HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity.

BACKGROUND: One of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 ("A2") that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH). METHODS: A CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2- HER2+ lung cancer cell lines but spare A2+ HER2+ lung cancer cell-lines with high specificity. The extensive analysis of lead candidates included T-cell activation and killing, assays of reversibility and durability in sequential challenges, target cell specificity in mixed 3D spheroids and 2D cultures, and the characterization of CAR expression level and cell-trafficking. RESULTS: A leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the 'on' and 'off' cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2+ cells in admix culture through aCAR dependent and independent mechanisms. LIR1 NOT gate CAR-T cells conferred protection against H1703-A2+ tumors and high efficacy against H1703-A2- tumors in-vivo. We observed that the iCAR is inactive in A2+ donors due to cis-binding, but Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout of HLA-A fully restored iCAR activity. CONCLUSIONS: We have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.

A pragmatic randomized prospective trial of cooled radiofrequency ablation of the medial branch nerves versus facet joint injection of corticosteroid for the treatment of lumbar facet syndrome: 12 month outcomes.

BACKGROUND: Lumbar medial branch radiofrequency ablation (LRFA) and intraarticular facet steroid injections (FJI) are commonly performed for recalcitrant facet joint-mediated pain. However, no study has compared clinical outcomes of the two treatments in patients selected using dual medial branch blocks (MBBs) with an 80% relief threshold. OBJECTIVE: Compare the effectiveness of cooled LRFA (C-LRFA) to FIJ as assessed by pain and functional improvements. DESIGN: Prospective randomized comparative trial. METHODS: Patients with dual MBB-confirmed facet joint-mediated pain were randomized to receive C-LRFA or FIJ. Outcomes were assessed at 1, 3, 6, and 12 months. The primary outcome was ≥50% improvement in numerical pain rating scale (NPRS) score at 3 months. Secondary outcomes included ≥30% Oswestry Disability Index (ODI) improvement and Patient Global Impression of Chance (PGIC) ≥6 points, among others. Data were analyzed using contingency tables and mixed-effects logistic regression models. RESULTS: Of 1128 patients screened, 32 met eligibility criteria, were randomized, and received their allocated study treatment. In total, 20 (62.5%) and 12 (37.5%) participants received C-LRFA and FIJ, respectively. In the C-LRFA group, 70% (95% CI 48-85), 55% (95% CI 34-74), and 45% (95% CI 26-66) of participants met the NPRS responder definition, compared to 25% (95%CI 9-53), 25% (95% CI 9-53), and 17% (95% CI 5-45) in the FJI group at 3, 6, and 12 months, respectively (P = .014 at 3 months). The PGIC responder proportion was higher in the C-LRFA compared to FJI group at 3 and 6 months (P < .05). CONCLUSIONS: C-LRFA demonstrated superior success rates compared to FJI across pain and functional outcome domains. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov (NCT03614793); August 3, 2018.

Cardiovascular Disease Risk Factors Predict the Development and Numbers of Common Musculoskeletal Disorders in a Prospective Cohort.

OBJECTIVE: The aim of the study is to assess risk of common musculoskeletal disorders (MSDs) based on cardiovascular disease (CVD) risk scores. METHODS: Data from a 9-year prospective cohort of 1224 workers in three states were analyzed. Baseline data included questionnaires, structured interviews, physical examinations, anthropometric measurements, nerve conduction studies, and individualized measurement of job physical factors. Monthly follow-ups were conducted. Framingham risk scores were calculated. A priori case definitions were constructed for carpal tunnel syndrome, lateral epicondylopathy, medial epicondylopathy, and rotator cuff tendinopathy. RESULTS: Adjusted RRs for one or more MSDs increased to 3.90 (95% confidence interval, 2.20-6.90) among those with 10-year cardiovascular disease risk scores greater than 15% and 17.4 (95% confidence interval, 3.85-78.62) among those with more than 4 disorders. CONCLUSIONS: Cardiovascular disease factors are strongly associated with the subsequent development of common MSDs. Risks among those with multiple MSDs are considerably stronger.

Evaluating the Taste Masking Ability of Two Novel Dispersible Tablet Platforms Containing Zinc Sulfate and Paracetamol Reconstituted in a Breast Milk Substitute.

