Publications by authors named "Stephen J Lewis"

165 Publications

Recognition of posterior thoracolumbar instrumentations used in spinal deformity surgery and techniques for implant removal.

J Clin Neurosci 2021 Apr 10;86:217-222. Epub 2021 Feb 10.

Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

Spinal surgeries requiring implant removals/revisions are becoming more common, as a long time has passed since contemporary spinal instrumentation was developed and utilized. Recognizing implants and manufacturers preoperatively from radiographs and preparing appropriate instruments for removal are mandatory. The objective of the present paper was to review the various designs of contemporary posterior thoracolumbar spinal implants along with their radiographic features to facilitate the identification of previously used systems in removal or revision surgeries. We focused on contemporary spinal implants that have been commonly used in spinal deformity surgery since the development of screw-and-rod constructs up to 2005. The pertinent information was requested from three major manufacturers (DePuy Synthes, Medtronic and Stryker). Characteristics of each system are reviewed with radiographic features, and the instruments needed for revision are summarized. We propose a systematic identification diagram. Rod loading can be categorized as offset-loading, side-loading or top-loading. Screw design can be cylindrical, conical or dual-core threading. Each system has unique features that can facilitate identification. Identifying the materials and diameters of the rod is also imperative. When removal of an unidentified system is needed or removal of an identified system fails, the short rod has to remain loaded on the screw and the implant removed en bloc as an isolated piece. Understanding the radiographic features of spinal implants used in previous surgeries will help surgeons prepare for the increasing incidence of revision surgeries.
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http://dx.doi.org/10.1016/j.jocn.2021.01.045DOI Listing
April 2021

Glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood-gas chemistry while prolonging fentanyl-induced analgesia.

Sci Rep 2021 Mar 26;11(1):6985. Epub 2021 Mar 26.

Department of Pediatrics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106-4984, USA.

There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-arterial gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO and sO and increases in pCO (all indicative of ventilatory depression), (3) an increase in Alveolar-arterial gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-arterial gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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http://dx.doi.org/10.1038/s41598-021-86458-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997982PMC
March 2021

Patient-Reported Outcomes After Complex Adult Spinal Deformity Surgery: 5-Year Results of the Scoli-Risk-1 Study.

Global Spine J 2021 Feb 9:2192568220988276. Epub 2021 Feb 9.

University of Virginia, Charlottesville, VA, USA.

Study Design: Prospective cohort.

Objective: To prospectively evaluate PROs up to 5-years after complex ASD surgery.

Methods: The Scoli-RISK-1 study enrolled 272 ASD patients undergoing surgery from 15 centers. Inclusion criteria was Cobb angle of >80°, corrective osteotomy for congenital or revision deformity, and/or 3-column osteotomy. The following PROs were measured prospectively at intervals up to 5-years postoperative: ODI, SF36-PCS/MCS, SRS-22, NRS back/leg. Among patients with 5-year follow-up, comparisons were made from both baseline and 2-years postoperative to 5-years postoperative. PROs were analyzed using mixed models for repeated measures.

Results: Seventy-seven patients (28.3%) had 5-year follow-up data. Comparing baseline to 5-year data among these 77 patients, significant improvement was seen in all PROs: ODI (45.2 vs. 29.3, < 0.001), SF36-PCS (31.5 vs. 38.8, < 0.001), SF36-MCS (44.9 vs. 49.1, = 0.009), SRS-22-total (2.78 vs. 3.61, < 0.001), NRS-back pain (5.70 vs. 2.95, < 0.001) and NRS leg pain (3.64 vs. 2.62, = 0.017). In the 2 to 5-year follow-up period, no significant changes were seen in any PROs. The percentage of patients achieving MCID from baseline to 5-years were: ODI (62.0%) and the SRS-22r domains of function (70.4%), pain (63.0%), mental health (37.5%), self-image (60.3%), and total (60.3%). Surprisingly, mean values ( > 0.05) and proportion achieving MCID did not differ significantly in patients with major surgery-related complications compared to those without.

Conclusions: After complex ASD surgery, significant improvement in PROs were seen at 5-years postoperative in ODI, SF36-PCS/MCS, SRS-22r, and NRS-back/leg pain. No significant changes in PROs occurred during the 2 to 5-year postoperative period. Those with major surgery-related complications had similar PROs and proportion of patients achieving MCID as those without these complications.
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http://dx.doi.org/10.1177/2192568220988276DOI Listing
February 2021

The Role of Carotid Sinus Nerve Input in the Hypoxic-Hypercapnic Ventilatory Response in Juvenile Rats.

Front Physiol 2020 17;11:613786. Epub 2020 Dec 17.

Department of Pediatrics, Division of Pulmonology, Allergy and Immunology, Case Western Reserve University, Cleveland, OH, United States.

In juvenile rats, the carotid body (CB) is the primary sensor of oxygen (O) and a secondary sensor of carbon dioxide (CO) in the blood. The CB communicates to the respiratory pattern generator via the carotid sinus nerve, which terminates within the commissural nucleus tractus solitarius (cNTS). While this is not the only peripheral chemosensory pathway in juvenile rodents, we hypothesize that it has a unique role in determining the interaction between O and CO, and consequently, the response to hypoxic-hypercapnic gas challenges. The objectives of this study were to determine (1) the ventilatory responses to a poikilocapnic hypoxic (HX) gas challenge, a hypercapnic (HC) gas challenge or a hypoxic-hypercapnic (HH) gas challenge in juvenile rats; and (2) the roles of CSN chemoafferents in the interactions between HX and HC signaling in these rats. Studies were performed on conscious, freely moving juvenile (P25) male Sprague Dawley rats that underwent sham-surgery (SHAM) or bilateral transection of the carotid sinus nerves (CSNX) 4 days previously. Rats were placed in whole-body plethysmographs to record ventilatory parameters (frequency of breathing, tidal volume and minute ventilation). After acclimatization, they were exposed to HX (10% O, 90% N), HC (5% CO, 21% O, 74% N) or HH (5% CO, 10% O, 85% N) gas challenges for 5 min, followed by 15 min of room-air. The major findings were: (1) the HX, HC and HH challenges elicited robust ventilatory responses in SHAM rats; (2) ventilatory responses elicited by HX alone and HC alone were generally additive in SHAM rats; (3) the ventilatory responses to HX, HC and HH were markedly attenuated in CSNX rats compared to SHAM rats; and (4) ventilatory responses elicited by HX alone and HC alone were not additive in CSNX rats. Although the rats responded to HX after CSNX, CB chemoafferent input was necessary for the response to HH challenge. Thus, secondary peripheral chemoreceptors do not compensate for the loss of chemoreceptor input from the CB in juvenile rats.
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http://dx.doi.org/10.3389/fphys.2020.613786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773764PMC
December 2020

Impact of New Motor Deficit on HRQOL After Adult Spinal Deformity Surgery: Subanalysis From Scoli Risk 1 Prospective Study.

Spine (Phila Pa 1976) 2021 Apr;46(7):E450-E457

Department of Neurosurgery and Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA.

Study Design: International, multicenter, prospective, longitudinal observational cohort.

Objective: To assess how new motor deficits affect patient reported quality of life scores after adult deformity surgery.

Summary Of Background Data: Adult spinal deformity surgery is associated with high morbidity, including risk of new postoperative motor deficit. It is unclear what effect new motor deficit has on Health-related Quality of Life scores (HRQOL) scores.

