Outreach tonsillectomy in a Very remote setting: a retrospective review of post-tonsillectomy haemorrhage incidence and management

Introduction

Tonsillectomy is a frequently performed procedure in both paediatric and adult populations in Australia, primarily for recurrent tonsillitis and obstructive sleep-disordered breathing (1). Post-tonsillectomy haemorrhage (PTH) is a recognised complication within the first two weeks after surgery, with severity ranging from minor blood-stained saliva to life-threatening haemorrhage necessitating urgent surgical intervention and blood transfusion (2).

PTH is classified as primary (within 24 hours of surgery) or secondary (more than 24 hours after surgery), with severity assessed using classification systems such as the Flinders modification of the Stammberger criteria (2). Reported incidence varies in the literature based on definition, but a large epidemiological study found the rate of return to theatre for PTH in Australia is approximately 1.6% (1% paediatric, 2.8% adults) (1). Secondary PTH rates in the Australian literature range from 1–8.3% (3,4) and peak on the 5th postoperative day (5). Identified risk factors include older age, male sex, and a history of recurrent tonsillitis or quinsy (1,6,7). The influence of surgical technique, such as extracapsular versus intracapsular, or thermal versus cold steel remains debated. The role of perioperative non-steroidal anti-inflammatory drugs (NSAIDs) also remains controversial; however, their use continues to be endorsed in clinical guidelines (8).

Several studies have demonstrated that PTH rates are not increased when tonsillectomy is performed in regional or rural Australia (9-12). Nonetheless, given the potential requirement for urgent surgical intervention, most Ear, Nose and Throat (ENT) surgeons in Australia recommend that patients remain within one hour of an ENT-serviced hospital for 10–14 days postoperatively (13). This recommendation poses significant social and financial challenges for patients and health services in many rural areas, particularly where the shortage of ENT surgeons limits emergency coverage (14). These barriers to access contribute to lower tonsillectomy rates among children residing in Very remote regions [Australian Statistical Geography Standard Remoteness Area (ASGS RA) 5, Modified Monash Model (MM) 7], particularly within socioeconomically disadvantaged households (15).

Longreach Hospital is a 25-bed facility providing emergency and inpatient services delivered by Rural Generalist practitioners. It is the major hospital of the Central West Queensland Hospital Health Service, which is classified as a Very remote region (ASGS RA-5, MM-7) and has a population of approximately 12,400 people in the whole service district (16). As there is no local ENT service, patients from this region are referred to Brisbane, which is approximately 1,200 kilometres away. This equates to 13 hours of travel by road, or a 2-hour commercial flight. Visiting ENT surgeons from Brisbane conduct outreach clinics and elective surgery at Longreach Hospital on a 4-monthly basis as part of a Queensland Health program.

While it is of considerable interest to both the ENT surgical community and the health service more broadly, evidence evaluating the safe geographical proximity for patients to stay close to where they had their tonsillectomy is limited (17). Consequently there is, to the best of our knowledge, no health department or ENT society guideline to inform the practice of outreach tonsillectomy in Australia. This study aims to review a ten-year experience of outreach tonsillectomy in a Very remote setting in Queensland, Australia, with a specific focus on the incidence, management, and outcomes of PTH.

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Metro North Health Human Research Ethics Committee (project ID: 120353) reviewed the protocol and deemed it exempt from full ethical review on the basis that it constituted a quality initiative. Individual consent for this retrospective analysis was waived. The study is reported according to the STROBE reporting guidelines (available at https://www.theajo.com/article/view/10.21037/ajo-25-66/rc).

A retrospective review was performed of all patients who underwent elective tonsillectomy at the Longreach Hospital, Queensland, between January 2014 and December 2024. Patients were identified from the Operating Room Management Information System, which has recorded procedures at Longreach Hospital since 2014, using the codes “tonsillectomy” and “adenotonsillectomy”. De-identified demographic, surgical and postoperative outcome data was extracted from the electronic medical record and The Viewer which captures all presentations to state-wide public emergency departments (EDs). As there are no private hospitals in the region, we are confident that all re-presentations requiring hospital-level care were captured. No patients were excluded from the analysis.