Milk is often used as a dispersion medium for medicines administration in young children but its taste-masking ability is unknown. A human taste panel was conducted to assess the potential of infant formula milk (Aptamil® 1) to mask the taste of two model WHO priority medicines, zinc sulfate and paracetamol, manufactured as dispersible tablets. Simultaneously, the palatability of powder blends of the tablet platforms was assessed. Twenty healthy adult volunteers performed a swirl-and-spit assessment of placebos and API-containing blends in either a lactose-based or a mannitol-based dispersible tablet platform, reconstituted in 10 mL of either water or Aptamil® 1. Eighteen samples were rated for aversion using a 100-mm Visual Analogue Scale, grittiness using a 5-point Likert scale, and "acceptability-as-a-medicine" evaluated as: "Would you find this sample acceptable to swallow as a medicine?" with binary answers of Yes/No. The API-containing formulations were more aversive than the placebos; the paracetamol-containing samples being more aversive than zinc sulfate samples. The platforms themselves were not aversive. Non-gritty samples had four-fold greater odds of being acceptable as a medicine. Aptamil® 1 masked the taste of zinc sulfate in the mannitol-based formulation but did not mask the taste of paracetamol in either platform, suggesting a limited taste-masking ability, which may be API and formulation dependent.

One-year results from a randomized comparative trial of targeted steroid injection via epidural catheter versus standard transforaminal epidural injection for the treatment of unilateral cervical radicular pain.

OBJECTIVES: The objective of this study was to evaluate the long-term effectiveness of catheter-directed cervical interlaminar epidural steroid injection with triamcinolone compared with cervical transforaminal steroid injection with dexamethasone for the treatment of refractory unilateral radicular pain. DESIGN: Prospective, randomized, comparative trial. METHODS: The primary outcome was the proportion of participants with ≥50% Numeric Rating Scale 'dominant pain' (the greater of arm vs neck) reduction from baseline. Secondary outcomes included ≥30% Neck Disability Index reduction and Patient Global Impression of Change response indicating 'much improved' or 'very much improved'. RESULTS: Data from 117 participants (55.6% women; 52.3±12.5 years of age; body mass index, 28.2±6.5 kg/m2) were analyzed. The proportion of participants who experienced ≥50% pain reduction at 1 month, 3 months, and 6 months has been previously reported. At 1 year, 61.2% (95% CI, 46.9% to 73.9%) of the catheter group compared with 51.9% (95% CI, 38.4% to 65.2%) of the transforaminal group reported ≥50% 'dominant' pain reduction (p=0.35). The proportion of participants who experienced ≥30% improvement in Neck Disability Index score was 60.4% (95% CI, 45.9% to 73.3%) and 47.1% (95% CI, 33.7% to 60.8%) in the catheter and transforaminal groups (p=0.18). Patient Global Impression of Change improvement was similar in both groups: 60.5% (95% CI, 44.2% to 74.8%) and 57.5% (95% CI, 41.7% to 71.9%) of the catheter and transforaminal groups reported being 'much improved' or 'very much improved', respectively (p=0.79). CONCLUSION: Both cervical catheter-directed interlaminar epidural injection and cervical transforaminal steroid injection were effective in reducing pain and disability in the majority of participants with refractory unilateral cervical radiculopathy for up to 1 year.

Changes in Interventional Pain Physician Decision-Making, Practice Patterns, and Mental Health During the Early Phase of the SARS-CoV-2 Global Pandemic.

BACKGROUND AND OBJECTIVES: The novel coronavirus outbreak (SARS-CoV-2) began in late 2019 and dramatically impacted health care systems. This study aimed to describe the impact of the early phase of the pandemic on physician decision-making, practice patterns, and mental health. METHODS: An anonymous survey was distributed to physician members of the Spine Intervention Society (SIS) on March 24 and April 7, 2020. Respondents provided information regarding changes in clinical volume, treatment, and mental health (Patient Health Questionnaire [PHQ-4]) before April 10, 2020. RESULTS: Of the 1,430 individuals who opened the survey, 260 completed it (18.2%). Overall clinical and procedural volume decreased to 69.6% and 13.0% of prepandemic volume, respectively. Mean in-person clinic visits were reduced to 17.7% of total prepandemic clinic volume. Ongoing clinical visits were predominantly completed via telemedicine (video) or telephone (74.5%), rather than in-person (25.5%). Telemedicine and telephone visits represented 24.6% and 27.3% of prepandemic clinical volume, respectively. Respondents decreased in-person visits of select groups of high-risk patients by 85.8-94.6%. Significantly more providers reported increasing rather than decreasing prescriptions of the following medications: opioids (28.8% vs 6.2% of providers, P < 0.001), muscle relaxants (22.3% vs 5.4%, P < 0.001), neuropathic pain medications (29.6% vs 3.8%, P < 0.001), and acetaminophen (26.2% vs 4.2%, P < 0.001). Respondents' mean PHQ-4 score was 3.1, with 19% reporting moderate or severe psychological distress. Several demographic factors were significantly associated with practice changes. CONCLUSIONS: The novel coronavirus pandemic dramatically altered the practice and prescribing patterns of interventional pain physicians.

