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Abstract Background The herpes simplex virus type 1 (HSV-1) ICP0 protein is an E3 ubiquitin ligase, which is encoded within the HSV-1 latency-associated locus. When ICP0 is not synthesized, the HSV-1 genome is acutely susceptible to cellular repression. Reciprocally, when ICP0 is synthesized, viral replication is efficiently initiated from virions or latent HSV-1 genomes. The current study was initiated to determine if ICP0's putative role as a viral interferon (IFN) antagonist may be relevant to the process by which ICP0 influences the balance between productive replication versus cellular repression of HSV-1. Results Wild-type (ICP0+) strains of HSV-1 produced lethal infections in scid or rag2-/- mice. The replication of ICP0- null viruses was rapidly repressed by the innate host response of scid or rag2-/- mice, and the infected animals remained healthy for months. In contrast, rag2-/- mice that lacked the IFN-α/β receptor (rag2-/- ifnar-/-) or Stat 1 (rag2-/- stat1-/-) failed to repress ICP0- viral replication, resulting in uncontrolled viral spread and death. Thus, the replication of ICP0- viruses is potently repressed in vivo by an innate immune response that is dependent on the IFN-α/β receptor and the downstream transcription factor, Stat 1. Conclusion ICP0's function as a viral IFN antagonist is necessary in vivo to prevent an innate, Stat 1-dependent host response from rapidly repressing productive HSV-1 replication. This antagonistic relationship between ICP0 and the host IFN response may be relevant in regulating whether the HSV-1 genome is expressed, or silenced, in virus-infected cells in vivo. These results may also be clinically relevant. IFN-sensitive ICP0- viruses are avirulent, establish long-term latent infections, and induce an adaptive immune response that is highly protective against lethal challenge with HSV-1. Therefore, ICP0- viruses appear to possess the desired safety and efficacy profile of a live vaccine against herpetic disease.

Abstract Background Although oral replacement with high doses of vitamin B12 is both effective and safe for the treatment of B12 deficiency, little is known about patients' views concerning the acceptability and effectiveness of oral B12. We investigated patient perspectives on switching from injection to oral B12 therapy. Methods This study involved a quantitative arm using questionnaires and a qualitative arm using semi-structured interviews, both to assess patient views on injection and oral therapy. Patients were also offered a six-month trial of oral B12 therapy. One hundred and thirty-three patients who receive regular B12 injections were included from three family practice units (two hospital-based academic clinics and one community health centre clinic) in Toronto. Results Seventy-three percent (63/86) of respondents were willing to try oral B12. In a multivariate analysis, patient factors associated with a "willingness to switch" to oral B12 included being able to get to the clinic in less than 30 minutes (OR 9.3, 95% CI 2.2–40.0), and believing that frequent visits to the health care provider (OR 5.4, 95% CI 1.1–26.6) or the increased costs to the health care system (OR 16.7, 95% CI 1.5–184.2) were disadvantages of injection B12. Fifty-five patients attempted oral therapy and 52 patients returned the final questionnaire. Of those who tried oral therapy, 76% (39/51) were satisfied and 71% (39/55) wished to permanently switch. Factors associated with permanently switching to oral therapy included believing that the frequent visits to the health care provider (OR 35.4, 95% CI 2.9–432.7) and travel/parking costs (OR 8.7, 95% CI 1.2–65.3) were disadvantages of injection B12. Interview participants consistently cited convenience as an advantage of oral therapy. Conclusion Switching patients from injection to oral B12 is both feasible and acceptable to patients. Oral B12 supplementation is well received largely due to increased convenience. Clinicians should offer oral B12 therapy to their patients who are currently receiving injections, and newly diagnosed B12-deficient patients who can tolerate and are compliant with oral medications should be offered oral supplementation.

Acute respiratory distress syndrome (ARDS) is a complication of pulmonary disease that produces life-threatening hypoxaemia. Despite ventilation and hyperoxic therapies, undetected hypoxia can manifest in capillary beds leading to multi-organ failure. Ox66™ is an ingestible, solid-state form of oxygen designed to supplement oxygen deficits. Twenty-four anaesthetized rats underwent a two-hit model of respiratory distress (ARDS), where a single dose (5 mg/kg) of lipopolysaccharide (LPS) was given intratracheally, and then the respiratory tidal volume was reduced by 40%. After 60 min, animals were randomized to receive Ox66™, or normal saline (NS; vehicle control) via gavage or supplemental inspired oxygen (40% FiO 2 ). A second gavage was administered at 120 min. Cardiovascular function and blood oximetry/chemistry were measured alongside the peripheral spinotrapezius muscle's interstitial oxygenation (P ISF O 2 ). ARDS reduced mean arterial pressure (MAP) and P ISF O 2 compared to baseline (BL) for all treatment groups. Treatment with Ox66 or NS did not improve MAP, but 40% FiO 2 caused a rapid return to BL. P ISF O 2 improved after treatment with Ox66 ™ and 40% FiO 2 and remained elevated for both groups against NS until study conclusion. Both oxygen treatments also suppressed the inflammatory response to LPS, suggesting that Ox66 ™ can deliver therapeutically-impactful levels of oxygen in situations of pulmonary dysfunction.

