Intrinsic physicochemical profile of marketed antibody-based biotherapeutics.

Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.

Fear Avoidance Beliefs in Upper-Extremity Musculoskeletal Pain Conditions: Secondary Analysis of a Prospective Clinical Study on Digital Care Programs.

BACKGROUND: Fear-avoidance beliefs (FAB) have been associated with poorer prognosis and decreased adherence to exercise-based treatments in musculoskeletal (MSK) pain. However, the impact of high FAB on adherence and outcomes in upper extremity MSK (UEMSK) pain is poorly explored, particularly through exercise-based digital care programs (DCP). OBJECTIVE: Assess the adherence levels, clinical outcomes and satisfaction in patients with UEMSK pain and elevated FAB after a fully remote multimodal DCP. Associations between FABQ-PA and clinical outcomes were conducted. METHODS: Secondary analysis of an ongoing clinical trial. Participants with UEMSK pain (shoulder, elbow, and wrist/hand) and elevated FAB-physical activity (FABQ-PA ≥ 15) were included. Adherence (completion rate, sessions/week, total exercise time) and mean change in clinical outcomes-disability (QuickDASH), numerical pain score, FABQ-PA, anxiety (GAD-7), and depression (PHQ-9)-between baseline and end-of-program were assessed. Associations between FABQ-PA and clinical outcomes were conducted. RESULTS: 520 participants were included, with mean baseline FABQ-PA of 18.02 (SD 2.77). Patients performed on average 29.3 exercise sessions (2.8 sessions/week), totalizing 338.2 exercise minutes. Mean satisfaction was 8.5/10 (SD 1.7). Significant improvements were observed in all clinical outcomes. Higher baseline FAB were associated with higher baseline disability (P < .001), and smaller improvements in disability (P < .001) and pain (P = .001). Higher engagement was associated with greater improvements in FABQ-PA (P = .043) and pain (P = 0.009). CONCLUSIONS: This study provides evidence of the potential benefits of a structured and multimodal home-based DCP in the management of UEMSK pain conditions in patients with elevated FAB in a real-world context.

Distal junctional kyphosis in adult cervical deformity patients: where does it occur?

PURPOSE: To evaluate the impact of the lowest instrumented vertebra (LIV) on Distal Junctional kyphosis (DJK) incidence in adult cervical deformity (ACD) surgery. METHODS: Prospectively collected data from ACD patients undergoing posterior or anterior-posterior reconstruction at 13 US sites was reviewed up to 2-years postoperatively (n = 140). Data was stratified into five groups by level of LIV: C6-C7, T1-T2, T3-Apex, Apex-T10, and T11-L2. DJK was defined as a kyphotic increase > 10° in Cobb angle from LIV to LIV-1. Analysis included DJK-free survival, covariate-controlled cox regression, and DJK incidence at 1-year follow-up. RESULTS: 25/27 cases of DJK developed within 1-year post-op. In patients with a minimum follow-up of 1-year (n = 102), the incidence of DJK by level of LIV was: C6-7 (3/12, 25.00%), T1-T2 (3/29, 10.34%), T3-Apex (7/41, 17.07%), Apex-T10 (8/11, 72.73%), and T11-L2 (4/8, 50.00%) (p < 0.001). DJK incidence was significantly lower in the T1-T2 LIV group (adjusted residual = -2.13), and significantly higher in the Apex-T10 LIV group (adjusted residual = 3.91). In covariate-controlled regression using the T11-L2 LIV group as reference, LIV selected at the T1-T2 level (HR = 0.054, p = 0.008) or T3-Apex level (HR = 0.081, p = 0.010) was associated with significantly lower risk of DJK. However, there was no difference in DJK risk when LIV was selected at the C6-C7 level (HR = 0.239, p = 0.214). CONCLUSION: DJK risk is lower when the LIV is at the upper thoracic segment than the lower cervical segment. DJK incidence is highest with LIV level in the lower thoracic or thoracolumbar junction.

Preclinical efficacy of humanized, non-FcγR-binding anti-CD3 antibodies in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy that accounts for ∼20% of ALL cases. Intensive chemotherapy regimens result in cure rates >85% in children and <50% in adults, warranting a search of novel therapeutic strategies. Although immune-based therapies have tremendously improved the treatment of B-ALL and other B-cell malignancies, they are not yet available for T-ALL. We report here that humanized, non-Fcγ receptor (FcγR)-binding monoclonal antibodies (mAbs) to CD3 have antileukemic properties in xenograft (PDX) models of CD3+ T-ALL, resulting in prolonged host survival. We also report that these antibodies cooperate with chemotherapy to enhance antileukemic effects and host survival. Because these antibodies show only minor, manageable adverse effects in humans, they offer a new therapeutic option for the treatment of T-ALL. Our results also show that the antileukemic properties of anti-CD3 mAbs are largely independent of FcγR-mediated pathways in T-ALL PDXs.

