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is considered the first choice for larger, ruptured adrenal tumor or malignancy. However,
the recent restructuring of the surgical department resulted in selection bias in favor of
the robotic surgery. Further studies are required to address the risk factors, selection
criteria for appropriate management, cost, and quality of life.
The American Society of Anesthesiologists (ASA) physical of the adoption of robotic surgery, but it did not impact the
status classification system was used for assessing the fitness of patients’ s outcome.
patients before surgery.
The study was conducted in full conformance with principles
TABLE 1 | Demographics, clinical presentation, management, and outcome of
of the “Declaration of Helsinki,” Good Clinical Practice (GCP),
patients with adrenal mass underwent surgical treatment (n = 124).
and within the laws and regulations of MoPH in Qatar. The
Medical Research Center (MRC-01-20-254) at Hamad Medical Variables Value Variables Value
Corporation has approved the study with a waiver of consent
as de-identified data with no direct contact with the patients Age 45.6 ± 12.4 ASA classification (n = 119)
were collected retrospectively. This study follows the STROBE Males 65 (52.4%) I 4 (3.4%)
checklist of items that should be included in reports of Females 59 (47.6%) II 74 (62.2%)
observational studies (Supplementary Table). Qatari 25 (20.2%) III 40 (33.6%)
Body mass index 29.1 ± 6.5 IV 1 (0.8%)
Statistical Analysis Clinical presentation Extra-adrenal 5 (4.1%)
Data were presented as frequency, mean ± standard deviation, Incidental 83 (66.9%) Surgical approach
and median and range, whenever appropriate. Patients were Abdominal pain 45 (36.3%) Open adrenalectomy 28 (22.6%)
categorized into three groups according to the interventional Fatigue 24 (19.4%) Robotic adrenalectomy 76 (61.3%)
approach, that is, open, robotic, or laparoscopic adrenalectomy. Muscle 24 (19.4%) Laparoscopic 20 (16.1%)
Differences in categorical variables were analyzed using χ 2 test weakness/cramping adrenalectomy
and Yates’ corrected Chi-square if the expected cell frequencies Headache 28 (22.6%) Additional procedure 8 (6.5%)
were below 5. The continuous variables between different groups with adrenalectomy
were compared using Student’s t-test or one-way analysis of Palpitations 7 (5.6%) Any conversion 2 (1.6%)
variance (ANOVA) test for more than 2 groups. Receiver Back pain 14 (11.3%) Operation laterality
Operating Characteristic (ROC) curve analysis was performed Weight loss 2 (1.6%) Left 76 (61.2%)
for the optimum tumor size cutoff, plotted against the open Hirsutism 3 (2.4%) Right 47 (38%)
surgical intervention. Patient groups were also compared based Seizures 1 (0.8%) Bilateral 1 (0.8%)
on the different tumor size. The area under the curve (AUC) Spine stress fracture 1 (0.8%) SICU admission 34 (27.4%)
and the C-statistic were calculated to evaluate the performance Multiple endocrine 3 (2.4%) SICU days 2 (1-6)
and discriminatory power of the tumor size. Two-tailed p values neoplasia type 1
(MEN1).
< 0.05 were considered as significantly different. Data analysis
Previous abdominal 22 (17.7%) Blood loss (ml) 100 (20-5250)
was carried out using the Statistical Package for Social Sciences
surgery
version 26 (SPSS Inc., Chicago, IL, United States).
