In several laboratory animal studies, it has been documented that the hearing, vision, and brain can be injured due to exposure to organic solvents. This finding formed the background for a pilot study (n = 16) aimed at identifying new ways of qualifying diagnostics, treatment, and rehabilitation of patients suffering from brain injury due to exposure to organic solvents, also referred to as toxic encephalopathy. Diagnosing toxic encephalopathy is complicated because the symptoms of this type of diffuse brain injury are non-specific. So, it was initially hypothesised that some of the difficulties involved in diagnosing toxic encephalopathy could be minimized by extending the diagnostic procedure. Apart from clinical interviewing and neuropsychological testing, the diagnosis should include the examination of hearing and vision. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty. On the basis of ranking, only one patient in the pilot study was considered to have a normal neuropsychological test profile, which was defined as a test profile without any marked deviations when compared with a normal population. A total of 10 patients were considered to have "discrete problems." These patients had a test profile showing either a few strikingly negative results or an array of results slightly below the expected level when compared with a normal population. A total of four patients were considered to suffer from "moderate problems" and one patient from "severe problems." The patients with "moderate problems" and "severe problems" showed consistent negative results and an unambiguous negative test profile. However, the overall results of all neuropsychological examinations performed revealed a dispersed picture. Quite remarkably, all the 13 patients who had their hearing examined showed a loss of hearing, 7 patients complained about tinnitus, and all patients had a history of exposure to both noise and organic solvents, which had not been observed at the initial examination, but seemed to have serious implications for their prognosis and future life.
Keywords: Concurrent effects between noise and solvents, examination procedures, handicap, multidisciplinary, neuropsychological impairment, toxic encephalopathy, work-related injury
|How to cite this article:|
Sorensen A M, Shapiro A, Lund S P, Brun B, Rosenberg T, Lykke J. Toxic encephalopathy and noise-induced hearing loss. Noise Health 2006;8:139-46
For more than a decade, noise-induced hearing loss has been among the most frequently reported work-related health effects in Denmark, and although, the number of reported cases has decreased, the number of approved cases has not [Table - 1]. The change in the number of reported cases may reflect several tendencies, one being the reduction in the exposure to noise in the industry. Noise-induced hearing loss is appearing gradually and the individual may not notice or want to reconcile the problems of hearing; therefore, both the number of reported and approved cases of hearing impairment may differ substantially from the figures in the statistics.
Another reported health effect is chronic toxic encephalopathy following exposure to organic solvents. For more than 25 years, the authorities in Denmark have recognized that workers exposed to organic solvents may develop toxic encephalopathy and compensations have been claimed and awarded to a number of cases each year. The diagnosis is primarily established on the basis of an extensive clinical examination made by an occupational physician, neurologist, and psychiatrist; a neuropsychological or neurobehavioral test; and a documented history of prolonged exposure to organic solvents.  Internationally, it has been recognized that the exposure to organic solvents may lead to toxic encephalopathy. In Denmark, this has led to a dramatic reduction in the application of organic solvents and the number of recognized cases per year [Table - 1] has decreased, primarily due to removal of the fumes at the source and substitution of the organic solvents with other substances like water-based paint, linseed oil for degreasing, etc. However, the fact that organic solvent exposure may lead to impairment of hearing and vision and the concurrent effects of exposure to organic solvents and noise are not commonly known and accepted in the Danish society.
Research investigations that were carried out as early as in the year 1800, indicated that people exposed to organic solvents may suffer damage to the central nervous system and display diffuse symptoms that manifest themselves, e.g., as impaired intellectual functions and changes in personality.  Towards the end of the 1900s, industry's demand for organic solvents increased dramatically. Consequently, a severe increase in diagnosed chronic damage to the brain ,, was demonstrated by epidemiologic studies in Northern Europe. In Denmark, since the 1980's, these scientific findings have been used as evidence by the painters' union, on behalf of its members, to raise a claim for compensation, which has been disagreed by the representatives of the employers' organizations.
