Exceptional Cases of Spinal Cord Stimulation for the Treatment of Refractory Cancer-Related Pain.

OBJECTIVES: Cancer pain has traditionally been managed with opioids, adjuvant medications, and interventions including injections, neural blockade, and intrathecal pump (ITP). Spinal cord stimulation (SCS), although increasingly used for conditions such as failed back surgery syndrome and complex regional pain syndrome, is not currently recommended for cancer pain. However, patients with cancer-related pain have demonstrated benefit with SCS. We sought to better characterize these patients and the benefit of SCS in exceptional cases of refractory pain secondary to progression of disease or evolving treatment-related complications. MATERIALS AND METHODS: This was a single-center, retrospective case series at a tertiary cancer center. Adults ≥18 years old with active cancer and evolving pain secondary to disease progression or treatment, whose symptoms were refractory to systemic opioids, and who underwent SCS trial followed by percutaneous implantation between 2016 and 2021 were included. Descriptive statistics included mean, SD, median, and interquartile range (IQR). RESULTS: Eight patients met the inclusion criteria. The average age at SCS trial was 60.0 (SD: ±11.6) years, and 50% were men. Compared with baseline, the median (IQR) change in pain score by numeric rating scale (NRS) after trial was -3 (2). At an average of 14 days after implant, the median (IQR) change in NRS and daily oral morphine equivalents were -2 (3.5) and -126 mg (1095 mg), respectively. At a median of 63 days after implant, the corresponding values were -3 (0.75) and -96 mg (711 mg). There was no significant change in adjuvant therapies after SCS implantation at follow-up. Six patients were discharged within two days after implantation. Two patients were readmitted for pain control within the follow-up period. CONCLUSIONS: In patients with cancer-related pain, SCS may significantly relieve pain, reduce systemic daily opioid consumption, and potentially decrease hospital length of stay and readmission for pain control. It may be appropriate to consider an SCS trial before ITP in select cases of cancer-related pain.

Cannabis, anesthesia and acute postoperative pain: known and unknown.

Tweetable abstract Cannabis use may significantly affect anesthetic, perioperative and acute pain management care; but research needs to be standardized, expanded and more inclusive.

The Economic Burden of Non-fatal Musculoskeletal Injuries in Northeastern Tanzania.

BACKGROUND: Although musculoskeletal injuries have increased in sub-Saharan Africa, data on the economic burden of non-fatal musculoskeletal injuries in this region are scarce. OBJECTIVE: Socioeconomic costs of orthopedic injuries were estimated by examining both the direct hospital cost of orthopedic care as well as indirect costs of orthopedic trauma using disability days and loss of work as proxies. METHODS: This study surveyed 200 patients seen in the outpatient orthopedic ward of the Kilimanjaro Christian Medical Center, a tertiary hospital in Northeastern Tanzania, during the month of July 2016. FINDINGS: Of the patients surveyed, 88.8% earn a monthly income of less than $250 and the majority of patients (73.7%) reported that the healthcare costs of their musculoskeletal injuries were a catastrophic burden to them and their family with 75.0% of patients reporting their medical costs exceeded their monthly income. The majority (75.3%) of patients lost more than 30 days of activities of daily living due to their injury, with a median (IQR) functional day loss of 90 (30). Post-injury disability led to 40.6% of patients losing their job and 86.7% of disabled patients reported a wage decrease post-injury. There were significant associations between disability and post-injury unemployment (p < .0001) as well as lower post-injury wages (p = .022). CONCLUSION: This exploratory study demonstrates that in this region of the world, access to definitive treatment post-musculoskeletal injury is limited and patients often suffer prolonged disabilities resulting in decreased employment and income.

Acetabular Global Insufficiency in Patients with Down Syndrome and Hip-Related Symptoms: A Matched-Cohort Study.