Antibodies with Weakly Basic Isoelectric Points Minimize Trade-offs between Formulation and Physiological Colloidal Properties.

The widespread interest in antibody therapeutics has led to much focus on identifying antibody candidates with favorable developability properties. In particular, there is broad interest in identifying antibody candidates with highly repulsive self-interactions in standard formulations (e.g., low ionic strength buffers at pH 5-6) for high solubility and low viscosity. Likewise, there is also broad interest in identifying antibody candidates with low levels of non-specific interactions in physiological solution conditions (PBS, pH 7.4) to promote favorable pharmacokinetic properties. To what extent antibodies that possess both highly repulsive self-interactions in standard formulations and weak non-specific interactions in physiological solution conditions can be systematically identified remains unclear and is a potential impediment to successful therapeutic drug development. Here, we evaluate these two properties for 42 IgG1 variants based on the variable fragments (Fvs) from four clinical-stage antibodies and complementarity-determining regions from 10 clinical-stage antibodies. Interestingly, we find that antibodies with the strongest repulsive self-interactions in a standard formulation (pH 6 and 10 mM histidine) display the strongest non-specific interactions in physiological solution conditions. Conversely, antibodies with the weakest non-specific interactions under physiological conditions display the least repulsive self-interactions in standard formulations. This behavior can be largely explained by the antibody isoelectric point, as highly basic antibodies that are highly positively charged under standard formulation conditions (pH 5-6) promote repulsive self-interactions that mediate high colloidal stability but also mediate strong non-specific interactions with negatively charged biomolecules at physiological pH and vice versa for antibodies with negatively charged Fv regions. Therefore, IgG1s with weakly basic isoelectric points between 8 and 8.5 and Fv isoelectric points between 7.5 and 9 typically display the best combinations of strong repulsive self-interactions and weak non-specific interactions. We expect that these findings will improve the identification and engineering of antibody candidates with drug-like biophysical properties.

Impacts of Digital Care Programs for Musculoskeletal Conditions on Depression and Work Productivity: Longitudinal Cohort Study.

BACKGROUND: Comorbidity between musculoskeletal (MSK) pain and depression is highly common, and is associated with a greater symptom burden and greater loss of work productivity than either condition alone. Multimodal care programs tackling both physical and mental health components may maximize productivity recovery and return to work. Digital delivery of such programs can facilitate access, ensure continuity of care, and enhance patient engagement. OBJECTIVE: The aim of this study was to assess the impact of a completely remote multimodal digital care program (DCP) for MSK pain on mental health and work-related outcomes stratified by baseline depression levels. METHODS: Ad hoc analysis of an interventional, single-arm, cohort study of individuals with MSK pain undergoing a DCP was performed. Three subgroups with different baseline depression severity levels were established based on responses to the Patient Health Questionnaire (PHQ-9): cluster 1 (score<5: minimal depression), cluster 2 (scores 5-10: mild depression), and cluster 3 (score≥10: moderate depression). The mean changes in depression, anxiety, fear-avoidance beliefs, work productivity, and activity impairment and adherence between baseline and end of program (8-12 weeks) were assessed across subgroups by latent growth curve analysis. RESULTS: From a total of 7785 eligible participants, 6137 (78.83%) were included in cluster 1, 1158 (14.87%) in cluster 2, and 490 (6.29%) in cluster 3. Significant improvements in depression and anxiety scores were observed in clusters 2 and 3 but not in cluster 1, with average end-of-the program scores in clusters 2 and 3 below the initially defined cluster thresholds (score of 5 and 10, respectively). All clusters reported significant improvements in productivity impairment scores (mean changes from -16.82, 95% CI -20.32 to -13.42 in cluster 1 to -20.10, 95% CI -32.64 to -7.57 in cluster 3). Higher adherence was associated with higher improvements in depression in clusters 2 and 3, and with greater recovery in activities of daily living in cluster 3. Overall patient satisfaction was 8.59/10.0 (SD 1.74). CONCLUSIONS: A multimodal DCP was able to promote improvements in productivity impairment scores comparable to those previously reported in the literature, even in participants with comorbid depression and anxiety. These results reinforce the need to follow a biopsychosocial framework to optimize outcomes in patients with MSK pain. TRIAL REGISTRATION: ClinicalTrials.gov NCT04092946; https://clinicaltrials.gov/ct2/show/NCT04092946.