History of other 9 (7.3%) Transfusion 16 (12.9%)
malignancy
RESULTS Co-morbidities Intra-operative 16 (12.9%)
Hypertension 66 (53.2%) Post-operative 2 (1.6%)
During the study period, a total of 124 patients with adrenal mass Diabetes 24 (19.4%) Operation time 185.6 ± 68.8
underwent adrenalectomy. Table 1 represents the demographics, Coronary artery disease 6 (4.8%) Length of hospital 5 (2-36)
clinical presentation, comorbidities, management, and outcomes stay (days)
of the study cohort. The mean age of patients was 45.6 ± 12.4 Hypotension 5 (4.0%) Duration of follow-up 746 (range
years and 52% were males. Adrenal tumors were incidentally (days) 7-5840)
discovered in 67% of the patients. The modalities of diagnosis and Radiological Post-operative 0 (0.0%)
ASA classification are shown in Table 1. investigations mortality
Figure 1 shows the nature of the adrenal mass in terms of CT scan 113 (91.1%) Death during 8 (6.4%)
functionality and hormone production. The mean tumor size was follow-up
7.04 ± 5.1 cm. The median tumor size was 3.5 cm (range 0.6– MRI 53 (42.7%) Cause of death
30), 8.0 cm (range 1.5–19), and 9.0 (4.5–30) in the functioning, PET CT scan 8 (6.5%) Cardiac arrest 2 (25%)
non-functioning, and malignant masses, respectively. MIBG scan, 2 (1.6%) Advance-adrenal 3 (37.5%)
iodine-131-meta- carcinoma/metastasis
Robotic adrenalectomy (61.3%) was the most frequent
iodobenzylguanidine
surgical approach followed by open (22.6%) and laparoscopic
Pre-operative biopsy 7 (5.6%) Hemorrhagic shock 1 (12.5%)
adrenalectomy (16%). Eight (6.5%) patients had additional
Pre-operative 3 (2.4%) Advance breast 1 (12.5%)
procedures along with adrenalectomy and two (1.6%) had a embolization carcinoma
conversion. About 61% of patients had left-sided, 38% had right- Functional adrenal 66 (53%) Advance colon cancer 1 (12.5%)
sided operation, and one patient was operated for bilateral tumor. mass
Adrenal carcinoma was discovered in 5 patients and metastasis Nonfunctional adrenal 58 (47%)
from extra-adrenal cancer was found in another 5 patients. mass
There were 2 cases that required conversion to open surgery Tumor size, cm 7.04 ± 5.1
due to bleeding from the adrenal vein during the early phase (range 0.6–30)
FIGURE 1 | The distribution of adrenal mass in terms of functionality and hormone production.
TABLE 2 | Demographics, clinical presentation, and hospital course based on the TABLE 3 | Clinical characteristics and surgical approach based on tumor size.
surgical approach.
Tumor size
Open Robotic Laparoscopic P-value
(n = 28) (n = 76) (n = 20) ≤ 4 cm >4–6 cm >6 cm P-value
(n = 45, (n = 22; (n = 57;
Age 40.9 ± 9.4 46.3 ± 12.8 49.4 ± 13.4 0.04 36%) 18%) 46%)
FIGURE 2 | Study design for surgical approaches based on tumor size, functionality, and malignancy.
TABLE 4 | Sensitivity and specificity of different tumor size (TS) cutoff in favor of TABLE 5 | Complications and outcome based on the surgical approach.
open surgery (vs. non-open surgical approaches).
Open (n = 28) Robotic Laparoscopic P-
TS >4 cm TS >5 cm TS >6 cm (n = 76) (n = 20) value
reports. Agcaoglue et al. (25) reported 1 conversion in the the laparoscopic and robotic approaches; however, the hospital
robotic group and 4 in the laparoscopic group. Aliyev et al. (16) length of stay was better in the robotic group in a meta-analysis of
compared laparoscopic and robotic interventions for patients 21 studies (37).
with pheochromocytoma; 1 out of 25 patients in the robotic
group and 3 out of 40 in the robotic group were converted
to open surgery. In our study, the average body mass index LIMITATIONS
(BMI) was 29.1 ± 6.5 and it did not differ significantly among
The retrospective design is one of the limitations of the
the 3 groups. Like our findings, Aksoy et al. (29) reported
present study. Being single center, the frequency of patients
no significant differences between the laparoscopic and robotic
who underwent adrenalectomy in different groups in our study
groups in patients with BMI ≤ 30 and > 30 kg/m2 .
are higher as compared to other published studies. Internal
Colvin et al. (30) prospectively reviewed 20 robotic surgery
and external validation of the study findings would be of
and 16 laparoscopic surgery cases and found no difference in
value in prospective and multicenter studies in the region.
