The T4-L1-Hip Axis: Sagittal Spinal Realignment Targets in Long-Construct Adult Spinal Deformity Surgery: Early Impact.

BACKGROUND: Our understanding of the relationship between sagittal alignment and mechanical complications is evolving. In normal spines, the L1-pelvic angle (L1PA) accounts for the magnitude and distribution of lordosis and is strongly associated with pelvic incidence (PI), and the T4-pelvic angle (T4PA) is within 4° of the L1PA. We aimed to examine the clinical implications of realignment to a normal L1PA and T4-L1PA mismatch. METHODS: A prospective multicenter adult spinal deformity registry was queried for patients who underwent fixation from the T1-T5 region to the sacrum and had 2-year radiographic follow-up. Normal sagittal alignment was defined as previously described for normal spines: L1PA = PI × 0.5 - 21°, and T4-L1PA mismatch = 0°. Mechanical failure was defined as severe proximal junctional kyphosis (PJK), displaced rod fracture, or reoperation for junctional failure, pseudarthrosis, or rod fracture within 2 years. Multivariable nonlinear logistic regression was used to define target ranges for L1PA and T4-L1PA mismatch that minimized the risk of mechanical failure. The relationship between changes in T4PA and changes in global sagittal alignment according to the C2-pelvic angle (C2PA) was determined using linear regression. Lastly, multivariable regression was used to assess associations between initial postoperative C2PA and patient-reported outcomes at 1 year, adjusting for preoperative scores and age. RESULTS: The median age of the 247 included patients was 64 years (interquartile range, 57 to 69 years), and 202 (82%) were female. Deviation from a normal L1PA or T4-L1PA mismatch in either direction was associated with a significantly higher risk of mechanical failure, independent of age. Risk was minimized with an L1PA of PI × 0.5 - (19° ± 2°) and T4-L1PA mismatch between -3° and +1°. Changes in T4PA and in C2PA at the time of final follow-up were strongly associated (r2 = 0.96). Higher postoperative C2PA was independently associated with more disability, more pain, and worse self-image at 1 year. CONCLUSIONS: We defined sagittal alignment targets using L1PA (relative to PI) and the T4-L1PA mismatch, which are both directly modifiable during surgery. In patients undergoing long fusion to the sacrum, realignment based on these targets may lead to fewer mechanical failures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Development of Measures for d/Deaf and Hard of Hearing Stigma: Introduction to the Special Supplement on Stigma Measurement Tools.

People who are d/Deaf or hard of hearing (d/DHH) often experience stigma and discrimination in their daily lives. Qualitative research describing their lived experiences has provided useful, in-depth insights into the pervasiveness of stigma. Quantitative measures could facilitate further investigation of the scope of this phenomenon. Thus, under the auspices of the Lancet Commission on Hearing Loss, we developed and preliminarily validated survey measures of different types of stigma related to d/Deafness and hearing loss in the United States (a high-income country) and Ghana (a lower-middle income country). In this introductory article, we first present working definitions of the different types of stigma; an overview of what is known about stigma in the context of hearing loss; and the motivation underlying the development of measures that capture different types of stigma from the perspectives of different key groups. We then describe the mixed-methods exploratory sequential approach used to develop the stigma measures for several key groups: people who are d/DHH, parents of children who are d/DHH, care partners of people who are d/DHH, healthcare providers, and the general population. The subsequent manuscripts in this special supplement of Ear and Hearing describe the psychometric validation of the various stigma scales developed using these methods.

Preliminary Validation of Measures of Experienced, Perceived, and Internalized Stigma Among Adults Who Are d/Deaf or Hard of Hearing in the United States and Ghana.