Racial and Ethnic Differences in Outcomes of a 12-Week Digital Rehabilitation Program for Musculoskeletal Pain: Prospective Longitudinal Cohort Study.

BACKGROUND: Musculoskeletal (MSK) pain disproportionately affects people from different ethnic backgrounds through higher burden and less access to care. Digital care programs (DCPs) can improve access and help reduce inequities. However, the outcomes of such programs based on race and ethnicity have yet to be studied. OBJECTIVE: We aimed to assess the impact of race and ethnicity on engagement and outcomes in a multimodal DCP for MSK pain. METHODS: This was an ad hoc analysis of an ongoing decentralized single-arm investigation into engagement and clinical-related outcomes after a multimodal DCP in patients with MSK conditions. Patients were stratified by self-reported racial and ethnic group, and their engagement and outcome changes between baseline and 12 weeks were compared using latent growth curve analysis. Outcomes included program engagement (number of sessions), self-reported pain scores, likelihood of surgery, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire 9-item, and Work Productivity and Activity Impairment. A minimum clinically important difference (MCID) of 30% was calculated for pain, and multivariable logistic regression was performed to evaluate race as an independent predictor of meeting the MCID. RESULTS: A total of 6949 patients completed the program: 65.5% (4554/6949) of them were non-Hispanic White, 10.8% (749/6949) were Black, 9.7% (673/6949) were Asian, 9.2% (636/6949) were Hispanic, and 4.8% (337/6949) were of other racial or ethnic backgrounds. The population studied was diverse and followed the proportions of the US population. All groups reported high engagement and satisfaction, with Hispanic and Black patients ranking first among satisfaction despite lower engagement. Black patients had a higher likelihood to drop out (odds ratio [OR] 1.19, 95% CI 1.01-1.40, P=.04) than non-Hispanic White patients. Hispanic and Black patients reported the highest level of pain, surgical intent, work productivity, and impairment in activities of daily living at baseline. All race groups showed a significant improvement in all outcomes, with Black and Hispanic patients reporting the greatest improvements in clinical outcomes. Hispanic patients also had the highest response rate for pain (75.8%) and a higher OR of meeting the pain MCID (OR 1.74, 95% CI 1.24-2.45, P=.001), when compared with non-Hispanic White patients, independent of age, BMI, sex, therapy type, education level, and employment status. No differences in mental health outcomes were found between race and ethnic groups. CONCLUSIONS: This study advocates for the utility of a DCP in improving access to MSK care and promoting health equity. Engagement and satisfaction rates were high in all the groups. Black and Hispanic patients had higher MSK burden at baseline and lower engagement but also reported higher improvements, with Hispanic patients presenting a higher likelihood of pain improvement.

In Vivo Stability Profiles of Anti-factor D Molecules Support Long-Acting Delivery Approaches.

The collection of aqueous humor (phase 1 b/2 Mahalo study) from patients dosed intravitreally with anti-factor D (AFD; FCFD4514S, lampalizumab), a humanized antibody fragment previously under investigation to treat geographic atrophy (GA) secondary to age-related macular degeneration, presented a unique opportunity to examine AFD properties in clinical samples. We investigated AFD stability and target-binding characteristics to set up strategies for engineering and evaluating optimized molecules that enable less frequent dosing. Two variants, AFD.v8 and AFD.v14, were evaluated as alternatives to AFD for longer-acting treatments. Mass spectrometry, surface plasmon resonance, and immunoassay were used to assess AFD stability and binding activity in aqueous humor samples from Mahalo patients. In vitro stability and binding activity of AFD, AFD.v8, and AFD.v14 were assessed in human vitreous humor versus buffer at 37 °C over 16 weeks and in vivo in rabbits over 28 days along with pharmacokinetic determinations. In human aqueous humor, AFD specific binding was >85% through 30 days, and deamidation was <3% through 60 days, consistent with the AFD stability and binding activity in vitreous humor from humans in vitro and rabbits in vivo. Target binding, stability, and rabbit pharmacokinetic parameters of AFD.v8 and AFD.v14 were similar to those of AFD. Physiological stability and activity of AFD translated across in vitro and in vivo studies in humans and rabbits. The two variants AFD.v8 and AFD.v14 demonstrated comparable potency and pharmacokinetics. These findings, along with previously demonstrated improved solubility of AFD.v8 and AFD.v14, provide proof-of-concept for developing other similar long-acting therapeutic variants.