the hospital length of stay in the two groups. Zhu et al. (26)
Our hospital is the only tertiary government not-for-profit
reported a shorter length of hospital stay in the laparoscopic
facility in the country. In addition, most of the earlier studies
group in comparison to the open surgery group. On the contrary,
mainly focused on two surgical approaches while we compared
our study showed prolonged hospital stay in the laparoscopic
the three surgical intervention groups. The follow-up period
adrenalectomy group than the open group. Notably, 80% of
was long and was justified to come up with conclusions
patients in the laparoscopic group had ASA III (severe systemic
about the immediate and long-term complications of the 3
disease) or IV (a severe systemic disease that has a threat to life)
approaches. Also, the present study did not address information
which may attribute to the observed differences. A systematic
regarding the hospital and surgeon volume, experience, and
review including 27 studies found that the robotic approach
skill of surgeons as it could relate to the patient’s outcomes.
had a significantly shorter hospital stay and longer operating
However prior data showed that surgical sub-specialty did
time compared to the laparoscopic approach; however, both
not significantly influence the perioperative results, but the
approaches had similar clinical outcomes in the selected set of
learning curve and volume workload play an important role
patients (31). A meta-analysis including 9 studies (32) showed
in the outcomes (14). Selection bias cannot be ignored as
that the operative times were similar, with no difference in
the compared groups in the study did not adjust for some
conversion rates or complication rates, but a significantly higher
factors such as the comorbidities, disease under treatment,
estimated blood loss and hospital stay were identified in the
and grade of anesthesia. To minimize the selection bias in
laparoscopic group compared with the robotic group. Notably,
terms of the surgical approach, we adopted the European
the laparoscopic group patients were more obese (32).
Society of Endocrine Surgeons recommendations for the surgical
In our series, open surgery resulted in more blood loss
management of adrenocortical carcinoma. Minimally invasive
followed by laparoscopic and robotic surgery, and the need
surgery was performed for Stage I or II with a diameter <10 cm
for intraoperative and post-operative blood transfusion was
(38). It appears that there is an immediate adoption of the robotic
also higher in the open surgery group. Brandao et al. (33)
platform for adrenalectomy, whereas some literature suggests a
reported that 1 out of 30 patients in the robotic group had
more gradual trend in the use of the robotic platform. Of note,
intraoperative and 2 had post-operative transfusions; whereas 4
the robotic approach has continued to increase among surgical
out of 46 patients in the laparoscopic group had intraoperative
procedures and hospitals that have adopted robotic surgery
and 2 had postoperative transfusions. In our study, one patient
programs had an immediate and diffuse increase in robotic
in the open intervention group had renal artery occlusion
surgery with a relative decrease in the laparoscopic approach (39).
secondary to preoperative angioembolization for rupture adrenal
Generally, open adrenalectomies were done for emergency cases
tumor with bleeding. Diaphragmatic injury and abdominal
presented with bleeding or large adrenal mass suspected to be
collection were reported in the laparoscopic group, and the
adrenocortical carcinoma.
robotic group had bleeding from the adrenal vein in 2 patients-
−1 had post-operative pneumonia and 1 had pleural effusion.
Consistent with our findings, an earlier study reported similar CONCLUSIONS
complications (34). In our study, none of the patients died post-
operatively; however, during clinical follow-up, 8 patients died. The study explored the three surgical adrenalectomy approaches
An earlier study reported lower 30-day mortality (0.5%) post- in a dedicated center for patients with adrenal pathology. It
laparoscopic adrenalectomy (35). A recent systematic review (36) showed that robotic adrenalectomy could be safe and effective
including 17 studies showed that although open surgery is the surgical approach in patients with benign functioning adrenal
gold standard approach, there were no significant differences tumors of a diameter less than <6 cm. However, the choice of
observed in the rate and time to recurrence and cancer- surgical intervention depends on the case presentation, patient
specific mortality between laparoscopic and open approaches fitness for surgery, type and sizes of the tumor, surgeon’s
(especially for tumor stage I-II). Although the robotic approach experience, and hospital resources. Open surgery is considered
has several advantages compared to the laparoscopic, the specific the first choice for larger, ruptured adrenal tumor, or malignancy.
indications of robotic approach in adrenal carcinoma remain However, the recent restructuring of the surgical department
unclear (36). The perioperative safety was found to be similar in resulted in selection bias in favor of robotic surgery. Further
studies are required to address the risk factors, selection AUTHOR CONTRIBUTIONS
criteria for appropriate management, and impact on cost and
quality of life. HA-T and NA-T: conceptualization, study design, and
manuscript writing and review. MA-S and AT: manuscript
review. MA and AE-M: data analysis, manuscript draft,
DATA AVAILABILITY STATEMENT and review. HA-T, NA-T, MA-S, and AT: data collection.
