Elective Spinal Transpedicular Ablation of the Basivertebral Nerve of the Vertebral Segment in Adult Spinal Deformity Patients.

BACKGROUND: Ablation of the basivertebral nerve (BVNA) innervating the vertebral endplate has become a standard treatment of vertebrogenic chronic low back pain (CLBP) arising from vertebral endplate damage. BVNA treatment of CLBP in clinical trials was successful and durable for pain relief and return to daily activities. This case review adds new information about older patients with adult degenerative spinal deformity (ASD) and associated comorbidities not previously described in clinical trials. METHODS: One hundred and eighteen ASD patients with vertebrogenic CLBP in a community practice setting underwent 503 levels of BVNA (average 4.3 levels). Forty-one patients with minimal comorbidities (Group A) were compared to 77 patients with significant comorbidities (Group B). Visual analog scale (VAS 10 cm) and Oswestry Disability Index (ODI 100-point scale) were obtained before BVNA and at a last follow-up (LFU). RESULTS: Group A VAS at LFU was an average of 2 cm, a 7 cm improvement. Group B VAS at LFU was 3 cm, a 6 cm improvement. At LFU, Group A ODI mean was 14 points or minimal disability, with a 39-point improvement, and Group B improved 28 points to 29 but remained moderately disabled. At LFU, the lumbar stenosis with laminectomy and BVNA subgroup of 26 had mean VAS 2 cm and ODI 28-point improvement but remained on average 21 points with a final low moderate disability. Eleven laminectomy and BVNA patients had continued posterior column pain related to radiculopathy, and or peripheral neuropathy, and sacroiliac joint pain in 30%. Mobile spondylolisthesis in 21 patients in Group B at LFU had a 6 cm improvement of VAS and 25-point improvement of ODI but remained moderately disabled on ODI. At LFU in group B, there was a 20% incidence of continued stenosis and radiculopathy symptoms. At LFU, Lumbar fusion was recommended in 9. Vertebral compression fracture (VCF) occurred in 9 after BVNA (10%) of Group B. These patients were older (mean 78 years), and all had significant osteoporosis. Eight fractures were within the area of the BVNA, and 1 was an S2 sacral fracture. These VCF patients were treated with vertebroplasty or kyphoplasty and continued preventive care with added teriparatide. At LFU, the VCF subgroup had a modest 6 cm improvement in VAS to 4 cm and continued to have significant severe to moderate disability (Oswestry Disability Index average of 38 points). CONCLUSION: Clinical trials of BVNA treatment of CLBP found success and durability for pain relief and daily activities. Patients with ASD without comorbidities showed durable pain relief of vertebrogenic CLBP and return of daily activities similar to clinical trials. In those with comorbidities, the result was an improvement in pain and disability that could be diminished by the complications related to the comorbidities. This is new information about BVNA for older patients with spinal deformity and other comorbidities. This study could impact research practice and policy to expand indications of BVNA to patients with adult spinal deformity. CLINICAL RELEVANCE: This case series represents the only literature regarding patients with adult spinal deformity treated with BVNA. The results were predictable and reproducible. Many patients were satisfied, would have the procedure again and would recommend BVNA to friends and family. This finding should encourage acceptance of patients with ASD for BVNA and, in fact, BVNA should probably be done before any fusion to limit and choose levels for inclusion in fusion.

The Impact of Cardiac Arrhythmias on Total Knee Arthroplasty Outcomes.

BACKGROUND: Cardiac comorbidities are common in patients undergoing total knee arthroplasty (TKA). While there is an abundance of research showing an association between cardiac abnormalities and poor postoperative outcomes, relatively little is published on specific pathologies. The aim of this study was to assess the impact of cardiac arrhythmias on postoperative outcomes in the setting of TKA. METHODS: This retrospective cohort study included all patients undergoing TKA from a national database, from 2016 to 2019. Patients who had cardiac arrhythmias were identified via International Classification of Diseases, Tenth Revision, and Clinical Modification/Procedure Coding System codes and served as the cohort of interest. Multivariate regression was performed to compare postoperative outcomes. Gamma regression was performed to assess length of stay and total charges, while negative binomial regression was used to assess 30-day readmission and reoperation. Patient demographic variables and comorbidities, measured via the Elixhauser comorbidity index, were controlled in our regression analysis. Out of a total of 1,906,670 patients, 224,434 (11.76%) had a diagnosed arrhythmia and were included in our analyses. RESULTS: Those who had arrhythmias had greater odds of both medical (odds ratio [OR] 1.52; P < .001) and surgical complications (OR 2.27; P < .001). They also had greater readmission (OR 2.49; P < .001) and reoperation (OR 1.93; P < .001) within 30 days, longer hospital stays (OR 1.07; P < .001), and greater total charges (OR 1.02; P < .001). CONCLUSIONS: Cardiac arrhythmia is a common comorbidity in the TKA population and is associated with worse postoperative outcomes. Patients who had arrhythmias had greater odds of both medical and surgical complications requiring readmission or reoperation. STUDY DESIGN: Level III; Retrospective Cohort Study.