Methods: Adult spinal deformity patients were enrolled prospectively at 15 sites worldwide. Other inclusion criteria included major Cobb more than 80°, C7-L2 curve apex, and any patient undergoing three column osteotomy. American Spinal Injury Association (ASIA) scores and standard HRQOL scores were recorded pre-op, 6 weeks, 6 months, and 2 years.

Results: Two hundred seventy two complex adult spinal deformity (ASD) patients enrolled. HRQOL scores were worse for patients with lower extremity motor score (LEMS). Mean HRQOL changes at 6 weeks and 2 years compared with pre-op for patients with motor worsening were: ODI (+12.4 at 6 weeks and -4.7 at 2 years), SF-36v2 physical (-4.5 at 6 weeks and +2.3 at 2 years), SRS-22r (0.0 at 6 weeks and +0.4 at 2 years). Mean HRQOL changes for motor-neutral patients were: ODI (+0.6 at 6 weeks and -12.1 at 2 years), SF-36v2 physical (-1.6 at 6 weeks and +5.9 at 2 years), and SRS-22r (+0.4 at 6 weeks and +0.7 at 2 years). For patients with LEMS improvement, mean HRQOL changes were: ODI (-0.6 at 6 weeks and -16.3 at 2 years), SF-36v2 physical (+1.0 at 6 weeks and +7.0 at 2 years), and SRS-22r (+0.5 at 6 weeks and +0.9 at 2 years).

Conclusion: In the subgroup of deformity patients who developed a new motor deficit, total HRQOLs and HRQOL changes were negatively impacted. Patients with more than 2 points of LEMS worsening had the worst changes, but still showed overall HRQOL improvement at 6 months and 2 years compared with pre-op baseline.Level of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000003852DOI Listing
April 2021

NADPH diaphorase detects S-nitrosylated proteins in aldehyde-treated biological tissues.

Sci Rep 2020 12 3;10(1):21088. Epub 2020 Dec 3.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH, 44106, USA.

NADPH diaphorase is used as a histochemical marker of nitric oxide synthase (NOS) in aldehyde-treated tissues. It is thought that the catalytic activity of NOS promotes NADPH-dependent reduction of nitro-blue tetrazolium (NBT) to diformazan. However, it has been argued that a proteinaceous factor other than NOS is responsible for producing diformazan in aldehyde-treated tissues. We propose this is a NO-containing factor such as an S-nitrosothiol and/or a dinitrosyl-iron (II) cysteine complex or nitrosated proteins including NOS. We now report that (1) S-nitrosothiols covalently modify both NBT and TNBT, but only change the reduction potential of NBT after modification, (2) addition of S-nitrosothiols or β- or α-NADPH to solutions of NBT did not elicit diformazan, (3) addition of S-nitrosothiols to solutions of NBT plus β- or α-NADPH elicited rapid formation of diformazan in the absence or presence of paraformaldehyde, (4) addition of S-nitrosothiols to solutions of NBT plus β- or α-NADP did not produce diformazan, (5) S-nitrosothiols did not promote NADPH-dependent reduction of tetra-nitro-blue tetrazolium (TNBT) in which all four phenolic rings are nitrated, (6) cytoplasmic vesicles in vascular endothelial cells known to stain for NADPH diaphorase were rich in S-nitrosothiols, and (7) procedures that accelerate decomposition of S-nitrosothiols, markedly reduced NADPH diaphorase staining in tissue sections subsequently subjected to paraformaldehyde fixation. Our results suggest that NADPH diaphorase in aldehyde-fixed tissues is not enzymatic but is due to the presence of NO-containing factors (free SNOs or nitrosated proteins such as NOS), which promote NADPH-dependent reduction of NBT to diformazan.
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http://dx.doi.org/10.1038/s41598-020-78107-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713249PMC
December 2020

Are Higher Global Alignment and Proportion Scores Associated With Increased Risks of Mechanical Complications After Adult Spinal Deformity Surgery? An External Validation.

Clin Orthop Relat Res 2021 02;479(2):312-320

K. Y. H. Kwan, The University of Hong Kong, Pokfulam, Hong Kong.

Background: The Global Alignment and Proportion (GAP) score, based on pelvic incidence-based proportional parameters, was recently developed to predict mechanical complications after surgery for spinal deformities in adults. However, this score has not been validated in an independent external dataset.

Questions/purposes: After adult spinal deformity surgery, is a higher GAP score associated with (1) an increased risk of mechanical complications, defined as rod fractures, implant-related complications, proximal or distal junctional kyphosis or failure; (2) a higher likelihood of undergoing revision surgery to treat a mechanical complication; and (3) is a lower (more proportioned) GAP score category associated with better validated outcomes scores using the Oswestry Disability Index (ODI), Scoliosis Research Society-22 (SRS-22) and the Short Form-36 questionnaires?

Methods: A total of 272 patients who had undergone corrective surgeries for complex spinal deformities were enrolled in the Scoli-RISK-1 prospective trial. Patients were included in this secondary analysis if they fulfilled the original inclusion criteria by Yilgor et al. From the original 272 patients, 14% (39) did not satisfy the radiographic inclusion criteria, the GAP score could not be calculated in 14% (37), and 24% (64) did not have radiographic assessment at postoperative 2 years, leaving 59% (159) for analysis in this review of data from the original trial. A total of 159 patients were included in this study,with a mean age of 58 ± 14 years at the time of surgery. Most patients were female (72%, 115 of 159), the mean number of levels involved in surgery was 12 ± 4, and three-column osteotomy was performed in 76% (120 of 159) of patients. The GAP score was calculated using parameters from early postoperative radiographs (between 3 and 12 weeks) including pelvic incidence, sacral slope, lumbar lordosis, lower arc lordosis and global tilt, which were independently obtained from a computer software based on centralized patient radiographs. The GAP score was categorized as proportional (scores of 0 to 2), moderately disproportional (scores of 3 to 6), or severely disproportional (scores higher than 7 to 13). Receiver operating characteristic area under curve (AUC) was used to assess associations between GAP score and risk of mechanical complications and risk of revision surgery. An AUC of 0.5 to 0.7 was classified as "no or low associative power", 0.7 to 0.9 as "moderate" and greater than 0.9 as "high". We analyzed differences in validated outcome scores between the GAP categories using Wilcoxon rank sum test.

Results: At a minimum of 2 years' follow-up, a higher GAP score was not associated with increased risks of mechanical complications (AUC = 0.60 [95% CI 0.50 to 0.70]). A higher GAP score was not associated with a higher likelihood of undergoing a revision surgery to treat a mechanical complication (AUC = 0.66 [95% 0.53 to 0.78]). However, a moderately disproportioned GAP score category was associated with better SF-36 physical component summary score (36 ± 10 versus 40 ± 11; p = 0.047), better SF-36 mental component summary score (46 ± 13 versus 51 ± 12; p = 0.01), better SRS-22 total score (3.4 ± 0.8 versus 3.7 ± 0.7, p = 0.02) and better ODI score (35 ± 21 versus 25 ± 20; p = 0.003) than severely disproportioned GAP score category.