BACKGROUND: The etiology of hip instability in Down syndrome is not completely understood. We investigated the morphology of the acetabulum and femur in patients with Down syndrome and compared measurements of the hips with those of matched controls. METHODS: Computed tomography (CT) images of the pelvis of 42 patients with Down syndrome and hip symptoms were compared with those of 42 age and sex-matched subjects without Down syndrome or history of hip disease who had undergone CT for abdominal pain. Each of the cohorts had 23 male and 19 female subjects. The mean age (and standard deviation) in each cohort was 11.3 ± 5.3 years. The lateral center-edge angle (LCEA), acetabular inclination angle (IA), acetabular depth-width ratio (ADR), acetabular version, and anterior and posterior acetabular sector angles (AASA and PASA) were compared. The neck-shaft angle and femoral version were measured in the patients with Down syndrome only. The hips of the patients with Down syndrome were further categorized as stable (n = 21) or unstable (n = 63) for secondary analysis. RESULTS: The hips in the Down syndrome group had a smaller LCEA (mean, 10.8° ± 12.6° compared with 25.6° ± 4.6°; p < 0.0001), a larger IA (mean, 17.4° ± 10.3° compared with 10.9° ± 4.8°; p < 0.0001), a lower ADR (mean, 231.9 ± 56.2 compared with 306.8 ± 31.0; p < 0.0001), a more retroverted acetabulum (mean acetabular version as measured at the level of the centers of the femoral heads [AVC], 7.8° ± 5.1° compared with 14.0° ± 4.5°; p < 0.0001), a smaller AASA (mean, 55.0° ± 9.9° compared with 59.7° ± 7.8°; p = 0.005), and a smaller PASA (mean, 67.1° ± 10.4° compared with 85.2° ± 6.8°; p < 0.0001). Within the Down syndrome cohort, the unstable hips showed greater femoral anteversion (mean, 32.7° ± 14.6° compared with 23.6° ± 10.6°; p = 0.002) and worse global acetabular insufficiency compared with the stable hips. No differences between the unstable and stable hips were found with respect to acetabular version (mean AVC, 7.8° ± 5.5° compared with 7.6° ± 3.8°; p = 0.93) and the neck-shaft angle (mean, 133.7° ± 6.7° compared with 133.2° ± 6.4°; p = 0.81). CONCLUSIONS: Patients with Down syndrome and hip-related symptoms had more retroverted and shallower acetabula with globally reduced coverage of the femoral head compared with age and sex-matched subjects. Hip instability among those with Down syndrome was associated with worse global acetabular insufficiency and increased femoral anteversion, but not with more severe acetabular retroversion. No difference in the mean femoral neck-shaft angle was observed between the stable and unstable hips in the Down syndrome cohort. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Survivorship of the Bernese Periacetabular Osteotomy: What Factors are Associated with Long-term Failure?