Objective: Robot-assisted (RA) technology is becoming more widely integrated and accepted in spine surgery. The authors sought to evaluate operative and patient-reported outcomes (PROs) in RA versus fluoroscopy-assisted (FA) pedicle screw placement during minimally invasive surgery (MIS) transforaminal lumbar interbody fusion (TLIF)., Methods: The authors retrospectively studied elective patients who underwent single- or multilevel MIS TLIF for degenerative indication using FA versus RA pedicle screw placement. Patients were selected from September 2021 to May 2023 at a single institution with multiple surgeons whose practice consists of primarily MIS. Outcomes included fluoroscopy dosage per screw, operative time per screw, anesthesia time per screw, estimated blood loss (EBL), screw revision rate, inpatient surgical complications, and minimal clinically important difference (MCID) of Oswestry Disability Index (ODI) and numeric rating scale (NRS) scores at the 6- and 12-month follow-ups. Comparability of groups was analyzed by univariate analysis. Multivariable analysis modeling fluoroscopy time per screw was performed, adjusting for confounders., Results: One hundred eighty-three patients (n = 133 in the FA group vs 50 in the RA group) were included. Patients in the RA cohort were significantly younger than those in the FA group (mean age 63.8 ± 11.9 vs 59.8 ± 11.0 years, p = 0.037). A total of 932 pedicle screws were placed (mean 5.1, range 4-8 per patient). The RA cohort demonstrated significantly lower intraoperative fluoroscopy dosage per screw (4.9 ± 7.6 mGy per screw vs 20.3 ± 14.0 mGy per screw, p < 0.001), significantly longer anesthesia time per screw (49.1 ± 12.6 vs 43.6 ± 9.2, p = 0.009), and similar operative time per screw (33.3 vs 30.7 minutes, p = 0.125). The screw revision rate for symptomatic radiculopathy was zero in both groups. Revision surgery requiring screw removal or reposition was performed in 4 total cases (RA group: 1/50 for infection; FA group: 2/133 for infection, 1/133 for foraminotomy). Both groups demonstrated significant improvement in PROs at 6 and 12 months compared with preoperatively. Moreover, both groups achieved MCID at similar rates., Conclusions: When implementing RA technology, one can expect similar perioperative outcomes as FA techniques in addition to significantly lower radiation exposure. Moreover, there is no statistically significant difference in postoperative PROs between RA and FA. Longer anesthesia times may also be encountered, as in this study, which is likely a result of more complex robotic setup and workflow.

Sepsis is a devastating complication of infection and injury that, through widespread endothelial dysfunction, can cause perfusion deficits and multi-organ failure. To address the recognised need for therapeutics targetting the endothelial barrier, a topical formulation (CUR; VASCEPTOR™; Vascarta Inc, Summit, NJ) was developed to transdermally deliver bio-active concentrations of curcumin-an anti-inflammatory and nitric oxide promoter. Male, Sprague Dawley rats were treated daily with lipopolysaccharide (LPS, 10 mg/kg, IP) to induce endotoxemia, and topical applications of Vehicle Control (LPS + VC; N  = 7) or Curcumin (LPS + CUR; N  = 7). A third group received neither LPS nor treatment (No-LPS; N  = 8). After 72 h, animals were surgically prepared for measurements of physiology and endothelial dysfunction in the exteriorised spinotrapezius muscle through the extravasation of 67 kDa TRITC-BSA (albumin) and 500 kDa FITC-dextran (dextran). At 72 h, LPS + VC saw weight loss, and increases to pulse pressure, lactate, pCO 2 , CXCL5 (vs No-LPS) and IL-6 (vs 0 h; p  < 0.05). LPS + CUR was similar to No-LPS, but with hypotension. Phenylephrine response was increased in LPS + CUR. Regarding endothelial function, LPS + CUR albumin and dextran extravasation were significantly reduced versus LPS + VC suggesting that Curcumin mitigated endotoxemic endothelial dysfunction. The speculated mechanisms are nitric oxide modulation of the endothelium and/or an indirect anti-inflammatory effect.

Background: The effect of preoperative symptom duration (PSD) on patient-reported outcomes (PROs) in anterior cervical discectomy and fusion (ACDF) for radiculopathy is unclear., Objective: To determine whether PSD is a predictor for PRO after ACDF for radiculopathy., Methods: The Michigan Spine Surgery Improvement Collaborative registry was queried between March, 2014, and July, 2019, for patients who underwent ACDF without myelopathy and PROs (baseline, 90 days, 1 year, 2 years). PROs were measured by numerical rating scales for neck/arm pain, Patient-Reported Outcomes Measurement Information System Short Form-Physical Function (PROMIS-PF), EuroQol-5D (EQ5D), and North American Spine Society satisfaction. Univariate analyses were used to evaluate the proportion of patients reaching minimal clinically important differences (MCID). PSD was <3 months, 3 month-1 year, or >1 years. Multiple logistic regression models were used to estimate the association between PSD and PRO reaching MCID. The discriminative ability of the model was evaluated by receiver operating characteristic curve., Results: We included 2233 patients who underwent ACDF with PSD <3 months (278, 12.4%), 3 month-1 year (669, 30%), and >1 years (1286, 57.6%). Univariate analyses demonstrated a greater proportion of patients achieving MCID in <3-month cohort for arm numerical rating scales, PROMIS-PF, EQ5D, and North American Spine Society Satisfaction. Multivariable analyses demonstrated using <3 months PSD as a reference, PSD >1 years was associated with decreased odds of achieving MCID for EQ5D (odds ratio 0.5, CI 0.32-0.80, P = .004). Private insurance and increased baseline PRO were associated with significantly higher odds for achieving PROMIS-PF MCID and EQ5D-MCID., Conclusion: Preoperative symptom duration greater than 1 year in patients who underwent ACDF for radiculopathy was associated with worse odds of achieving MCID for multiple PROs., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Study Design: Longitudinal cohort study., Purpose: To determine the effect of change in interspace height on fusion and postoperative neck pain., Overview of Literature: The optimal height of a cervical interbody device (cage) in anterior cervical discectomy and fusion (ACDF) is not well defined. In addition, the effect of interspace distraction on fusion and postoperative neck pain remains unclear., Methods: We retrospectively reviewed the charts of consecutive patients who underwent one- or two-level ACDF using polyetheretherketone cages by multiple surgeons from January 2015 to June 2016. We excluded patients younger than 18 years old, patients who had prior surgery at the same level (s), those with two-stage procedures, and those with less than 3 months of followup. Fusion was determined using the "Song" criteria. Ordinal regression was used to determine predictors of fusion. Patient-reported outcomes (PRO) were analyzed., Results: We identified 323 consecutive patients. Twenty-two patients met the exclusion criteria. A total of 435 operative levels were included in the 301 remaining patients. Interspace fusion did not significantly vary by increasing interspace height with fusion rates between 76.2% and 82.8% at a mean follow-up of 17.9±12.6 months. The effect of an increase in interspace height and neck pain PRO was available for 163 patients who underwent one-level ACDF at a mean follow-up period of 16.2±13.1 months. We found no significant difference in fusion rate or neck pain score with increasing interspace height from 1 to 8 mm. Ordinal regression demonstrated no significant predictors of fusion., Conclusions: Interspace distraction from 1 to 8 mm did not result in significantly different pseudarthrosis rates or postoperative neck pain.

