Return to Sporting Activities Following Long Fusions to the Pelvis in Adult Spinal Deformity.

BACKGROUND CONTEXT: Returning to recreational sporting activities after adult spinal deformity (ASD) correction may significantly impact the patient's perceived quality of life. PURPOSE: This study sought to characterize participation in sporting activities before and after ASD surgery, and to identify factors associated with impaired return to sports. STUDY DESIGN: Cross-sectional survey and retrospective review of prospectively collected data. PATIENT SAMPLE: Patients who underwent posterior-only thoracolumbar ASD surgery between 2016-2021 with ≥1 year follow-up and ≥3 levels of fusion to the pelvis were included. OUTCOME MEASURES: Preoperative and postoperative participation in sports, timing of return to these activities, and reasons for limited sports participation postoperatively were assessed. METHODS: A survey was used to evaluate outcome measures. Differences in demographic, surgical, and perioperative variables between patients who reported improved, unchanged, or worsened activity tolerance were evaluated. RESULTS: Ninety-five patients were included (mean age: 64.3±10.1 years; BMI: 27.3±6.1 kg/m2; median levels fused: 7). The survey was completed at an average of 43.5 ± 15.9 months after surgery. Sixty-eight (72%) patients participated in sports preoperatively. The most common sports were swimming (n=33, 34.7%), yoga (n=23, 24.2%), weightlifting (n=20, 21.1%), elliptical (n=19, 20.0%), and golf (n=11, 11.6%). Fifty-seven (83.8%) returned to at least one sport postoperatively, most commonly 6-12 months after surgery (45%). Elliptical had the highest rate of equal or improved participation (53%). Patients generally returned below their preoperative level to all other sports. Reasons for reduced sporting activities included physical limitation (51.4%), fear (20.0%), pain (17.1%), and surgeon advice (8.6%). There were no differences in the demographic, surgical, or perioperative characteristics between those who returned to sports at the same or better level compared with those who returned at a lower level. CONCLUSIONS: 84% of patients successfully resumed sporting activities after undergoing fusion to the sacrum/pelvis for ASD. However, this return is typically at a lower level of participation than their preoperative participation, particularly in higher demand sports. Understanding trends in sporting activity may be valuable for counseling patients and setting expectations.

Post-Operative Hyperextension Bracing Has the Potential to Reduce Proximal Junctional Kyphosis: A Propensity Matched Analysis of Braced versus Non-braced Cohorts.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Determine effects of bracing on proximal junctional kyphosis (PJK) after adult deformity correction. METHODS: Patients were identified from a single-surgeon dataset of posterior-only fusions for ASD (pelvis to UIV of T9-12) with a minimum of 1-year follow up. Starting in 2021, all lower thoracic fusions were braced using a hyperextension brace. Patients wore the brace at all times (unless in bed) for the first 6 weeks after surgery. A 1:1 propensity-match was performed based on age, number of levels, 3 column osteotomies, and magnitude of correction to identify a comparative non-braced cohort. RESULTS: 141 patients (113 non-brace, 28 brace) were evaluated. After matching, 56 patients were identified to form similar cohorts. Non-matched and matched groups had no statistically significant differences in demographics, comorbid conditions, surgical characteristics (except shorter operative time and lower EBL in the braced group), and preoperative radiographic parameters. For the overall cohort, the change in proximal junctional angle at 1-year was higher in the non-braced group (7.6° vs 8.1°, P = .047), and non-braced patients had a higher incidence of PJK at 1-year in both the overall cohort (36% vs 14%, P = .045) and matched cohort (43% vs 14%, P = .038). There was no difference in proximal junctional failure between groups. CONCLUSION: This pilot study shows that our protocol for extension bracing may reduce rates of PJK. These findings can form the basis for future multi-center trials examining the effect of extension bracing on junctional complications.

Decisional regret following corrective adult spinal deformity surgery: a single institution study of incidence and risk factors.