Does the Contrast Dispersion Pattern During Fluoroscopically Guided Cervical Transforaminal Epidural Steroid Injection Predict Short-Term Pain and Functional Outcomes? An Exploratory Analysis of Prospective Cohort Data.

SUMMARY OF BACKGROUND DATA: No study has evaluated the relationship between contrast dispersion patterns and outcomes after fluoroscopically guided cervical transforaminal epidural steroid injection (CTFESI). OBJECTIVES: Determine whether contrast dispersion patterns predict pain and functional outcomes after CTFESI. METHODS: Secondary analysis of data collected during two prospective studies of CTFESI for the treatment of refractory radicular pain. Contrast dispersion patterns visualized by true anteroposterior (AP) projections during CTFESIs were categorized by flow: 1) completely external to the lateral border of the neuroforamen (zone 1); 2) within the neuroforamen but without entry into the lateral epidural space (zone 2); and 3) with extension into the lateral epidural space (zone 3). At baseline and at 1 month post-CTFESI, neck pain, arm pain, and "dominant index pain" (the greater of arm or neck pain) were evaluated using a numeric rating scale (NRS); physical function was assessed using the Five-Item Version of the Neck Disability Index (NDI-5). RESULTS: One-month post-CTFESI, neck pain, arm pain, and "dominant index pain" reductions of ≥50% were observed in 39.4% (95% confidence interval [CI], 28.2-51.8), 55.6% (95% CI, 43.0-67.5), and 44.1% (95% CI, 32.7-56.2) of participants, respectively. Regarding "dominant index pain," 72.7% (95% CI, 40.8-91.2), 39.4% (95% CI, 24.2-57.0), and 37.5% (95% CI, 20.5-58.2) of participants reported ≥50% pain reduction when zone 1, zone 2, and zone 3 contrast flow patterns were observed. Contrast dispersion zone was not significantly associated with subgroup differences in neck pain, arm pain, or NDI-5 scores (P>0.05). CONCLUSION: Improvements in pain and function 1 month after treatment with CTFESI did not differ significantly based on the contrast dispersion pattern. Future study is needed to confirm or refute these findings in other procedural settings, in broader patient populations, and with longer-term outcome assessment.

A Randomized Comparative Trial of Targeted Steroid Injection via Epidural Catheter vs Standard Transforaminal Epidural Injection for the Treatment of Unilateral Cervical Radicular Pain: Six-Month Results.

OBJECTIVES: Compare the effectiveness of catheter-directed cervical interlaminar epidural steroid injection (C-CIESI) with triamcinolone to cervical transforaminal steroid injection (CTFESI) with dexamethasone for the treatment of refractory unilateral radicular pain. DESIGN: Prospective, randomized, comparative trial. METHODS: Primary outcome: proportion of participants with ≥50% numeric rating scale pain score reduction from baseline "dominant pain" (the greater of arm vs neck) at one month postinjection. Secondary outcomes: ≥30% Neck Disability Index (NDI-5) reduction and Patient Global Impression of Change (PGIC) response indicating "much improved" or "very much improved." RESULTS: One hundred twenty participants (55.6% females, 52.3 ± 12.5 years of age, BMI 28.2 ± 6.5 kg/m2), were enrolled. The proportions of participants who experienced ≥50% pain reduction at one, three, and six months were 68.5% (95% CI = 54.9-79.5%), 59.3% (95% CI = 45.7-71.6%), and 60.8% (95% CI = 46.7-73.2%), respectively, in the C-CIESI group compared with 49.1% (95% CI = 36.4-62.0%), 46.4% (95% CI = 33.8-59.6%), and 51.9% (95% CI = 38.4-65.2%), respectively, in the CTFESI group. The between-group difference at one month was significant (P = 0.038). The proportions of participants who experienced a ≥30% NDI-5 score improvement were 64.0% (95% CI = 49.8-76.1%) and 54.9% (95% CI = 41.1-68.0%) in the C-CIESI and CTFESI groups (P = 0.352). Participants reported similar PGIC improvement in both groups: At six months, 53.2% (95% CI 38.9-67.1%) and 54.5% (95% CI = 39.7-68.7%) of the C-CIESI and CTFESI groups reported being "much improved" or "very much improved," respectively (P = 0.897). CONCLUSIONS: Both C-CIESI with triamcinolone and CTFESI with dexamethasone are effective in reducing pain and disability associated with refractory unilateral cervical radiculopathy in a substantial proportion of participants for at least six months.