Introduction: Pulmonary dysfunction (PD) and its associated hypoxia present a complication to the care of many service members and can arise intrinsically via comorbidities or extrinsically by infection or combat-related trauma (burn, smoke inhalation, and traumatic acute lung injury). Current supportive treatments (e.g., ventilation and supplemental oxygen) relieve hypoxia but carry a significant risk of further lung injury that drives mortality. Ox66 is a novel, solid-state oxygenating compound capable of delivering oxygen via intravenous infusion., Materials and Methods: Male Sprague Dawley rats (N = 21; 250-300 g) were surgically prepared for cardiovascular monitoring, fluid infusion, mechanical ventilation, and intravital and phosphorescence quenching microscopy (interstitial oxygen tension; PISFO2) of the spinotrapezius muscle. Baselines (BL) were collected under anesthesia and spontaneous respiration. PD was simulated via hypoventilation (50% tidal volume reduction) and was maintained for 3 hours. Groups were randomized to receive Ox66, normal saline (NS; vehicle control), or Sham (no treatment) and were treated immediately following PD onset. Arterial blood samples (65 µL) and intravital images were taken hourly to assess blood gases and chemistry and changes in arteriolar diameter, respectively. Significance was taken at P < .05., Results: PD reduced PISFO2 for all groups; however, by 75 minutes, both NS and Sham were significantly lower than Ox66 and remained so until the end of PD. Serum lactate levels were lowest in the Ox66 group-even decreasing relative to BL-but only significant versus Sham. Furthermore, all Ox66 animals survived the full PD challenge, while one NS and two Sham animals died. No significant vasoconstrictive or vasodilative effect was noted within or between experimental groups., Conclusion: Treatment with intravenous Ox66 improved interstitial oxygenation in the spinotrapezius muscle-a recognized bellwether for systemic capillary function-suggesting an improvement in oxygen delivery. Ox66 offers a novel approach to supplemental oxygenation that bypasses lung injury and dysfunction., (© The Association of Military Surgeons of the United States 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Design: Retrospective analysis of prospectively collected registry data using multivariable analyses of imputed data., Objective: We sought to demonstrate that age would not be associated with complications in patients undergoing anterior cervical discectomy and fusion (ACDF)., Summary of Background Data: Elderly patients (≥70 yrs) undergoing ACDF are considered a higher risk for complications. However, conclusive evidence is lacking. The Michigan Spine Surgery Improvement Collaborative (MSSIC) is a quality improvement collaborative with 30 hospitals across Michigan., Methods: The study included all patients who had 1 to 4 level ACDF (September 2015-August 2019) for 90-day complications. Major and minor complications were defined using a validated classification. Multiple imputations were used to generate complete covariate datasets. Generalized estimating equation model was used to identify associations with complications using the whole cohort and elderly subgroup analyses. Bonferroni correction was used., Results: Nine thousand one hundred thirty five patients (11.1% ≥ 70 yrs and 88.9% <70 yrs) with 2266 complications were analyzed. Comparing elderly versus non-elderly, the elderly had a significantly higher rate of any complications (31.5% vs. 24.0%, P < 0.001) and major complications (14.1% vs. 7.0%, P < 0.001). On multivariable analysis, age was not independently associated with any complication. POD#0 ambulation and preop independent ambulation were independently associated with significantly decreased odds of any complication. In the elderly, independent preoperative ambulation was protective for any complication (odds ratio [OR] 0.53, 0.39-0.73 95% confidence interval [CI]), especially major complications (OR 0.41, 0.27-0.61 95% CI)., Conclusion: Age was not an independent risk factor for complications in patients that underwent ACDF. In the elderly, independent preoperative ambulation was especially protective for major complications.Level of Evidence: 3., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is increasingly used to treat lumbar degenerative pathology. Its effect on sagittal parameters remains controversial. Static and expandable lordotic interbody devices (cages) were developed to improve segmental and overall lumbar lordosis. This study aimed to compare the radiographic and patient-reported outcomes (PROs) between static lordotic and non-lordotic titanium cages in patients undergoing 1-2 level MI-TLIF for degenerative conditions.  Methods We reviewed consecutive eligible patients who underwent 1-2 level MI-TLIF (7/2017-11/2019) at a single institution by multiple surgeons. Standing X-rays and PROs were collected at preoperative, 1-month, and 6-month postoperative intervals. Using univariate analyses, we compared the two cohorts regarding confounders, radiographic parameters, and proportions of patients reaching minimal clinically important difference (MCID) for PROs. Results One-hundred-twenty-five patients were reviewed. Forty-seven had lordotic and seventy-eight non-lordotic cages. The lordotic cohort was significantly younger than the non-lordotic (55.9 years vs. 60.7 years, p= 0.042). The baseline radiographic parameters were not significantly different between cohorts. At the preoperative-6-month interval, the lordotic cohort had significant improvement in lumbar lordosis versus non-lordotic cohort (2.95° ± 7.2° vs. -0.3° ± 7.1°, p=0.024). Both cohorts showed improvement in segmental lordosis, anterior and posterior interspace height, and low subsidence grade with no significant difference between cohorts at all intervals. Overall, 69.1-83.8% of patients achieved MCID in all PROs with no significant difference between cohorts. Conclusions The use of a static lordotic titanium cage in 1-2 level MI-TLIF did not result in significantly different radiographic improvements or PROs compared with a non-lordotic cage., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Lawless et al.)