BACKGROUND: The Bernese periacetabular osteotomy (PAO) continues to be a commonly performed nonarthroplasty option to treat symptomatic developmental hip dysplasia, but there are few long-term followup studies evaluating results after PAO. QUESTIONS/PURPOSES: (1) What is the long-term survivorship of the hip after PAO? (2) What were the validated outcomes scores among patients who had PAO more than 14 years ago? (3) What factors are associated with long-term failure? METHODS: One hundred fifty-eight dysplastic hips (133 patients) underwent PAO between May 1991 and September 1998 by a single surgeon. Of those, 37 hips (34 patients [26%]) were lost to followup; an additional seven patients (5% [eight hips]) had not been seen in the last 5 years. The 121 hips (in 99 patients) were retrospectively evaluated at a mean of 18 years (range, 14-22 years). Survivorship was assessed using Kaplan-Meier analysis with total hip arthroplasty (THA) as the endpoint. Hips were evaluated for activity, pain, and general health using the UCLA Activity Score, modified Harris hip score, WOMAC, and Hip disability and Osteoarthritis Outcome Score (HOOS). Failure was defined as a WOMAC pain subscale score ≥ 10 or having undergone THA. Hips were divided into three groups: asymptomatic (did not meet any failure criteria at any point in time), symptomatic (met WOMAC pain failure criteria at previous or most recent followup), and replaced (having undergone THA). A multinomial logistic regression model using a general estimating equations approach was used to assess factors associated with failure. RESULTS: Kaplan-Meier analysis with THA as the endpoint revealed a survival rate (95% confidence interval [CI]) of 74% (66%-83%) at 18 years. Twenty-six hips (21%) underwent THA at an average of 9 ± 5 years from the surgery. Sixty-four hips (53%) remained asymptomatic and did not meet any failure criteria at most recent followup. Thirty-one hips (26%) were symptomatic and considered failed based on a WOMAC pain score of ≥ 10 with a mean ± SD of 11 ± 4 out of 20 at most recent followup. Although some failed initially by pain, their most recent WOMAC score may have been < 10. Of the 16 symptomatic hips that failed early by pain (reported a WOMAC pain subscale score ≥ 10 in the prior study), two were lost to followup, two underwent THA at 16 and 17 years, four still failed because of pain at most recent followup, and the remaining eight had WOMAC pain scores < 10 at most recent followup. Asymptomatic hips reported better UCLA Activity Scores (asymptomatic: mean ± SD, 7 ± 2; symptomatic: 6 ± 2, p = 0.001), modified Harris hip scores (pain, function, and activity sections; asymptomatic: 80 ± 11; symptomatic: 50 ± 15, p < 0.001), WOMAC (asymptomatic: 2 ± 2, symptomatic: 11 ± 4, p < 0.001), and HOOS (asymptomatic: 87 ± 11, symptomatic: 52 ± 20, p < 0.001) compared with symptomatic hips at long-term followup. Age older than 25 years at the time of PAO (symptomatic: odds ratio [OR], 3.6; 95% CI, 1.3-9.8; p = 0.01; replaced: OR, 8.9; 95% CI, 2.6-30.9; p < 0.001) and a preoperative joint space width ≤ 2 mm (replaced: OR, 0.3; 95% CI, 0.12-0.71; p = 0.007) or ≥ 5 mm (replaced: OR, 0.121; 95% CI, 0.03-0.56; p = 0.007) were associated with long-term failure while controlling for poor or fair preoperative joint congruency. CONCLUSIONS: This study demonstrates the durability of the Bernese PAO at long-term followup. In a subset of patients, there was progression to failure over time. Factors of progression to THA or more severe symptoms include age older than 25 years, poor or fair preoperative hip congruency, and a preoperative joint space width that is less than 2 mm or more than 5 mm. Future studies should focus on evaluating the two failure groups that we have identified in our study: those that failed early and went on to THA and those that are symptomatic at long-term followup. LEVEL OF EVIDENCE: Level III, therapeutic study.

Both 3-T dGEMRIC and Acetabular-Femoral T2 Difference May Detect Cartilage Damage at the Chondrolabral Junction.

BACKGROUND: In addition to case reports of gadolinium-related toxicities, there are increasing theoretical concerns about the use of gadolinium for MR imaging. As a result, there is increasing interest in noncontrast imaging techniques for biochemical cartilage assessment. Among them, T2 mapping holds promise because of its simplicity, but its biophysical interpretation has been controversial. QUESTIONS/PURPOSES: We sought to determine whether (1) 3-T delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping are both capable of detecting cartilage damage at the chondrolabral junction in patients with femoroacetabular impingement (FAI); and (2) whether there is a correlation between these two techniques for acetabular and femoral head cartilage assessment. METHODS: Thirty-one patients with hip-related symptoms resulting from FAI underwent a preoperative 3-T MRI of their hip that included dGEMRIC and T2 mapping (symptomatic group, 16 women, 15 men; mean age, 27 ± 8 years). Ten volunteers with no symptoms according to the WOMAC served as a control (asymptomatic group, seven women, three men; mean age, 28 ± 3 years). After morphologic cartilage assessment, acetabular and femoral head cartilages were graded according to the modified Outerbridge grading criteria. In the midsagittal plane, single-observer analyses of precontrast T1 values (volunteers), the dGEMRIC index (T1Gd, patients), and T2 mapping values (everyone) were compared in acetabular and corresponding femoral head cartilage at the chondrolabral junction of each hip by region-of-interest analysis. RESULTS: In the symptomatic group, T1Gd and T2 values were lower in the acetabular cartilage compared with corresponding femoral head cartilage (T1Gd: 515 ± 165 ms versus 650 ± 191 ms, p < 0.001; T2: 39 ± 8 ms versus 46 ± 10 ms, p < 0.001). In contrast, the asymptomatic group demonstrated no differences in T1 and T2 values for the acetabular and femoral cartilages with the numbers available (T1: 861 ± 130 ms versus 860 ± 182 ms, p = 0.98; T2: 43 ± 7 ms versus 42 ± 6 ms, p = 0.73). No correlation with the numbers available was noted between the modified Outerbridge grade and T1, T1Gd, or T2 as well as between T2 and either T1 or T1Gd. CONCLUSIONS: Without the need for contrast media application, T2 mapping may be a viable alternative to dGEMRIC when assessing hip cartilage at the chondrolabral junction. However, acquisition-related phenomena as well as regional variations in the microstructure of hip cartilage necessitate an internal femoral head cartilage control when interpreting these results. LEVEL OF EVIDENCE: Level IV, diagnostic study.