Prospective multi-centric evaluation of upper cervical and infra-cervical sagittal compensatory alignment in patients with adult cervical deformity.

PURPOSE: Reciprocal mechanisms for standing alignment have been described in thoraco-lumbar deformity but have not been studied in patients with primary cervical deformity (CD). The purpose of this study is to report upper- and infra-cervical sagittal compensatory mechanisms in patients with CD and evaluate their changes post-operatively. METHODS: Global spinal alignment was studied in a prospective database of operative CD patients. Inclusion criteria were any of the following: cervical kyphosis (CK) > 10°, cervical scoliosis > 10°, cSVA (C2-C7 Sagittal vertical axis) > 4 cm or CBVA (Chin Brow Vertical Angle) > 25°. For this study, patients who had previous fusion outside C2 to T4 segments were excluded. Patients were sub-classified by increasing severity of cervical kyphosis [CL (cervical lordosis): < 0°, CK-low 0°-10°, CK-high > 10°] and cSVA (cSVA-low 0-4 cm, cSVA-mid 4-6 cm, cSVA-high > 6 cm) and were compared for pre- and 3-month post-operative regional and global sagittal alignment to determine compensatory recruitment. RESULTS: 75 CD patients (mean age 61.3 years, 56% women) were included. Patients with progressively larger CK had a progressive increase in C0-C2 (CL = 34°, CK-low = 37°, CK-high = 44°, p = 0.004), C2Slope and T1Slope-CL (p < 0.05). As the cSVA increased, there was progressive increase in C2Slope, T1Slope and TS-CL (p < 0.05) and patients compensated through increasing C0-C2 (cSVA-low = 33°, cSVA-mid = 40°, cSVA-high = 43°, p = 0.007) and pelvic tilt (cSVA-low = 14.9°, cSVA-mid = 24.1°, cSVA-high = 24.9°, p = 0.02). At 3 months post-op, with significant improvement in cervical alignment, there was relaxation of C0-C2 (39°-35°, p = 0.01) which positively correlated with magnitude of deformity correction. CONCLUSIONS: Patients with cervical malalignment compensate with upper cervical hyper-lordosis, presumably for the maintenance of horizontal gaze. As cSVA increases, patients also tend to exhibit increased pelvic retroversion. Following surgical treatment, there was relaxation of upper cervical compensation.

External validation of the adult spinal deformity (ASD) frailty index (ASD-FI).

PURPOSE: To assess the ability of the recently developed adult spinal deformity frailty index (ASD-FI) to predict odds of perioperative complications, odds of reoperation, and length of hospital stay after adult spinal deformity (ASD) surgery using a database other than the one used to create the index. METHODS: We used the ASD-FI to calculate frailty scores for 266 ASD patients who had minimum postoperative follow-up of 2 years in the European Spine Study Group (ESSG) database. Patients were enrolled from 2012 through 2013. Using ASD-FI scores, we categorized patients as not frail (NF) (< 0.3 points), frail (0.3-0.5 points), or severely frail (SF) (> 0.5 points). Multivariable logistic regression, adjusted for preoperative and surgical factors such as operative time and blood loss, was performed to determine the relationship between ASD-FI category and odds of major complications, odds of reoperation, and length of hospital stay. RESULTS: We categorized 135 patients (51%) as NF, 90 patients (34%) as frail, and 41 patients (15%) as SF. Overall mean ASD-FI score was 0.29 (range 0-0.8). The adjusted odds of experiencing a major intraoperative or postoperative complication (OR 4.5, 95% CI 2.0-10) or having a reoperation (OR 3.9, 95% CI 1.7-8.9) were higher for SF patients compared with NF patients. Mean hospital stay was 2.1 times longer (95% CI 1.8-2.4) for SF patients compared with NF patients. CONCLUSIONS: Greater patient frailty, as measured by the ASD-FI, is associated with longer hospital stays and greater odds of major complications and reoperation. These slides can be retrieved under Electronic Supplementary Material.

Development of a validated computer-based preoperative predictive model for pseudarthrosis with 91% accuracy in 336 adult spinal deformity patients.