Background: The alternative NF-κB pathway is activated by the NF-κB-inducing kinase (NIK) mediated phosphorylation of the inhibitor of κ-B kinase α (IKKα). IKKα then phosphorylates p100/NFKB2 to result in its processing to the active p52 subunit. Evidence suggests that basal breast cancers originate within a subpopulation of luminal progenitor cells which is expanded by signaling to IKKα., Objective: To determine the role of IKKα in the development of basal tumors., Methods: Kinase dead IkkαAA/AA mice were crossed with the C3(1)-TAg mouse model of basal mammary cancer. Tumor growth and tumor numbers in WT and IkkαAA/AA mice were assessed and immunopathology, p52 expression and stem/progenitor 3D colony forming assays were performed. Nik-/- mammary glands were isolated and mammary colonies were characterized., Results: While tumor growth was slower than in WT mice, IkkαAA/AA tumor numbers and pathology were indistinguishable from WT tumors. Both WT and IkkαAA/AA tumors expressed p52 except those IkkαAA/AA tumors where NIK, IKKαAA/AA and ErbB2 were undetectable. Colonies formed by WT and IkkαAA/AA mammary cells were nearly all luminal/acinar however, colony numbers and sizes derived from IkkαAA/AA cells were reduced. In contrast to IkkαAA/AA mice, virgin Nik-/- mammary glands were poorly developed and colonies were primarily derived from undifferentiated bipotent progenitor cells., Conclusions: C3(1)-TAg induced mammary tumors express p100/p52 even without functional IKKα. Therefore the development of basal-like mammary cancer does not strictly rely on IKKα activation. Signal-induced stabilization of NIK may be sufficient to mediate processing of p100NFKB2 which can then support basal-like mammary tumor formation. Lastly, in contrast to the pregnancy specific role of IKKα in lobuloalveogenesis, NIK is obligatory for normal mammary gland development.

Background Context: Postoperative pain control following posterior lumbar fusion continues to be challenging and often requires high doses of opioids for pain relief. The use of ketorolac in spinal fusion is limited due to the risk of pseudarthrosis. However, recent literature suggests it may not affect fusion rates with short-term use and low doses., Purpose: We sought to demonstrate noninferiority regarding fusion rates in patients who received ketorolac after undergoing minimally invasive (MIS) posterior lumbar interbody fusion. Additionally, we sought to demonstrate ketorolac's opioid-sparing effect on analgesia in the immediate postoperative period., Study Design/setting: This is a prospective, randomized, double-blinded, placebo-controlled trial. We are reporting our interim analysis., Patient Sample: Adults with degenerative spinal conditions eligible to undergo a one to three-level MIS transforaminal lumbar interbody fusion (TLIF)., Outcome Measures: Six-month and 1-year radiographic fusion as determined by Suk criteria, postoperative opioid consumption as measured by intravenous milligram morphine equivalent, length of stay, and drug-related complications. Self-reported and functional measures include validated visual analog scale, short-form 12, and Oswestry Disability Index., Methods: A double-blinded, randomized placebo-controlled, noninferiority trial of patients undergoing 1- to 3-level MIS TLIF was performed with bone morphogenetic protein (BMP). Patients were randomized to receive a 48-hour scheduled treatment of either intravenous ketorolac (15 mg every 6 hours) or saline in addition to a standardized pain regimen. The primary outcome was fusion. Secondary outcomes included 48-hour and total postoperative opioid use demonstrated as milligram morphine equivalence, pain scores, length of stay (LOS), and quality-of-life outcomes. Univariate analyses were performed. The present study provides results from a planned interim analysis., Results: Two hundred and forty-six patients were analyzed per protocol. Patient characteristics were comparable between the groups. There was no significant difference in 1-year fusion rates between the two treatments (p=.53). The difference in proportion of solid fusion between the ketorolac and placebo groups did not reach inferiority (p=.072, 95% confidence interval, -.07 to .21). There was a significant reduction in total/48-hour mean opioid consumption (p<.001) and LOS (p=.001) for the ketorolac group while demonstrating equivalent mean pain scores in 48 hours postoperative (p=.20). There was no significant difference in rates of perioperative complications., Conclusions: Short-term use of low-dose ketorolac in patients who have undergone MIS TLIF with BMP demonstrated noninferior fusion rates. Ketorolac safely demonstrated a significant reduction in postoperative opioid use and LOS while maintaining equivalent postoperative pain control., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute respiratory distress syndrome (ARDS) features pulmonary dysfunction capable of causing life-threatening hypoxaemia. Ventilation and hyperoxic therapies force oxygen through dysfunctional alveoli but risk exacerbating damage. Ox66™ is an ingestible, solid-state oxygen product designed for oxygen supplementation. Eighteen anaesthetized, ventilated rats were subjected to a 40% reduction in tidal volume to produce a hypoventilatory simulation of the hypoxia in ARDS (HV-ARDS). After 60 min, animals were randomized to receive either normal saline (Saline; volume control) or Ox66 ™ gavage. Cardiovascular function and blood oximetry/chemistry were measured alongside interstitial oxygenation (P ISF O 2 ) of the peripheral spinotrapezius muscle. HV-ARDS reduced mean arterial pressure by ∼20% and P ISF O 2 by ∼35% for both groups. Ox66 ™ gavage treatment at 60 min improved P ISF O 2 over Saline ( p  < .0001), restoring baseline values, however, the effect was temporary. A second bolus at 120 min repeated the OX66 ™ P ISF O 2 response, which remained elevated over Saline ( p  < .01) until study end and was supported by systemic parameters of lactate, P a O 2 , SO 2 , and base deficit. Saline remained hypotensive, whereas Ox66 ™ became normotensive. Vasoconstriction was observed in the Saline, but not Ox66 ™ group. Supplemental oxygenation through Ox66 ™ gavage increased peripheral tissue oxygenation, warranting further study for disorders featuring dysfunction of pulmonary perfusion like ARDS.

