Radiographic alignment outcomes after the single-position prone transpsoas approach: a multi-institutional retrospective review of 363 cases

Neurosurg Focus 54(1):E3, 2023

The aim of this paper was to evaluate the changes in radiographic spinopelvic parameters in a large cohort of patients undergoing the prone transpsoas approach to the lumbar spine.

METHODS A multicenter retrospective observational cohort study was performed for all patients who underwent lateral lumber interbody fusion via the single-position prone transpsoas (PTP) approach. Spinopelvic parameters from preoperative and first upright postoperative radiographs were collected, including lumbar lordosis (LL), pelvic incidence (PI), and pelvic tilt (PT). Functional indices (visual analog scale score), and patient-reported outcomes (Oswestry Disability Index) were also recorded from pre- and postoperative appointments.

RESULTS Of the 363 patients who successfully underwent the procedure, LL after fusion was 50.0° compared with 45.6° preoperatively (p < 0.001). The pelvic incidence–lumbar lordosis mismatch (PI-LL) was 10.5° preoperatively versus 2.9° postoperatively (p < 0.001). PT did not significantly change (0.2° ± 10.7°, p > 0.05).

CONCLUSIONS The PTP approach allows significant gain in lordotic augmentation, which was associated with good functional results at follow-up.

An externally validated deep learning model for the accurate segmentation of the lumbar paravertebral muscles

European Spine Journal (2022) 31:2156–2164

Imaging studies about the relevance of muscles in spinal disorders, and sarcopenia in general, require the segmentation of the muscles in the images which is very labour-intensive if performed manually and poses a practical limit to the number of investigated subjects. This study aimed at developing a deep learning-based tool able to fully automatically perform an accurate segmentation of the lumbar muscles in axial MRI scans, and at validating the new tool on an external dataset.

Methods A set of 60 axial MRI images of the lumbar spine was retrospectively collected from a clinical database. Psoas major, quadratus lumborum, erector spinae, and multifidus were manually segmented in all available slices. The dataset was used to train and validate a deep neural network able to segment muscles automatically. Subsequently, the network was externally validated on images purposely acquired from 22 healthy volunteers.

Results The median Jaccard index for the individual muscles calculated for the 22 subjects of the external validation set ranged between 0.862 and 0.935, demonstrating a generally excellent performance of the network, although occasional failures were noted. Cross-sectional area and fat fraction of the muscles were in agreement with published data.

Conclusions The externally validated deep neural network was able to perform the segmentation of the paravertebral muscles in an accurate and fully automated manner, although it is not without limitations. The model is therefore a suitable research tool to perform large-scale studies in the field of spinal disorders and sarcopenia, overcoming the limitations of non-automated methods.

Topping-off technique for stabilization of lumbar degenerative instabilities in 322 patients

J Neurosurg Spine 32:366–372, 2020

Semi-rigid instrumentation (SRI) was introduced to take advantage of the concept of load sharing in surgery for spinal stabilization. The authors investigated a topping-off technique in which interbody fusion is not performed in the uppermost motion segment, thus creating a smooth transition from stabilized to free motion segments. SRI using the topping-off technique also reduces the motion of the adjacent segments, which may reduce the risk of adjacent segment disease (ASD), a frequently observed sequela of instrumentation and fusion, but this technique may also increase the possibility of screw loosening (SL). In the present study the authors aimed to systematically evaluate reoperation rates, clinical outcomes, and potential risk factors and incidences of ASD and SL for this novel approach.

METHODS The authors collected data for the first 322 patients enrolled at their institution from 2009 to 2015 who underwent surgery performed using the topping-off technique. Reoperation rates, patient satisfaction, and other outcome measures were evaluated. All patients underwent pedicle screw–based semi-rigid stabilization of the lumbar spine with a polyetheretherketone (PEEK) rod system.

RESULTS Implantation of PEEK rods during revision surgery was performed in 59.9% of patients. A median of 3 motion segments (range 1–5 segments) were included and a median of 2 motion segments (range 0–4 segments) were fused. A total of 89.4% of patients underwent fusion, 73.3% by transforaminal lumbar interbody fusion (TLIF), 18.4% by anterior lumbar interbody fusion (ALIF), 3.1% by extreme lateral interbody fusion (XLIF), 0.3% by oblique lumbar interbody fusion (OLIF), and 4.9% by combined approaches in the same surgery. Combined radicular and lumbar pain according to a visual analog scale was reduced from 7.9 ± 1.0 to 4.0 ± 3.1, with 56.2% of patients indicating benefit from surgery. After maximum follow-up (4.3 ± 1.8 years), the reoperation rate was 16.4%.