OBJECTIVEPseudarthrosis can occur following adult spinal deformity (ASD) surgery and can lead to instrumentation failure, recurrent pain, and ultimately revision surgery. In addition, it is one of the most expensive complications of ASD surgery. Risk factors contributing to pseudarthrosis in ASD have been described; however, a preoperative model predicting the development of pseudarthrosis does not exist. The goal of this study was to create a preoperative predictive model for pseudarthrosis based on demographic, radiographic, and surgical factors.METHODSA retrospective review of a prospectively maintained, multicenter ASD database was conducted. Study inclusion criteria consisted of adult patients (age ≥ 18 years) with spinal deformity and surgery for the ASD. From among 82 variables assessed, 21 were used for model building after applying collinearity testing, redundancy, and univariable predictor importance ≥ 0.90. Variables included demographic data along with comorbidities, modifiable surgical variables, baseline coronal and sagittal radiographic parameters, and baseline scores for health-related quality of life measures. Patients groups were determined according to their Lenke radiographic fusion type at the 2-year follow-up: bilateral or unilateral fusion (union) or pseudarthrosis (nonunion). A decision tree was constructed, and internal validation was accomplished via bootstrapped training and testing data sets. Accuracy and the area under the receiver operating characteristic curve (AUC) were calculated to evaluate the model.RESULTSA total of 336 patients were included in the study (nonunion: 105, union: 231). The model was 91.3% accurate with an AUC of 0.94. From 82 initial variables, the top 21 covered a wide range of areas including preoperative alignment, comorbidities, patient demographics, and surgical use of graft material.CONCLUSIONSA model for predicting the development of pseudarthrosis at the 2-year follow-up was successfully created. This model is the first of its kind for complex predictive analytics in the development of pseudarthrosis for patients with ASD undergoing surgical correction and can aid in clinical decision-making for potential preventative strategies.

Three-column osteotomy for correction of cervical and cervicothoracic deformities: alignment changes and early complications in a multicenter prospective series of 23 patients.

PURPOSE: Three-column osteotomy (3CO), including pedicle subtraction osteotomy (PSO) and vertebral column resection (VCR), can provide powerful alignment correction for adult cervical deformity (ACD). Our objective was to assess alignment changes and early complications associated with 3CO for ACD. METHODS: ACD patients treated with 3CO with minimum 90-day follow-up were identified from a prospectively collected multicenter ACD database. Complications within 90-days of surgery and pre- and postoperative radiographs were collected. RESULTS: All 23 ACD patients treated with 3CO (14 PSO/9 VCR) had minimum 90-day follow-up (mean age 62.3 years, previous cervical/cervicothoracic instrumentation in 52.2% and thoracic/thoracolumbar instrumentation in 47.8%). The primary diagnosis was kyphosis in 91.3% and coronal deformity in 8.7%. The mean number of fusion levels was 12 (range 6-18). The most common 3CO levels were T1 (39.1%), T2 (30.4%) and T3 (21.7%). Eighteen (12 major/6 minor) complications affected 13 (56.5%) patients. The most common complications were neurologic deficit (17.4%), wound infection (8.7%), distal junctional kyphosis (DJK 8.7%), and cardiorespiratory failure (8.7%). Three (13.0%) patients required re-operation within 90-days (1 each for nerve root motor deficit, DJK, and implant pain/prominence). Cervical alignment improved significantly following 3CO, including cervical lordosis (-2.8° to -12.9°, p = 0.036), C2-7 sagittal vertical axis (64.6-42.3 mm, p < 0.001), and T1 slope minus cervical lordosis (46.4°-27.0°, p < 0.001). CONCLUSIONS: Among 23 ACD patients treated with 3CO, cervical alignment improved significantly following surgery. Thirteen (56.5%) patients had at least one complication. The most common complications were neurologic deficit, infection, DJK, and cardiorespiratory failure.

Potential of predictive computer models for preoperative patient selection to enhance overall quality-adjusted life years gained at 2-year follow-up: a simulation in 234 patients with adult spinal deformity.