Toxic encephalopathy appears as a diffuse brain injury and is characterized by a broad spectrum of non-specific symptoms of intellectual, emotional, and social deficiencies as well as by a number of physical symptoms such as balance problems. , However, no single symptom is considered to be sufficient for the diagnosis of toxic encephalopathy. As a consequence, it is difficult to determine whether, for instance, a patient's intellectual deficiencies are a symptom of toxic encephalopathy, a symptom of excessive drinking, or the result of a fairly low intelligence. ,
A pilot study aimed at identifying new ways of qualifying diagnostic procedures, treatment, and rehabilitation of patients suffering from toxic encephalopathy was initiated. The study was primarily based on laboratory animal studies indicating that exposure to neurotoxic solvents cause damage not only to the brain but also to the senses such as the vision ,, and hearing. ,, This led to the hypothesis that some of the complexity involved in diagnosing toxic encephalopathy could be overcome simply by extending the diagnostic procedures to include testing of the patients' vision and hearing. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty.
The pilot study was a multidisciplinary research project carried out by a biologist from the Danish National Institute of Occupational Health, an ophthalmologist from the Danish National Eye Clinic for the Visually Impaired, an otologist from Bispebjerg Hospital's department of audiology, and a psychiatrist and several psychologists from Sankt Hans Hospital, which is in fact a psychiatric hospital but also houses a special facility ward M9 for inpatient treatment and rehabilitation of patients suffering from toxic encephalopathy and other types of brain damage. The examined patients were selected from M9's list of former patients who had previously been diagnosed as suffering from toxic encephalopathy and had all been through rehabilitation at Sankt Hans Hospital during the period 1993-1998 for more than three months.
The pilot study should have retested 20 patients for all modalities, but some patients did not agree to participate in the neuropsychological testing and some other patients refused to participate in the testing of hearing or vision. Of the 20 patients, 16 patients participated in the neuropsychological testing, 13 patients participated in the testing of hearing, 15 patients participated in the testing of vision, and thus, there were 13 patients who participated in all the tests. Overall, the results from all the neuropsychological tests performed revealed a disperse picture. However, all the 13 patients had a history of exposure to both noise and organic solvents and they all suffered from a hearing loss, which had not been observed at the initial examination, but seemed to have serious implications on their prognosis and future life.
| Materials and Methods|| |
The examined patients previously lead active working lives by working as either painters or in the printing industry, and thus, they were exposed to noise and to toxic substances such as toluene and white spirit.
Neuropsychological examination was conducted before and after the course of rehabilitation. The neuropsychological examination reported in the present study was conducted during the period of December 1999-April 2000 at Sankt Hans Hospital. At this point, the patients were also subjected to neuropsychiatric interviewing, which included the registration of work history and types of exposure. The examination of vision reported in the present study was conducted during the period of December 1999-April 2000 in the Danish National Eye Clinic for the Visually Impaired, and the examination of hearing was conducted in the same period at Bispebjerg Hospital's department of audiology.
The patients in the study were selected from a group of patients who were diagnosed as suffering from toxic encephalopathy and rehabilitated at Sankt Hans Hospital within the last 10 years. The selection was based on only one pragmatic criterion that the patients should be able to get to the examinations independently.
Neuropsychological examination method
The neuropsychological examination was conducted as a comprehensive assessment of cognitive and behavioral functions using a set of standardized tests and procedures. Moreover, it also included measures of intellectual functioning and assessments of the patients' personal and emotional state. The neuropsychological examination was 4-6 hours long and was divided into two parts. It was initiated with a clinical interview in order to familiarize the psychologist with the patients' problems and to elicit signs and symptoms of psychiatric or neurological illnesses. The interview also focussed on the patients' perception of their hearing and vision. The interview was followed by the formal neuropsychological testing, which included paper-and-pencil tests as well as mechanical and computerized test procedures tests.
Several domains of the patients' cognitive abilities were assessed in the tests. Memory : The patients were asked to learn and remember new information (word lists, geometric designs, and faces). The patients' ability to recall information learned in the past was also assessed. Language : The patients' ability to name objects, comprehend, and follow directions, and their ability to speak, read, and repeat was assessed in different ways. Spatial and perceptual : The patients' ability to analyze visual designs, assemble puzzles, or estimate spatial relations was measured with specific tests. Attention and concentration: The patients' ability to concentrate for short or long periods of time was assessed using arithmetic and verbal tests. The patients' ability to concentrate in presence of distraction was also assessed through tests requiring them to perform two tasks simultaneously. Motor and sensory abilities : The patients were asked to perform some computerized tasks in which the fine motor coordination was assessed or were asked to respond quickly to sensory input.