OBJECTIVES: In this article, we examine the psychometric performance of 3 scales measuring experienced, perceived, and internalized d/Deaf or hard of hearing (d/DHH) stigma among adult (18 and older) populations of individuals who are d/DHH, including those who have been d/DHH since before they developed language (lifelong) and those who became d/DHH after they developed language (acquired) in the United States and Ghana. DESIGN: The preliminary validation study took place in the Greater Accra and Eastern regions of Ghana and across the United States. In the United States, all data were collected online via self-administered surveys in English. In Ghana, trained interviewers who are d/DHH and fluent in Ghanaian Sign Language conducted interviews with participants who are lifelong d/DHH using a video survey. Ghanaian participants with acquired d/DHH status were surveyed by trained hearing interviewers. We calculated polychoric correlation matrices between the measures to remove redundant and unrelated items and used exploratory factor analysis to create the final scales. We also tested the association between the factor scores and a simple summing method for calculating the scale. RESULTS: The study sample included people who have been d/DHH since before they developed language (Ghana: n = 171, United States n = 100) and people who became d/DHH after they developed language (Ghana: n = 174, United States: n = 219). The final experienced, perceived, and internalized scales included six, seven, and five items, respectively. All three scales performed well as unidimensional measures across all four samples. Across the four samples, the experienced, perceived, and internalized stigma scales yielded ordinal αs ranging from 0.725 to 0.947, 0.856 to 0.935, and 0.856 to 0.935, respectively. It would be acceptable to operationalize all stigma scales as sum-of-item scores. CONCLUSIONS: The scales performed well and appear to provide a valid means of measuring different types of stigma among diverse groups of people who are d/DHH. Future work should refine and validate these scales in additional contexts.

Research Agenda and Applications for Preliminarily Validated Measures of d/Deaf and Hard of Hearing Stigma.

In this special supplement of Ear and Hearing, we have presented preliminarily validated measures for stigma related to being d/Deaf or hard of hearing (d/DHH) in the United States and Ghana. In this concluding article, we suggest avenues for the future refinement and use of these measures. First, the measures should be further validated. Second, they should be used to assess the current state of d/DHH stigma and the importance of different kinds of stigma in different populations, which should in turn drive the development of interventions to reduce d/DHH stigma. Third, these measures can assist in evaluating the effectiveness and cost-effectiveness of those interventions. The evidence from this work can then inform investment cases and cost-of-condition studies, which will support advocacy efforts and policy development for reducing stigma and improving the lives of people who are d/DHH.

Quality, supply chain, and use of Trypanocidal drugs among camel keepers in north-eastern Kenya: A cross-sectional study.

The non-cyclic trypanosomiasis (surra), caused by Trypanosoma evansi, and mechanically transmitted by biting flies, hinders camel productivity in Kenya. Trypanocides are the most commonly used drugs to control surra. However, emergence of drug resistance by the parasites is a major limitation to control efforts. There is limited information on the quality of trypanocides, the supply chain and drug-use practices among camel keepers potentially contributing to development of drug resistance in Kenya. We sought to fill this gap by conducting a cross-sectional study among camel keepers in Isiolo and Marsabit counties, Kenya. We mapped the trypanocide drugs supply chain through quantitative and qualitative surveys. We administered a semi-structured questionnaire to camel keepers to generate data on trypanocides-use practices, including the types, sources, person who administers treatment, reconstitution, dosage, route and frequency of administration, among others. Additionally, we tested the quality of trypanocidal drugs retailed in the region. We mapped a total of 55 and 49 agro-veterinary outlets and general (ordinary) shops retailing veterinary drugs in the two counties, respectively. These comprised of 29 and 26 agro-veterinary outlets, as well as 24 and 25 general shops in Isiolo and Marsabit counties, respectively. Overall, the respondents experienced 283 surra cases in the three-month recall period, which were treated with trypanocides. The majority of these cases were diagnosed by camel owners (71.7%) and herders (24.1%). A significant proportion of the cases were treated by camel owners (54.8%), herders (35.3%), the owner's son (3.2%) and veterinary personnel (1.1%) (χ2 = 24.99, p = 0.000). Most of the households sourced the drugs from agro-veterinary outlets (59.0%), followed by general shops (19.8%), veterinary personnel (2.1%), and open-air markets (0.4%) (χ2 = 319.24, p = 0.000). Quinapyramine was the most (56.9%) predominantly used trypanocide in treatment of surra, followed by homidium (19.8%), isometamidium (15.9%), diminazene aceturate (6.7%), and ethidium (0.7%) (χ2 = 340.75, p < 0.000). Only a meager proportion of respondents (15.2%) used the drugs correctly as instructed by the manufacturers. We recorded an association between correct drug usage, with the person who administers the treatment (χ2 = 17.7, p = 0.003), and the type of trypanocide used (χ2 = 19.4, p < 0.001). All the drug samples tested had correct concentrations of active ingredient (100.0%), and therefore of good quality. We have demonstrated that whereas the trypanocides retailed in the region by authorized vendors are of good quality, there is widespread incorrect handling and use of the drugs by unqualified individuals, which may contribute to treatment failure and emergence of trypanocide resistance.