OBJECTIVE Patients with adult spinal deformity (ASD) experience significant quality of life improvements after surgery. Treatment, however, is expensive and complication rates are high. Predictive analytics has the potential to use many variables to make accurate predictions in large data sets. A validated minimum clinically important difference (MCID) model has the potential to assist in patient selection, thereby improving outcomes and, potentially, cost-effectiveness. METHODS The present study was a retrospective analysis of a multiinstitutional database of patients with ASD. Inclusion criteria were as follows: age ≥ 18 years, radiographic evidence of ASD, 2-year follow-up, and preoperative Oswestry Disability Index (ODI) > 15. Forty-six variables were used for model training: demographic data, radiographic parameters, surgical variables, and results on the health-related quality of life questionnaire. Patients were grouped as reaching a 2-year ODI MCID (+MCID) or not (-MCID). An ensemble of 5 different bootstrapped decision trees was constructed using the C5.0 algorithm. Internal validation was performed via 70:30 data split for training/testing. Model accuracy and area under the curve (AUC) were calculated. The mean quality-adjusted life years (QALYs) and QALYs gained at 2 years were calculated and discounted at 3.5% per year. The QALYs were compared between patients in the +MCID and -MCID groups. RESULTS A total of 234 patients met inclusion criteria (+MCID 129, -MCID 105). Sixty-nine patients (29.5%) were included for model testing. Predicted versus actual results were 50 versus 40 for +MCID and 19 versus 29 for -MCID (i.e., 10 patients were misclassified). Model accuracy was 85.5%, with 0.96 AUC. Predicted results showed that patients in the +MCID group had significantly greater 2-year mean QALYs (p = 0.0057) and QALYs gained (p = 0.0002). CONCLUSIONS A successful model with 85.5% accuracy and 0.96 AUC was constructed to predict which patients would reach ODI MCID. The patients in the +MCID group had significantly higher mean 2-year QALYs and QALYs gained. This study provides proof of concept for using predictive modeling techniques to optimize patient selection in complex spine surgery.

An assessment of frailty as a tool for risk stratification in adult spinal deformity surgery.

OBJECTIVE The goal of this study was to analyze the value of an adult spinal deformity frailty index (ASD-FI) in preoperative risk stratification. Preoperative risk assessment is imperative before procedures known to have high complication rates, such as ASD surgery. Frailty has been associated with risk of complications in trauma surgery, and preoperative frailty assessments could improve the accuracy of risk stratification by providing a comprehensive analysis of patient factors that contribute to an increased risk of complications. METHODS Using 40 variables, the authors calculated frailty scores with a validated method for 417 patients (enrolled between 2010 and 2014) with a minimum 2-year follow-up in an ASD database. On the basis of these scores, the authors categorized patients as not frail (NF) (< 0.3 points), frail (0.3-0.5 points), or severely frail (SF) (> 0.5 points). The correlation between frailty category and incidence of complications was analyzed. RESULTS The overall mean ASD-FI score was 0.33 (range 0.0-0.8). Compared with NF patients (n = 183), frail patients (n = 158) and SF patients (n = 109) had longer mean hospital stays (1.2 and 1.6 times longer, respectively; p < 0.001). The adjusted odds of experiencing a major intraoperative or postoperative complication were higher for frail patients (OR 2.8) and SF patients ( 4.1) compared with NF patients (p < 0.01). For frail and SF patients, respectively, the adjusted odds of developing proximal junctional kyphosis (OR 2.8 and 3.1) were higher than those for NF patients. The SF patients had higher odds of developing pseudarthrosis (OR 13.0), deep wound infection (OR 8.0), and wound dehiscence (OR 13.4) than NF patients (p < 0.05), and they had 2.1 times greater odds of reoperation (p < 0.05). CONCLUSIONS Greater patient frailty, as measured by the ASD-FI, was associated with worse outcome in many common quality and value metrics, including greater risk of major complications, proximal junctional kyphosis, pseudarthrosis, deep wound infection, wound dehiscence, reoperation, and longer hospital stay.

Contribution of Antibody Hydrodynamic Size to Vitreal Clearance Revealed through Rabbit Studies Using a Species-Matched Fab.

