Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vi... more Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30-40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A "halo" of GDNF expression was observed diffusing from...
Virtual reality (VR) simulation-based technologies play an important role in neurosurgical reside... more Virtual reality (VR) simulation-based technologies play an important role in neurosurgical resident training. The Congress of Neurological Surgeons (CNS) Simulation Committee developed a simulation-based curriculum incorporating VR simulators to train residents in the management of common neurosurgical disorders. To enhance neurosurgical resident training for ventriculostomy placement using simulation-based training. A course-based neurosurgical simulation curriculum was introduced at the Neurosurgical Simulation Symposium at the 2011 and 2012 CNS annual meetings. A trauma module was developed to teach ventriculostomy placement as one of the neurosurgical procedures commonly performed in the management of traumatic brain injury. The course offered both didactic and simulator-based instruction, incorporating written and practical pretests and posttests and questionnaires to assess improvement in skill level and to validate the simulators as teaching tools. Fourteen trainees participated in the didactic component of the trauma module. Written scores improved significantly from pretest (75%) to posttest (87.5%; P < .05). Seven participants completed the ventriculostomy simulation. Significant improvements were observed in anatomy (P < .04), burr hole placement (P < .03), final location of the catheter (P = .05), and procedure completion time (P < .004). Senior residents planned a significantly better trajectory (P < .01); junior participants improved most in terms of identifying the relevant anatomy (P < .03) and the time required to complete the procedure (P < .04). VR ventriculostomy placement as part of the CNS simulation trauma module complements standard training techniques for residents in the management of neurosurgical trauma. Improvement in didactic and hands-on knowledge by course participants demonstrates the usefulness of the VR simulator as a training tool.
Obesity is a growing public health problem. A considerable number of patients undergoing cervical... more Obesity is a growing public health problem. A considerable number of patients undergoing cervical spine surgery are obese, but the correlation between obesity and surgical outcome is still unclear. In this study, we investigated the impact of body mass index (BMI) on patients' and surgeons' perception of spine surgery outcomes. We analyzed a prospectively collected spine surgery registry with patient-reported outcome measures and surgeon ratings. Mixed-effects linear models and linear regression models were applied to investigate the relationship between different World Health Organization obesity classifications and surgical outcome. A total of 88 patients had surgery for degenerative cervical spine disease, with 97.72% follow-up at 3 months and 94.31% at 6 months postoperatively. Mean BMI was 27.92 ± 7.9 kg/m(2); 28.57% were overweight (BMI 25-29.9), and 31.57% were obese (Class I obesity, BMI 30-34.9). We found a positive correlation between BMI and VAS at 6 months (R = 0.298, P < 0.05) and between BMI and change in Neck Disability Index (R = 0.385, P < 0.01), suggesting that obese patients had less improvement and more pain 6 months postoperatively than nonobese patients. Overweight patients had worse MCS values (R = -0.275, P < 0.05) and obese patients had worse visual analog scale values 6 months after surgery (R = 0.284, P < 0.03). Interestingly, surgeon ratings matched the aforementioned results. Patients with greater BMI had worse surgeon ratings 3 and 6 months postoperatively (R = 0.555, P < 0.05), whereas normal-weight patients had better outcomes when rated from the surgeon's perspective (R = -0.536, P < 0.05). Obese patients had worse postoperative patient-reported outcome scores and less overall patient-rated improvement compared with nonobese patients. Patients with BMI >25 reported less improvement after surgery both in the patients' and in the surgeons' perspectives.