Tonsillectomy was performed by a visiting consultant ENT surgeon or registrar, and anaesthetic provided by a visiting consultant Paediatric Anaesthetist. Both remained in Longreach overnight to manage any early complications. The surgical technique was extracapsular tonsillectomy, performed with monopolar diathermy, bipolar diathermy or cold steel dissection. Haemostasis was achieved with bipolar diathermy. Patients were assessed as suitable for surgery in Longreach if they were at least 3 years of age and had no major medical comorbidities requiring high dependency unit level postoperative care. As part of the consent process, the risk of PTH—including the potential need for urgent surgical management and implications of delay in this remote setting—was explicitly discussed with patients. Patients who opted to have their procedure and postoperative convalescence in a metropolitan setting were referred accordingly.

Postoperative care included routine discharge with a course of oral antibiotics, regular paracetamol and ibuprofen or celecoxib for analgesia, and oxycodone as required. Patients were recommended to remain within one hour of Longreach Hospital for the 2 weeks following surgery and to return to the ED in the event of bleeding. From 2020 onwards, some patients were also prescribed oral tranexamic acid (TXA) on discharge to be taken as prophylaxis, or to commence in the event of bleeding while seeking ED review. Documentation regarding TXA dose, timing and adherence was inconsistent, precluding formal analysis of its association with PTH outcomes. Severity of PTH was graded using the Flinders modification of Stammberger criteria, where category A denotes a minor reported bleed or blood-stained sputum without active bleeding on examination, category B denotes larger reported bleed or active bleeding on examination responsive to nonsurgical measures, and category C–E describe severe haemorrhage requiring return to theatre (C), blood transfusion (D) or causing death (E) (2). We considered the transfer time from triage at the remote ED to triage at the receiving ENT-serviced hospital.

Statistical analysis

Descriptive statistics were presented as number and percentage for categorical variables. Continuous variables were assessed for normality using histograms and the Shapiro-Wilk test. Normally distributed variables were summarised with mean and standard deviation (SD) and non-normally distributed variables were summarised with median and interquartile range (IQR). Differences in baseline demographics between patients with and without PTH were assessed for continuous variables with the Mann-Whitney U test, and categorical variables with Fisher’s exact or Chi-squared tests, as well as univariate logistic regression. P values <0.05 were considered significant from the outset. All statistical analyses were performed using Python version 3.12.7 (Anaconda Inc., Austin, TX, USA).

Results

A total of 144 patients underwent tonsillectomy procedures at Longreach Hospital between 2014 and 2024. Patient demographic and surgical details are summarized in Table 1. The cohort was predominantly paediatric (n=99, 68.8% <16 years) with a median age of 8 years (IQR, 5–18 years) and had a slight female predominance (n=79, 54.9%). Most patients resided in the Longreach postcode (n=67, 46.5%), followed by Barcaldine (n=29, 20.1%), Blackall (n=20, 13.9%) and Winton (n=8, 5.6%). Nearly all patients were otherwise healthy, with 97.9% classified as American Society of Anaesthesiologists class 1 or 2.

The main indications for surgery were recurrent tonsillitis (n=56, 46.7%) and sleep disordered breathing/obstructive sleep apnoea (n=47, 39.2%), with the remainder having both indications. All patients were intubated with an endotracheal tube, except for one case managed with a laryngeal mask airway. Surgery was performed by an ENT consultant in 83 cases (57.6%), and a registrar in the remaining 61 cases (42.4%). Operative technique was most frequently monopolar cautery (80.6%), followed by cold steel dissection (10.4%) and bipolar cautery (9%). Patients routinely stayed for one night postoperatively, except for one same-day discharge (due to close proximity to hospital), and four patients who stayed a second night for oximetry monitoring or pain control.

PTH occurred in 11 patients (6.7%) with a mean age of 16.2 years (SD 6.9 years). A breakdown of PTH cases is provided in Table 2. Patients with PTH were older than those without (median age 17 vs. 8 years, P=0.045) however age was not an independent predictor of PTH on univariate logistic regression [odds ratio (OR) per year 1.04, 95% confidence interval (CI): 0.98–1.09, P=0.12]. All haemorrhages were secondary, occurring a mean of 7.4 days postoperatively (SD 2.3 days). Most cases were graded as Modified Stammberger class A and the remaining were Modified Stammberger class B. No patients required a return to theatre or blood transfusion as part of their management.