We have developed a tool Fab fragment of a rabbit monoclonal antibody that is useful for early evaluation in rabbit models of technologies for long acting delivery (LAD) of proteins to the eye. Using this Fab we show that vitreal clearance can be slowed through increased hydrodynamic size. Fab (G10rabFab) and Fab' (G10rabFab') fragments of a rabbit monoclonal antibody (G10rabIgG) were expressed in Chinese hamster ovary (CHO) cells and purified using antigen-based affinity chromatography. G10rabFab retains antigen-binding upon thermal stress (37 °C) for 8 weeks in phosphate-buffered saline (PBS) and can be detected in rabbit tissues using an antigen-based ELISA. Hydrodynamic radius, measured using quasi-elastic light scattering (QELS), was increased through site-specific modification of the G10rabFab' free cysteine with linear methoxy-polyethylene glycol(PEG)-maleimide of 20000 or 40000 molecular weight. Pharmacokinetic studies upon intravitreal dosing in New Zealand white rabbits were conducted on the G10rabFab and PEGylated G10rabFab'. Results of single and multidose pharmacokinetic experiments yield reproducible results and a vitreal half-life for G10rabFab of 3.2 days. Clearance from the eye is slowed through increased hydrodynamic size, with vitreal half-life showing a linear dependence on hydrodynamic radius (RH). A linear dependence of vitreal half-life on RH suggests that molecule diffusivity makes an important contribution to vitreal clearance. A method for prediction of vitreal half-life from RH measurements is proposed.

A comparative analysis of the prevalence and characteristics of cervical malalignment in adults presenting with thoracolumbar spine deformity based on variations in treatment approach over 2 years.

PURPOSE: Characteristics specific to cervical deformity (CD) concomitant with adult thoracolumbar deformity (TLD) remains uncertain, particularly regarding treatment. This study identifies cervical malalignment prevalence following surgical and conservative TLD treatment through 2 years. METHODS: Retrospective analysis of a prospective, multicenter adult spinal deformity (ASD) database. CD was defined in operative and non-operative ASD patients according to the following criteria: T1 Slope minus Cervical Lordosis (T1S-CL) ≥20°, C2-C7 Cervical Sagittal Vertical Axis (cSVA) ≥40 mm, C2-C7 kyphosis >10°. Differences in rates, demographics, health-related quality of life (HRQoL) scores for Oswestry Disability Index (ODI) and Scoliosis Research Society Questionnaire (SRS-22r), and radiographic variables were assessed between treatment groups (Op vs. Non-Op) and follow-up periods (baseline, 1-year, 2-year). RESULTS: Three hundred and nineteen (200 Op, 199 Non-Op) ASD patients were analyzed. Op patients' CD rates at 1 and 2 years were 78.9, and 63.0 %, respectively. Non-Op CD rates were 21.1 and 37.0 % at 1 and 2 years, respectively. T1S-CL mismatch and cSVA malalignment characterized Op CD at 1 and 2 years (p < 0.05). Op and Non-Op CD groups had similar cervical/global alignment at 1 year (p > 0.05 for all), but at 2 years, Op CD patients had worse thoracic kyphosis (TK), T1S-CL, CL, cSVA, C2-T3 SVA, and global SVA compared to Non-Ops (p < 0.05). Op CD patients had worse ODI, and SRS Activity at 1 and 2 years post-operative (p < 0.05), but had greater 2-year SRS Satisfaction scores (p = 0.019). CONCLUSIONS: In the first study to compare cervical malalignment at extended follow-up between ASD treatments, CD rates rose overall through 2 years. TLD surgery, resulting in higher CD rates characterized by T1S-CL and cSVA malalignment, produced poorer HRQoL. This information can aid in treatment method decision-making when cervical deformity is present concomitant with TLD.

Recovery following adult spinal deformity surgery: the effect of complications and reoperation in 149 patients with 2-year follow-up.

PURPOSE: To identify the effect of complications and reoperation on the recovery process following adult spinal deformity (ASD) surgery by examining health-related quality of life (HRQOL) measures over time via an integrated health state analysis (IHS). METHODS: A retrospective review of a multicenter, prospective ASD database was conducted. Complication number, type, and need for reoperation (REOP) or not (NOREOP) were recorded. Patients were stratified as having no complication (NOCOMP), any complication (COMP), only minor complications (MINOR) and any major complications (MAJOR). HRQOL measures included Oswestry Disability Index (ODI), Short Form-36 (SF-36), and Scoliosis Research Society-22 (SRS22) at baseline, 6 weeks, 1 and 2 years postoperatively. All HRQOL scores were normalized to each patient's baseline scores and an IHS was then calculated. RESULTS: 149 patients were included. COMP, MINOR, and MAJOR had significantly lower normalized SRS mental scores at 1 and 2 years than NOCOMP (p < 0.05). REOP had significantly worse normalized 1 and 2 year mental component score (MCS), SRS mental, and total score than NOCOMP (p < 0.05). COMP, MINOR, and MAJOR all had significantly lower SRS mental IHSs than NOCOMP (p < 0.05). REOP had significantly lower IHSs for MCS and SRS satisfaction than NOREOP (p < 0.05). REOP had a significantly lower MCS and SRS mental IHS than NOCOMP (p < 0.05). CONCLUSION: An IHS analysis suggests there was a significantly protracted mental recovery phase associated with patients that had at least one complication, as well as either a minor and major complication. The addition of a reoperation also adversely affected the mental recovery as well as overall satisfaction.