Acute hydrocephalus (HCP) after aneurysmal subarachnoid hemorrhage (SAH) often persists. Our prev... more Acute hydrocephalus (HCP) after aneurysmal subarachnoid hemorrhage (SAH) often persists. Our previous study described factors that singly and combined in a formula correlate with permanent CSF diversion. We now aimed to determine whether the same parameters are applicable at an institution with different HCP management practice. We reviewed records of 181 consecutive patients who presented with SAH and received an external ventricular drain (EVD) for acute HCP. After exclusion and inclusion criteria were met, 71 patients were analyzed. Data included admission Fisher and Hunt and Hess grades, aneurysm location, treatment modality, ventricle size, CSF cell counts and protein levels, length of stay (LOS) in the hospital, and the presence of craniectomy. Outcome measures were: (1) initial EVD challenge outcome; (2) shunting within 3 months; and (3) LOS. Shunting correlated with Hunt and Hess grade, CSF protein, and the presence of craniectomy. The formula derived in our previous study demonstrated a weaker correlation with initial EVD challenge failure. Several parameters that correlated with shunting in the previous study were instead associated with LOS in this study. The decision to shunt depends on management choices in the context of a disease process that may improve over time. Based on the treatment strategy, the shunting rate may be lowered but LOS increased. Markers of disease severity in patients with HCP after SAH correlate with both shunt placement and LOS. This is the first study to directly evaluate the effect of different practice styles on the shunting rate. Differences in HCP management practices should inform the design of prospective studies.
Although the concept of minimum clinically important difference (MCID) as a measurement of surgic... more Although the concept of minimum clinically important difference (MCID) as a measurement of surgical outcome has been extensively studied, there is lack of consensus on the most valid or clinically relevant MCID calculation approach. To compare the range of MCID threshold values obtained by different anchor-based and distribution-based approaches to determine the best clinically meaningful and statistically significant MCID for our studied group. Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were analyzed from a prospective blinded database. Preoperative, 3-, and 6-month postoperative patient reported outcome (PRO) scores and blinded surgeon ratings were collected. Four calculation methods were used to calculate MCID threshold values: average change, change difference, minimum detectable change, and receiver operating characteristic (ROC) curve. Three anchors were used to evaluate meaningful improvement postsurgery: health transition item, patient overall status, and surgeon ratings. On average, all patients had a statistically significant improvement (P < .001) postoperatively for neck disability index (score 27.42 preoperatively to 19.42 postoperatively), physical component of the Short Form of the Medical Outcomes Study (SF-36) (33.02-42.23), mental component of the SF-36 (44-50.74), and visual analog scale (2.85-1.93). The 4 MCID approaches yielded a range of values for each PRO: 2.23 to 16.59 for physical component of the SF-36, 0.11 to 16.27 for mental component of the SF-36, and 2.72 to 12.08 for neck disability index. In comparison with health transition item and patient overall status anchors, the area under the ROC curve was consistently greater for surgeon ratings for all 4 PROs. Minimum detectable change together with surgeon ratings anchor appears to be the most appropriate MCID method. Based on our findings, this combination offers the greatest area under the ROC curve (threshold above the 95% confidence interval). The choice of the anchor did not significantly affect this result.
Immunology of the central nervous system (CNS) is a growing field of study. Until recently the br... more Immunology of the central nervous system (CNS) is a growing field of study. Until recently the brain was considered an 'immunologically privileged' site. It is increasingly apparent that the CNS has a significant but tightly regulated capability to mount an inflammatory and immune response. This article serves as an introduction to the special section at the start of this issue on neuroimmunology. We also focus on several immunological concepts that are particularly relevant in the context of neuroimmunology-cross-reactivity, the immunological synapse and the nature of the immune response to transplantation in the CNS. We conclude that the fundamental concepts are common to all branches of immunology. Better understanding of the basic mechanisms will blur the borders between the different areas of immunology.
Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this st... more Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this study was to establish if human neural stem cells (HNSCs) could survive in the nonhuman primate brain after an ischemic event. Three adult cynomolgus monkeys received a unilateral occlusion of the M, segment of the right middle cerebral artery (MCA). One week later each animal received five magnetic resonance (MR) image-guided stereotactic intracerebral injections of HNSC neurospheres labeled with bromodeoxyuridine (BrdU) in the areas surrounding the ischemic lesion as defined in T1- and T2-weighted images. On the day of transplantation and throughout the study the monkeys received oral cyclosporine (10 mg/kg twice a day), and plasma levels were monitored routinely. The animals were killed at 45, 75, or 105 days after transplantation. Magnetic resonance images revealed a cortical and subcortical infarction in the MCA distribution area. Postmortem morphological brain analyses confirmed the distribution of the infarcted area seen in the MR images, with loss of tissue and necrosis in the ischemic region. Cells that were positive for BrdU were present in the three experimental monkeys, mainly along injection tracks. Double-label immunofluorescence for BrdU and betaIII-tubulin (a marker of young neurons) revealed colocalization of few HNSCs, most of which were observed outside the immediate injection site. Colocalization with nestin was also observed, indicating an early neural/glial fate. In a model of stroke in nonhuman primates, HNSCs can survive up to 105 days when transplanted 1 week after an ischemic event and can partly undergo neuronal differentiation.