After the examination, the results were scored and evaluated. The psychologist, who performed the examination, conducted a feedback session with each patient.
In the examination in the present study, the research designers decided to use a test battery approach in which the same group of tests was conducted for all patients regardless of the presented problems. The test battery was similar to the test battery administered at admission and discharge from rehabilitation years back. A few more tests were administered at admission.
Three different approaches were used in combination to evaluate the results of the neuropsychological examination. The first approach : In accordance with the psychometric tradition, the patients' test results were related to reference values derived from a general population sample and adjusted for age, gender, and education. The second approach : The style of the patients' problem solving strategy was analyzed qualitatively by relating the content of the response to other responses, response latencies, response stability, etc. in accordance with the process concept of contemporary cognitive psychology. The third approach : The members of the group were compared with each other and inter-scaled.
The test battery contained more than one measure (subtest) of the same ability. If the measures were congruent, more confidence could be placed in the results. If a patient's results were abnormal, it did not necessarily mean that the patient was cognitively impaired. Various emotional conditions (depression, anxiety, confusion, and anhedonia) can also influence the neuropsychological test performance. Because of this, the neuropsychologist took into account all reasonable explanations when interpreting the results.
Eye and hearing examination methods
A total of 15 patients were subjected to diagnostic ophthalmic examination-full-field electroretinography with recordings of dark adapted rod responses to flashes (A- and B-waves and oscillatory potentials) and the light adapted cone responses to single flashes and 30 Hz flicker as well as the isolated red, green, and blue cone responses.
A total of 13 patients were subjected to the testing of hearing, which was performed by pure-tone audiometry, speech audiometry by speech reception threshold and discrimination score in noise,  and finally testing for retro cochlear changes by measurements of auditory brain stem responses (ABR). According to the changes in the audiogram, the individual degree of hearing loss was divided into the following five categories: No loss (0: <20 dB better ear hearing level (BEHL) 0.5-4 kHz), mild loss (20-40 dB), mild-to-moderate loss (40-60 dB), moderate-to-severe loss (60-80 dB), and severe loss (>80 dB).
| Results|| |
Neuropsychological examination results
On the basis of ranking, only one patient in the pilot study was considered as having a normal neuropsychological test profile, which was defined as a test profile without any marked deviations when compared with a normal population. This was observed when the patients' test results were related to reference values derived from a general population sample and adjusted for age, gender, and education (first evaluation). Additionally, on the basis of ranking, 10 patients were considered to have "discrete problems." These patients had a test profile showing either a few strikingly negative results or an array of results slightly below the expected level when compared with a normal population. A total of four patients were considered to suffer from "moderate problems" and one patient from "severe problems." The patients with "moderate problems" and "severe problems" had consistent negative results and an unambiguous negative test profile.
The patients' problem solving strategy was also analyzed qualitatively by relating the content of a response to other responses, response latencies, and response stability. The results from the present neuropsychological testing were compared with the results from the previous neuropsychological testing that was performed before and after the three months' course of rehabilitation, which the patients followed in the period 1993 - 1998. It was found that of the 16 tested patients, 15 had single marked deviations (-2 SD) in their test profiles (second evaluation). However, an overall comparison of present and previous test results revealed that the subtests in which the patients had marked deviations differed over time to such an extent that the only pattern it was possible to detect and define was an uneven picture analogous to the findings in other studies. 
Hearing examination results
The hearing was tested in 13 patients, of which, 12 had a history of occupational noise exposure and only two claimed to have been using hearing protectors; the history of noise exposure for the last patient was not reported. Seven of the patients had tinnitus in varying degrees and only one of the 13 patients showed no signs of hearing loss, but was suffering from more or less constant tinnitus. The degree of hearing loss in the rest of the patients ranged from mild to moderate with no difference between right and left ear or the better and worse ear. Speech discrimination score in noise was 93%, ranging from 80% to 100%.
One patient with constant tinnitus and moderate-to-severe hearing loss (~80 dB) had tried to acquire compensation for occupational hearing loss, but this was refused. The patient also had a history of a relative severe head trauma in a motorcycle accident, but claimed that he did not have any problems with hearing following the accident. Overall, only one patient had more or less normal hearing, but was suffering from tinnitus.