Multimodal smoking cessation treatment combining repetitive transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths remain the leading cause of preventable death in the United States. Veterans suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies suggest the insula is integrally involved in the neurocircuitry of TUD. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a form of repetitive transcranial magnetic stimulation (rTMS) called intermittent theta burst stimulation (iTBS). iTBS has the advantage of allowing for a patterned form of stimulation delivery that we will administer at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the right post-central gyrus and the right posterior insula, withdrawal symptoms and short-term smoking cessation outcomes will improve. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n = 25) or sham-iTBS + CBT + NRT (n = 25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Intraoperative fluid management in adult spinal deformity surgery: variation analysis and association with outcomes.

PURPOSE: To evaluate the variability in intraoperative fluid management during adult spinal deformity (ASD) surgery, and analyze the association with complications, intensive care unit (ICU) requirement, and length of hospital stay (LOS). METHODS: Multicenter comparative cohort study. Patients ≥ 18 years old and with ASD were included. Intraoperative intravenous (IV) fluid data were collected including: crystalloids, colloids, crystalloid/colloid ratio (C/C), total IV fluid (tIVF, ml), normalized total IV fluid (nIVF, ml/kg/h), input/output ratio (IOR), input-output difference (IOD), and normalized input-output difference (nIOD, ml/kg/h). Data from different centers were compared for variability analysis, and fluid parameters were analyzed for possible associations with the outcomes. RESULTS: Seven hundred ninety-eight patients with a median age of 65.2 were included. Among different surgical centers, tIVF, nIVF, and C/C showed significant variation (p < 0.001 for each) with differences of 4.8-fold, 3.7-fold, and 4.9-fold, respectively. Two hundred ninety-two (36.6%) patients experienced at least one in-hospital complication, and ninety-two (11.5%) were IV fluid related. Univariate analysis showed significant relations for: LOS and tIVF (ρ = 0.221, p < 0.001), IOD (ρ = 0.115, p = 0.001) and IOR (ρ = -0.138, p < 0.001); IV fluid-related complications and tIVF (p = 0.049); ICU stay and tIVF, nIVF, IOD and nIOD (p < 0.001 each); extended ICU stay and tIVF (p < 0.001), nIVF (p = 0.010) and IOD (p < 0.001). Multivariate analysis controlling for confounders showed significant relations for: LOS and tIVF (p < 0.001) and nIVF (p = 0.003); ICU stay and IOR (p = 0.002), extended ICU stay and tIVF (p = 0.004). CONCLUSION: Significant variability and lack of standardization in intraoperative IV fluid management exists between different surgical centers. Excessive fluid administration was found to be correlated with negative outcomes. LEVEL OF EVIDENCE: III.

The FAM114A proteins are adaptors for the recycling of Golgi enzymes.

Golgi-resident enzymes remain in place while their substrates flow through from the endoplasmic reticulum to elsewhere in the cell. COPI-coated vesicles bud from the Golgi to recycle Golgi residents to earlier cisternae. Different enzymes are present in different parts of the stack, and one COPI adaptor protein, GOLPH3, acts to recruit enzymes into vesicles in part of the stack. Here, we used proximity biotinylation to identify further components of intra-Golgi vesicles and found FAM114A2, a cytosolic protein. Affinity chromatography with FAM114A2, and its paralogue FAM114A1, showed that they bind to Golgi-resident membrane proteins, with membrane-proximal basic residues in the cytoplasmic tail being sufficient for the interaction. Deletion of both proteins from U2OS cells did not cause substantial defects in Golgi function. However, a Drosophila orthologue of these proteins (CG9590/FAM114A) is also localised to the Golgi and binds directly to COPI. Drosophila mutants lacking FAM114A have defects in glycosylation of glue proteins in the salivary gland. Thus, the FAM114A proteins bind Golgi enzymes and are candidate adaptors to contribute specificity to COPI vesicle recycling in the Golgi stack.