Five patients required inter-hospital transfer for ENT review. Transfer destinations included Queensland Children’s Hospital (n=2), Royal Brisbane and Women’s Hospital (n=1), Rockhampton Hospital (n=1) and Townsville University Hospital (n=1). All transfers were conducted via Royal Flying Doctors Service (RFDS) fixed-wing aircraft with a mean transfer time of 9.4 hours (SD 3.2 hours). Two patients (18% of those with PTH) experienced a recurrent haemorrhage, one requiring a second retrieval. Non-haemorrhagic presentations to the ED occurred in 19 patients (13.2%), most commonly for pain, with additional presentations for nausea and upper respiratory tract infection. One intraoperative instrument-related burn was noted and managed conservatively.

Discussion

The decision to perform outreach tonsillectomy in a Very remote setting requires careful consideration of patient safety, resource availability, and cost implications. Over an 11-year period [2014–2024], 144 patients underwent tonsillectomy at Longreach Hospital via an outreach model of care. The overall PTH rate of 6.7% is consistent with other Australian studies (18,19) and importantly, no patients experienced severe haemorrhage requiring return to theatre or blood transfusion. These safety outcomes are comparable to other studies of regional and rural tonsillectomy (9-12).

Five patients (3.5%) required an inter-hospital transfer for PTH management. All transfers were performed by fixed-wing aeromedical retrieval through the RFDS, with a mean transfer time of 9.4 hours—more than twice the 4.1 hours in regional Victoria reported by Jones et al. (10). Common challenges contributed to prolonged retrieval times in these cases, including inclement weather, refuelling and availability (20). All patients who were transferred for PTH were recommended to remain within 30–60 minutes of an ENT-serviced hospital for the remainder of the two week postoperative window due to the risk of recurrent bleeding, which can be more severe and has a higher rate of operative intervention (21,22). Two patients in our cohort experienced recurrent PTH, both after transfer for their first bleed, and one of which had returned to another rural location requiring a second aeromedical retrieval. These cases highlight the challenges of a Very remote setting, where the necessity for aeromedical retrieval can lead to considerable delay to ENT review and intervention. It is possible that some retrieved PTH cases may have proceeded to operative management had there not been such delays, and future guidelines will need to consider these logistical constraints when determining safe models of care.

The remaining six PTH cases received medical management locally. Most were mild, self-limiting bleeds and patients were either observed for a short time in ED or admitted overnight. These results raise the possibility that minor haemorrhages can be safely managed in hospitals without an on-site ENT service, provided that appropriate assessment, monitoring and safety-netting protocols are in place. The presence of Rural Generalist practitioners with advanced skills training in emergency medicine, anaesthetics and surgical procedures was an important factor in the decision to offer outreach tonsillectomy in Longreach. However, only one of these patients had documented discussions with the ENT on-call, raising the possibility that more patients may have been transferred had these discussions taken place. Non-haemorrhagic postoperative issues such as pain, nausea and upper respiratory infection were also managed locally, with an ED presentation rate of 13.2%, similar to published rates (5).

A considerable amount of research has examined risk factors for PTH (6,7,19). Previous studies suggest that while adults are more likely to suffer from PTH, children may be at a greater risk of severe bleeding (21,23). In our cohort, patients with PTH were older but age was not an independent predictor, likely due to the limited sample size. Other surgical and demographic characteristics did not differ significantly between groups. The majority of tonsillectomies in this cohort were performed using monopolar dissection, which remains the standard technique among visiting surgeons at this site. Although evidence comparing extracapsular techniques remains mixed, recent evidence suggests that intracapsular tonsillotomy may be associated with lower rates of PTH in children with sleep-disordered breathing (24). The feasibility of incorporating intracapsular techniques into an outreach model warrants consideration; however, its implementation would require assessment of equipment availability, surgeon and staff training, and cost-benefit analysis.