Eye examination results
Ophthalmic diagnostic examinations including refractometry, visual acuity, external inspection, motility, slit lamp inspection, and ophthalmoscopy after dilation of the pupils were performed on 15 patients and none demonstrated deviations from normal. No single parameter of the retinogram seemed to reveal specific changes, but 4 out of the 15 patients had marked changes in their electroretinograms, where two patients had deviations in 3 of the 4 parameters assessed by the electroretinographic testing and two had deviations in 1 of the 2 parameters assessed by the electroretinographic testing. As for the other patients, only one showed deviations in 1 of the 20 parameters assessed by the electroretinographic testing, while the rest of the patients seemed to deviate in 1 of 20 or lesser parameters.
Three case stories from the pilot-study sample of patients
In the following section, a brief discussion will consider the general complexities involved in diagnosing toxic encephalopathy as well as the specific difficulties that accompany the attempts made in the present pilot study for strengthening the diagnostic procedures by means of supplementing them with the relative objective and concise measures of the functioning of the patients' hearing and vision. In preparation for this discussion, three cases from the pilot study representing three patients and the description of the problems they experience due to organic solvent exposure are presented.
The three cases are selected on the basis of their neuropsychological test performance and the hearing examination results. The first case (patient no. 3) represents the patient who was defined as normal and placed in the second category of mild-to-moderate hearing loss. The second case (patient no. 12) represents one of the four patients who were defined as suffering from moderate cognitive problems. This patient was placed in the third category of moderate-to-severe hearing loss. The third case (patient no. 7) represents the patient who was defined as suffering from severe cognitive problems and was placed in the fourth category of severe hearing loss [Figure - 1].
Patient number 3
This patient suffers from impaired hearing, tinnitus, and for a period a hazy sight. During the neuropsychological examination this patient also complained about a number of physical ailments such as enuresis, sexual problems after several operations in his urinary system, insomnia, stomach ache, headache, and pain in his back, extremities, and knees and wrists indicating as it seems an early ageing process.
He has eight years of schooling, and it was assumed that he had average intelligence prior to his brain injury. Apart from a few deviant results that were indicated via a fluctuating psychomotor pace and a markedly reduced ability to respond auditorily, his neuropsychological test results, both prior to the course of rehabilitation at Sankt Hans Hospital and later when he participated in the pilot study, were completely normal. However, this was incongruent with the results of a Rorschach-test administered in connection with the rehabilitation treatment, which indicated that the patient had unstable attention and that he was easily distracted. The neuropsychological test results were also incongruent with the patient's personal experience.
The patient reports many cognitive difficulties, and demonstrates marked changes such as being socially withdrawn, ambivalent, unstable, and getting easily emotional, irritable, and irascible. He describes that in his everyday life, he experiences difficulty in remembering what he is in the midst of doing as well as his appointments. He also describes that it is difficult for him to concentrate and that he is easily distracted by noise and sometimes even by people around him. Furthermore, he panics in situations of stress or conflict and his mind goes blank or he becomes apathetic. He says that it is difficult for him to understand and keep track of conversations in social settings, which forces him to withdraw from social participation. Finally, he also reports that he is experiencing marital problems.
Patient number 12
During the neuropsychological examination, this patient provides a description which contradicts his description at the audiological examination. He states that his hearing has deteriorated and that he experiences difficulties in hearing low pitch sounds. Furthermore, he experiences a certain dizziness and a "curtain" effect in his eye-sight, particularly, when he is out in the sun or when he watches TV.
This patient has seven years of schooling, and his schooling reflects the fact that his family was often on a move. He has weak linguistic skills and suffers from dyslexia. It is estimated that prior to his brain injury, his intelligence was below average.
According to the patient's own descriptions, difficulties with regard to his memory often manifest themselves in his daily life. The patient has a tendency to forget names and telephone numbers. He also forgets to whom he spoke on the telephone recently, or messages that he promised to pass on. On the other hand, he claims that he remembers TV programs and that his sense of direction is fairly good, as long as he remembers to fix some distinctive landmarks. The patient is a pensioner and not working predominantly, but due to financial short-comings, he sometimes works as a painter. He further describes that he experiences a lack of concentration, stress, and a tendency to make the same mistakes over and over again.