Patient-Specific Rods in Adolescent and Adult Spinal Deformity Surgery: A Narrative Review.

Spinal deformity surgery often requires complex surgical interventions that can have a drastic effect on both patient quality of life and functional capacity. Modern-day corrective solutions for these deformities include spinal osteotomies, pedicle screw instrumentation, and dual/multirod constructs. These solutions are efficacious and are currently considered standard practice for spinal surgeons, but they lack individualization. Patient-specific rods (PSRs) are a novel technology that attempts to offer a personalized approach to spinal deformity correction based on preoperative computerized tomography scans. Moreover, PSRs may offer several advantages to conventional rods, which include achievement of desired rod contour angles according to surgical planning alignment goals, reduced operative time, and reduced blood loss. In adolescent idiopathic scoliosis, those instrumented with PSR have observed coronal Cobb reductions up to 74%. In adult spinal deformity, PSRs have offered superior correction in radiographic parameters such as sagittal vertical axis and pelvic incidence minus lumbar lordosis. However, there still remains a paucity of research in this area, mainly in health care expenditure, cost-effectiveness, and longitudinal clinical outcomes. The purpose of this article is to survey the current body of knowledge of PSR instrumentation in both adolescent and adult spinal deformity populations. The current strength, limitations, and future directions of PSRs are highlighted throughout this article.

Use of the kickstand rod improves coronal alignment and maintains correction compared to control at 2 year follow-up.

PURPOSE: To assess and compare coronal alignment correction at 2 year follow-up in adult spinal deformity (ASD) patients treated with and without the kickstand rod (KSR) construct. METHODS: ASD patients who underwent posterior spinal fusion at a single-center with a preoperative coronal vertical axis (CVA) ≥ 3 cm and a minimum of 2 year clinical and radiographic follow-up were identified. Patients were divided into two groups: those treated with a KSR and those who were not. Patients were propensity score-matched (PSM) controlling for preoperative CVA and instrumented levels to limit potential biases that my influence the magnitude of coronal correction. RESULTS: One hundred sixteen patients were identified (KSR = 42, Control = 74). There were no statistically significant differences in patient characteristics (p > 0.05). At baseline, the control group presented with a greater LS curve (29.0 ± 19.6 vs. 21.5 ± 10.8, p = 0.0191) while the KSR group presented with a greater CVA (6.3 ± 3.6 vs. 4.5 ± 1.8, p = 0.0036). After 40 PSM pairs were generated, there were no statistically significant differences in baseline patient and radiographic characteristics. Within the matched cohorts, the KSR group demonstrated greater CVA correction at 1 year (4.7 ± 2.4 cm vs. 2.9 ± 2.2 cm, p = 0.0012) and 2 year follow-up (4.7 ± 2.6 cm vs. 3.1 ± 2.6 cm, p = 0.0020) resulting in less coronal malalignment one (1.5 ± 1.3 cm vs. 2.4 ± 1.6 cm, p = 0.0056) and 2 year follow-up (1.6 ± 1.0 vs. 2.5 ± 1.5 cm, p = 0.0110). No statistically significant differences in PROMs, asymptomatic mechanical complications, reoperations for non-mechanical complications were observed at 2 year follow-up. However, the KSR group experienced a lesser rate of mechanical complications requiring reoperations (7.1% vs. 24.3%. OR = 0.15 [0.03-0.72], p = 0.0174). CONCLUSIONS: Patients treated with a KSR had a greater amount of coronal realignment at the 2 year follow-up time period and reported less mechanical complications requiring reoperation. However, 2 year patient-reported outcomes were similar between the two groups.

Cranial sagittal vertical axis to the hip as the best sagittal alignment predictor of patient-reported outcomes at 2 years postoperatively in adult spinal deformity surgery.