MA-S, MA, AE-M, and AT: interpretation. All authors have
All data had been shown in the results section, tables, and figures. a substantial contribution in the study and approved the
Access to raw data will need agreement from the medical research manuscript submission.
center at HMC, Doha (mrchelpdesk@hamad.qa).
ACKNOWLEDGMENTS
ETHICS STATEMENT We thank the staff in the Surgery Department team of the Hamad
The study was conducted in full conformance with principles General Hospital, Qatar.
of the “Declaration of Helsinki”, Good Clinical Practice (GCP),
and within the laws and regulations of MoPH in Qatar. The SUPPLEMENTARY MATERIAL
Medical Research Center (MRC-01-20-254) at Hamad Medical
Corporation has approved the study with a waiver of consent as The Supplementary Material for this article can be found
de-identified data with no direct contact with the patients were online at: https://www.frontiersin.org/articles/10.3389/fsurg.
collected retrospectively. 2022.848565/full#supplementary-material
REFERENCES 13. Pahwa M. Robot-assisted adrenalectomy: current perspectives. Robot Surg Res
Rev. (2017) 4:1. doi: 10.2147/RSRR.S100887
1. Hammarstedt L, Muth A, Wängberg B, Björneld L, Sigurjónsdóttir HA, 14. Mihai R, Donatini G, Vidal O, Brunaud L. Volume-outcome correlation
Götherström G, et al. Adrenal lesion frequency: a prospective, cross-sectional in adrenal surgery—an ESES consensus statement. Langenbecks Arch Surg.
CT study in a defined region, including systematic re-evaluation. Acta radiol. (2019) 404:795–806. doi: 10.1007/s00423-019-01827-5
(2010) 51:1149–56. doi: 10.3109/02841851.2010.516016 15. Sessa L, Nomine C, Germain A, Ayav A, Bresler L, Brunaud L. Right robotic
2. Birsen O, Akyuz M, Dural C, Aksoy E, Aliyev S, Mitchell J, et al. new adrenalectomy for a 8 cm pheochromocytoma (with video). J Visc Surg. (2015)
risk stratification algorithm for the management of patients with adrenal 152:334–5. doi: 10.1016/j.jviscsurg.2015.06.010
incidentalomas. Surgery. (2014) 156:959–66. doi: 10.1016/j.surg.2014.06.042 16. Aliyev S, Karabulut K, Agcaoglu O, Wolf K, Mitchell J, Siperstein A, et al.
3. Bovio S, Cataldi A, Reimondo G, Sperone P, Novello S, Berruti Robotic versus laparoscopic adrenalectomy for pheochromocytoma. Ann Surg
A, et al. Prevalence of adrenal incidentaloma in a contemporary Oncol. (2013) 20:4190–4. doi: 10.1245/s10434-013-3134-z
computerized tomography series. J endocrinol invest. (2006) 17. Al-Thani H, El-Menyar A, Al-Sulaiti M, ElGohary H, Al-Malki A,
29:298–302. doi: 10.1007/BF03344099 Asim M, et al. Adrenal mass in patients who underwent abdominal
4. Patel D. Surgical approach to patients with pheochromocytoma. Gland Surg. computed tomography examination. N Am J Med Sci. (2015) 7:212–
(2020) 9:32–42. doi: 10.21037/gs.2019.10.20 9. doi: 10.4103/1947-2714.157482
5. Alshahrani MA, Saeedan MB, Alkhunaizan T, Aljohani IM, Azzumeea FM. 18. Azhar RA, Elkoushy MA, Aldousari S. Robot-assisted urological surgery in
Bilateral adrenal abnormalities: imaging review of different entities. Abdom the Middle East: where are we and how far can we go? Arab J Urol. (2019)
Radiol. (2019) 44:154–79. doi: 10.1007/s00261-018-1670-5 17:106–13. doi: 10.1080/2090598X.2019.1601003
6. Shiroky JS, Lerner-Ellis JP, Govindarajan A, Urbach DR, Devon KM. 19. Yousef HB, Al Zahrani A, Ahmed M, Al Arifi A, Mahfouz A, Hussain