CONCLUSIONS The PEEK rod concept including the topping-off principle seems safe, with at least average patient satisfaction in this patient group. Considering the low rate of first-tier surgeries, the presented results seem at least comparable to those of most other series. Follow-up studies are needed to determine long-term outcomes, particularly with respect to ASD, which might be reduced by the presented approach.

Design and Testing of 2 Novel Scores That Predict Global Sagittal Alignment Utilizing Cervical or Lumbar Plain Radiographs

Neurosurgery 82:163–171, 2018

Global sagittal deformity is an established cause of disability. However, measurements of sagittal alignment are often ignored when patients present with symptoms localizing to the cervical or lumbar spine.

OBJECTIVE: To develop scoring scales to predict the risk of sagittal malalignment in patients with only cervical or lumbar spine radiographs.

METHODS: A retrospective review of a prospectively maintained multicenter adult spinal deformity database was performed. Primary outcome (sagittal malalignment) was defined as a C7 plumbline ≥ 50 mm. Two multivariate logistic regressions were performed using patient characteristics and measurements derived from cervical or lumbar radiographs as covariates. Point scores were assigned to age, body mass index (BMI), and lumbar lordosis or T1 slope by rounding their ß coefficients to the nearest integer.

RESULTS: Nine hundred seventy-nine patients were included, with 652 randomly assigned to the derivation cohort (used to build the score) and 327 comprising the validation set. Final cervical score for the primary outcome included BMI ≥ 25 (1 point), age ≥ 55 yr (2 points), and T1 slope ≥ 27º (2 points). Final lumbar score for the primary outcome included BMI≥25 (1 point), age≥55 yr (1 point), and lumbar lordosis ≥45º (–1 points). High scores for both the cervical and lumbar spine presented with high specificity and positive likelihood ratios of sagittal malalignment.

CONCLUSION: We developed scoring scales to predict global sagittal malalignment utilizing clinical covariates and cervical or lumbar radiographs. Patients with high scores may prompt imaging with long-cassette plain films to evaluate for global sagittal imbalance.

Pelvic retroversion: a compensatory mechanism for lumbar stenosis

J Neurosurg Spine 27:137–144, 2017

The flexed posture of the proximal (L1–3) or distal (L4–S1) lumbar spine increases the diameter of the spinal canal and neuroforamina and can relieve symptoms of neurogenic claudication. Distal lumbar flexion can result in pelvic retroversion; therefore, in cases of flexible sagittal imbalance, pelvic retroversion may be compensatory for lumbar stenosis and not solely compensatory for the sagittal imbalance as previously thought. The authors investigate underlying causes for pelvic retroversion in patients with flexible sagittal imbalance.

METHODS One hundred thirty-eight patients with sagittal imbalance who underwent a total of 148 fusion procedures of the thoracolumbar spine were identified from a prospective clinical database. Radiographic parameters were obtained from images preoperatively, intraoperatively, and at 6-month and 2-year follow-up. A cohort of 24 patients with flexible sagittal imbalance was identified and individually matched with a control cohort of 23 patients with fixed deformities. Flexible deformities were defined as a 10° change in lumbar lordosis between weight-bearing and non–weight-bearing images. Pelvic retroversion was quantified as the ratio of pelvic tilt (PT) to pelvic incidence (PI).

RESULTS The average difference between lumbar lordosis on supine MR images and standing radiographs was 15° in the flexible cohort. Sixty-eight percent of the patients in the flexible cohort were diagnosed preoperatively with lumbar stenosis compared with only 22% in the fixed sagittal imbalance cohort (p = 0.0032). There was no difference between the flexible and fixed cohorts with regard to C-2 sagittal vertical axis (SVA) (p = 0.95) or C-7 SVA (p = 0.43). When assessing for postural compensation by pelvic retroversion in the stenotic patients and nonstenotic patients, the PT/PI ratio was found to be significantly greater in the patients with stenosis (p = 0.019).