OBJECTIVE: The objective was to discern whether the cranial sagittal vertical axis (CrSVA) can best predict the trajectory of patient-reported outcome measures (PROMs) at 2 years postoperatively. METHODS: This was a retrospective cohort study of prospectively collected adult spinal deformity patient data. CrSVA relative to the sacrum, hip (CrSVA-H), knee, and ankle was measured as the horizontal distance to the vertical plumb line from the nasion-inion midpoint, with positive values indicating an anterior cranium. Standard sagittal alignment parameters were also collected. Outcome variables were PROMs as measured by Scoliosis Research Society-22r questionnaire (SRS-22r) total and subdomain scores and the Oswestry Disability Index. Pearson's correlation coefficients and univariate regressions were performed to investigate associations between predictors and PROMs. Two conceptual multivariable linear regression models for each 2-year outcome measure were built after adjusting for the impact of preoperative SRS-22r scores. Model 1 assessed pre- and postoperative alignment only relative to C2 and C7, while model 2 assessed alignment relative to C2 and C7 as well as the cranium. RESULTS: There was a total of 363 patients with 2 years of radiographic and PROM follow-up (68.0% female, mean [standard error of the mean] age 60.8 [0.78] years, BMI 27.5 [0.29], and total number of instrumented levels 12.8 [0.22]). CrSVA measures were significantly associated with the 2-year SRS-22r total and subdomain scores. In univariate regression, revision surgery, number of prior surgeries, frailty, BMI, total number of osteotomies, and lower baseline total SRS-22r score as well as postoperative sagittal alignment were significantly associated with worse 2-year SRS-22r scores. In multivariable regression, after adjusting for baseline SRS-22r scores, greater preoperative C2 to sacrum sagittal vertical axis (SVA) and C7 SVA were found to be the only independent predictors of 2-year total SRS-22r score (ß = -0.011 [p = 0.0026] and ß = 0.009 [p = 0.0211], respectively) when alignment was considered only relative to C2. However, in the subsequent model, CrSVA-H replaced C7 SVA as the independent factor driving postoperative SRS-22r total scores (ß = -0.006, p < 0.0001). That is, when the model included alignment relative to the cranium, C2, and C7, greater or more anterior CrSVA-H resulted in worse SRS-22r scores, while smaller or more posterior CrSVA-H resulted in better scores. Similar models for subdomains again found CrSVA-H to be the best predictor of function (ß = -0.0095, p < 0.0001), pain (ß = -0.0091, p < 0.0001), self-image (ß = -0.0084, p = 0.0004), and mental health (ß = -0.0059, p = 0.0026). CONCLUSIONS: In multivariable regression, C7 SVA was supplanted by CrSVA-H alignment as a significant, independent predictor of 2-year SRS-22r scores in patients with adult spinal deformity and should be considered as one of the standard postoperative sagittal alignment target goals.

Spinal cord injury in high-risk complex adult spinal deformity surgery: review of incidence and outcomes from the Scoli-RISK-1 study.

STUDY DESIGN: Clinical case series. OBJECTIVE: To describe the cause, treatment and outcome of 6 cases of perioperative spinal cord injury (SCI) in high-risk adult deformity surgery. SETTING: Adult spinal deformity patients were enrolled in the multi-center Scoli-RISK-1 cohort study. METHODS: A total of 272 patients who underwent complex adult deformity surgery were enrolled in the prospective, multi-center Scoli-RISK-1 cohort study. Clinical follow up data were available up to a maximum of 2 years after index surgery. Cases of perioperative SCI were identified and an extensive case review was performed. RESULTS: Six individuals with SCI were identified from the Scoli-RISK-1 database (2.2%). Two cases occurred intraoperatively and four cases occurred postoperatively. The first case was an incomplete SCI due to a direct intraoperative insult and was treated postoperatively with Riluzole. The second SCI case was caused by a compression injury due to overcorrection of the deformity. Three cases of incomplete SCI occurred; one case of postoperative hematoma, one case of proximal junctional kyphosis (PJK) and one case of adjacent segment disc herniation. All cases of post-operative incomplete SCI were managed with revision decompression and resulted in excellent clinical recovery. One case of incomplete SCI resulted from infection and PJK. The patient's treatment was complicated by a delay in revision and the patient suffered persistent neurological deficits up to six weeks following the onset of SCI. CONCLUSION: Despite the low incidence in high-risk adult deformity surgeries, perioperative SCI can result in devastating consequences. Thus, appropriate postoperative care, follow up and timely management of SCI are essential.