Further, due to his brain injury, he reports psychological changes such as getting easily exhausted, irascible, and emotional. He explains that these psychological changes used to cause problems between him and his wife. However, he claims that now his wife, who is an occupational therapist, has learned to "read the signs" when he is about to "fly into a temper" and that she prevents the conflicts by encouraging him to go for a walk or take a nap.
Patient number 7
During the neuropsychological examination, apart from a hearing loss, tinnitus, and dizziness, this patient demonstrates that he suffers from eczema in the ears. Furthermore, he describes that he is bothered by noise and light and that his sight gets blurred when he tries to concentrate.
He has eight years of schooling, and it was estimated that he had average intelligence, prior to his brain injury. With regards to his intellectual problems, he reports a failing ability to concentrate as well as an exhaustion that usually sets in rather quickly. He is easily distracted and although he spends a lot of energy trying to regulate his train of thoughts, he often ends up exhausted, confused and with a headache or he goes off into a trance loosing track of things completely. Additionally, while making such efforts, sometimes, he tends to experience a hazy eye sight.
Despite his quick exhaustion, he claims that he handles everyday routines such as cooking, cleaning, and shopping fairly well. But at the same time several outdoor activities hasten his exhaustion. He also experiences other difficulties that prevent him from participating in several activities, and he reports difficulties while trying to remember faces, names, and telephone numbers of relatives and close friends, and also the details of TV programs he has watched or books he has read recently.
In addition, he reports emotional difficulties. He has also attempted suicide twice a couple of years prior to rehabilitation. He further explains that the failures, which he experiences in his everyday life, generally contribute to his low self-esteem. He claims that he has become easily irascible and that he suffers from mood swings. He also reports that he is easily affected emotionally when he is alone, and finds it equally difficult to enjoy the company of others.
All three patients report a failing ability to concentrate in general as well as under pressure, an enhanced distractibility, emotional unstableness, and irascibility. Based on the information obtained from the pilot study, it is difficult to determine whether these problems are equally distinct for all three patients. The neuropsychological test results indicate that patient no. 7 suffers from severe cognitive problems and patient no. 12 from moderate problems, while patient no. 3 functions at a completely normal level, as illustrated in [Table - 2]. However, their self-reports disclose the same pattern of experienced difficulties in concentration and memory; the descriptions provided by patient no. 3 are very much similar to those of patient no. 7 and patient no. 12.
This contradiction can be explained in three possible ways. First, the test results reflect the truth about the patient's cognitive ability, and the patient could be exaggerating or even malingering while describing the problems he experiences. The second possibility is that both the test results and the patient's description reflect the truth since the patient's premorbid level of cognitive functioning is extremely high, but his present level of cognitive functioning is lowered due to the brain injury, even though he can be considered normal compared to the general population. Thirdly, the test results reflect the truth about the patient's level of cognitive functioning in the test-situation that only lasts for a short period of time and is well-structured which makes it possible for him to be attentive and concentrate, while his own description of his problems reflects the truth about the problems he experiences in situations that are less well-structured and ambiguous. In principle, all three explanations are plausible and there is no cogent way of selecting any one of the explanations.
Correspondingly, the description of memory impairment provided by patient no. 7 appears to be more comprehensive than that of patient no. 3 and patient no. 12. Additionally, patient no. 7 reports that he has lost the ability to remember faces of close relatives and friends, while patient no. 3 and patient no. 12 do not report a loss of such ability.
No special examination of patient no. 7 was carried through, but the fact that he was suffering from prosopagnosia or faceblindness cannot be ruled out. , Prosopagnosia is a rare disability that is either inherited or acquired due to a blow, a disease or some other form of influence that injures the part of the brain that recognizes faces. Since this special disability of patient no. 7 was neglected in the pilot study, it was not possible to determine whether the prosopagnosia in his case was inherited or acquired, and if acquired, whether it was due to the exposure to toxic solvents or some other reason. However, even if such information had been obtained, it probably would not have been sufficient to determine exposure to toxic solvents as the cause of his prosopagnosia. It would also be difficult to determine the degree at which his prosopagnosia influenced other problems.
| Discussion|| |
The initial hypothesis of the pilot study was that some of the complexities involved in diagnosing toxic encephalopathy could be minimized by extending the diagnostic procedure. Apart from clinical interviewing and neuropsychological testing, the diagnosis should include the examination of hearing and vision. This will help in achieving new measures that could improve in diagnosing toxic encephalopathy with more certainty.