PURPOSE: To assess the characteristics and risk factors for decisional regret following corrective adult spinal deformity (ASD) surgery at our hospital. METHODS: This is a retrospective cohort study of a single-surgeon ASD database. Adult patients (> 40 years) who underwent ASD surgery from May 2016 to December 2020 with minimum 2-year follow-up were included (posterior-only, ≥ 4 levels fused to the pelvis) (n = 120). Ottawa decision regret questionnaires, a validated and reliable 5-item Likert scale, were sent to patients postoperatively. Regret scores were defined as (1) low regret: 0-39 (2) medium to high regret: 40-100. Risk factors for medium or high decisional regret were identified using multivariate models. RESULTS: Ninety patients were successfully contacted and 77 patients consented to participate. Nonparticipants were older, had a higher incidence of anxiety, and higher ASA class. There were 7 patients that reported medium or high decisional regret (9%). Ninety percentage of patients believed that surgery was the right decision, 86% believed that surgery was a wise choice, and 87% would do it again. 8% of patients regretted the surgery and 14% believed that surgery did them harm. 88% of patients felt better after surgery. On multivariate analysis, revision fusion surgery was independently associated with an increased risk of medium or high decisional regret (adjusted odds ratio: 6.000, 95% confidence interval: 1.074-33.534, p = 0.041). CONCLUSIONS: At our institution, we found a 9% incidence of decisional regret. Revision fusion was associated with increased decisional regret. Estimates for decisional regret should be based on single-institution experiences given differences in patient populations.

Why Didn't You Walk Yesterday? Factors Associated With Slow Early Recovery After Adult Spinal Deformity Surgery.

STUDY DESIGN: This is a retrospective case-control study. OBJECTIVES: The objectives of this study are to identify (1) risk factors for delayed ambulation following adult spinal deformity (ASD) surgery and (2) complications associated with delayed ambulation. METHODS: One-hundred and ninety-one patients with ASD who underwent posterior-only fusion (≥5 levels, LIV pelvis) were reviewed. Patients who ambulated with physical therapy (PT) on POD2 or later (LateAmb, n = 49) were propensity matched 1:1 to patients who ambulated on POD0-1 (NmlAmb, n = 49) based on the extent of fusion and surgical invasiveness score (ASD-S). Risk factors, as well as inpatient medical complications were compared. Logistic regressions were used to identify risk factors for late ambulation. RESULTS: Of the patients who did not ambulate on POD0-1, 32% declined participation secondary to pain or dizziness/fatigue, while 68% were restricted from participation by PT/nursing due to fatigue, inability to follow commands, nausea/dizziness, pain, or hypotension. Logistic regression showed that intraoperative estimated blood loss (EBL) >2L (OR = 5.57 [1.51-20.55], P = .010) was independently associated with an increased risk of delayed ambulation, with a 1.25 times higher risk for every 250 mL increase in EBL (P = .014). Modified 5-Item Frailty Index (mFI-5) was also independently associated with delayed ambulation (OR = 2.53 [1.14-5.63], P = .023). LateAmb demonstrated a higher hospital LOS (8.4 ± 4.0 vs 6.2 ± 2.6, P < .001). The LateAmb group trended toward an increase in medical complications on POD3+ (14.3% vs 26.5%, P = .210). CONCLUSIONS: EBL demonstrates a dose-response relationship with risk for delayed ambulation. Delayed ambulation increases LOS and may impact medical complications.