CONCLUSIONS For flexible sagittal imbalance, preoperative attention should be given to the root cause of the sagittal misalignment, which could be compensation for lumbar stenosis. Pelvic retroversion can be compensatory for both the lumbar stenosis as well as for sagittal imbalance.


ALIF and total disc replacement versus 2-level circumferential fusion with TLIF: a prospective, randomized, clinical and radiological trial


Eur Spine J (2016) 25:1558–1566

Study design: Prospective, randomized trial.

Purpose: The treatment of degenerative disc disease (DDD) with two-level fusion has been associated with a reasonable rate of complications. The aim of the present study was to compare (Hybrid) stand-alone anterior lumbar interbody fusion (ALIF) at L5/S1 with total disc replacement at L4/5 (TDR) as an alternative surgical strategy to (Fusion) 2-level circumferential fusion employing trans- foraminal lumbar interbody fusion (TLIF) with transpedicular stabilization at L4–S1.

Methods: A total of 62 patients with symptomatic DDD of segments L5/S1 (Modic ≥2°) and L4/5 (Modic ≤2°; positive discography) were enrolled; 31 were treated with Hybrid and 31 with Fusion. Preoperatively, at 0, 12, and a mean follow-up of 37 months, clinical (ODI, VAS) and radiological evaluations (plain/extension-flexion radiographs evaluated for implant failure, fusion, global and segmental lordosis, and ROM) were performed.

Results: In 26 of 31 Hybrid and 24 of 31 Fusion patients available at the final follow-up, we found a significant clinical improvement compared to preoperatively. Hybrid patients had significantly lower VAS scores immediately postoperatively and at follow-up compared to Fusion patients. The complication rates were low and similar between the groups. Lumbar lordosis increased in both groups. The increase was mainly located at L4–S1 in the Hybrid group and at L1–L4 in the Fusion group. Hybrid patients presented with increased ROM at L4/5 and L3/4, and Fusion patients presented with increased ROM at L3/4, with significantly greater ROM at L3/4 compared to Hybrid patients at follow-up.

Conclusions Hybrid surgery is a viable surgical alternative for the presented indication. Approach-related inferior trauma and the balanced restoration of lumbar lordosis resulted in superior clinical outcomes compared to two-level circumferential fusion with TLIF.

Repeated 3.0 Tesla Magnetic Resonance Imaging After Clinically Successful Lumbar Disc Surgery

Repeated 3.0 Tesla Magnetic Resonance Imaging After Clinically Successful Lumbar Disc Surgery

Spine 2016;41:239–245

Study Design. Prospective cohort study.

Objective. To describe the naturally occurring magnetic resonance imaging (MRI) findings after successful microsurgical removal of lumbar disc herniation with repeated MRI examinations.

Summary of Background Data. The interpretation of MRI after spinal surgery may be particularly challenging and image findings do not always correlate to clinical findings. Early postoperative MRI has limited value in the evaluation of patients after surgery for lumbar disc herniation.

Methods. Prospective study of 30 successfully operated patients, which underwent 3.0 T MRI within 24 h after surgery for lumbar disc herniation and repeated at 6 weeks and 3 months postoperatively. Postoperative image findings (nerve root enhancement, nerve root thickening, displacement or compression of the nerve root, and residual mass size and signal) were assessed quantitatively. Inter-rater reliability was tested.

Results. Inter-rater reliability between neuroradiologists was moderate for assessed MRI variables. In the immediate postoperative phase, compression or dislocation of the nerve root at the operated level was common. A residual mass at the operated level was seen in 80%, 47%, and 33% after 24 h, 6 weeks, and 3 months, respectively. Postoperative dislocation or compression of the nerve root from residual masses was seen in 67%, 24%, and 14% after 24 h, 6 weeks, and 3 months, respectively. A residual mass with a higher signal than muscle on T2-weighted images was seen in 80%, 30%, and 17% after 24 h, 6 weeks, and 3 months, respectively.

Conclusion. A residual mass with compression or dislocation of the nerve root at the operated level, that disappears over 3 months, is a common MRI finding in patients successfully operated for symptomatic lumbar disc herniation. An expectant approach instead of early reoperations may perhaps be preferred in patients with residual pain and root compression due to residual masses with high T2-signal since these often seem to resolve spontaneously.