The recognised PTH risk period is within the first 14 days postoperatively, peaking in the first week (5); all cases in our study occurred during this window, with a mean onset of 7.4 days (SD 2.29 days). Adjunctive medical management in our cohort was broadly consistent with current practice (25). Patients routinely received NSAIDs and antibiotics postoperatively, noting that current evidence suggests they are unlikely to have a significant influence on PTH rates (17). In more recent years oral TXA was prescribed on discharge; either as prophylaxis, or to commence at the onset of bleeding. Due to variability in prescribing practices and documentation, no conclusions can be drawn regarding its effect on PTH outcomes in this cohort. While definitive evidence is lacking, TXA may reduce the need for operative intervention in paediatric patients (26), and is common amongst Australian PTH management protocols (25).

Two prior retrospective studies in regional Australia provide useful comparison, employing similar low-risk selection criteria for their patients. Key et al. (9) reported a PTH rate of 2.9% and transfer rate of 1% in paediatric patients undergoing outreach tonsillectomy at an Outer regional hospital in Victoria (ASGS RA-3, MM-4). Patients were required to remain within 30 minutes of a 24-hour ED for 14 days postoperatively. The timing and method of transfer was not reported, but all transferred patients were managed nonoperatively. In New South Wales, Jones et al. (10) reported a PTH rate of 4% for adult and paediatric patients treated at an ENT-serviced Inner regional hospital (ASGA RA-2, MM-3), but placed no restrictions on the geographic proximity of patients postoperatively. Of their cohort, 360 patients returned home more than 100 km away and five of these patients required transfer for PTH. Patients that required retrieval had a median transfer time of 4.1 hours via road ambulance, although some were delayed for more than 15 hours. These studies suggest that with appropriate patient selection, outreach tonsillectomy can achieve complication rates comparable to metropolitan benchmarks, even in regional centres with variable proximity to acute services. Our findings extend this evidence to a Very remote setting, where despite longer retrieval times, PTH rates and outcomes were similarly consistent with the wider literature.

Beyond clinical safety, outreach surgery has health system and patient-level cost considerations (27). Aeromedical retrieval is resource intensive, with estimated costs of approximately $5,000 per engine hour (28). Although outreach and emergency retrieval costs fall to the health department, patients and families bear significant personal and social costs when travel to metropolitan centres is required for elective tonsillectomy, including transport, accommodation, time away from work and disruption of family support (29). Experimental choice studies suggest that patients are often prepared to accept higher levels of surgical risk in order to be treated locally (30), underscoring how these personal costs can be a significant barrier to health access (31).

Our findings must be interpreted in the context of several limitations. As a retrospective analysis, data completeness and consistency were variable, and some risk factors (e.g., tonsil size, comorbidities, perioperative medications including TXA) were not consistently recorded and therefore unable to be evaluated. While all ED presentations were captured, self-limiting bleeds managed at home may have been missed, potentially underestimating the true PTH rate, as in other studies (32). Our small sample size and single location limit generalisability, though this is offset by the value of reporting outcomes in a Very remote setting for the first time.

A further limitation of this study is the absence of severe PTH cases requiring blood transfusion or urgent surgical intervention. This finding should be interpreted cautiously, as it may reflect the low incidence of these events rather than the safety of the current protocol. Consequently, we cannot determine how a Very remote location impacts outcomes for this rare but high-risk subset of patients. Survey data suggests that most ENT surgeons in Australia would not offer tonsillectomy to patients who live more than one hour from an ENT-serviced hospital for this reason (13). This highlights an important ethical dilemma in remote service delivery: balancing improved access to care for the majority against the risk that a minority of patients could experience significant treatment delay for a life-threatening complication. These considerations underscore the need for ongoing reflection on the suitability of rural outreach tonsillectomy and potential refinement of patient selection criteria and surgical technique to lower haemorrhage rates, along with clear postoperative proximity expectations and retrieval pathways to manage PTH. Further research, including a comprehensive cost-benefit analysis, qualitative assessments of patient experience and review of the RFDS retrieval outcomes for PTH across regional and remote Queensland, would help inform evidence-based guidelines for safe and sustainable outreach tonsillectomy.