The Association of Lumbar Plexus Lengthening with Neurologic Deficit After Adult Spinal Deformity Surgery.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: This study aimed to evaluate the association between nerve lengthening after adult deformity correction and motor deficits dervied from the upper lumbar plexus or femoral nerve. SUMMARY OF BACKGROUND DATA: Adult spinal deformity (ASD) surgery is associated with high rates of neurological deficits. Certain postoperative deficits may be related to lengthening of the upper lumbar plexus (ULP) and/or femoral nerve (FN) after correction of lumbar deformity. METHODS: Patients with ASD who underwent posterior-only corrective surgery from the sacrum to L3 or above were included. The length of each lumbar nerve root (NR) was calculated geometrically using the distance from the foramen to the midpoint between the anterosuperior iliac crest and pubic symphysis on AP and lateral radiographs. The mean lengths of the L1-3 and L2-4 NRs were used to define the lengths of the ULP and FN, respectively. Pre- to postoperative changes in nerve length were calculated. Neurological examination was performed at discharge. Proximal weakness (PW) was defined as the presence of weakness compared to baseline in either hip flexors or knee extensors. Multiple linear regression analysis was used for estimating the postoperative lengthening according to the magnitude of preoperative curvature and postoperative correction angles. RESULTS: A total of 202 sides were analyzed in 101 patients, and PW was present on 15 (7.4%) sides in 10 patients. Excluding the 10 cases with three-column osteotomies, those with PW had a significantly higher rate of pure sagittal deformity (P<.001) and greater nerve lengthening than those without PW (ULP 24 vs 15 mm, P=0.02; FN 18 vs 11 mm, P=0.05). No patient had advanced imaging showing neural compression, and complete recovery of PW occurred in 8 patients at 1-year follow-up. CONCLUSIONS: After ASD surgery, lengthening of the ULP was associated with PW. In preoperative planning, surgeons must consider how the type of correction may influence the risk for nerve lengthening, which may contribute to postoperative neurologic deficit. LEVEL OF EVIDENCE: 3.

Cellular senescence and the blood-brain barrier: Implications for aging and age-related diseases.

The blood-brain barrier (BBB) is a critical physiochemical interface that regulates communication between the brain and blood. It is comprised of brain endothelial cells which regulate the BBB's barrier and interface properties and is surrounded by supportive brain cell types including pericytes and astrocytes. Recent reports have suggested that the BBB undergoes dysfunction during normative aging and in disease. In this review, we consider the effect of cellular senescence, one of the nine hallmarks of aging, on the BBB. We first characterize known normative age-related changes at the BBB, and then evaluate changes in neurodegenerative diseases, with an emphasis on if/how cellular senescence is influencing these changes. We then discuss what insight has been gained from in vitro and in vivo studies of cellular senescence at the BBB. Finally, we evaluate mechanisms by which cellular senescence in peripheral pathologies can indirectly or directly affect BBB function.

Physical associations of microglia and the vascular blood-brain barrier and their importance in development, health, and disease.

Brain endothelial cells (BEC) of the vascular blood-brain barrier (BBB) interact with many different cell types in the brain, including microglia, the brain's resident immune cells. Physical associations of microglia with the BBB and the importance of these interactions in health and disease are an emerging area of study and likely involved in neuroimmune communication. In this mini-review, we consider how microglia and the BBB are intrinsically linked in the developing brain, discuss possible mechanisms that attract microglia to the vasculature in healthy physiological conditions, and examine the known microglial-vascular associated changes in systemic infection and various disease states. Our findings shed light on the complexities of microglial-vascular interactions and highlight the contributions of microglia to the functions of the neurovascular unit.

Amyloid Beta Pathology Exacerbates Weight Loss and Brain Cytokine Responses following Low-Dose Lipopolysaccharide in Aged Female Tg2576 Mice.

Systemic inflammation has been implicated in the progression of Alzheimer's disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aß) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16-18-month-old female Tg2576 (Tg) mice, which overproduce human Aß and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aß, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1ß, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1ß/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aß pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aß. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aß pathology could contribute to poor outcomes following a systemic inflammatory insult.

Interactions of SARS-CoV-2 with the Blood-Brain Barrier.

Emerging data indicate that neurological complications occur as a consequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The blood-brain barrier (BBB) is a critical interface that regulates entry of circulating molecules into the CNS, and is regulated by signals that arise from the brain and blood compartments. In this review, we discuss mechanisms by which SARS-CoV-2 interactions with the BBB may contribute to neurological dysfunction associated with coronavirus disease of 2019 (COVID-19), which is caused by SARS-CoV-2. We consider aspects of peripheral disease, such as hypoxia and systemic inflammatory response syndrome/cytokine storm, as well as CNS infection and mechanisms of viral entry into the brain. We also discuss the contribution of risk factors for developing severe COVID-19 to BBB dysfunction that could increase viral entry or otherwise damage the brain.