Conclusion: Based on the findings of this external validation study, we found that alignment targets based on the GAP score alone were not associated with increased risks of mechanical complications and mechanical revisions in patients with complex adult spinal disorders. Parameters not included in the original GAP score needed to be considered to reduce the likelihood of mechanical complications.

Level Of Evidence: Level III, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899533PMC
February 2021

Advances in D-Amino Acids in Neurological Research.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Department Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.

D-amino acids have been known to exist in the human brain for nearly 40 years, and they continue to be a field of active study to today. This review article aims to give a concise overview of the recent advances in D-amino acid research as they relate to the brain and neurological disorders. This work has largely been focused on modulation of the N-methyl-D-aspartate (NMDA) receptor and its relationship to Alzheimer's disease and Schizophrenia, but there has been a wealth of novel research which has elucidated a novel role for several D-amino acids in altering brain chemistry in a neuroprotective manner. D-amino acids which have no currently known activity in the brain but which have active derivatives will also be reviewed.
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http://dx.doi.org/10.3390/ijms21197325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582301PMC
October 2020

Lumbosacral osteotomy to correct PI-LL mismatch in the presence of abnormally high pelvic incidence.

Spine Deform 2021 Mar 28;9(2):609-614. Epub 2020 Sep 28.

Division of Orthopaedic Surgery, The Hospital for Sick Children, Toronto, ON, Canada.

Study Design: A case report. It is important to achieve optimal sagittal balance in spinal deformity surgery by matching LL to PI. A Lumbar osteotomy to increase lordosis is often the method used to achieve this in adult patients. However, in patients with high PI with compensatory lumbar hyperlordosis, providing further lordosis does not address the root cause. The paper will describe a technique of lumbosacral osteotomy to address sagittal malalignment with associated coronal imbalance and pelvic incidence (PI)-lumbar lordosis (LL) mismatch.

Methods: A 16-year-old female patient presented with low back pain and right leg pain. Standing anteroposterior X-ray showed scoliosis with a Cobb angle of 34º and 5.7 cm of coronal imbalance. Lateral X-ray showed a sacralized L5 with a PI of 85º and LL of 47º. Pedicle subtraction osteotomy through the sacralized L5 addressed the malalignment secondary to a high PI-LL mismatch of 38º.

Results: Following alar resection, an osteotomy was performed below the L5 pedicles. The cranial parts including the superior endplate and intervertebral disc were removed. Osteotomy closure was achieved using the central rod technique. L5 incidence was reduced from 59º to 33º with reduced coronal malalignment. Back pain was significantly improved and PI-LL mismatch was improved to 10º two years post-operatively with no local loss of sagittal correction.

Conclusions: A lumbosacral osteotomy at the lumbosacral junction is useful to improve high PI - LL mismatch in patients with abnormally high PI with compensatory lumbar hyperlordosis.
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http://dx.doi.org/10.1007/s43390-020-00210-5DOI Listing
March 2021

Chronic Electrical Stimulation of the Superior Laryngeal Nerve in the Rat: A Potential Therapeutic Approach for Postmenopausal Osteoporosis.

Biomedicines 2020 Sep 22;8(9). Epub 2020 Sep 22.

Department of Autonomic Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.

Electrical stimulation of myelinated afferent fibers of the superior laryngeal nerve (SLN) facilitates calcitonin secretion from the thyroid gland in anesthetized rats. In this study, we aimed to quantify the electrical SLN stimulation-induced systemic calcitonin release in conscious rats and to then clarify effects of chronic SLN stimulation on bone mineral density (BMD) in a rat ovariectomized disease model of osteoporosis. Cuff electrodes were implanted bilaterally on SLNs and after two weeks recovery were stimulated (0.5 ms, 90 microampere) repetitively at 40 Hz for 8 min. Immunoreactive calcitonin release was initially measured and quantified in systemic venous blood plasma samples from conscious healthy rats. For chronic SLN stimulation, stimuli were applied intermittently for 3-4 weeks, starting at five weeks after ovariectomy (OVX). After the end of the stimulation period, BMD of the femur and tibia was measured. SLN stimulation increased plasma immunoreactive calcitonin concentration by 13.3 ± 17.3 pg/mL (mean ± SD). BMD in proximal metaphysis of tibia ( = 0.0324) and in distal metaphysis of femur ( = 0.0510) in chronically SLN-stimulated rats was 4-5% higher than that in sham rats. Our findings demonstrate chronic electrical stimulation of the SLNs produced enhanced calcitonin release from the thyroid gland and partially improved bone loss in OVX rats.
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http://dx.doi.org/10.3390/biomedicines8090369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555126PMC
September 2020

Factors Affecting Length of Stay Following 3-Column Spinal Osteotomies in Pediatric Patients.

Global Spine J 2021 Mar 26;11(2):154-160. Epub 2019 Dec 26.

The Hospital for Sick Children, Toronto, Ontario, Canada.

Study Design: A retrospective analysis.

Objectives: Length of stay (LOS) is one of the important indicators for the quality of patient care. Although perioperative complications are known to be associated with longer LOS in general, little has been understood regarding LOS after 3-column spinal osteotomy for the rigid spinal deformity in pediatric population. The main objective of the article is to identify factors affecting the LOS in pediatric patients undergoing 3-column posterior spinal osteotomies.

Methods: Following research ethics approval, a retrospective review was performed of 35 consecutive posterior 3-column spinal osteotomies performed on pediatric patients in a single academic institution. Patients' demographic data, preoperative comorbidities, details of operative procedures, intraoperative complications, and postoperative complications were investigated, and LOS was compared among the groups.

Results: The mean LOS was 9.0 days, and the median LOS was 7 days (range = 4-23 days). Low body weight and syndromic deformity were associated with longer LOS. Operation time ≥6 hours and total perioperative fluid administration greater than or equal to twice the estimated blood volume were associated with longer LOS. Among postoperative complications, those with respiratory complication had prolonged stay.

Conclusions: Preoperative low body weight and syndromic scoliosis had longer LOS after 3-column osteotomies. Excessive fluid administration and respiratory complications were associated with longer LOS.
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http://dx.doi.org/10.1177/2192568219895225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882824PMC
March 2021

Impact of Various Weights in the Intraoperative Skull-Skeletal Traction on Correction of Adolescent Idiopathic Scoliosis.

Global Spine J 2020 Dec 21;10(8):1015-1021. Epub 2019 Oct 21.

7979The Hospital for Sick Children, Toronto, Ontario, Canada.

Study Design: A retrospective study.

Objectives: Intraoperative skull-skeletal traction (ISST) facilitates the surgical scoliosis correction, but it is also associated with neurological risk. The objective of the present study was to investigate the impact of various traction weights on neurophysiological change and curve correction in surgery for adolescent idiopathic scoliosis (AIS).

Methods: A retrospective review of a consecutive series of posterior spinal fusions for AIS patients undergoing corrections with the use of ISST by 2 surgeons in one institution was performed. Intraoperative prone, post-traction radiographs were performed on all cases. The cases were divided into 2 groups, high and low traction weights, based on whether the weight used was ≥35% or <35% of body weight. The frequency of neurophysiological changes and the curve correction were compared between the 2 groups.

Results: The intraoperative correction magnitudes by ISST were significantly larger in the high ISST group than in the low ISST group (35° vs 26°, < .001). Changes in motor-evoked potential (MEP) were more frequently observed in the high ISST group (47% vs 26%, = .049). A multivariate analysis showed that high ISST was associated with 3 times higher risk of MEP change (95% confidence interval = 1.1-8.0, = .03) and higher final postoperative correction rates (68% vs 60%, = .001).

Conclusions: The high ISST for AIS was associated with increased intraoperative and ultimate curve corrections, and potentially facilitated better final correction. However, the high weight group was associated with an increased frequency of intraoperative MEP changes.
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http://dx.doi.org/10.1177/2192568219882348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645081PMC
December 2020

Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Department of Pediatric Pulmonology.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase-independent (sGC-independent) effects are stereoselective - that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) - and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified. Here, we have used 2 complementary affinity chromatography assays - followed by unbiased proteomic analysis - to identify voltage-gated K+ channel (Kv) proteins as binding partners for L-CSNO. Stereoselective L-CSNO-Kv interaction was confirmed structurally and functionally using surface plasmon resonance spectroscopy; hydrogen deuterium exchange; and, in Kv1.1/Kv1.2/Kvβ2-overexpressing cells, patch clamp assays. Remarkably, these sGC-independent L-CSNO effects did not involve S-nitrosylation of Kv proteins. In isolated rat and mouse respiratory control (petrosyl) ganglia, L-CSNO stereoselectively inhibited Kv channel function. Genetic ablation of Kv1.1 prevented this effect. In intact animals, L-CSNO injection at the level of the carotid body dramatically and stereoselectively increased minute ventilation while having no effect on blood pressure; this effect was inhibited by the L-CSNO congener S-methyl-l-cysteine. Kv proteins are physiologically relevant targets of endogenous L-CSNO. This may be a signaling pathway of broad relevance.
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http://dx.doi.org/10.1172/jci.insight.134174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526540PMC
September 2020

Postoperative Distal Coronal Decompensation After Fusion to L3 for Adolescent Idiopathic Scoliosis Is Affected by Sagittal Pelvic Parameters.

Spine (Phila Pa 1976) 2020 Nov;45(21):E1416-E1420

Division of Orthopaedics, Hospital for Sick Children, Toronto, Ontario, Canada.

Study Design: Retrospective study.

Objective: To identify on early postoperative radiographs the risk factors for late distal decompensation in adolescent idiopathic scoliosis (AIS) patients undergoing posterior fusion surgery to L3.

Summary Of Background Data: Sparing distal fusion levels in AIS surgery is considered beneficial for postoperative mobility and outcomes; nonetheless, late distal decompensation is of concern. L3 is often advocated as lower instrumented vertebra in posterior fusion, but progressive angulation of the L3/4 disc is commonly observed.

Methods: A retrospective analysis was conducted on 78 AIS patients who underwent posterior fusion to L3 from 2007 to 2014. Patients' demographic data, early and 2-year postoperative standing radiographs by biplanar imaging system were investigated. Late decompensation was defined as progressive increase of L3-4 disc wedging angle at 2-year follow-up. Coronal, sagittal, and rotational radiographic parameters were compared between those with and without decompensation. SRS-30 scores were reviewed.

Results: Mean age was 14.5-year, and fusion levels averaged 12.0 (range: 6-15); 43 out of 78 patients (55%) experienced progressive L3-4 disc wedging, with 6 showing wedging >5°. L3 translation from the central sacral vertical line (13.9 vs. 11.1 mm, P = 0.13) and increased pelvic tilt (13.3° vs. 8.6°, P = 0.06) on the early postoperative radiograph were associated with increased L3-4 disc wedging. Multivariate analysis revealed that larger pelvic tilt was a significant risk factor for decompensation (odds ratio = 1.1 per 1°, 95% confidence interval: 1.0-1.1, P = 0.04). SRS-30 scores did not differ significantly between the two groups (4.0 vs. 4.1, P = 0.44).

Conclusions: Pelvic retroversion and increased translation of L3 from the central sacral line on the early postoperative radiograph were associated with late L3-4 disc wedging in AIS fusions to L3. Careful surgical planning and correction of sagittal alignment are imperative to ensure the long-term outcomes.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000003616DOI Listing
November 2020

Laterality Influences Central Integration of Baroreceptor Afferent Input in Male and Female Sprague Dawley Rats.

Front Physiol 2020 27;11:499. Epub 2020 May 27.

Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, United States.

We explored the effects of baroreceptor afferents laterality and sexual dimorphism on the expression of cardiovascular reflex responses to baroreflex activation in Sprague Dawley (SD) rats. Under urethane anesthesia, rats of either sex (total = 18) were instrumented for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were matched for the diestrus phase of the estrus cycle. Left, right and bilateral ADN stimulation evoked frequency-dependent drops in MAP, HR, and MVR, and increases in FVR. Irrespective of sex, left and bilateral ADN stimulation as compared to right-sided stimulation mediated greater reflex reductions in MAP, HR, and MVR but not in FVR. In males, reflex bradycardic responses were greater in response to bilateral stimulation relative to both left- and right-sided stimulation. In females, left ADN stimulation evoked the largest increase in FVR. Left and bilateral ADN stimulations evoked greater reductions in MAP and MVR while left-sided stimulation produced larger increases in FVR in females compared with males. All other reflex responses to ADN stimulation were relatively comparable between males and females. These results show a differential baroreflex processing of afferent neurotransmission promoted by left versus right baroreceptor afferent inputs and sexual dimorphism in the expression of baroreflex responses in rats of either sex. Collectively, these data add to our understanding of physiological mechanisms pertaining to baroreflex control in both males and females.
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http://dx.doi.org/10.3389/fphys.2020.00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269127PMC
May 2020

Factors associated with early postoperative feeding: An observational study in a colorectal surgery population.

Clin Nutr ESPEN 2020 04 8;36:99-105. Epub 2020 Feb 8.

National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol, Bristol, UK; Bristol Medical School, University of Bristol, Bristol, UK.

Background And Aims: Early post-operative feeding is recommended within enhanced recovery after surgery programmes. This study aimed to describe post-operative feeding patterns and associated factors among patients following colorectal surgery, using a post-hoc analysis of observational data from a previous RCT on chewing gum after surgery.

Methods: Data from 301 participants (59% male, median age 67 years) were included. Amounts of meals consumed on post-operative days (POD) 1-5 were recorded as: none, a quarter, half, three-quarters, all. 'Early' consumers were those who ate ≥a quarter of a meal on POD1. 'Early' tolerance was the consumption of at least half of three meals on POD1 or 2 without vomiting. Exploration of selected peri-operative factors with early feeding and tolerance were assessed using logistic regression.

Results: 222 people (73.8%) consumed solid food early, and 109 people (36.2%) tolerated solid food early. Several factors were associated with postoperative feeding: provision of pre-operative bowel preparation was associated with delayed consumption [odds ratio (OR) 0.34, 95% confidence interval (CI) 0.14-0.83] and tolerance (OR 0.35, 95% CI 0.16-0.81) of food; and laparoscopic/laparoscopic assisted (vs. open/converted to open surgery) was associated with early tolerance of food (OR 1.99, 95% CI 1.17-3.39).

Conclusions: While three-quarters of the study population ate solid food early, only one-third tolerated solid food early. Findings suggest that bowel preparation and surgery type are factors warranting further investigation in future studies to improve uptake of early post-operative feeding.
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http://dx.doi.org/10.1016/j.clnesp.2020.01.009DOI Listing
April 2020

Network-based prediction of drug-target interactions using an arbitrary-order proximity embedded deep forest.

Bioinformatics 2020 05;36(9):2805-2812

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Motivation: Systematic identification of molecular targets among known drugs plays an essential role in drug repurposing and understanding of their unexpected side effects. Computational approaches for prediction of drug-target interactions (DTIs) are highly desired in comparison to traditional experimental assays. Furthermore, recent advances of multiomics technologies and systems biology approaches have generated large-scale heterogeneous, biological networks, which offer unexpected opportunities for network-based identification of new molecular targets among known drugs.

Results: In this study, we present a network-based computational framework, termed AOPEDF, an arbitrary-order proximity embedded deep forest approach, for prediction of DTIs. AOPEDF learns a low-dimensional vector representation of features that preserve arbitrary-order proximity from a highly integrated, heterogeneous biological network connecting drugs, targets (proteins) and diseases. In total, we construct a heterogeneous network by uniquely integrating 15 networks covering chemical, genomic, phenotypic and network profiles among drugs, proteins/targets and diseases. Then, we build a cascade deep forest classifier to infer new DTIs. Via systematic performance evaluation, AOPEDF achieves high accuracy in identifying molecular targets among known drugs on two external validation sets collected from DrugCentral [area under the receiver operating characteristic curve (AUROC) = 0.868] and ChEMBL (AUROC = 0.768) databases, outperforming several state-of-the-art methods. In a case study, we showcase that multiple molecular targets predicted by AOPEDF are associated with mechanism-of-action of substance abuse disorder for several marketed drugs (such as aripiprazole, risperidone and haloperidol).

Availability And Implementation: Source code and data can be downloaded from https://github.com/ChengF-Lab/AOPEDF.
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http://dx.doi.org/10.1093/bioinformatics/btaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203727PMC
May 2020

Accuracy Analysis of Iliac Screw Using Freehand Technique in Spinal Surgery : Relation between Screw Breach and Revision Surgery.

J Korean Neurosurg Soc 2020 Mar 15;63(2):210-217. Epub 2020 Jan 15.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objective: To analyze the accuracy of iliac screws using freehand technique performed by the same surgeon. We also analyzed how the breach of iliac screws was related to the clinical symptoms resulting in revision surgery.

Methods: From January 2009 to November 2015, 100 patients (193 iliac screws) were analyzed using postoperative computed tomography scans. The breaches were classified based on the superior, inferior, lateral, and medial iliac wall violation by the screw. According to the length of screw extrusion, the classification grades were as follows : grade 1, screw extrusion <1 cm; grade II, 1 cm ≤ screw extrusion <2 cm; grade III, 2 cm ≤ screw extrusion <3 cm; and grade IV, 3 cm ≤ screw extrusion. We also reviewed the revision surgery associated with iliac screw misplacement.

Results: Of the 193 inserted screws, 169 were correctly located and 24 were misplaced screws. There were eight grade I, six grade II, six grade III, and four grade IV screw breaches, and 11, 8, 2, and 3 screws violated the medial, lateral, superior, and inferior walls, respectively. Four revision surgeries were performed for the grade III or IV iliac screw breaches in the lateral or inferior direction with respect to its related symptoms.

Conclusion: In iliac screw placement, 12.4% breaches developed. Although most breaches were not problematic, symptomatic violations (2.1%) could result in revision surgery. Notably, the surgeon should keep in mind that lateral or inferior wall breaches longer than 2 cm can be risky and should be avoided.
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http://dx.doi.org/10.3340/jkns.2019.0090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054120PMC
March 2020

A distal start point facilitates safer insertion of S2-alar-iliac screws fixation.

J Clin Neurosci 2020 Feb 8;72:102-107. Epub 2020 Jan 8.

Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

This study aimed to show that a more distal insertion of S2-alar-iliac screws (S2AI) towards the S2 foramen facilitates a more natural trajectory and results in fewer breaches of the iliac wing due to the anteroposterior relationship of the sacrum and pelvis. Thirty-six consecutive patients who had received S2AI and postoperative computed tomography (CT) imaging were retrospectively reviewed. A freehand technique was used to insert all screws. Screws were stratified into two groups (Zone A and Zone B) based on the insertion point within the sacrum. Zone A was defined as screw insertion proximal to the second sacral foramen. Zone B was defined as screw insertion at or distal to the level of the second sacral foramen. CT imaging was reviewed to identify passage of the screw through either the fibrous or bony sacroiliac joint, and to check for instrumentation breach of the iliac wing. Sixty-two S2AI in 36 patients were identified. Twenty-six screws (42%) were inserted into Zone A and 36 (58%) into Zone B. There were 11 instrumentation breaches of the iliac wing in Zone A (42%) and 0 in Zone B (p < 0.0001). In Zone A, 24 screws (92%) passed through the upper, fibrous portion of the sacroiliac joint. In Zone B, no screws passed through this region (p < 0.0001). In conclusion, insertion of S2AI at or distal to the second sacral foramen facilitates improved screw placement due to the anteroposterior relationship of the sacrum and pelvis at this level.
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http://dx.doi.org/10.1016/j.jocn.2019.12.058DOI Listing
February 2020

Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes.

Nat Biotechnol 2019 12 11;37(12):1446-1451. Epub 2019 Nov 11.

Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in β-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.
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http://dx.doi.org/10.1038/s41587-019-0295-8DOI Listing
December 2019

-Nitrosylation of CHIP Enhances F508Del-CFTR Maturation.

Am J Respir Cell Mol Biol 2019 12;61(6):765-775

Pediatric Pulmonology Division, Department of Pediatrics, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio.

-nitrosothiols (SNOs) are endogenous signaling molecules that have numerous beneficial effects on the airway via cyclic guanosine monophosphate-dependent and -independent processes. Healthy human airways contain SNOs, but SNO levels are lower in the airways of patients with cystic fibrosis (CF). In this study, we examined the interaction between SNOs and the molecular cochaperone C-terminus Hsc70 interacting protein (CHIP), which is an E3 ubiquitin ligase that targets improperly folded CF transmembrane conductance regulator (CFTR) for subsequent degradation. Both CFBE41o cells expressing either wild-type or F508del-CFTR and primary human bronchial epithelial cells express CHIP. Confocal microscopy and IP studies showed the cellular colocalization of CFTR and CHIP, and showed that -nitrosoglutathione inhibits the CHIP-CFTR interaction. SNOs significantly reduced both the expression and activity of CHIP, leading to higher levels of both the mature and immature forms of F508del-CFTR. In fact, SNO inhibition of the function and expression of CHIP not only improved the maturation of CFTR but also increased CFTR's stability at the cell membrane. -nitrosoglutathione-treated cells also had more -nitrosylated CHIP and less ubiquitinated CFTR than cells that were not treated, suggesting that the -nitrosylation of CHIP prevents the ubiquitination of CFTR by inhibiting CHIP's E3 ubiquitin ligase function. Furthermore, the exogenous SNOs -nitrosoglutathione diethyl ester and -nitro--acetylcysteine increased the expression of CFTR at the cell surface. After CHIP knockdown with siRNA duplexes specific for CHIP, F508del-CFTR expression increased at the cell surface. We conclude that SNOs effectively reduce CHIP-mediated degradation of CFTR, resulting in increased F508del-CFTR expression on airway epithelial cell surfaces. Together, these findings indicate that -nitrosylation of CHIP is a novel mechanism of CFTR correction, and we anticipate that these insights will allow different SNOs to be optimized as agents for CF therapy.
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http://dx.doi.org/10.1165/rcmb.2018-0314OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890399PMC
December 2019

Tracheomalacia in bronchopulmonary dysplasia: Trachealis hyper-relaxant responses to S-nitrosoglutathione in a hyperoxic murine model.