Level of Evidence: 3

Management of lumbar spinal stenosis: a survey among Dutch spine surgeons

lumbar stenosis

Acta Neurochir (2014) 156:2139–2145

Various surgical and non-surgical treatments for lumbar spinal stenosis (LSS) are widely adopted in clinical practice, but high quality randomised controlled trials to support these are often lacking, especially in terms of their relative benefit and risk compared with other treatment options. Therefore, an evaluation of agreement among clinicians regarding the indications and the choice for particular treatments seems appropriate.

Methods One hundred and six Dutch neurosurgeons and orthopaedic spine surgeons completed a questionnaire, which evaluated treatment options for LSS and expectations regarding the effectiveness of surgical and non-surgical treatments.

Results Responders accounted for 6,971 decompression operations and 831 spinal fusion procedures for LSS annually. Typical neurogenic claudication, severe pain/disability, and a pronounced constriction of the spinal canal were considered the most important indications for surgical treatment by the majority of responders. Non-surgical treatment was generally regarded as ineffective and believed to be less effective than surgical treatment. Interlaminar decompression was the preferred technique by 68 % of neurosurgeons and 52 % orthopaedic surgeons for the treatment of LSS. Concomitant fusion was applied in 12% of all surgery for LSS. Most surgeons considered spondylolisthesis as an indication and spinal instability as a definite indication for additional fusion.

Conclusions The current survey demonstrates a wide variety of preferred treatments of symptomatic LSS by Dutch spine surgeons. To minimise variety, national and international protocols based on high-quality randomised controlled trials and systematic reviews are necessary to give surgeons more tools to support everyday decision-making.

Major vascular injury following lateral transpsoas approach

Major vascular injury following lateral transpsoas approach

J Neurosurg Spine 21:794–798, 2014

Extreme lateral interbody fusion (XLIF) has gained popularity among spine surgeons for treating multiple conditions of the lumbar spine. In contrast to the anterior lumbar interbody fusion (ALIF) approach, the minimally invasive XLIF approach affords wide access to the lumbar disc space without an access surgeon and causes minimal tissue disruption. The XLIF approach offers many advantages over other lumbar spine approaches, with a reportedly low complication profile.

The authors describe the first fatality reported in the literature following an XLIF approach. They describe the case of a 50-year-old woman who suffered a fatal intraoperative injury to the great vessels during a lateral transpsoas approach to the L4–5 disc space.

Minimally invasive transforaminal lumbar interbody fusions and fluoroscopy

Minimally invasive transforaminal lumbar interbody fusions and fluoroscopy

Neurosurg Focus 35 (2):E8, 2013

There is an increasing awareness of radiation exposure to surgeons and the lifelong implications of such exposure. One of the main criticisms of minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) is the amount of ionizing radiation required to perform the procedure. The goal in this study was to develop a protocol that would minimize the fluoroscopy time and radiation exposure needed to perform an MIS TLIF without compromising visualization of the anatomy or efficiency of the procedure.

Methods. A retrospective review of a prospectively collected database was performed to review the development of a low-dose protocol for MIS TLIFs in which a combination of low-dose pulsed fluoroscopy and digital spot images was used. Total fluoroscopy time and radiation dose were reviewed for 50 patients who underwent single-level MIS TLIFs.

Results. Fifty patients underwent single-level MIS TLIFs, resulting in the placement of 200 pedicle screws and 57 interbody spacers. There were 28 women and 22 men with an average age of 58.3 years (range 32–78 years). The mean body mass index was 26.2 kg/m2 (range 17.1–37.6 kg/m2). Indications for surgery included spondylolisthesis (32 patients), degenerative disc disease with radiculopathy (12 patients), and recurrent disc herniation (6 patients). Operative levels included 7 at L3–4, 40 at L4–5, and 3 at L5–S1. The mean operative time was 177 minutes (range 139–241 minutes). The mean fluoroscopic time was 18.72 seconds (range 7–29 seconds). The mean radiation dose was 0.247 mGy*m2 (range 0.06046–0.84054 mGy*m2). No revision surgery was required for any of the patients in this series.

Conclusions. Altering the fluoroscopic technique to low-dose pulse images or digital spot images can dramatically decrease fluoroscopy times and radiation doses in patients undergoing MIS TLIFs, without compromising image quality, accuracy of pedicle screw placement, or efficiency of the procedure.