Extending the Calpain-Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma.

The calpain-cathepsin hypothesis posits a key role for elevated calpain-1 and cathepsin-B activity in the neurodegeneration underlying neurotrauma and multiple disorders including Alzheimer's disease (AD). AD clinical trials were recently halted on alicapistat, a selective calpain-1 inhibitor, because of insufficient exposure of neurons to the drug. In contrast to neuroprotection, the ability of calpain-1 and cathepsin-B inhibitors to protect the blood-brain barrier (BBB), is understudied. Since cerebrovascular dysfunction underlies vascular dementia, is caused by ischemic stroke, and is emerging as an early feature in the progression of AD, we studied protection of brain endothelial cells (BECs) by selective and nonselective calpain-1 and cathepsin-B inhibitors. We show these inhibitors protect both neurons and murine BECs from ischemia-reperfusion injury. Cultures of primary BECs from ALDH2 -/- mice that manifest enhanced oxidative stress were sensitive to ischemia, leading to reduced cell viability and loss of tight junction proteins; this damage was rescued by calpain-1 and cathepsin-B inhibitors. In ALDH2 -/- mice 24 h after mild traumatic brain injury (mTBI), BBB damage was reflected by significantly increased fluorescein extravasation and perturbation of tight junction proteins, eNOS, MMP-9, and GFAP. Both calpain and cathepsin-B inhibitors alleviated BBB dysfunction caused by mTBI. No clear advantage was shown by selective versus nonselective calpain inhibitors in these studies. The lack of recognition of the ability of calpain inhibitors to protect the BBB may have led to the premature abandonment of this therapeutic approach in AD clinical trials and requires further mechanistic studies of cerebrovascular protection by calpain-1 inhibitors.

Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.

Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC50 =78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.

Interaction of oxidative stress and neurotrauma in ALDH2-/- mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury.

Oxidative stress induced by lipid peroxidation products (LPP) accompanies aging and has been hypothesized to exacerbate the secondary cascade in traumatic brain injury (TBI). Increased oxidative stress is a contributor to loss of neural reserve that defines the ability to maintain healthy cognitive function despite the accumulation of neuropathology. ALDH2-/- mice are unable to clear aldehyde LPP by mitochondrial aldehyde dehydrogenase-2 (Aldh2) detoxification and provide a model to study mild TBI (mTBI), therapeutic interventions, and underlying mechanisms. The ALDH2-/- mouse model presents with elevated LPP-mediated protein modification, lowered levels of PSD-95, PGC1-α, and SOD-1, and mild cognitive deficits from 4 months of age. LPP scavengers are neuroprotective in vitro and in ALDH2-/- mice restore cognitive performance. A single-hit, closed skull mTBI failed to elicit significant effects in WT mice; however, ALDH2-/- mice showed a significant inflammatory cytokine surge in the ipsilateral hemisphere 24 h post-mTBI, and increased GFAP cleavage, a biomarker for TBI. Known neuroprotective agents, were able to reverse the effects of mTBI. This new preclinical model of mTBI, incorporating significant perturbations in behavior, inflammation, and clinically relevant biomarkers, allows mechanistic study of the interaction of LPP and neurotrauma in loss of neural reserve.

Correction to Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors.

[This corrects the article DOI: 10.1021/acsmedchemlett.7b00126.].

Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective Inhibitors.

Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biological evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based 3g and 3n exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, respectively. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 µM. The cytotoxicity of 3g and 3n was evaluated in neuroblastoma cell lines, and 3n displayed concentration-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of 3g and 3n was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.

Variation of the aryl substituent on the piperazine ring within the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold unveils potent, non-competitive inhibitors of the inflammatory caspases.

The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar Ki values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases.