traumatic brain injury [16]. Nevertheless, any statistically significant difference in age or absolute concentration of Cr was not detected between the study and control group in the current paper (p > 0.05).
5. Conclusions
In summary, the military personnel had an increased mI/Cr ratio in the frontal lobes, and to the lesser extent in the occipital lobes, as well as a decreased NAA/Cr ratio in the frontal and occipital lobes, in comparison to healthy, age-matched controls. In soldiers preferring a right shooting position the mI/Cr ratio was higher and the NAA/Cr ratio was lower in the right hemisphere compared to the left. These changes are associated with astrogliosis and neuronal loss, presumably secondary to repetitive mild traumatic brain injury, and may be a first sign of chronic traumatic encephalopathy. The most frequent findings in the MRI examinations of the heads of soldiers were: asymmetric lateral ventricles, dilated perivascular spaces, enlargement of the subarachnoid spaces as well as the presence of cavum septum pellucidum and cavum vergae. The accompanying high frequency of sinus disease should also be noted.
Conceptualization, A.U.; methodology, A.U. and I.K.; validation, P.G., M.B. and W.G.; formal analysis, I.K.; investigation, A.U. and I.K.; data curation, I.K., P.G., M.B. and W.G.; writing—original draft preparation, I.K.; writing—review and editing, A.U., P.G., M.B. and W.G.; supervision, A.U. and W.G. All authors have read and agreed to the published version of the manuscript.
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Jagiellonian University Ethics Committee (approval No 1072.6120.196.2019, date of approval 19 September 2019).
Not applicable.
The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.
The authors declare no conflict of interest.
Footnotes
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Enlarge this image.Figure 1. Exemplary 1HMRS spectra obtained from volumes of interest in the brains of (A) a healthy control and (B) a soldier.
Magnetic resonance imaging scan parameters used in the present study.
| Sequence | TR [ms] | TE [ms] | NEX | Slice Thickness [mm] |
|---|---|---|---|---|
| T1 BRAVO | 8.6 | 3.2 | 0.5 | 2 |
| T2 | 4374 | 102 | 1 | 5 |
| T2 CUBE | 2500 | 114.7 | 1 | 1.4 |
| PRESS | 1500 | 35 | 8 | 20 |
TE—echo time, TR—repetition time, NEX—number of excitations, PRESS—point-resolved spectroscopy sequence.
Anatomic variations and abnormalities observed in magnetic resonance imaging examinations of the heads of soldiers.
| Neurocranium | Viscerocranium | ||||
|---|---|---|---|---|---|
| Finding | % of Soldiers | No. of Soldiers | Finding | % of Soldiers | No. of Soldiers |
| Asymmetry of the lateral ventricles | 11.1% | 6 | Sinusitis | 38.9% | 21 |
| Dilated perivascular spaces | 7.4% | 4 | Paranasal sinus retention cyst | 14.8% | 8 |
| Enlargement of the subarachnoid spaces | 7.4% | 4 | Sinonasal polyps | 3.7% | 2 |
| Cavum septum pellucidum and cavum vergae | 5.6% | 3 | |||
| Post-ischemic encephalomalacia | 3.7% | 2 | |||
| Pineal cyst | 3.7% | 2 | |||
| White matter hyperintensities | 1.9% | 1 | |||
| Empty sella | 1.9% | 1 | |||
| Meningioma | 1.9% | 1 | |||
The comparison of mean relative concentrations of metabolites in the frontal and occipital lobes between soldiers and controls.
| Location | Metabolite | Soldiers | Control Group | |||
|---|---|---|---|---|---|---|
| Mean ± SD | 95% CI | Mean ± SD | 95% CI | p Value | ||
| Frontal lobes | NAA/Cr | 1.981 ± 0.282 | 1.905–2.058 | 2.220 ± 0.380 | 2.107–2.333 | 0.001 |
| Cho/Cr | 0.943 ± 0.125 | 0.909–0.977 | 0.907 ± 0.100 | 0.878–0.937 | 0.121 | |
| mI/Cr | 1.936 ± 1.009 | 1.637–2.236 | 1.374 ± 0.538 | 1.214–1.534 | 0.005 | |
| Occipital lobes | NAA/Cr | 1.959 ± 0.232 | 1.896–2.023 | 2.108 ± 0.287 | 2.023–2.193 | 0.005 |
| Cho/Cr | 0.822 ± 0.347 | 0.727–0.917 | 0.794 ± 0.071 | 0.773–0.815 | 0.714 | |
| mI/Cr | 0.821 ± 0.096 | 0.795–0.848 | 0.785 ± 0.092 | 0.758–0.812 | 0.056 | |
CI—confidence interval, Cho—choline, Cr—creatine, mI—myoinositol, NAA—N-acetylaspartate, SD—standard deviation
The comparison of the relative concentrations of metabolites in the right and left frontal and occipital lobes of soldiers preferring a right shooting position.
| Location | Metabolite | Right Side | Left Side | |||
|---|---|---|---|---|---|---|
| Mean ± SD | 95% CI | Mean ± SD | 95% CI | p Value | ||
| Frontal lobes | NAA/Cr | 2.009 ± 0.407 | 1.896–2.122 | 1.936 ± 0.435 | 1.815–2.057 | 0.240 |
| Cho/Cr | 0.926 ± 0.151 | 0.885–0.968 | 0.950 ± 0.201 | 0.894–1.006 | 0.514 | |
| mI/Cr | 2.446 ± 1.277 | 2.099–2.848 | 0.845 ± 0.251 | 0.783–0.927 | <0.001 | |
| Occipital lobes | NAA/Cr | 1.875 ± 0.279 | 1.797–1.953 | 2.056 ± 0.332 | 1.963–2.148 | 0.003 |
| Cho/Cr | 0.773 ± 0.112 | 0.737–0.805 | 0.781 ± 0.122 | 0.745–0.818 | 0.640 | |
| mI/Cr | 0.805 ± 0.113 | 0.774–0.837 | 0.831 ± 0.127 | 0.796–0.867 | 0.230 | |
CI—confidence interval, Cho—choline, Cr—creatine, mI—myoinositol, NAA—N-acetylaspartate, SD—standard deviation
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; Guła, Przemysław 2 ; Brożyna, Maciej 2 ; Guz, Wiesław 2 1 Department of Radiology, Jagiellonian University Medical College, 19 Kopernika Street, 31-501 Krakow, Poland
2 Collegium of Medical Sciences, University of Rzeszow, 2a Waclaw Kopisto Avenue, 35-959 Rzeszow, Poland