Journal of Neurology, Neurosurgery & Psychiatry, 1990
The clinicopathological findings are presented of two cases of mesolimbocortical dementia. Both c... more The clinicopathological findings are presented of two cases of mesolimbocortical dementia. Both cases were characterised by late onset slowly progressive personality changes and progressive intellectual deterioration without clinical Parkinsonism. Neuropathological findings revealed non-specific neuronal degeneration, Holzer and GFAP positive gliosis primarily affecting the limbic system, caudate, thalamus and substantia nigra. The pathological findings coincide with the distribution of the non-striatal dopaminergic pathways and suggest an intrinsic involvement of these pathways to account for the clinical and pathological manifestations.
Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease characterized by xanthomata of ... more Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease characterized by xanthomata of tendons, osteoporosis, cataracts, cerebellar ataxia, spastic paresis, and dementia. Though electroencephalographic (EEG) abnormalities are frequent in CTX, epileptic seizures have not been recognized as a major feature. A CTX patient is reported who presented with a generalized epileptic seizure and was evaluated with EEG and neuropsychological testing. Epilepsy should be considered a feature of CTX, and CTX considered as a possible, though rare, cause of symptomatic seizures.
Few have studied the correlation between patients&amp... more Few have studied the correlation between patients' and spine surgeons' perception on outcomes, or compared these with patient-reported outcome scores. Outcomes studies are increasingly important in evaluating costs and benefits to patients and surgeons, and in developing metrics for payer evaluation and health care policy-making. To compare patients' and surgeons' assessment of spine treatment outcome in a prospective blinded patient-driven spine surgery outcomes registry, and to correlate perceived outcomes ratings to validated outcomes scores. Patients filled out surveys at baseline, 3 months and 6 months postoperatively, including Visual Analog Scale (VAS), and Neck Disability Index (NDI) or Oswestry Disability Index (ODI). Outcome was rated independently by patients and surgeons on a 7-point Likert-type scale. Two-hundred and sixty-five consecutive adult patients were surgical candidates. Of these, 154 (58.1 %) opted for surgery, with 69 (44.8 %) cervical and 85 (55.2 %) lumbar patients. One hundred and thirty-five (87.7 %) had both patient and surgeon postoperative ratings. Surgeons' and patients' ratings correlated strongly (Spearman rho = 0.53, p < 0.0001, 45.9 % identical, 88.2 % +/- 1 grade). The surgeon rated outcomes were better than patients in 29.8 % and worse in 21.15 %. Patient rating correlated better with the most recent NDI/ODI and pain scores than with incremental change from baseline. In multivariate analysis, age, location (cervical vs lumbar), pain ratings, and functional scores (NDI, ODI) did not have significant impact on the discrepancy between patient and surgeon ratings. Patients' and surgeons' global outcome ratings for spinal disease correlate highly. Patients' ratings correlate better with most recent functional scores, rather than incremental change from baseline.
Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vi... more Human neural progenitor cells (hNPCs) have been proposed as a potential source of cells for ex vivo gene therapy. In this pilot study, three 5-year-old female cynomolgus monkeys received a single intracarotid infusion of MPTP, followed 1 week later by MRI-guided stereotaxic intrastriatal and intranigral injections of male hNPCs transgenic for GDNF. Immunosupression with oral cyclosporine (30-40 mg/kg) began 48 h before hNPC transplants and continued throughout the study. We monitored the animals using a clinical rating scale (CRS). Three months postsurgery, we euthanized the animals by transcardiac perfusion, then retrieved and processed their brains for morphological analysis. Our findings include the following. 1) hNPCs survived and produced GDNF in all animals 3 months postsurgery. 2) hNPCs remained in the areas of injection as observed by GDNF immunostaining and in situ hybridization for the human Y chromosome. 3) A "halo" of GDNF expression was observed diffusing from...
Virtual reality (VR) simulation-based technologies play an important role in neurosurgical reside... more Virtual reality (VR) simulation-based technologies play an important role in neurosurgical resident training. The Congress of Neurological Surgeons (CNS) Simulation Committee developed a simulation-based curriculum incorporating VR simulators to train residents in the management of common neurosurgical disorders. To enhance neurosurgical resident training for ventriculostomy placement using simulation-based training. A course-based neurosurgical simulation curriculum was introduced at the Neurosurgical Simulation Symposium at the 2011 and 2012 CNS annual meetings. A trauma module was developed to teach ventriculostomy placement as one of the neurosurgical procedures commonly performed in the management of traumatic brain injury. The course offered both didactic and simulator-based instruction, incorporating written and practical pretests and posttests and questionnaires to assess improvement in skill level and to validate the simulators as teaching tools. Fourteen trainees participated in the didactic component of the trauma module. Written scores improved significantly from pretest (75%) to posttest (87.5%; P < .05). Seven participants completed the ventriculostomy simulation. Significant improvements were observed in anatomy (P < .04), burr hole placement (P < .03), final location of the catheter (P = .05), and procedure completion time (P < .004). Senior residents planned a significantly better trajectory (P < .01); junior participants improved most in terms of identifying the relevant anatomy (P < .03) and the time required to complete the procedure (P < .04). VR ventriculostomy placement as part of the CNS simulation trauma module complements standard training techniques for residents in the management of neurosurgical trauma. Improvement in didactic and hands-on knowledge by course participants demonstrates the usefulness of the VR simulator as a training tool.
Obesity is a growing public health problem. A considerable number of patients undergoing cervical... more Obesity is a growing public health problem. A considerable number of patients undergoing cervical spine surgery are obese, but the correlation between obesity and surgical outcome is still unclear. In this study, we investigated the impact of body mass index (BMI) on patients' and surgeons' perception of spine surgery outcomes. We analyzed a prospectively collected spine surgery registry with patient-reported outcome measures and surgeon ratings. Mixed-effects linear models and linear regression models were applied to investigate the relationship between different World Health Organization obesity classifications and surgical outcome. A total of 88 patients had surgery for degenerative cervical spine disease, with 97.72% follow-up at 3 months and 94.31% at 6 months postoperatively. Mean BMI was 27.92 ± 7.9 kg/m(2); 28.57% were overweight (BMI 25-29.9), and 31.57% were obese (Class I obesity, BMI 30-34.9). We found a positive correlation between BMI and VAS at 6 months (R = 0.298, P < 0.05) and between BMI and change in Neck Disability Index (R = 0.385, P < 0.01), suggesting that obese patients had less improvement and more pain 6 months postoperatively than nonobese patients. Overweight patients had worse MCS values (R = -0.275, P < 0.05) and obese patients had worse visual analog scale values 6 months after surgery (R = 0.284, P < 0.03). Interestingly, surgeon ratings matched the aforementioned results. Patients with greater BMI had worse surgeon ratings 3 and 6 months postoperatively (R = 0.555, P < 0.05), whereas normal-weight patients had better outcomes when rated from the surgeon's perspective (R = -0.536, P < 0.05). Obese patients had worse postoperative patient-reported outcome scores and less overall patient-rated improvement compared with nonobese patients. Patients with BMI >25 reported less improvement after surgery both in the patients' and in the surgeons' perspectives.