Study Design: Retrospective review of prospectively collected data at a single institution., Objective: To compare perioperative and clinical outcomes in morbidly obese patients who underwent minimally invasive transforaminal lumbar interbody fusion (MiTLIF)., Summary of Background Data: Obesity remains a serious public health concern. Obese patients who undergo lumbar fusion have historically thought to be at higher risk for complications and fare worse regarding quality-of-life outcomes. However, recent literature may demonstrate comparable risk and outcomes in obese patients. An increasing number of patients are categorized as morbidly obese (body mass index [BMI] ≥ 40 kg/m2). Perioperative and patient-reported outcomes (PROs) are lacking in this patient population., Methods: The authors retrospectively reviewed a prospectively collected database of all morbidly obese and non-obese patients that underwent MiTLIF between 2015 and 2018 for degenerative conditions who had minimum 1-year follow-up for outcome assessment. An inverse propensity/probability of treatment weighting was utilized to create a synthetic weighted sample in which covariates were independent of obesity designation to adjust for imbalance between groups. Generalized estimating equations (GEE) was used to estimate the association of morbid obesity and complications and 1-year PROs., Results: A total of 292 patients were analyzed with 234 non-obese patients and 58 morbidly obese patients. Multivariate analysis failed to demonstrate any association between morbid obesity and achieving minimal clinically important difference (MCID) for Oswestry disability index (ODI), visual analog scale (VAS), or short form-12 (SF-12) physical component score. However, morbid obesity was associated with significant decrease in odds of achieving MCID for SF-12 mental component score (P = 0.001). Increased surgery duration was significantly associated with morbid obesity (P = 0.001). Morbid obesity exhibited no statistically significant association with postoperative complications, readmission, pseudarthrosis, or adjacent segment disease (ASD)., Conclusion: Morbidly obese patients who undergo MiTLIF can achieve meaningful clinical improvement comparable to nonobese patients. Morbid obesity was associated with longer surgical times but was not associated with postoperative complications, readmission, or ASD.Level of Evidence: 3., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Spine surgery research has improved considerably over the last few decades. Its' most recent growth is in large part due to the mounting increase in studies conducted using national databases and registries. With easy access to a large number of patients, the benefit of these registries has become evident. However, as with any research, this type of data must be used responsibly with the appropriate strengths and limitations kept in mind. Inappropriate use of these registries continues to be a growing concern as potentially false or inaccurate conclusions can adversely impact clinical practice. It is, therefore, the author and the readers' responsibility to acknowledge and understand the limitations of this type of data. Knowledge of methodological requirements in the use and analyses of registry data is essential to ensuring quality evidence with proper interpretation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Design: Retrospective review of a multi-institutional data registry., Objective: The authors sought to determine the association between age and complications & patient-reported outcomes (PRO) in patients undergoing multilevel transforaminal interbody lumbar fusion (MTLIF)., Summary of Background Data: Elderly patients undergoing MTLIF are considered high risk. However, data on complications and PRO are lacking. Additionally, safety of multilevel lumbar fusion in the elderly remains uncertain., Methods: Patients ≥50-year-old who underwent MTLIF for degenerative lumbar spine conditions were analyzed. Ninety-day complications and PROs (baseline, 90-d, 1-y, 2-y) were queried using the MSSIC database. PROs were measured by back & leg visual analog scale (VAS), Patient-reported Outcomes Measurement Information System (PROMIS), EuroQol-5D (EQ-5D), and North American Spine Society (NASS) Patient Satisfaction Index. Univariate analyses were used to compare among elderly and complication cohorts. Generalized estimating equation (GEE) was used to identify predictors of complications and PROs., Results: A total of 3120 patients analyzed with 961 (31%) ≥ 70-y-o and 2159 (69%) between 50-69. A higher proportion of elderly experienced postoperative complications (P = .003) including urinary retention (P = <.001) and urinary tract infection (P = .002). Multivariate analysis demonstrated that age was not independently associated with complications. Number of operative levels was associated with any (P = .001) and minor (P = .002) complication. Incurring a complication was independently associated with worse leg VAS and PROMIS scores (P = <.001). Preoperative independent ambulation was independently associated with improved PROMIS, and EQ5D (P = <.001). Within the elderly, preoperative independent ambulation and lower BMI were associated with improved PROMIS (P = <.001). Complications had no significant effect on PROs in the elderly., Conclusions: Age was not associated with complications nor predictive of functional outcomes in patients who underwent MTLIF. Age alone, therefore, may not be an appropriate surrogate for risk. Furthermore, baseline preoperative independent ambulation was associated with better clinical outcomes and should be considered during preoperative surgical counseling.Level of Evidence: 3., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Hemolytic anemia (HA) is reduced blood oxygen-carrying capacity resulting from the depletion of red blood cells. Treatment for severe cases involves transfusion to improve oxygen delivery (Do 2 ), which carries risk. In humans, a total hemoglobin (tHb) concentration of 8 g/dL is severe, and <7 g/dL indicates transfusion. Some evidence suggests that compensatory mechanisms maintaining Do 2 are not compromised until <5 g/dL rendering transfusion at 7 g/dL premature. A Sprague-Dawley rat model of phenylhydrazine-induced HA was assessed over decreasing tHb for a Do 2 decompensation point. Three groups (100, 50, or 25% tHb, equating to 16.4, 7.4, or 3.2 g/dL) were generated. Cardiopulmonary, blood chemistry, and oxygenation parameters were measured under anesthesia. Vasoconstrictive responsiveness to phenylephrine was assessed in the exteriorized spinotrapezius. For 50% tHb, cardiopulmonary parameters, Do 2 , and lactate levels were similar to those for 100% tHb. Enhanced vasoconstriction occurred with 50% tHb ( P < 0.0001), not 25% tHb. The 25% group showed decreases in cardiopulmonary parameters, Do 2 , and lactate levels compared with the 100% and 50% groups ( P < 0.05). Do 2 showed a positive correlation with lactate levels at 25% tHb, but decompensation, defined by peripheral hypoxia, was not reached. This is the first study relating Do 2 to tHb in rats. A 50% reduction in tHb was supported by vascular compensation, whereas 25% tHb levied the cardiopulmonary system. A decompensation point was not identified. A rising need for treatment as tHb levels decline below 8 g/dL is evident, but, as compensatory mechanisms remain intact as tHb approaches 3.2 g/dL in rats, a transfusion limit of 5 g/dL in healthy patients is supported. NEW & NOTEWORTHY Early, chronic compensation to severe hemolytic anemia is vascular, switching to cardiopulmonary support as hemoglobin levels decline. Oxygen delivery does not correlate with serum lactate level until total hemoglobin is reduced by 75%.