Impact of Prior Cervical Fusion on Patients Undergoing Thoracolumbar Deformity Correction.

STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: Evaluate the impact of prior cervical constructs on upper instrumented vertebrae (UIV) selection and postoperative outcomes among patients undergoing thoracolumbar deformity correction. BACKGROUND: Surgical planning for adult spinal deformity (ASD) patients involves consideration of spinal alignment and existing fusion constructs. METHODS: ASD patients with (ANTERIOR or POSTERIOR) and without (NONE) prior cervical fusion who underwent thoracolumbar fusion were included. Demographics, radiographic alignment, patient-reported outcome measures (PROMs), and complications were compared. Univariate and multivariate analyses were performed on POSTERIOR patients to identify parameters predictive of UIV choice and to evaluate postoperative outcomes impacted by UIV selection. RESULTS: Among 542 patients, with 446 NONE, 72 ANTERIOR, and 24 POSTERIOR patients, mean age was 64.4 years and 432 (80%) were female. Cervical fusion patients had worse preoperative cervical and lumbosacral deformity, and PROMs (P<0.05). In the POSTERIOR cohort, preoperative LIV was frequently below the cervicothoracic junction (54%) and uncommonly (13%) connected to the thoracolumbar UIV. Multivariate analyses revealed that higher preoperative cervical SVA (coeff=-0.22, 95%CI=-0.43--0.01, P=0.038) and C2SPi (coeff=-0.72, 95%CI=-1.36--0.07, P=0.031), and lower preoperative thoracic kyphosis (coeff=0.14, 95%CI=0.01-0.28, P=0.040) and thoracolumbar lordosis (coeff=0.22, 95%CI=0.10-0.33, P=0.001) were predictive of cranial UIV. Two-year postoperatively, cervical patients continued to have worse cervical deformity and PROMs (P<0.05) but had comparable postoperative complications. Choice of thoracolumbar UIV below or above T6, as well as the number of unfused levels between constructs, did not affect patient outcomes. CONCLUSIONS: Among patients who underwent thoracolumbar deformity correction, prior cervical fusion was associated with more severe spinopelvic deformity and PROMs preoperatively. The choice of thoracolumbar UIV was strongly predicted by their baseline cervical and thoracolumbar alignment. Despite their poor preoperative condition, these patients still experienced significant improvements in their thoracolumbar alignment and PROMs after surgery, irrespective of UIV selection. LEVEL OF EVIDENCE: IV.

Does an improvement in cord-level intraoperative neuromonitoring data lead to a reduced risk for postoperative neurologic deficit in spine deformity surgery?

PURPOSE: To determine if an improvement in cord-level intraoperative neuromonitoring (IONM) data following data loss results in a reduced risk for new postoperative motor deficit in pediatric and adult spinal deformity surgery. METHODS: A consecutive series of 1106 patients underwent spine surgery from 2015 to 2023 by a single surgeon. Cord alerts were defined by Somatosensory-Evoked Potentials (SSEP; warning criteria: 10% increase in latency or > 50% loss in amplitude) and Motor-Evoked Potentials (MEP; warning criteria: 75% loss in amplitude without return to acceptable limits after stimulation up 100 V above baseline level). Timing of IONM loss and recovery, interventions, and baseline/postoperative day 1 (POD1) lower extremity motor scores were analyzed. RESULTS: IONM Cord loss was noted in 4.8% (53/11,06) of patients and 34% (18/53) with cord alerts had a POD1 deficit compared to preoperative motor exam. MEP and SSEP loss attributed to 98.1% (52/53) and 39.6% (21/53) of cord alerts, respectively. Abnormal descending neurogenic-evoked potential (DNEP) was seen in 85.7% (12/14) and detected 91.7% (11/12) with POD1 deficit. Abnormal wake-up test (WUT) was seen in 38.5% (5/13) and detected 100% (5/5) with POD1 deficit. Most cord alerts occurred during a three-column osteotomy (N = 23/53, 43%); decompression (N = 12), compression (N = 7), exposure (N = 4), and rod placement (N = 14). Interventions were performed in all 53 patients with cord loss and included removing rods/less correction (N = 11), increasing mean arterial pressure alone (N = 10), and further decompression with three-column osteotomy (N = 9). After intervention, IONM data improved in 45(84.9%) patients (Full improvement: N = 28; Partial improvement: 17). For those with full and partial IONM improvement, the POD1 deficit was 10.7% (3/28) and 41.2% (7/17), respectively. For those without any IONM improvement (15.1%, 8/53), 100% (8/8) had a POD1 deficit, P < 0.001. CONCLUSION: A full or partial improvement in IONM data loss after intraoperative intervention was significantly associated with a lower risk for POD1 deficit with an absolute risk reduction of 89.3% and 58.8%, respectively. All patients without IONM improvement had a POD1 neurologic deficit.

Optimizing Renal Transporter Immunodetection: Consequences of Freeze-Thaw during Sample Preparation.

Renal transporters (co-transporters, channels, claudins) mediate homeostasis of fluids and electrolytes and are targets of hormonal and therapeutic regulators. Assessing renal transporter abundance with antibody probes by immunoblotting is an essential tool for mechanistic studies. While journals require authors to demonstrate antibody specificity, there are no consensus guidelines for kidney sample preparation leading to lab-to-lab variability in immunoblot results. In this study, we determined the impact of sample preparation, specifically freeze-thawed (Froz) versus freshly-processed (Fresh) kidneys (female and male rats and mice) on immunoblot signal detection of fifteen renal transporters, and the impact of protease inhibitors during homogenization. In female Sprague Dawley rat kidneys homogenized with: aprotinin, Na2EDTA, PMSF, and phosphatase inhibitors, immunodetection signals were ~50% lower in Frozen versus Fresh samples for most transporters. Inclusion of additional inhibitors (Roche cOmpleteTM Protease Inhibitor, "+") only partially increased transporter immunoblot signals to near Fresh levels. In male Sprague Dawley rats, immunoblot signal density was lower in Froz+ versus Fresh+ despite additional inhibitors. In C57BL/6 male mice, immunoblot signals from proximal tubule transporters were lower in Froz vs Fresh by ~25-50% and was greater in Froz+. In contrast, female mice exhibited selective transporter signal degradation in Froz not improved with additional protease inhibitors. Thus, kidney sample preparation variables, including freeze-thaw and protease inhibition, have substantial transporter-specific effects on quantification of renal transporter abundance by immunoblot. These findings underscore the critical importance of assessing and reporting the impact of sample preparation protocols on transporter recovery to ensure robust rigor and reproducibility.

Hip Osteoarthritis in Patients Undergoing Surgery for Severe Adult Spinal Deformity: Prevalence and Impact on Spine Surgery Outcomes.

BACKGROUND: Hip osteoarthritis (OA) is common in patients with adult spinal deformity (ASD). Limited data exist on the prevalence of hip OA in patients with ASD, or on its impact on baseline and postoperative alignment and patient-reported outcome measures (PROMs). Therefore, this paper will assess the prevalence and impact of hip OA on alignment and PROMs. METHODS: Patients with ASD who underwent L1-pelvis or longer fusions were included. Two independent reviewers graded hip OA with the Kellgren-Lawrence (KL) classification and stratified it by severity into non-severe (KL grade 1 or 2) and severe (KL grade 3 or 4). Radiographic parameters and PROMs were compared among 3 patient groups: Hip-Spine (hip KL grade 3 or 4 bilaterally), Unilateral (UL)-Hip (hip KL grade 3 or 4 unilaterally), or Spine (hip KL grade 1 or 2 bilaterally). RESULTS: Of 520 patients with ASD who met inclusion criteria for an OA prevalence analysis, 34% (177 of 520) had severe bilateral hip OA and unilateral or bilateral hip arthroplasty had been performed in 8.7% (45 of 520). A subset of 165 patients had all data components and were examined: 68 Hip-Spine, 32 UL-Hip, and 65 Spine. Hip-Spine patients were older (67.9 ± 9.5 years, versus 59.6 ± 10.1 years for Spine and 65.8 ± 7.5 years for UL-Hip; p < 0.001) and had a higher frailty index (4.3 ± 2.6, versus 2.7 ± 2.0 for UL-Hip and 2.9 ± 2.0 for Spine; p < 0.001). At 1 year, the groups had similar lumbar lordosis, yet the Hip-Spine patients had a worse sagittal vertebral axis (SVA) measurement (45.9 ± 45.5 mm, versus 25.1 ± 37.1 mm for UL-Hip and 19.0 ± 39.3 mm for Spine; p = 0.001). Hip-Spine patients also had worse Veterans RAND-12 Physical Component Summary scores at baseline (25.7 ± 9.3, versus 28.7 ± 9.8 for UL-Hip and 31.3 ± 10.5 for Spine; p = 0.005) and 1 year postoperatively (34.5 ± 11.4, versus 40.3 ± 10.4 for UL-Hip and 40.1 ± 10.9 for Spine; p = 0.006). CONCLUSIONS: This study of operatively treated ASD revealed that 1 in 3 patients had severe hip OA bilaterally. Such patients with severe bilateral hip OA had worse baseline SVA and PROMs that persisted 1 year following ASD surgery, despite correction of lordosis. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Looking ahead to CD3, T-cell engager bispecific antibodies for hematological malignancies.