As part of the clinical interview, the patients were subjected to neuropsychological examination. These neuropsychological test results appeared to complicate the diagnosis rather than simplify; this can be illustrated by studying the three case stories. Rather than differ and thereby reflect the positions they were placed in on the grounds of the results of the neuropsychological testing and the hearing examination they went through, many of the physical, intellectual, emotional and social problems the patients in the three case stories described appear to be remarkably similar. Moreover, the nature of the problems make it difficult to compare the cases and determine the degree of their severity. A qualified estimation such as the relationship between exposure time and neuroticism score  cannot be ruled out. Such estimations will make a comparison and ranking more meaningful. Nevertheless, it would still be difficult to determine the proportions and interplay between the problems  for each patient.
The fact that the patients' hearing problems could have influenced their test performance was not taken into consideration. Apart from that, the neuropsychological test results outlined an overall dispersed picture. Although, of the 16 tested patients, 15 did in fact share the significant characteristics that they had marked deviations in single subtests. However, there is no cogent way of making use of this information in the effort to simplify the diagnostic procedure. Traditionally, marked deviations in single subtests are interpreted either as errors indicating that the patient was exhausted momentarily while he was tested or as an indication of the fact that the patient failed to understand the instructions provided prior to the subtest. When viewed in connection with the other subtest results, the marked deviations are traditionally reckoned, thereby contributing to an overall interpretation of the patient's test performance as more or less abnormal depending on how many marked deviations in single subtests the patient had demonstrated.
An uneven picture emerged from the comparison between the results of the present neuropsychological examination and those of the neuropsychological examination that the patients had been through during the period 1993 - 1998. This finding that patients suffering from toxic encephalopathy seldom have an unambiguous test profile is analogous to the findings of other recent studies. Compared with others they are likely to have an increased number of relatively abnormal neuropsychological test performances  thereby pointing to a generalized brain injury.  The computed axial tomography (CAT/CCT) scan images of the brain support the finding that toxic encephalopathy is not a localized brain injury. 
The examination of vision did not show any deviations from normal, and no parameter of the retinogram seemed to reveal any specific changes; however, the marked changes observed in the electroretinograms of four patients supported the notion that uneven examination results is a characteristic of patients suffering from toxic encephalopathy. Unfortunately, the examination of vision did not include the examination of color vision. In many studies, color vision impairment has been observed when the patient has been exposed to white spirits. ,,
The most consistent finding was that the quite extensive exposure to noise and organic solvents can lead to the loss of hearing. Of all the patients, 7 had tinnitus in varying degrees, and only one of the 13 patients had no signs of hearing loss but he was suffering from more or less constant tinnitus. The selection of patients in the study was in accordance with the WHO classification system  but not in accordance with the categories established at the International Solvent Workshop at Raleigh, North Carolina, USA, in 1986  and possibly this could be one of the methodological weaknesses. Overall, the patients shared resemblance with type 2A or 2B of toxic encephalopathy as explained in the latter system. Type 2A is characterized by marked and sustained change in personality and other irreversible mixed symptoms. Type 2B is characterized by objective evidence of impairment of concentration and memory and a decrease in learning capacity in addition to the 2A criteria. However, the fact that the patients were not selected on the basis of hearing problems is important for this study.
Overall, the hearing loss in these patients was an important finding. The hearing loss might be caused by exposure to noise or organic solvents or both; however, in either of the cases, it is essential that the ill-effects of the exposure on hearing are recognized and, if possible, treated by using hearing aid in order to prevent the social isolation of these patients. Thus, a hearing examination should always be performed for a patient with a history of organic solvent exposure. Additionally, it is equally important to investigate about a patient's exposure to organic solvents in case of occupationally induced hearing loss so that possible symptoms of toxic encephalopathy are not overlooked.
| Acknowledgement|| |
The authors wish to thank Ivan P. Nielsen's foundation for the financial support provided for the pilot project and Dr. Anne-Marie Hauch from Bispebjerg Hospital's department of audiology who conducted the hearing examinations.
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S P Lund
National Institute of Occupational Health, Lers° ParkallÚ 105, DK-2100 Copenhagen
Source of Support: None, Conflict of Interest: None
[Figure - 1]
[Table - 1], [Table - 2], [Table - 3]