Background: Full-endoscopic decompression surgery has been shown to be safe and efficacious in the lumbar spine, while its role remains to be determined in the cervical spine. We describe the utility of cervical endoscopic unilateral laminotomy for bilateral decompression (CE-ULBD) in a series of elderly patients with severe central stenosis, significant medical comorbidity, and existing cervical deformity., Methods: A prospectively collected spine surgery registry at the University of Washington was retrospectively queried for patients with cervical spondylotic myelopathy receiving CE-ULBD. Demographic data, operative details, imaging, and patient reported outcomes, including visual analogue scale (VAS) for neck and upper extremity pain, Nurick grade, and the modified Japanese Orthopedic Association (mJOA) score, were reviewed. Description of the surgical technique is provided. Descriptive statistics were calculated., Results: From 2014 through 2018, 10 patients with an average age of 70.2±5.0 years underwent CE-ULBD for symptomatic upper cervical stenosis due to ligamentum flavum buckling. Half of these patients had one stenotic segment, the other half had two stenotic segments. The most commonly affected segment was C3/4 (5/10 patients). Average length of surgery was 128±18.4 minutes. Average length of stay was 1.2±0.2 days. Average clinical follow-up time was 22.0±4.7 months; clinical outcomes at most recent follow-up were improved via both the Nurick grade (1.2±0.4, P<0.01) and modified Japanese Orthopedic Association (14.6±1.0, P<0.001) compared with pre-operative values. One patient experienced a transient loss of motor evoked potentials intraoperatively, but there were no cases of permanent neurological deficit., Conclusions: Severe central cervical stenosis is a safe and viable target for full-endoscopic decompression via an interlaminar approach., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jss.2020.01.03). The series “Full-endoscopic Spine Surgery” was commissioned by the editorial office without any funding or sponsorship. Dr. Hofstetter reports other from Johnson and Johnson, other from joimax®, other from Globus Medical, outside the submitted work. The other authors have no other conflicts of interest to declare., (2020 Journal of Spine Surgery. All rights reserved.)

Deletion of murine Thm1, an intraflagellar transport A (IFT-A) component that mediates ciliary protein trafficking, causes hyperphagia, obesity, and metabolic syndrome. The role of Thm1 or IFT-A in adipogenesis and insulin sensitivity is unknown. Here, we report that Thm1 knockdown in 3T3-L1 pre-adipocytes promotes adipogenesis and enhances insulin sensitivity in vitro. Yet, pre-obese Thm1 conditional knockout mice show systemic insulin resistance. While insulin-induced AKT activation in Thm1 mutant adipose depots and skeletal muscle are similar to those of control littermates, an attenuated insulin response arises in the mutant liver. Insulin treatment of control and Thm1 mutant primary hepatocytes results in similar AKT activation. Moreover, pair-feeding Thm1 conditional knockout mice produces a normal insulin response, both in the liver and systemically. Thus, hyperphagia caused by a cilia defect, induces hepatic insulin resistance via a non-cell autonomous mechanism. In turn, hepatic insulin resistance drives systemic insulin resistance prior to an obese phenotype. These data demonstrate that insulin signaling across cell types is regulated differentially, and that the liver is particularly susceptible to hyperphagia-induced insulin resistance and a critical determinant of systemic insulin resistance., (© 2019 Federation of American Societies for Experimental Biology.)

OBJECTIVEThe purpose of this study was to compare total cost and length of stay (LOS) between spine surgery patients enrolled in an enhanced perioperative care (EPOC) pathway and patients receiving traditional perioperative care (TRDC).METHODSAll spine surgery candidates were screened for inclusion in the EPOC pathway. This cohort was compared to a retrospective cohort of patients who received TRDC and a concurrent group of patients who met inclusion criteria but did not receive the EPOC (no pathway care [NOPC] group). Direct and indirect costs as well as hospital and intensive care LOSs were analyzed between the 3 groups.RESULTSTotal costs after pathway implementation decreased by $19,344 in EPOC patients compared to a historical cohort of patients who received TRDC and $5889 in a concurrent cohort of patients who did not receive EPOC (NOPC group). Hospital and intensive care LOS were significantly lower in EPOC patients compared to TRDC and NOPC patients.CONCLUSIONSThe implementation of a multimodal EPOC pathway decreased LOS and cost in major elective spine surgeries.