Pediatr Pulmonol 2019 12 4;54(12):1989-1996. Epub 2019 Sep 4.

Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, Ohio.

Background: Bronchopulmonary dysplasia (BPD) with airway hyperreactivity is a long-term pulmonary complication of prematurity. The endogenous nonadrenergic, noncholinergic signaling molecule, S-nitrosoglutathione (GSNO) and its catabolism by GSNO reductase (GSNOR) modulate airway reactivity. Tracheomalacia is a major, underinvestigated complication of BPD. We studied trachealis, left main bronchus (LB), and intrapulmonary bronchiolar (IPB) relaxant responses to GSNO in a murine hyperoxic BPD model.

Methods: Wild-type (WT) or GSNOR knockout (KO) newborn mice were raised in 60% (BPD) or 21% (control) oxygen during the first 3 weeks of life. After room air recovery, adult trachealis, LB, and IPB smooth muscle relaxant responses to GSNO (after methacholine preconstriction) were studied using wire myographs. Studies were repeated after GSNOR inhibitor (GSNORi) pretreatment and in KO mice.

Results: GSNO relaxed all airway preparations. GSNO relaxed WT BPD trachealis substantially more than WT controls (P < .05). Pharmacologic or genetic ablation of GSNOR abolished the exaggerated BPD tracheal relaxation to GSNO and also augmented BPD IPB relaxation to GSNO. LB ring contractility was not significantly different between groups or conditions. Additionally, GSNORi treatment induced relaxation of WT IPBs but not trachealis or LB.

Conclusion: GSNO dramatically relaxed the trachealis in our BPD model, an effect paradoxically reversed by loss of GSNOR. Conversely, GSNOR inhibition augmented IBP relaxation. These data suggest that GSNOR inhibition could benefit both the BPD trachealis and distal airways, restoring relaxant responses to those of room air controls. Because therapeutic options are limited in this high-risk population, future studies of GSNOR inhibition are needed.
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http://dx.doi.org/10.1002/ppul.24513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329187PMC
December 2019

The Effect of Tobacco Smoking on Adverse Events Following Adult Complex Deformity Surgery: Analysis of 270 Patients From the Prospective, Multicenter Scoli-RISK-1 Study.

Spine (Phila Pa 1976) 2020 Jan;45(1):32-37

University of Toronto Spine Program and Toronto Western Hospital, Toronto, Ontario, Canada.

Study Design: Post-hoc analysis of a prospective, multicenter cohort study.

Objective: To analyze the impact of smoking on rates of postoperative adverse events (AEs) in patients undergoing high-risk adult spine deformity surgery.

Summary Of Background Data: Smoking is a known predictor of medical complications after adult deformity surgery, but the effect on complications, implant failure and other AEs has not been adequately described in prospective studies.

Methods: Twenty-six patients with a history of current smoking were identified out of the 272 patients enrolled in the SCOLI-RISK-1 study who underwent complex adult spinal deformity surgery at 15 centers, with 2-year follow-up. The outcomes and incidence of AEs in these patients were compared to the nonsmoking cohort (n = 244) using univariate analysis, with additional multivariate regression to adjust for the effect of patient demographics, complexity of surgery, and other confounders.

Results: The number of levels and complexity of surgery in both cohorts were comparable. In the univariate analysis, the rates of implant failure were almost double (odds ratio 2.28 [0.75-6.18]) in smoking group (n = 7; 26.9%)) that observed in the nonsmoking group (n = 34; 13.9%), but this was not statistically significant (P = 0.088). Surgery-related excessive bleeding (>4 L) was significantly higher in the smoking group (n = 5 vs. n = 9; 19.2% vs. 3.7%; OR 6.22[1.48 - 22.75]; P = 0.006). Wound infection rates and respiratory complications were similar in both groups. In the multivariate analysis, the smoking group demonstrated a higher incidence of any surgery-related AEs over 2 years (n = 13 vs. n = 95; 50.0% vs. 38.9%; OR 2.12 [0.88-5.09]) (P = 0.094).

Conclusion: In this secondary analysis of patients from the SCOLI-RISK-1 study, a history of smoking significantly increased the risk of excessive intraoperative bleeding and nonsignificantly increased the rate of implant failure or surgery-related AEs over 2 years. The authors therefore advocate a smoking cessation program in patients undergoing complex adult spine deformity surgery.

Level Of Evidence: 2.
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http://dx.doi.org/10.1097/BRS.0000000000003200DOI Listing
January 2020

Early enteral nutrition within 24 hours of lower gastrointestinal surgery versus later commencement for length of hospital stay and postoperative complications.

Cochrane Database Syst Rev 2019 07 22;7:CD004080. Epub 2019 Jul 22.

NIHR Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Education and Research Centre, Upper Maudlin Street, Bristol, Avon, UK, BS2 8AE.

Background: This is an update of the review last published in 2011. It focuses on early postoperative enteral nutrition after lower gastrointestinal surgery. Traditional management consisted of 'nil by mouth', where patients receive fluids followed by solids after bowel function has returned. Although several trials have reported lower incidence of infectious complications and faster wound healing upon early feeding, other trials have shown no effect. The immediate advantage of energy intake (carbohydrates, protein or fat) could enhance recovery with fewer complications, and this warrants a systematic evaluation.

Objectives: To evaluate whether early commencement of postoperative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LoS), fewer complications, mortality and adverse events in patients undergoing lower gastrointestinal surgery (distal to the ligament of Treitz).

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid MEDLINE (1950 to 15 November 2017), Ovid Embase (1974 to 15 November 2017). We also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (15 November 2017). We handsearched reference lists of identified studies and previous systematic reviews.

Selection Criteria: We included randomised controlled trials (RCT) comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult participants undergoing lower gastrointestinal surgery.

Data Collection And Analysis: Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data. Data analyses were conducted according to the Cochrane recommendations.We rated the quality of evidence according to GRADE.Primary outcomes were LoS and postoperative complications (wound infections, intraabdominal abscesses, anastomotic dehiscence, pneumonia).Secondary outcomes were: mortality, adverse events (nausea, vomiting), and quality of life (QoL).LoS was estimated using mean difference (MD (presented as mean +/- SD). For other outcomes we estimated the common risk ratio (RR) and calculated the associated 95% confidence intervals. For analysis, we used an inverse-variance random-effects model for the primary outcome (LoS) and Mantel-Haenszel random-effects models for the secondary outcomes. We also performed Trial Sequential Analyses (TSA).