Motion characteristics of the vertebral segments with lumbar degenerative spondylolisthesis in elderly patients

Motion characteristics of the vertebral segments with lumbar degenerative spondylolisthesis in elderly patients

Eur Spine J (2013) 22:425–431

Although some studies have reported on the kinematics of the lumbar segments with degenerative spondylolisthesis (DS), few data have been reported on the in vivo 6 degree-of-freedom kinematics of different anatomical structures of the diseased levels under physiological loading conditions. This research is to study the in vivo motion characteristics of the lumbar vertebral segments with L4 DS during weight-bearing activities.

Methods Nine asymptomatic volunteers (mean age 54.4) and 9 patients with L4 DS (mean age 73.4) were included. Vertebral kinematics was obtained using a combined MRI/ CT and dual fluoroscopic imaging technique. During functional postures (supine, standing upright, flexion, and extension), disc heights, vertebral motion patterns and instability were compared between the two groups.

Results Although anterior disc heights were smaller in the DS group than in the normal group, the differences were only significant at standing upright. Posterior disc heights were significantly smaller in DS group than in the normal group under all postures. Different vertebral motion patterns were observed in the DS group, especially in the left–right and cranial–caudal directions during flexion and extension of the body. However, the range of motions of the both groups were much less than the reported criteria of lumbar spinal instability.

Conclusion The study showed that lumbar vertebra with DS has disordered motion patterns. DS did not necessary result in vertebral instability. A restabilization process may have occurred and surgical treatment should be planned accordingly.

Biomechanical evaluation of the Total Facet Arthroplasty System

Eur Spine J (2012) 21:1660–1673. DOI 10.1007/s00586-012-2253-8

To gain insight into a new technology, a novel facet arthroplasty device (TFAS) was compared to a rigid posterior fixation system (UCR). The axial and bending loads through the implants and at the bone-implant interfaces were evaluated using an ex vivo biomechanical study and matched finite element analysis. Kinematic behaviour has been reported for TFAS, but implant loads have not. Implant loads are important indicators of an implant’s performance and safety. The rigid posterior fixation system is used for comparison due to the extensive information available about these systems.

Methods Unconstrained pure moments were applied to 13 L3–S1 cadaveric spine segments. Specimens were tested intact, following decompression, UCR fixation and TFAS implantation at L4–L5. UCR fixation was via standard pedicle screws and TFAS implantation was via PMMAcemented transpedicular stems. Three-dimensional 10 Nm moments and a 600 N follower load were applied; L4–L5 disc pressures and implant loads were measured using a pressure sensor and strain gauges, respectively. A finite element model was used to calculate TFAS bone-implant interface loads.

Results UCR experienced greater implant loads in extension (p<0.004) and lateral bending (p<0.02). Under flexion, TFAS was subject to greater implant moments (p<0.04). At the bone-implant interface, flexion resulted in the smallest TFAS (average = 0.20 Nm) but greatest UCR (1.18 Nm) moment and axial rotation resulted in the greatest TFAS (3.10 Nm) and smallest UCR (0.40 Nm) moments. Disc pressures were similar to intact for TFAS but not for UCR (p<0.04).

Conclusions These results are most applicable to the immediate post-operative period prior to remodelling of the bone-implant interface since the UCR and TFAS implants are intended for different service lives (UCR—until fusion, TFAS—indefinitely). TFAS reproduced intact-like anterior column load-sharing—as measured by disc pressure. The highest bone-implant moment of 3.1 Nm was measured in TFAS and for the same loading condition the UCR interface moment was considerably lower (0.4 Nm). For other loading conditions, the differences between TFAS and UCR were smaller, with the UCR sometimes having larger values and for others the TFAS was larger. The long-term physiological meaning of these findings is unknown and demonstrates the need for a better understanding of the relationship between spinal arthroplasty devices and the host tissue as development of next generation motionpreserving posterior devices that hope to more accurately replicate the natural functions of the native tissue continues.