INTRODUCTION: Since the approval of the bispecific antibody blinatumomab in 2017 for the treatment of acute lymphoblastic leukemia in relapse, the development of numerous bispecific antibody constructs has dramatically expanded in hematologic malignancies. Many have recently received Food Drug Administration and European Medicines Agency approvals in various stages of treatment for lymphomas, leukemias, and multiple myeloma. AREAS COVERED: The purpose of this review is to provide an overview of bispecific antibody treatment including the mechanisms leading to effector T cells targeting tumor-associated antigens, the treatment indications, efficacies, toxicities, and challenges of the different constructs. A literature search was performed through access to PubMed and clinicaltrials.gov. EXPERT OPINION: While there has been substantial success in the treatment of NHL, MM, and ALL, there are still hematologic malignancies such as AML where there has been limited progress. It is important to continue to investigate new designs, tumor antigen targets, and further refine where current approved bispecific antibodies fit in terms of sequencing of therapy. Hopefully, with the knowledge gained in recent years and the explosion of these therapies, patients with blood cancers will continue to benefit from these treatments for years to come.

A programmable and automated optical electrowetting-on-dielectric (oEWOD) driven platform for massively parallel and sequential processing of single cell assay operations.

Recently, there has been an increasing emphasis on single cell profiling for high-throughput screening workflows in drug discovery and life sciences research. However, the biology underpinning these screens is often complex and is insufficiently addressed by singleplex assay screens. Traditional single cell screening technologies have created powerful sets of 'omic data that allow users to bioinformatically infer biological function, but have as of yet not empowered direct functional analysis at the level of each individual cell. Consequently, screening campaigns often require multiple secondary screens leading to laborious, time-consuming and expensive workflows in which attrition points may not be queried until late in the process. We describe a platform that harnesses droplet microfluidics and optical electrowetting-on-dielectric (oEWOD) to perform highly-controlled sequential and multiplexed single cell assays in massively parallelised workflows to enable complex cell profiling during screening. Soluble reagents or objects, such as cells or assay beads, are encapsulated into droplets of media in fluorous oil and are actively filtered based on size and optical features ensuring only desirable droplets (e.g. single cell droplets) are retained for analysis, thereby overcoming the Poisson probability distribution. Droplets are stored in an array on a temperature-controlled chip and the history of individual droplets is logged from the point of filter until completion of the workflow. On chip, droplets are subject to an automated and flexible suite of operations including the merging of sample droplets and the fluorescent acquisition of assay readouts to enable complex sequential assay workflows. To demonstrate the broad utility of the platform, we present examples of single-cell functional workflows for various applications such as antibody discovery, infectious disease, and cell and gene therapy.

A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers.

(R,S)-Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)-Hydroxynorketamine (RR-HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR-HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six-level single-ascending dose (SAD) (0.1-4 mg/kg) and a two-level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40-minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR-HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR-HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR-HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose-proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma-power oscillations demonstrated increases of gamma power in some participants at the lower/mid-range doses examined. Cerebrospinal fluid examination confirmed RR-HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR-HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.