Radius additivity score: a novel combination index for tumour growth inhibition in fixed-dose xenograft studies.

The effect of combination therapies in many cancers has often been shown to be superior to that of monotherapies. This success is commonly attributed to drug synergies. Combinations of two (or more) drugs in xenograft tumor growth inhibition (TGI) studies are typically designed at fixed doses for each compound. The available methods for assessing synergy in such study designs are based on combination indices (CI) and model-based analyses. The former methods are suitable for screening exercises but are difficult to verify in in vivo studies, while the latter incorporate drug synergy in semi-mechanistic frameworks describing disease progression and drug action but are unsuitable for screening. In the current study, we proposed the empirical radius additivity (Rad-add) score, a novel CI for synergy detection in fixed-dose xenograft TGI combination studies. The Rad-add score approximates model-based analysis performed using the semi-mechanistic constant-radius growth TGI model. The Rad-add score was compared with response additivity, defined as the addition of the two response values, and the bliss independence model in combination studies derived from the Novartis PDX dataset. The results showed that the bliss independence and response additivity models predicted synergistic interactions with high and low probabilities, respectively. The Rad-add score predicted synergistic probabilities that appeared to be between those predicted with response additivity and the Bliss model. We believe that the Rad-add score is particularly suitable for assessing synergy in the context of xenograft combination TGI studies, as it combines the advantages of CI approaches suitable for screening exercises with those of semi-mechanistic TGI models based on a mechanistic understanding of tumor growth.

Nanoparticle surface stabilizing agents influence antibacterial action.

The antibacterial properties of nanoparticles are of particular interest because of their potential to serve as an alternative therapy to combat antimicrobial resistance. Metal nanoparticles such as silver and copper nanoparticles have been investigated for their antibacterial properties. Silver and copper nanoparticles were synthesized with the surface stabilizing agents cetyltrimethylammonium bromide (CTAB, to confer a positive surface charge) and polyvinyl pyrrolidone (PVP, to confer a neutral surface charge). Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and viable plate count assays were used to determine effective doses of silver and copper nanoparticles treatment against Escherichia coli, Staphylococcus aureus and Sphingobacterium multivorum. Results show that CTAB stabilized silver and copper nanoparticles were more effective antibacterial agents than PVP stabilized metal nanoparticles, with MIC values in a range of 0.003 µM to 0.25 µM for CTAB stabilized metal nanoparticles and 0.25 µM to 2 µM for PVP stabilized metal nanoparticles. The recorded MIC and MBC values of the surface stabilized metal nanoparticles show that they can serve as effective antibacterial agents at low doses.

Determining bioequivalence possibilities of long acting injectables through population PK modelling.

Long acting injectables (LAI) products are a popular intervention for treating a number of chronic conditions, with their long drug release reducing the administration frequency and thus improving patient adherence. The extended release, however, can provide a major challenge to bioequivalence (BE) testing since the long absorption half-life results in a long washout period, meaning that a traditional BE study can be many months or years in length. The unique PK profile for LAI products also means that it is critical to have appropriate metrics to summarise the plasma concentration profile. In this work, we use paliperidone as a case study to demonstrate how Population PK modelling can be utilised to explore sensitivity of summary metrics to different products. We also determine a range of products that are bioequivalent after both multiple dosing and single dosing. Finally, we show how the modelling can be used in a (virtual) PK study as an alternative approach to determining bioequivalence. This work demonstrates the potential for Population PK modelling in bioequivalence assessment, opening doors to more streamlined product development.

Exploring a model-based analysis of patient derived xenograft studies in oncology drug development.

PURPOSE: To assess whether a model-based analysis increased statistical power over an analysis of final day volumes and provide insights into more efficient patient derived xenograft (PDX) study designs. METHODS: Tumour xenograft time-series data was extracted from a public PDX drug treatment database. For all 2-arm studies the percent tumour growth inhibition (TGI) at day 14, 21 and 28 was calculated. Treatment effect was analysed using an un-paired, two-tailed t-test (empirical) and a model-based analysis, likelihood ratio-test (LRT). In addition, a simulation study was performed to assess the difference in power between the two data-analysis approaches for PDX or standard cell-line derived xenografts (CDX). RESULTS: The model-based analysis had greater statistical power than the empirical approach within the PDX data-set. The model-based approach was able to detect TGI values as low as 25% whereas the empirical approach required at least 50% TGI. The simulation study confirmed the findings and highlighted that CDX studies require fewer animals than PDX studies which show the equivalent level of TGI. CONCLUSIONS: The study conducted adds to the growing literature which has shown that a model-based analysis of xenograft data improves statistical power over the common empirical approach. The analysis conducted showed that a model-based approach, based on the first mathematical model of tumour growth, was able to detect smaller size of effect compared to the empirical approach which is common of such studies. A model-based analysis should allow studies to reduce animal use and experiment length providing effective insights into compound anti-tumour activity.