Study Design: Retrospective consecutive case series., Objective: The objective of this case series was to demonstrate the safety of a modified transfacet pedicle-sparing decompression and instrumented fusion in patients with thoracic disc herniations (TDHs)., Methods: Consecutive patients undergoing operative management of TDH from July 2007 to December 2011 using a posterior unilateral modified transfacet pedicle-sparing approach were identified. All patients underwent open or minimally invasive modified transfacet pedicle-sparing discectomy and segmental instrumentation with interbody fusion, performed by four different surgeons. Pre- and postoperative visual analog scale (VAS) pain scores, Nurick grade, and American Spinal Injury Association Impairment Scale (AIS) were analyzed from a retrospective chart review. Estimated blood loss and complications were also obtained., Results: Fifty-one patients were included that had operations for TDH. Thirty-nine patients had single level decompression and 12 had multilevel decompression. The total number of levels operated on was 64. Five patients were treated with minimally invasive surgery. A herniated disc level of T11-12 (n = 17) was treated most often. One major complication of epidural hematoma occurred. Minor complications such as malpositioned hardware, postoperative hematoma, wound infection, pseudoarthrosis, and pulmonary complications occurred in a few patients. Follow-up ranged from 1 to 46 months with 1 patient lost to follow-up. From preoperative to final postoperative: mean VAS scores improved from 8.31 to 4.05, AIS in all patients remained stable or improved, and Nurick scores improved from 3 to 2.6 on average. No intraoperative or permanent neurological deficit occurred., Conclusion: In our surgical series, 51 consecutive patients underwent modified transfacet pedicle-sparing approach to TDHs and experienced improvement of functional status as well as improvement of objective pain scales with no neurological complications. The posterior unilateral modified transfacet pedicle-sparing decompression and instrumented fusion approach to the thoracic spine is a safe and reproducible procedure for the treatment of TDHs., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Probes on a microarray represent a frozen view of a genome and are quickly outdated when new sequencing studies extend our knowledge, resulting in significant measurement error when analyzing any microarray experiment. There are several bioinformatics approaches to improve probe assignments, but without in-house programming expertise, standardizing these custom array specifications as a usable file (e.g. as Affymetrix CDFs) is difficult, owing mostly to the complexity of the specification file format. However, without correctly standardized files there is a significant barrier for testing competing analysis approaches since this file is one of the required inputs for many commonly used algorithms. The need to test combinations of probe assignments and analysis algorithms led us to develop ArrayInitiative, a tool for creating and managing custom array specifications., Results: ArrayInitiative is a standalone, cross-platform, rich client desktop application for creating correctly formatted, custom versions of manufacturer-provided (default) array specifications, requiring only minimal knowledge of the array specification rules and file formats. Users can import default array specifications, import probe sequences for a default array specification, design and import a custom array specification, export any array specification to multiple output formats, export the probe sequences for any array specification and browse high-level information about the microarray, such as version and number of probes. The initial release of ArrayInitiative supports the Affymetrix 3' IVT expression arrays we currently analyze, but as an open source application, we hope that others will contribute modules for other platforms., Conclusions: ArrayInitiative allows researchers to create new array specifications, in a standard format, based upon their own requirements. This makes it easier to test competing design and analysis strategies that depend on probe definitions. Since the custom array specifications are easily exported to the manufacturer's standard format, researchers can analyze these customized microarray experiments using established software tools, such as those available in Bioconductor.

The hydrogel system of poly(methacrylic acid-co-N-vinyl pyrrolidone) was evaluated for use as an oral delivery system for growth hormone and salmon calcitonin. These proteins were selected because of their therapeutic importance and the insight provided by evaluating the delivery of a therapeutic agent with a high molecular weight (growth hormone) and a drug with a high isoelectric point (salmon calcitonin). Growth hormone loading and release studies were performed for both P(MAA-co-NVP) and P(MAA-g-PEG). Loading efficiencies for the respective systems were 50.9 ± 1.8% and 57.8 ± 4.1%; weight incorporation of the protein was determined to be 3.5 ± 0.1% and 4.0 ± 0.3%. At pH 7.4, growth hormone release of 90% occurred within 45 min for P(MAA-co-NVP) microparticles; 90% release was not achieved with P(MAA-g-PEG) microparticles until 180 min. At pH 1.2, no release occurred from P(MAA-co-NVP) microparticles but 10% release occurred from P(MAA-g-PEG) microparticles. Salmon calcitonin loading and release were shown to be affected by the negative charges of deprotonated MAA; for systems with monomer molar feed ratios of 4:1, 1:1 and 1:4 MAA:NVP, loading efficiencies were determined to be 70.6 ± 3.0%, 25.3 ± 1.2%, and 1.6 ± 1.3%. Salmon calcitonin release was minimal from the copolymer with 4:1 MAA:NVP monomer feed at pH 7.4. The release improved when the pH was raised above physiological levels. These studies confirmed that P(MAA-co-NVP) was an effective oral delivery system for high molecular weight drugs, but improvements are needed before the system could be utilized for high isoelectric point therapeutic delivery.

Hydrogels of poly(methacrylic acid-co-N-vinyl pyrrolidone) were synthesized and evaluated for their use as carriers for oral protein delivery. Insulin loading efficiencies were determined to be near 90% for carriers crosslinked with ethylene glycol dimethacrylate with corresponding weight incorporation levels near 12%. Although no insulin was released in gastric conditions, as desired, near instantaneous release occurred when the pH was raised to values typical of the intestinal area. Cytocompatibility studies with Caco-2 and Caco-2/HT29-MTX cultures demonstrated that microparticles did not elicit toxic effects at concentrations up to 5.0 mg/mL. Insulin transport studies revealed that the carriers did not disrupt the cell layer and thus did not change the insulin permeability in the apical-to-basolateral direction. Therefore, microparticles of this system were best suited for oral delivery of therapeutic agents that do not require transport facilitation., ((c) 2009 Wiley Periodicals, Inc.)

The combination of materials design and advances in nanotechnology has led to the development of new therapeutic protein delivery systems. The pulmonary, nasal, buccal and other routes have been investigated as delivery options for protein therapy, but none result in improved patient compliances and patient quality of life as the oral route. For the oral administration of these new systems, an understanding of protein transport is essential because of the dynamic nature of the gastrointestinal tract and the barriers to transport that exist.Models have been developed to describe the transport between the gastrointestinal lumen and the bloodstream, and laboratory techniques like cell culture provide a means to investigate the absorption and transport of many therapeutic agents. Biomaterials, including stimuli-sensitive complexation hydrogels, have been investigated as promising carriers for oral delivery. However, the need to develop models that accurately predict protein blood concentration as a function of the material structure and properties still exists.