Planar dGEMRIC Maps May Aid Imaging Assessment of Cartilage Damage in Femoroacetabular Impingement.

BACKGROUND: Three-dimensional (3-D) delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) helps quantify biochemical changes in articular cartilage that correlate with early-stage osteoarthritis. However, dGEMRIC analysis is performed slice by slice, limiting the potential of 3-D data to give an overall impression of cartilage biochemistry. We previously developed a computational algorithm to produce unfolded, or "planar," dGEMRIC maps of acetabular cartilage, but have neither assessed their application nor determined whether MRI-based grading of cartilage damage or dGEMRIC measurements predict intraoperative findings in hips with symptomatic femoroacetabular impingement (FAI). QUESTIONS/PURPOSES: (1) Does imaging-based assessment of acetabular cartilage damage correlate with intraoperative findings in hips with symptomatic FAI? (2) Does the planar dGEMRIC map improve this correlation? (3) Does the planar map improve the correlation between the dGEMRIC index and MRI-based grading of cartilage damage in hips with symptomatic FAI? (4) Does the planar map improve imaging-based evaluation time for hips with symptomatic FAI? METHODS: We retrospectively studied 47 hips of 45 patients with symptomatic FAI who underwent hip surgery between 2009 and 2013 and had a 1.5-T 3-D dGEMRIC scan within 6 months preoperatively. Our cohort included 25 males and 20 females with a mean ± SD age at surgery of 29 ± 11 years. Planar dGEMRIC maps were generated from isotropic, sagittal oblique TrueFISP and T1 sequences. A pediatric musculoskeletal radiologist with experience in hip MRI evaluated studies using radially reformatted sequences. For six acetabular subregions (anterior-peripheral [AP]; anterior-central [AC]; superior-peripheral [SP]; superior-central [SC]; posterior-peripheral [PP]; posterior-central [PC]), modified Outerbridge cartilage damage grades were recorded and region-of-interest T1 averages (the dGEMRIC index) were measured. Beck's intraoperative cartilage damage grades were compared with the Outerbridge grades and dGEMRIC indices. For a subset of 26 hips, 13 were reevaluated with the map and 13 without the map, and total evaluation times were recorded. RESULTS: There were no meaningful differences in the correlations obtained with versus without referencing the planar maps. Planar map-independent Outerbridge grades had a notable (p < 0.05) Spearman's rank correlation (ρ) with Beck's grades that was moderate in AP, SC, and PC (0.3 < ρ < 0.5) and strong in SP (ρ > 0.5). For map-dependent Outerbridge grades, ρ was moderate in AP, AC, and SC and strong in SP. Map-independent dGEMRIC indices had a ρ with Beck's grades that was moderate in AP and SC (-0.3 > ρ > -0.5) and strong in SP (ρ < -0.5). For map-dependent dGEMRIC indices, ρ was moderate in SC and strong in SP. Similarly, there were no meaningful, map-dependent differences in the correlations. When comparing Outerbridge grades and dGEMRIC indices, there were notable correlations across all subregions. Without the planar map, ρ was moderate in AC and PC and strong in AP, SP, SC, and PP. With the map, ρ was strong in all six subregions. In AC, there was a notable map-dependent improvement in this correlation (p < 0.001). Finally, referencing the planar dGEMRIC map during evaluation was associated with a decrease in mean evaluation time, from 207 ± 32 seconds to 152 ± 33 seconds (p = 0.001). CONCLUSIONS: Our work challenges the weak correlation between dGEMRIC and intraoperative findings of cartilage damage that was previously reported in hips with symptomatic FAI, suggesting that dGEMRIC has potential diagnostic use for this patient population. The planar dGEMRIC maps did not meaningfully alter the correlation of imaging-based evaluation of cartilage damage with intraoperative findings; however, they notably improved the correlation of dGEMRIC and MRI-based grading in AC, and their use incurred no additional time cost to imaging-based evaluation. Therefore, the planar maps may improve dGEMRIC's use as a continuous proxy for an otherwise discrete and simplified MRI-based grade of cartilage damage in hips with symptomatic FAI. LEVEL OF EVIDENCE: Level III, diagnostic study.