Ability of electromyographic monitoring to determine the presence of malpositioned pedicle screws in the lumbosacral spine: analysis of 2450 consecutively placed screws

J Neurosurg Spine 15:130–135, 2011.DOI: 10.3171/2011.3.SPINE101

Pedicle screws provide efficient stabilization along all 3 columns of the spine, but they can be technically demanding to place, with malposition rates ranging from 5% to 10%. Intraoperative electromyographic (EMG) monitoring has the capacity to objectively identify a screw breaching the medial pedicle cortex that is in proximity to a nerve root. The purpose of this study is to describe and evaluate the authors’ 7-year institutional experience with intraoperative EMG monitoring during placement of lumbar pedicle screws and to determine the clinical utility of intraoperative EMG monitoring.

Methods. The authors retrospectively studied 2450 consecutive lumbar pedicle screws placed in 418 patients from June 2002 through June 2009. All screws were inserted using a free-hand technique and anatomical landmarks, stimulated at 10.0 mA, and evaluated with CT scanning within 48 hours postoperatively. Medial pedicle screw breach was defined as having greater than 25% of the screw diameter extend outside of the pedicle, as confirmed on CT scanning or intraoperatively by a positive EMG response indicating a medial breach. The sensitivity and specificity of intraoperative EMG monitoring in detecting the presence of a medial screw breach was evaluated based on the following definitions: 1) true positive (a positive response to EMG stimulation confirmed as a breach intraoperatively or on postoperative CT scans); 2) false positive (positive response to EMG stimulation confirmed as a correctly positioned screw on postoperative CT scans); 3) true negative (no response to EMG stimulation confirmed as a correctly positioned screw on postoperative CT scans); or 4) false negative (no response to EMG stimulation but confirmed as a breach on postoperative CT scans).

Results. One hundred fifteen pedicle screws (4.7%) showed positive stimulation during intraoperative EMG monitoring. At stimulation thresholds less than 5.0, 5.0–8.0, and > 8.0 mA, the specificity of a positive response was 99.9%, 97.9%, and 95.9%, respectively. The sensitivity of a positive response at these thresholds was only 43.4%, 69.6%, and 69.6%, respectively. At a threshold less than 5.0 mA, 91% of screws with a positive EMG response were confirmed as true medial breaches. However, at thresholds of 5.0–8.0 mA or greater than 8.0 mA, a positive EMG response was associated with 89% and 100% false positives (no breaches), respectively.

Conclusions. When using intraoperative EMG monitoring, a positive response at screw stimulation thresholds less than 5.0 mA was highly specific for a medial pedicle screw breach but was poorly sensitive. A positive response to stimulation thresholds greater 5.0 mA was associated with a very high rate of false positives. The authors’ experience suggests that pedicle screws showing positive stimulation below 5.0 mA warrants intraoperative investigation for malpositioning while responses at higher thresholds are less reliable at accurately representing a medial breach

SPORT: Does Incidental Durotomy Affect Longterm Outcomes in Cases of Spinal Stenosis?

Neurosurgery 69:38–44, 2011 DOI: 10.1227/NEU.0b013e3182134171

Incidental durotomy is a familiar encounter during surgery for lumbar spinal stenosis. The impact of durotomy on long-term outcomes remains a matter of debate.

OBJECTIVE: To determine the impact of durotomy on the long-term outcomes of patients in the Spine Patient Outcomes Research Trial (SPORT).

METHODS: The SPORT cohort participants with a confirmed diagnosis of spinal stenosis, without associated spondylolisthesis, undergoing standard, first-time, open decompressive laminectomy, with or without fusion, were followed up from baseline at 6 weeks, and 3, 6, and 12 months and yearly thereafter at 13 spine clinics in 11 US states. Patient data from this prospectively gathered database were reviewed. As of May 2009, the mean follow-up among all analyzed patients was 43.8 months.

RESULTS: Four hundred nine patients underwent first-time open laminectomy with or without fusion. Thirty-seven of these patients (9%) had an incidental durotomy. No significant differences were observed with or without durotomy in age; sex; race; body mass index; the prevalence of smoking, diabetes mellitus, and hypertension; decompression level; number of levels decompressed; or whether an additional fusion was performed. The durotomy group had significantly increased operative duration, operative blood loss, and inpatient stay. There were, however, no differences in incidence of nerve root injury, mortality, additional surgeries, or primary outcomes (Short Form-36 Bodily Pain or Physical Function scores or Oswestry Disability Index) at yearly follow-ups to 4 years.

CONCLUSIONS: Incidental durotomy during first-time lumbar laminectomy for spinal stenosis did not impact long-term outcomes in affected patients.