Purpose: To assess differences in medical care expenditures and informal care received for adults and children by individuals' self-reported epilepsy status and to estimate the total economic impact of epilepsy in the United States., Methods: Pooled medical expenditure panel survey data from 1996-2004 were used. Children's regression analyses were adjusted for race, sex, general self-reported health status, family size, and age. Adults' analyses were also adjusted for income and education. The national annual economic impact was estimated by multiplying the average individual differences by previously published national prevalence data., Results: The results of regressions appropriately weighted to account for study design indicate excess medical expenditures for those with epilepsy of $4,523 [95% confidence interval: $3,184-$5,862]. Excess expenditures were similar for adults and children. Adults with epilepsy received 1.2 extra days of informal care [95% confidence interval: 0.2-2.3]. The national impact included $9.6 billion of medical expenditures and informal care., Discussion: Epilepsy has significant impact on individual medical expenditure and generates a national impact in the billions of dollar.

Polymeric networks and the ensuing hydrogels of MAA and NVP were successfully synthesized using a UV-initiated free radical polymerization and characterized to assess their applicability as carriers for directed drug delivery. FT-IR spectroscopy revealed shifts in peak absorbances that indicated the presence of hydrogen bonding complexes between functional groups, while SEM imaging showed that the different comonomers affect the surface morphology of the microparticles. Dynamic pH swelling studies demonstrated the pH responsiveness of the carriers in gastric and intestinal conditions and revealed that systems containing higher concentrations of MAA experienced the highest degree of hydrogen bonding complexation in gastric conditions. The presence of NVP in the systems enhanced swelling. Equilibrium swelling studies revealed that the mesh size was sufficiently large to allow drug diffusion across the networks.

Objective: To evaluate the feasibility for Rift Valley fever virus (RVFV) to enter the continental United States by various routes as well as to identify states in which domestic and wild ruminant and human populations would be most vulnerable to exposure to RVFV., Study Design: Pathways analysis., Sample Population: Animals, commodities, and humans transported from RVFV-endemic countries to the continental United States between 2000 and 2005., Procedures: Initially, agent, host, and environmental factors important in the epidemiologic aspects of RVFV were used to develop a list of potential pathways for release of RVFV into the continental United States. Next, the feasibility of each pathway was evaluated by use of data contained in governmental and public domain sources. Finally, entry points into the continental United States for each feasible pathway were used to identify the domestic and wild ruminant and human populations at risk for exposure to RVFV., Results: Feasible pathways for entry of RVFV into the continental United States were importation of RVFV-infected animals, entry of RVFV-infected people, mechanical transport of RVFV-infected insect vectors, and smuggling of live virus., Conclusions and Clinical Relevance: Domestic ruminant livestock, ruminant wildlife, and people in 14 states (Alabama, California, Florida, Georgia, Maine, Maryland, Massachusetts, Minnesota, New Jersey, New York, Pennsylvania, South Carolina, Texas, and Virginia) appeared to be most vulnerable to exposure to RVFV. Pathways analysis can provide the requisite information needed to construct an effective targeted surveillance plan for RVFV to enable rapid detection and response by animal health and public health officials.

Epilepsy as an issue for the public health community has a relatively short history in the United States. Not since the 1970s, when Congress established the Commission for the Control of Epilepsy and Its Consequences and the publication of its formal report, "Plan for Nationwide Action on Epilepsy," has significant attention been paid to the public health implications of epilepsy. In fact, until the U.S. Congress established a small epilepsy program at the Centers for Disease Control and Prevention (CDC) 12 years ago, the condition was practically invisible at all levels of organized public health. Since then, two major conferences, and the recommendations arising from them, have generated a substantially increased level of activity in research, surveillance, and the production and distribution of public education materials, as well as a national initiative to improve access to care and to prevent epilepsy's negative social impact. Even at the state level, long devoid of any attention to epilepsy in public health planning or provision of services, things are beginning to change, and new demonstration programs designed to identify and serve vulnerable populations with epilepsy are underway. This review highlights these activities, reflects a new and heightened level of attention to epilepsy, and speculates on what may lie ahead in the ongoing effort to give epilepsy greater visibility and higher priority in the public health arena.

This paper describes two interactive templates for representing spatially indexed estimates. Both templates use a matrix layout of small panels. The first template, called linked micromap plots, can represent multivariate estimates associated with each spatially indexed study unit. The second template, called conditioned choropleth maps, shows the connection between a dependent variable, as represented in a classed choropleth map, and two explanatory variables. The paper describes the cognitive considerations that motivate the layouts and representation details. The discussion also addresses topics of data quality and access, hypothesis generation, and interactive features such as pan and zoom and dynamic conditioning via sliders. The examples show epidemiological (mortality rates) and environmental (toxic concentrations) applications., (Copyright 2000 John Wiley & Sons, Ltd.)

MSA2 is a strain variable blood-stage merozoite surface antigen of Plasmodium falciparum. We have derived the MSA2 nucleotide sequence for four cloned parasite isolates. Comparison with three other published sequences suggests that variation may be limited, and that the architecture of the gene can be conveniently described by segregation into four distinct regions. The N and C terminal regions (Regions 1 and 4) are highly conserved in all seven genes. Six of these seven MSA2 genes can be grouped in a single family, within which variation is largely limited to a region characterized by the presence of tandem repeats (Region 2). We have observed two new forms of repeat in a Gly, Ser, Ala-rich block, and noted the absence of repeat in this block of the CAMP strain. The region downstream of the repeat region (Region 3) is highly conserved within this family. Immunochemical analysis reveals that MSA2 is one of the antigens recognized by immune antibodies eluted from intact merozoites. Regions 2 and 3, expressed as recombinant proteins, are recognized by these antibodies, suggesting that these regions are exposed at the surface of the intact merozoite.