Main Results: We identified 17 RCTs with 1437 participants undergoing lower gastrointestinal surgery. Most studies were at high or unclear risk of bias in two or more domains. Six studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies. With regards to performance and deception bias; 14 studies reported no attempt to blind participants and blinding of personnel was not discussed either. Only one study was judged as low risk of bias for blinding of outcome assessor. With regards to incomplete outcome data, three studies were judged to be at high risk because they had more than 10% difference in missing data between groups. For selective reporting, nine studies were judged as unclear as protocols were not provided and eight studies had issues with either missing data or incomplete reporting of results.LOS was reported in 16 studies (1346 participants). The mean LoS ranged from four days to 16 days in the early feeding groups and from 6.6 days to 23.5 days in the control groups. Mean difference (MD) in LoS was 1.95 (95% CI, -2.99 to -0.91, P < 0.001) days shorter in the early feeding group. However, there was substantial heterogeneity between included studies (I = 81, %, Chi = 78.98, P < 0.00001), thus the overall quality of evidence for LoS is low. These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.We found no differences in the incidence of postoperative complications: wound infection (12 studies, 1181 participants, RR 0.99, 95%CI 0.64 to 1.52, very low-quality evidence), intraabdominal abscesses (6 studies, 554 participants, RR 1.00, 95%CI 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1232 participants, RR 0.78, 95%CI 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 participants, RR 0.88, 95%CI 0.32 to 2.42, low-quality evidence; NNTB = 333).Mortality was reported in 12 studies (1179 participants), and showed no between-group differences (RR = 0.56, 95%CI, 0.21 to 1.52, P = 0.26, I = 0%, Chi = 3.08, P = 0.96, low-quality evidence). The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction.Seven studies (613 participants) reported vomiting (RR 1.23, 95%CI, 0.96 to 1.58, P = 0.10, I = 0%, Chi = 4.98, P = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and two studies (118 participants) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence). Four studies reported combined nausea and vomiting (RR 0.94, 95%CI 0.51 to 1.74, very low-quality evidence). One study reported QoL assessment; the scores did not differ between groups at 30 days after discharge on either QoL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence).

Authors' Conclusions: This review suggests that early enteral feeding may lead to a reduced postoperative LoS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence. For all other outcomes (postoperative complications, mortality, adverse events, and QoL) the findings are inconclusive, and further trials are justified to enhance the understanding of early feeding for these. In this updated review, only a few additional studies have been included, and these were small and of poor quality.To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring postoperative complications to allow for better comparison between studies. However due to the introduction of fast track protocols which already include an early feeding component, future trials may be challenging. A more feasible trial may be to investigate the effect of differing postoperative energy intake regimens on relevant outcomes.
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http://dx.doi.org/10.1002/14651858.CD004080.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645186PMC
July 2019

Responding to Intraoperative Neuromonitoring Changes During Pediatric Coronal Spinal Deformity Surgery.

Global Spine J 2019 May 8;9(1 Suppl):15S-21S. Epub 2019 May 8.

AOSpine Knowledge Forum Deformity, Davos, Switzerland.

Study Design: Retrospective case study on prospectively collected data.

Objectives: The purpose of this explorative study was: 1) to determine if patterns of spinal cord injury could be detected through intra-operative neuromonitoring (IONM) changes in pediatric patients undergoing spinal deformity corrections, 2) to identify if perfusion based or direct trauma causes of IONM changes could be distinguished, 3) to observe the effects of the interventions performed in response to these events, and 4) to attempt to identify different treatment algorithms for the different causes of IONM alerts.

Methods: Prospectively collected neuromonitoring data in pre-established forms on consecutive pediatric patients undergoing coronal spinal deformity surgery at a single center was reviewed. Real-time data was collected on IONM alerts with >50% loss in signal. Patients with alerts were divided into 2 groups: unilateral changes (direct cord trauma), and bilateral MEP changes (cord perfusion deficits).

Results: A total of 97 pediatric patients involving 71 females and 26 males with a mean age of 14.9 (11-18) years were included in this study. There were 39 alerts in 27 patients (27.8% overall incidence). All bilateral changes responded to a combination of transfusion, increasing blood pressure, and rod removal. Unilateral changes as a result of direct trauma, mainly during laminotomies for osteotomies, improved with removal of the causative agent. Following corrective actions in response to the alerts, all cases were completed as planned. Signal returned to near baseline in 20/27 patients at closure, with no new neurological deficits in this series.

Conclusion: A high incidence of alerts occurred in this series of cases. Dividing IONM changes into perfusion-based vs direct trauma directed treatment to the offending cause, allowing for safe corrections of the deformities. Patients did not need to recover IONM signal to baseline to have a normal neurological examination.
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http://dx.doi.org/10.1177/2192568219836993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512195PMC
May 2019

Effect of Serious Adverse Events on Health-related Quality of Life Measures Following Surgery for Adult Symptomatic Lumbar Scoliosis.

Spine (Phila Pa 1976) 2019 Sep;44(17):1211-1219

Department of Orthopedic Surgery, Washington University School of Medicine, St Louis, MO.

Study Design: Secondary analysis of prospective multicenter cohort.

Objective: To assess effect of serious adverse events (SAEs) on 2- and 4-year patient-reported outcomes measures (PROMs) in patients surgically treated for adult symptomatic lumbar scoliosis (ASLS).

Summary Of Background Data: Operative treatment for ASLS can improve health-related quality of life, but has high rates of SAEs. How these SAEs effect health-related quality of life remain unclear.

Methods: The ASLS study assessed operative versus nonoperative ASLS treatment, with randomized and observational arms. Patients were 40- to 80-years-old with ASLS, defined as lumbar coronal Cobb ≥30° and Oswestry Disability Index (ODI) ≥20 or Scoliosis Research Society-22 (SRS-22) ≤4.0 in pain, function, and/or self-image domains. SRS-22 subscore and ODI were compared between operative patients with and without a related SAE and nonoperative patients using an as-treated analysis combining randomized and observational cohorts.

Results: Two hundred eighty-six patients were enrolled, and 2- and 4-year follow-up rates were 90% and 81%, respectively, although at the time of data extraction not all patients were eligible for 4-year follow-up. A total of 97 SAEs were reported among 173 operatively treated patients. The most common were implant failure/pseudarthrosis (n = 25), proximal junctional kyphosis/failure (n = 10), and minor motor deficit (n = 8). At 2 years patients with an SAE improved less than those without an SAE based on SRS-22 (0.52 vs. 0.79, P = 0.004) and ODI (-11.59 vs. -17.34, P = 0.021). These differences were maintained at 4-years for both SRS-22 (0.51 vs. 0.86, P = 0.001) and ODI (-10.73 vs. -16.69, P = 0.012). Despite this effect, patients sustaining an operative SAE had greater PROM improvement than nonoperative patients (P<0.001).

Conclusion: Patients affected by SAEs following surgery for ASLS had significantly less improvement of PROMs at 2- and 4-year follow-ups versus those without an SAE. Regardless of SAE occurrence, operatively treated patients had significantly greater improvement in PROMs than those treated nonoperatively.

Level Of Evidence: 2.
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http://dx.doi.org/10.1097/BRS.0000000000003036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697202PMC
September 2019

Operative Versus Nonoperative Treatment for Adult Symptomatic Lumbar Scoliosis.

J Bone Joint Surg Am 2019 Feb;101(4):338-352

Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, Missouri.

Background: The effectiveness of operative compared with nonoperative treatment at initial presentation (no prior fusion) for adult lumbar scoliosis has not, to our knowledge, been evaluated in controlled trials. The goals of this study were to evaluate the effects of operative and nonoperative treatment and to assess the benefits of these treatments to help treating physicians determine whether patients are better managed operatively or nonoperatively.