Patients with spinal deformity over the age of 75: a retrospective analysis of operative versus non-operative management.

PURPOSE: The goal of the present study was to compare the outcomes of operative and non-operative patients with adult spinal deformity (ASD) over 75 years of age. METHODS: A retrospective review of a multicenter prospective adult spinal deformity database was conducted examining patients with ASD over the age of 75 years. Demographics, comorbidities, operation-related variables, complications, radiographs, and Health-related quality of life (HRQOL) measures collected included Oswestry Disability Index, Short Form-36, and Scoliosis Research Society-22 preoperatively, and at 1 and 2 years later. Minimum clinically important difference (MCID) was calculated and also compared. RESULTS: 27 patients (12 operative, 15 non-operative) were studied. There were no significant differences (p > 0.05) between operative and non-operative patients for age, body mass-index, and comorbidities, but operative patients had worse baseline HRQOL than non-operative patients. Operative patients had a significant improvement in radiographic parameters in 2-year HRQOL, whereas non-operative patients did not (p > 0.05). Operative patients were significantly more likely to reach MCID (range 41.7-81.8 vs. 0-33.3 %, p < 0.05). In the surgical group, 9 (75 %) patients had at least 1 complication (24 total complications). CONCLUSIONS: In the largest series to date comparing operative and non-operative management of adult spinal deformity in elderly patients greater than 75 years of age, reconstructive surgery provides significant improvements in pain and disability over a 2-year period. Furthermore, operative patients were more likely to reach MCID than non-operative patients. When counseling elderly patients with ASD, such data may be helpful in the decision-making process regarding treatment.

Maintenance of radiographic correction at 2 years following lumbar pedicle subtraction osteotomy is superior with upper thoracic compared with thoracolumbar junction upper instrumented vertebra.

PURPOSE: The goal of this study was to characterize the spino-pelvic realignment and the maintenance of that realignment by the upper-most instrumented vertebra (UIV) for adult deformity spinal (ASD) patients treated with lumbar pedicle subtraction osteotomy (PSO). METHODS: ASD patients were divided by UIV, classified as upper thoracic (UT: T1-T6) or Thoracolumbar (TL: T9-L1). Complications were recorded and radiographic parameters included thoracic kyphosis (TK, T2-T12), lumbar lordosis (LL, L1-S1), sagittal vertical axis (SVA), pelvic tilt, and the mismatch between pelvic incidence and LL. Patients were also classified by the Scoliosis Research Society (SRS)-Schwab modifier grades. Changes in radiographic parameters and SRS-Schwab grades were evaluated between the two groups. Additional analyses were performed on patients with pre-operative SVA ≥ 15 cm. RESULTS: 165 patients were included (UT: 81 and TL: 84); 124 women, 41 men, with average age 59.9 ± 11.1 years (range 25-81). UT had a lower percentage of patients above the radiographic thresholds for disability than TL. UT had a significantly higher percentage of patients that improved in SRS-Schwab global alignment grade than the TL group at 2 years. Within the patients with pre-operative SVA ≥ 15 cm, TL developed significantly increased SVA and had a significantly higher percentage of patients above the SVA threshold at 3 months, and 1 and 2 years than UT. CONCLUSIONS: Patients undergoing a single-level PSO for ASD who have fixation extending to the UT region (T1-T6) are more likely to maintain sagittal spino-pelvic alignment, lower overall revision rates and revision rate for proximal junctional kyphosis than those with fixation terminating in the TL region (T9-L1).

Anatomy and biomechanics of the craniovertebral junction.

The craniovertebral junction (CVJ) has unique anatomical structures that separate it from the subaxial cervical spine. In addition to housing vital neural and vascular structures, the majority of cranial flexion, extension, and axial rotation is accomplished at the CVJ. A complex combination of osseous and ligamentous supports allow for stability despite a large degree of motion. An understanding of anatomy and biomechanics is essential to effectively evaluate and address the various pathological processes that may affect this region. Therefore, the authors present an up-to-date narrative review of CVJ anatomy, normal and pathological biomechanics, and fixation techniques.