Characteristics of adrenal masses in familial adenomatous polyposis. R, et al. Laparoscopic vs. open adrenalectomy: experience at King Faisal
Dis Colon Rectum. (2018) 61:679–85. doi: 10.1097/DCR.00000000000 Specialist Hospital and Research Centre, Riyadh. Ann Saudi Med. (2003)
01008 23:36–8. doi: 10.5144/0256-4947.2003.36
7. Palui R, Kamalanathan S, Sahoo J, Dorairajan LN, Badhe B, Gochhait D. 20. Kapoor A, Morris T, Rebello R. Guidelines for the management of the
Adrenal adenoma in von Hippel–Lindau syndrome: a case report with review incidentally discovered adrenal mass. Can Urol Assoc J. (2011) 5:241–
of literature. J Cancer Res Ther. (2019) 15:163. doi: 10.4103/jcrt.JCRT_127_18 7. doi: 10.5489/cuaj.11135
8. Almeida MQ, Bezerra-Neto JE, Mendonça BB, Latronico AC, Fragoso 21. Young Jr WF. Management approaches to adrenal incidentalomas: a view
MCBV. Primary malignant tumors of the adrenal glands. Clinics. (2018) from Rochester, Minnesota. Endocrinol Metab Clin North Am. (2000) 29:159–
73:e756s. doi: 10.6061/clinics/2018/e756s 85. doi: 10.1016/S0889-8529(05)70122-5
9. Chatzellis E, Kaltsas G. Adrenal Incidentalomas. In: Feingold KR, Anawalt 22. Zeiger M, Thompson G, Duh QY, Hamrahian A, Angelos P, Elaraj D, et al.
B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): American Association of Clinical Endocrinologists and American Association
MDText.com, Inc.; 2000-. Available online at: https://www.ncbi.nlm.nih.gov/ of Endocrine Surgeons medical guidelines for the management of adrenal
books/NBK279021/. (accessed November 7, 2019) incidentalomas. Endocrine Practice. (2009) 15:1–20. doi: 10.4158/EP.15.S1.1
10. Bowen JS, Parker A, Bellur SS, Anilkumar B, Dove D, Sadler GP, et al. 23. Sturgeon C, Shen WT, Clark OH, Duh QY, Kebebew E. Risk
Management of adrenal incidentaloma: size still matters. Case Reports. (2011) assessment in 457 adrenal cortical carcinomas: how much does tumor
2011:bcr0820114709. doi: 10.1136/bcr.08.2011.4709 size predict the likelihood of malignancy? J Am Coll Surg. (2006)
11. Young Jr WF. The incidentally discovered adrenal mass. New England J Med. 202:423–30. doi: 10.1016/j.jamcollsurg.2005.11.005
(2007) 356:601–10. doi: 10.1056/NEJMcp065470 24. Wong PY, Prinz RA. Surgical management of adrenal neoplasms: laparoscopic
12. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The versus open adrenalectomy. In: Holzheimer RG, Mannick JA, editors. Surgical
clinically inapparent adrenal mass: update in diagnosis and management. Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt.
Endocr Rev. (2004) 25:309–40. doi: 10.1210/er.2002-0031 (2001). Available online at: https://www.ncbi.nlm.nih.gov/books/NBK6997/
25. Agcaoglu O, Aliyev S, Karabulut K, Mitchell J, Siperstein A, Berber E. Robotic 35. Gupta PK, Natarajan B, Pallati PK, Gupta H, Sainath J, Fitzgibbons RJ.
versus laparoscopic resection of large adrenal tumors. Ann Surg Oncol. (2012) Outcomes after laparoscopic adrenalectomy. Surg Endosc. (2011) 25:784–
19:2288–94. doi: 10.1245/s10434-012-2296-4 94. doi: 10.1007/s00464-010-1256-y
26. Zhu W, Wang S, Du G, Liu H, Lu J, Yang W. Comparison of retroperitoneal 36. Cavallaro G, Tarallo M, Chiappini A, Crocetti D, Polistena A, Petramala L,
laparoscopic versus open adrenalectomy for large pheochromocytoma: et al. Surgical management of adrenocortical carcinoma: current highlights.