Conclusions

This study presents the first published cohort of outreach tonsillectomy in a Very remote Australian setting. Although this study demonstrates PTH rates and retrieval outcomes comparable to the wider literature, the absence of severe PTH limits conclusions about rare but life-threatening cases. Our findings provide useful preliminary data for health services exploring the feasibility of outreach models. Further evaluation of safety, cost and outcomes is warranted to determine the role of outreach tonsillectomy in improving access for rural and remote patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://www.theajo.com/article/view/10.21037/ajo-25-66/rc

Data Sharing Statement: Available at https://www.theajo.com/article/view/10.21037/ajo-25-66/dss

Peer Review File: Available at https://www.theajo.com/article/view/10.21037/ajo-25-66/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://www.theajo.com/article/view/10.21037/ajo-25-66/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was reviewed by the Chairperson of the Metro North Health Human Research Ethics Committee (project ID: 120353) and deemed exempt from full ethical review on the basis that it is a quality initiative. Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Li JC, Forer M, Veivers D. Reference rate for post-tonsillectomy haemorrhage in Australia—A 2000-2020 national hospital morbidity database analysis. PLoS One 2022;17:e0273320. Erratum in: PLoS One 2025;20:e0321297. [Crossref] [PubMed]
2. Rogers MA, Frauenfelder C, Woods C, et al. Bleeding following coblation tonsillectomy: a 10-year, single-surgeon audit and modified grading system. J Laryngol Otol 2015;129:S32-7. [Crossref] [PubMed]
3. Attard S, Carney AS. Paediatric patient bleeding and pain outcomes following subtotal (tonsillotomy) and total tonsillectomy: a 10-year consecutive, single surgeon series. ANZ J Surg 2020;90:2532-6. [Crossref] [PubMed]
4. Griffin AS, Jumeau P. A total of 3,840 tonsillectomies by one Australian surgeon: haemorrhage rates, techniques, and comparisons. Aust J Otolaryngol 2023;6:12.
5. Tran AHL, Chin KL, Horne RSC, et al. Hospital revisits after paediatric tonsillectomy: a cohort study. J Otolaryngol Head Neck Surg 2022;51:1. [Crossref] [PubMed]
6. Tomkinson A, Harrison W, Owens D, et al. Risk factors for postoperative hemorrhage following tonsillectomy. Laryngoscope 2011;121:279-88. [Crossref] [PubMed]
7. Unit RCoSoECE. National prospective tonsillectomy audit: final report of an audit carried out in England and Northern Ireland between July 2003 and September 2004. Royal College of Surgeons of England; 2005.
8. Mitchell RB, Archer SM, Ishman SL, et al. Clinical Practice Guideline: Tonsillectomy in Children (Update). Otolaryngol Head Neck Surg 2019;160:S1-S42. [Crossref] [PubMed]
9. Key S, Alnimri F, Ney B, et al. Paediatric tonsillectomy and adenotonsillectomy in a rural setting: a retrospective study over a period of 6-years. ANZ J Surg 2022;92:1401-6. [Crossref] [PubMed]
10. Jones A, Grant A, Saputra L, et al. Tonsillectomy in regional Australia: management and outcomes. Aust J Otolaryngol 2021;4:41.
11. Bigdeli R, Jabbour J, Budiono G, et al. A comparison of tonsillectomy techniques: a 10-year retrospective audit of a large regional hospital in Australia. Aust J Otolaryngol 2022;5:13.
12. O'Leary S, Vorrath J. Postoperative bleeding after diathermy and dissection tonsillectomy. Laryngoscope 2005;115:591-4. [Crossref] [PubMed]
13. Anning R, Cope D, Treble A, et al. Tonsillectomy: does proximity from otolaryngology care influence the intra-operative or post-operative plan? Aust J Otolaryngol 2021;4:25.
14. Royal Australasian College of Surgeons.2021.[cited Workforce & activities reports]. Available online: https://www.surgeons.org/resources/reports-guidelines-publications/workforce-activities-reports