Acute hydrocephalus (HCP) after aneurysmal subarachnoid hemorrhage (SAH) often persists. Our prev... more Acute hydrocephalus (HCP) after aneurysmal subarachnoid hemorrhage (SAH) often persists. Our previous study described factors that singly and combined in a formula correlate with permanent CSF diversion. We now aimed to determine whether the same parameters are applicable at an institution with different HCP management practice. We reviewed records of 181 consecutive patients who presented with SAH and received an external ventricular drain (EVD) for acute HCP. After exclusion and inclusion criteria were met, 71 patients were analyzed. Data included admission Fisher and Hunt and Hess grades, aneurysm location, treatment modality, ventricle size, CSF cell counts and protein levels, length of stay (LOS) in the hospital, and the presence of craniectomy. Outcome measures were: (1) initial EVD challenge outcome; (2) shunting within 3 months; and (3) LOS. Shunting correlated with Hunt and Hess grade, CSF protein, and the presence of craniectomy. The formula derived in our previous study demonstrated a weaker correlation with initial EVD challenge failure. Several parameters that correlated with shunting in the previous study were instead associated with LOS in this study. The decision to shunt depends on management choices in the context of a disease process that may improve over time. Based on the treatment strategy, the shunting rate may be lowered but LOS increased. Markers of disease severity in patients with HCP after SAH correlate with both shunt placement and LOS. This is the first study to directly evaluate the effect of different practice styles on the shunting rate. Differences in HCP management practices should inform the design of prospective studies.
Although the concept of minimum clinically important difference (MCID) as a measurement of surgic... more Although the concept of minimum clinically important difference (MCID) as a measurement of surgical outcome has been extensively studied, there is lack of consensus on the most valid or clinically relevant MCID calculation approach. To compare the range of MCID threshold values obtained by different anchor-based and distribution-based approaches to determine the best clinically meaningful and statistically significant MCID for our studied group. Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were analyzed from a prospective blinded database. Preoperative, 3-, and 6-month postoperative patient reported outcome (PRO) scores and blinded surgeon ratings were collected. Four calculation methods were used to calculate MCID threshold values: average change, change difference, minimum detectable change, and receiver operating characteristic (ROC) curve. Three anchors were used to evaluate meaningful improvement postsurgery: health transition item, patient overall status, and surgeon ratings. On average, all patients had a statistically significant improvement (P < .001) postoperatively for neck disability index (score 27.42 preoperatively to 19.42 postoperatively), physical component of the Short Form of the Medical Outcomes Study (SF-36) (33.02-42.23), mental component of the SF-36 (44-50.74), and visual analog scale (2.85-1.93). The 4 MCID approaches yielded a range of values for each PRO: 2.23 to 16.59 for physical component of the SF-36, 0.11 to 16.27 for mental component of the SF-36, and 2.72 to 12.08 for neck disability index. In comparison with health transition item and patient overall status anchors, the area under the ROC curve was consistently greater for surgeon ratings for all 4 PROs. Minimum detectable change together with surgeon ratings anchor appears to be the most appropriate MCID method. Based on our findings, this combination offers the greatest area under the ROC curve (threshold above the 95% confidence interval). The choice of the anchor did not significantly affect this result.
Immunology of the central nervous system (CNS) is a growing field of study. Until recently the br... more Immunology of the central nervous system (CNS) is a growing field of study. Until recently the brain was considered an 'immunologically privileged' site. It is increasingly apparent that the CNS has a significant but tightly regulated capability to mount an inflammatory and immune response. This article serves as an introduction to the special section at the start of this issue on neuroimmunology. We also focus on several immunological concepts that are particularly relevant in the context of neuroimmunology-cross-reactivity, the immunological synapse and the nature of the immune response to transplantation in the CNS. We conclude that the fundamental concepts are common to all branches of immunology. Better understanding of the basic mechanisms will blur the borders between the different areas of immunology.
Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this st... more Neural cell transplantation has been proposed as a treatment after stroke. The purpose of this study was to establish if human neural stem cells (HNSCs) could survive in the nonhuman primate brain after an ischemic event. Three adult cynomolgus monkeys received a unilateral occlusion of the M, segment of the right middle cerebral artery (MCA). One week later each animal received five magnetic resonance (MR) image-guided stereotactic intracerebral injections of HNSC neurospheres labeled with bromodeoxyuridine (BrdU) in the areas surrounding the ischemic lesion as defined in T1- and T2-weighted images. On the day of transplantation and throughout the study the monkeys received oral cyclosporine (10 mg/kg twice a day), and plasma levels were monitored routinely. The animals were killed at 45, 75, or 105 days after transplantation. Magnetic resonance images revealed a cortical and subcortical infarction in the MCA distribution area. Postmortem morphological brain analyses confirmed the distribution of the infarcted area seen in the MR images, with loss of tissue and necrosis in the ischemic region. Cells that were positive for BrdU were present in the three experimental monkeys, mainly along injection tracks. Double-label immunofluorescence for BrdU and betaIII-tubulin (a marker of young neurons) revealed colocalization of few HNSCs, most of which were observed outside the immediate injection site. Colocalization with nestin was also observed, indicating an early neural/glial fate. In a model of stroke in nonhuman primates, HNSCs can survive up to 105 days when transplanted 1 week after an ischemic event and can partly undergo neuronal differentiation.
Journal of Neurology, Neurosurgery & Psychiatry, 1990
The clinicopathological findings are presented of two cases of mesolimbocortical dementia. Both c... more The clinicopathological findings are presented of two cases of mesolimbocortical dementia. Both cases were characterised by late onset slowly progressive personality changes and progressive intellectual deterioration without clinical Parkinsonism. Neuropathological findings revealed non-specific neuronal degeneration, Holzer and GFAP positive gliosis primarily affecting the limbic system, caudate, thalamus and substantia nigra. The pathological findings coincide with the distribution of the non-striatal dopaminergic pathways and suggest an intrinsic involvement of these pathways to account for the clinical and pathological manifestations.
Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease characterized by xanthomata of ... more Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease characterized by xanthomata of tendons, osteoporosis, cataracts, cerebellar ataxia, spastic paresis, and dementia. Though electroencephalographic (EEG) abnormalities are frequent in CTX, epileptic seizures have not been recognized as a major feature. A CTX patient is reported who presented with a generalized epileptic seizure and was evaluated with EEG and neuropsychological testing. Epilepsy should be considered a feature of CTX, and CTX considered as a possible, though rare, cause of symptomatic seizures.
Few have studied the correlation between patients&amp... more Few have studied the correlation between patients' and spine surgeons' perception on outcomes, or compared these with patient-reported outcome scores. Outcomes studies are increasingly important in evaluating costs and benefits to patients and surgeons, and in developing metrics for payer evaluation and health care policy-making. To compare patients' and surgeons' assessment of spine treatment outcome in a prospective blinded patient-driven spine surgery outcomes registry, and to correlate perceived outcomes ratings to validated outcomes scores. Patients filled out surveys at baseline, 3 months and 6 months postoperatively, including Visual Analog Scale (VAS), and Neck Disability Index (NDI) or Oswestry Disability Index (ODI). Outcome was rated independently by patients and surgeons on a 7-point Likert-type scale. Two-hundred and sixty-five consecutive adult patients were surgical candidates. Of these, 154 (58.1 %) opted for surgery, with 69 (44.8 %) cervical and 85 (55.2 %) lumbar patients. One hundred and thirty-five (87.7 %) had both patient and surgeon postoperative ratings. Surgeons' and patients' ratings correlated strongly (Spearman rho = 0.53, p < 0.0001, 45.9 % identical, 88.2 % +/- 1 grade). The surgeon rated outcomes were better than patients in 29.8 % and worse in 21.15 %. Patient rating correlated better with the most recent NDI/ODI and pain scores than with incremental change from baseline. In multivariate analysis, age, location (cervical vs lumbar), pain ratings, and functional scores (NDI, ODI) did not have significant impact on the discrepancy between patient and surgeon ratings. Patients' and surgeons' global outcome ratings for spinal disease correlate highly. Patients' ratings correlate better with most recent functional scores, rather than incremental change from baseline.
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