An agent-based model for mRNA export through the nuclear pore complex.

mRNA export from the nucleus is an essential step in the expression of every protein- coding gene in eukaryotes, but many aspects of this process remain poorly understood. The density of export receptors that must bind an mRNA to ensure export, as well as how receptor distribution affects transport dynamics, is not known. It is also unclear whether the rate-limiting step for transport occurs at the nuclear basket, in the central channel, or on the cytoplasmic face of the nuclear pore complex. Using previously published biophysical and biochemical parameters of mRNA export, we implemented a three-dimensional, coarse-grained, agent-based model of mRNA export in the nanosecond regime to gain insight into these issues. On running the model, we observed that mRNA export is sensitive to the number and distribution of transport receptors coating the mRNA and that there is a rate-limiting step in the nuclear basket that is potentially associated with the mRNA reconfiguring itself to thread into the central channel. Of note, our results also suggest that using a single location-monitoring mRNA label may be insufficient to correctly capture the time regime of mRNA threading through the pore and subsequent transport. This has implications for future experimental design to study mRNA transport dynamics.

Putative N-acylphosphatidylethanolamine synthase from Arabidopsis thaliana is a lysoglycerophospholipid acyltransferase.

AT1G78690, a gene found in Arabidopsis thaliana, has been reported to encode a N-acyltransferase that transfers an acyl chain from acyl-CoA to the headgroup of phosphatidylethanolamine (PE) to form N-acylphosphatidylethanolamine (N-acyl-PE). Our investigation suggests that At1g78690p is not a PE-dependent N-acyltransferase but is instead a lysoglycerophospholipid O-acyltransferase. We overexpressed AT1G78690 in Escherichia coli, extracted the cellular lipids, and identified the accumulating glycerophospholipid as acylphosphatidylglycerol (acyl-PG). Electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-MS) analysis yielded [M - H](-) ions, corresponding by exact mass to acyl-PG rather than N-acyl-PE. Collision-induced dissociation mass spectrometry (MS/MS) yielded product ions consistent with acyl-PG. In addition, in vitro enzyme assays using both (32)P- and (14)C-radiolabeled substrates showed that AT1G78690 acylates 1-acyllysophosphatidylethanolamine (1-acyllyso-PE) and 1-acyllysophosphatidylglycerol (1-acyllyso-PG), but not PE or phosphatidylglycerol (PG), to form a diacylated product that co-migrates with PE and PG, respectively. We analyzed the diacylated product formed by AT1G78690 using a combination of base hydrolysis, phospholipase D treatment, ESI-MS, and MS/MS to show that AT1G78690 acylates the sn-2-position of 1-acyllyso-PE and 1-acyllyso-PG.