15. Australian Commission on Safety and Quality in Health Care, Australian Institute of Health and Welfare. Tonsillectomy hospitalisation, 17 years and under. In: The Fourth Australian Atlas of Healthcare Variation. Sydney, 2021. Available online: https://www.safetyandquality.gov.au/our-work/healthcare-variation/fourth-atlas-2021/ear-nose-and-throat-surgery-children-and-young-people/31-tonsillectomy-hospitalisations-17-years-and-under
16. Queensland Health. Central Health West Hospital and Health Service. 2025. Available online: https://www.centralwest.health.qld.gov.au/home
17. New South Wales Health Department Agency for Clinical Innovation. Evidence brief: Post-tonsillectomy bleeding and pain. 2024. Available online: https://aci.health.nsw.gov.au/__data/assets/pdf_file/0009/931194/Evidence-Brief-Post-tonsillectomy-bleeding-and-pain.pdf
18. Cadd B, Rogers M, Patel H, et al. (Ton)silly seasons? Do atmospheric conditions actually affect post-tonsillectomy secondary haemorrhage rates? J Laryngol Otol 2015;129:702-5. [Crossref] [PubMed]
19. Kwok M, Subramaniyan M, Rimmer J, et al. Post-tonsillectomy haemorrhage in Australia—a multivariable analysis of risk factors. Australian Journal of Otolaryngology 2018;1:6.
20. Ramadas R, Hendel S, MacKillop A. Civilian aeromedical retrievals (the Australian experience). BJA Education 2015;16:186-90.
21. Sarny S, Ossimitz G, Habermann W, et al. Hemorrhage following tonsil surgery: a multicenter prospective study. Laryngoscope 2011;121:2553-60. [Crossref] [PubMed]
22. Cheung PKF, Walton J, Hobson ML, et al. Management of Recurrent and Delayed Post-Tonsillectomy and Adenoidectomy Hemorrhage in Children. Ear Nose Throat J 2023;102:244-50. [Crossref] [PubMed]
23. Windfuhr JP, Schloendorff G, Baburi D, et al. Life-threatening posttonsillectomy hemorrhage. Laryngoscope 2008;118:1389-94. [Crossref] [PubMed]
24. Russo E, Festa BM, Costantino A, et al. Postoperative Morbidity of Different Tonsillectomy Techniques: A Systematic Review and Network Meta-Analysis. Laryngoscope 2024;134:1696-704. [Crossref] [PubMed]
25. Lee TJ, Wood J, Ooi EH. Variation in management of post-tonsillectomy haemorrhage: a survey of Australian Society of Otolaryngology Head and Neck Surgery Consultants and Registrars. Australian Journal of Otolaryngology 2022;5:21-21.
26. Smith AL, Cornwall HL, Zhen E, et al. The therapeutic use of tranexamic acid reduces reintervention in paediatric secondary post-tonsillectomy bleeding. Aust J Otolaryngol 2020;3:10.
27. Jacups SP, Kinchin I. A rapid review of evidence to inform an ear, nose and throat service delivery model in remote Australia. Rural Remote Health 2021;21:5611. [Crossref] [PubMed]
28. Wieland L, Abernethy G. Aeromedical retrievals as a measure of potentially preventable hospitalisations and cost comparison with provision of GP-led primary health care in a remote Aboriginal community. Rural Remote Health 2023;23:7676. [Crossref] [PubMed]
29. Stewart GD, Long G, Tulloh BR. Surgical service centralisation in Australia versus choice and quality of life for rural patients. Med J Aust 2006;185:162-3. [Crossref] [PubMed]
30. Bühn S, Holstiege J, Pieper D. Are patients willing to accept longer travel times to decrease their risk associated with surgical procedures? A systematic review. BMC Public Health 2020;20:253. [Crossref] [PubMed]
31. Australian Institute of Health and Welfare. Rural and remote health. Canberra, 2024. Available online: https://www.aihw.gov.au/reports/rural-remote-australians/rural-and-remote-health
32. Harris RL, Mitchell JE, Jonathan DA. A telephone audit in parallel with the UK national tonsillectomy audit to investigate re-admission as a measure of secondary haemorrhage rate. Auris Nasus Larynx 2008;35:220-3. [Crossref] [PubMed]