a single-center retrospective study. World J Surg Oncol. (2019) Biomedicines. (2021) 9:909. doi: 10.3390/biomedicines9080909
17:111. doi: 10.1186/s12957-019-1649-x 37. Perivoliotis K, Baloyiannis I, Sarakatsianou C, Tzovaras G. Comparing the
27. Bancos I, Tamhane S, Shah M, Delivanis DA, Alahdab F, Arlt W, et efficacy and safety of laparoscopic and robotic adrenalectomy: a meta-
al. The diagnostic performance of adrenal biopsy: a systematic review analysis and trial sequential analysis. Langenbecks Arch Surg. (2020) 405:125–
and meta-analysis. Eur J Endocrinol. (2016) 175:R65–80. doi: 10.1530/EJE- 35. doi: 10.1007/s00423-020-01860-9
16-0297 38. Gaujoux S, Mihai R. Joint working group of ESES and ENSAT. European
28. Sormaz IC, Tunca F, Poyanli A, Senyürek YG. Preoperative adrenal Society of Endocrine Surgeons (ESES) and European Network for the
artery embolization followed by surgical excision of giant hypervascular Study of Adrenal Tumours (ENSAT) recommendations for the surgical
adrenal masses: report of three cases. Acta Chir Belg. (2018) 118:113– management of adrenocortical carcinoma. Br J Surg. (2017) 104:358–
9. doi: 10.1080/00015458.2017.1312080 76. doi: 10.1002/bjs.10414
29. Aksoy E, Taskin HE, Aliyev S, Mitchell J, Siperstein A, Berber E. Robotic 39. Sheetz KH, Claflin J, Dimick JB. Trends in the adoption of robotic
versus laparoscopic adrenalectomy in obese patients. Surg Endosc. (2013) surgery for common surgical procedures. JAMA Netw Open. (2020)
27:1233–6. doi: 10.1007/s00464-012-2580-1 3:e1918911. doi: 10.1001/jamanetworkopen.2019.18911
30. Colvin J, Krishnamurthy V, Jin J, Shin J, Siperstein A, Berber E, et al.
comparison of robotic versus laparoscopic adrenalectomy in patients with Conflict of Interest: The authors declare that the research was conducted in the
primary hyperaldosteronism. Surg Laparosc Endosc Percutan Tech. (2017) absence of any commercial or financial relationships that could be construed as a
27:391–3. doi: 10.1097/SLE.0000000000000455 potential conflict of interest.
31. Economopoulos KP, Mylonas KS, Stamou AA, Theocharidis V,
Sergentanis TN, Psaltopoulou T, et al. Laparoscopic versus robotic Publisher’s Note: All claims expressed in this article are solely those of the authors
adrenalectomy: a comprehensive meta-analysis. Int J Surg. (2017) and do not necessarily represent those of their affiliated organizations, or those of
38:95–104. doi: 10.1016/j.ijsu.2016.12.118
the publisher, the editors and the reviewers. Any product that may be evaluated in
32. Brandao LF, Autorino R, Laydner H, Haber GP, Ouzaid I, De Sio M,
this article, or claim that may be made by its manufacturer, is not guaranteed or
et al. Robotic versus laparoscopic adrenalectomy: a systematic review and
meta-analysis. Eur Urol. (2014) 65:1154–61. doi: 10.1016/j.eururo.2013. endorsed by the publisher.
09.021
33. Brandao LF, Autorino R, Zargar H, Krishnan J, Laydner H, Copyright © 2022 Al-Thani, Al-Thani, Al-Sulaiti, Tabeb, Asim and El-Menyar.
Akca O, et al. Robot-assisted laparoscopic adrenalectomy: step- This is an open-access article distributed under the terms of the Creative Commons
by-step technique and comparative outcomes. Eur Urol. (2014) Attribution License (CC BY). The use, distribution or reproduction in other forums
66:898–905. doi: 10.1016/j.eururo.2014.04.003 is permitted, provided the original author(s) and the copyright owner(s) are credited
34. Ramachandran MS, Reid JA, Dolan SJ, Farling PA, Russell CF. Laparoscopic and that the original publication in this journal is cited, in accordance with accepted
adrenalectomy versus open adrenalectomy: results from a retrospective academic practice. No use, distribution or reproduction is permitted which does not
comparative study. Ulster Med J. (2006) 75:126. comply with these terms.