Methods: Patients with adult symptomatic lumbar scoliosis (aged 40 to 80 years, with a coronal Cobb angle measurement of ≥30° and an Oswestry Disability Index [ODI] score of ≥20 or Scoliosis Research Society [SRS]-22 score of ≤4.0) from 9 North American centers were enrolled in concurrent randomized or observational cohorts to evaluate operative versus nonoperative treatment. The primary outcomes were differences in the mean change from baseline in the SRS-22 subscore and ODI at 2-year follow-up. For the randomized cohort, the initial sample-size calculation estimated that 41 patients per group (82 total) would provide 80% power with alpha equal to 0.05, anticipating 10% loss to follow-up and 20% nonadherence in the nonoperative arm. However, an interim sample-size calculation estimated that 18 patients per group would be sufficient.

Results: Sixty-three patients were enrolled in the randomized cohort: 30 in the operative group and 33 in the nonoperative group. Two hundred and twenty-three patients were enrolled in the observational cohort: 112 in the operative group and 111 in the nonoperative group. The intention-to-treat analysis of the randomized cohort found that, at 2 years of follow-up, outcomes did not differ between the groups. Nonadherence was high in the randomized cohort (64% nonoperative-to-operative crossover). In the as-treated analysis of the randomized cohort, operative treatment was associated with greater improvement at the 2-year follow-up in the SRS-22 subscore (adjusted mean difference, 0.7 [95% confidence interval (CI), 0.5 to 1.0]) and in the ODI (adjusted mean difference, -16 [95% CI, -22 to -10]) (p < 0.001 for both). Surgery was also superior to nonoperative care in the observational cohort at 2 years after treatment on the basis of SRS-22 subscore and ODI outcomes (p < 0.001). In an overall responder analysis, more operative patients achieved improvement meeting or exceeding the minimal clinically important difference (MCID) in the SRS-22 subscore (85.7% versus 38.7%; p < 0.001) and the ODI (77.4% versus 38.3%; p < 0.001). Thirty-four revision surgeries were performed in 24 (14%) of the operative patients.

Conclusions: On the basis of as-treated and MCID analyses, if a patient with adult symptomatic lumbar scoliosis is satisfied with current spine-related health, nonoperative treatment is advised, with the understanding that improvement is unlikely. If a patient is not satisfied with current spine health and expects improvement, surgery is preferred.

Level Of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
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http://dx.doi.org/10.2106/JBJS.18.00483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738555PMC
February 2019

Potential roles of artificial intelligence learning and faecal immunochemical testing for prioritisation of colonoscopy in anaemia.

Br J Haematol 2019 04 3;185(2):311-316. Epub 2019 Feb 3.

Department of Haemato-oncology, Barts Health NHS Trust, University Hospitals Plymouth NHS trust, London, UK.

Iron deficiency anaemia (IDA) is the most common cause of anaemia and a frequent indication for colonoscopy, although the prevalence of colorectal cancer (CRC) in IDA is low. Measurement of faecal haemoglobin by immunochemical techniques (FIT) is used to detect symptomatic patients. We studied FIT in patients with anaemia attending a gastroenterology clinic in Plymouth and looked at an artificial intelligence (AI) learning algorithm (ColonFlag™) in these patients, together with a cohort who had undergone colonoscopy for IDA in London. Of 592 patients referred on the basis of haemoglobin concentration, 21 (3.5%) had CRC. Using ColonFlag™, rather than haemoglobin concentration, in combination with symptoms, would have resulted in prioritisation of 304 patients for urgent referral rather than 592. One CRC would have been missed but might have been detected by FIT, which was not available in this case. In patients aged <55 years in whom the incidence of CRC is low, 15 rather than 109 patients would have been prioritised for urgent referral with no cancers missed. FIT has a high negative predictive value in IDA so its use may enable some patients to avoid investigation and AI learning may be a more useful trigger than haemoglobin concentration for urgent referral for colonoscopy.
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http://dx.doi.org/10.1111/bjh.15776DOI Listing
April 2019

Factors Associated With Opioid Use in Presurgical Knee, Hip, and Spine Osteoarthritis Patients.

Arthritis Care Res (Hoboken) 2019 09 3;71(9):1178-1185. Epub 2019 Aug 3.

Arthritis Program and Krembil Research Institute, University Health Network and University of Toronto, Toronto, Ontario, Canada.

Objective: To evaluate rates of prescription opioid use among patients with presurgical knee, hip, and spine osteoarthritis (OA) and associations between use and sociodemographic and health status characteristics.

Methods: Participants were patients with presurgical, end-stage OA of the knee (n = 77), hip (n = 459), and spine (n = 168). Data were collected on current use of opioids and other pain medications, as well as measures of sociodemographic and health status variables and depression and pain (0-10 numeric rating scale). Rates of opioid use were calculated by sex, age, and surgical site. Multivariable logistic regression was used to examine associations between opioid use (sometimes/daily versus never) and other study variables.

Results: The mean age of participants was 65.6 years; 55.5% were women, 15% of patients reported "sometimes" using opioids, and 15% reported "daily use." Use of opioids was highest among patients with spine OA (40%) and similar among patients with knee and hip OA (28% and 30%, respectively). Younger women (ages <65 years) reported the greatest use of opioids overall, particularly among patients with spine OA. From multivariable logistic regression, greater likelihood of opioid use was significantly associated with spine OA (versus knee OA), obesity, being a current or former smoker, higher symptomatic joint count, greater depressive symptoms, greater pain, and current use of other prescription pain medication.

Conclusion: Nearly one-third of patients with presurgical OA used prescription opioid medication. Given the questionable efficacy of opioids in OA and risk of adverse effects, higher opioid use among younger individuals and those with depressive symptoms is of concern and warrants further investigation.
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http://dx.doi.org/10.1002/acr.23831DOI Listing
September 2019

Discovery of potent and selective 5-azaindazole inhibitors of leucine-rich repeat kinase 2 (LRRK2) - Part 1.

Bioorg Med Chem Lett 2019 02 1;29(4):668-673. Epub 2018 Dec 1.

LifeArc, Accelerator Building, Open Innovation Campus, Stevenage SG1 2FX, UK.

Parkinson's disease is a relatively common neurological disorder with incidence increasing with age. Present treatments merely alleviate the symptoms and do not alter the course of the disease, thus identification of disease modifying therapies represents a significant unmet medical need. Mutations in the LRRK2 gene are risk-factors for developing PD and it has been hypothesized that the increased kinase activity of certain LRRK2 mutants are responsible for the damage of the dopaminergic neurons, thus LRRK2 inhibitors offer the potential to target an underlying cause of the disease. In this communication, we describe hit-to-lead medicinal chemistry program on a novel series of 5-azaindazoles. Compound 1, obtained from high-throughput screening was optimized to a highly potent, selective series of molecules with promising DMPK properties. Introduction of heterocycles at the 3-position were found to significantly increase the potency and kinase selectivity, whilst changes to the 4-chlorobenzyl group improved the physicochemical properties. Our series was licensed to a major pharmaceutical company for further development.
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http://dx.doi.org/10.1016/j.bmcl.2018.11.058DOI Listing
February 2019