Effect of low-dose lidocaine on objective upper extremity strength and immediate pain relief following cervical interlaminar epidural injections: a double-blinded randomized controlled trial.

BACKGROUND: Low-dose lidocaine is a common diluent for analgesia following cervical interlaminar epidural steroid injection (CIESI). Concerns with this practice exist. A single-arm cohort reported that 20% of patients develop postprocedural upper extremity weakness when using lidocaine as a diluent. Furthermore, a high-cervical spinal block with unintended intrathecal or subdural administration is possible. OBJECTIVE: Determine if low-dose lidocaine as a diluent during CIESI causes clinically meaningful (1) upper extremity weakness and (2) immediate pain relief when compared with saline. DESIGN: Double-blinded randomized control trial. METHODS: Patients with cervical radicular pain scheduled for CIESI were enrolled. Participants received lidocaine (CIESI-L) or saline (CIESI-S) as a diluent for the epidural injectate. Myotomal strength was measured with dynamometry before and between 20 and 30 min after CIESI. Pre-pain and post-pain scores were obtained. Primary and secondary outcomes were post-CIESI weakness of ≥20% (minimal clinically important difference (MCID)) in >1 myotome and ≥50% pain reduction on the numerical scale. RESULTS: 120 participants (64 females (53%), mean age, 56 (SD 13.7) years) completed the study and were analyzed (CIESI-L n=60; CIESI-S n=60). There was no significant between-group difference in the proportion of participants with postprocedural weakness, CIESI-L 41.7% (95% CI, 29.8% to 54.5%), CIESL-S 50% (95% CI, 37.5% to 62.5%). Between-group comparison showed no significant difference in pain reduction, relative risk 1.53 (95% CI, 0.82 to 2.86). CONCLUSION: Low-dose lidocaine as a diluent in CIESI does not significantly increase the risk of post-CIESI myotomal weakness when compared with saline, but also does not substantially increase the likelihood of immediate, meaningful pain relief. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov (NCT03127137); December 26, 2017.

The Effectiveness of Cervical Medial Branch Radiofrequency Ablation for Chronic Facet Joint Syndrome in Patients Selected by a Practical Medial Branch Block Paradigm.

BACKGROUND: Cervical medial branch radiofrequency ablation (CMBRFA) is an effective treatment for facetogenic pain in patients selected by Spine Intervention Society (SIS) guidelines of 100% symptom improvement with dual medial branch blocks (MBBs) ± placebo block. Patient selection for CMBRFA using ≥80% symptom improvement after dual concordant MBBs is common; however, this has not been studied. OBJECTIVE: To evaluate the effectiveness of CMBRFA and compare outcomes in individuals selected by 80-99% vs 100% symptom improvement with dual concordant MBBs. DESIGN: Cross-sectional cohort study. METHODS: Medical records of 87 consecutive patients were reviewed; 50 met inclusion criteria. A standardized telephone survey was performed at six or more months post-CMBRFA to query numerical rating scale (NRS) pain and patient global impression of change (PGIC) scores. The primary outcomes were the proportion of patients reporting ≥50% reduction of index pain. RESULTS: At a mean follow-up time of 16.9 ± 12.7 months, 54% (95% confidence interval [CI] = 35-73%) and 54% (95% CI = 32-74%) of the 80-99% and 100% MBBs groups, respectively, reported ≥50% pain reduction. Between-group comparison showed a relative risk of 0.99 (95% CI = 0.59-1.66) for meeting the primary outcome. Seventy percent (95% CI = 56-81%) of patients reported a PGIC score consistent with "improved or very much improved" at follow-up. CONCLUSIONS: CMBRFA is an effective treatment in patients who report ≥80% symptom relief with dual concordant MBBs. The present study demonstrated an overall ≥50% pain reduction rate of 54% and no significant difference between those selected by 80-99% vs 100% symptom relief with dual concordant MBBs.

The Effectiveness of Radiofrequency Ablation of Medial Branch Nerves for Chronic Lumbar Facet Joint Syndrome in Patients Selected by Guideline-Concordant Dual Comparative Medial Branch Blocks.

OBJECTIVES: Although the effectiveness of lumbar medial branch radiofrequency ablation (RFA) for the treatment of zygapophyseal joint (z-joint)-mediated low back pain has been characterized, few studies have described outcomes in patients selected using a guideline-concordant paradigm of ≥80% pain relief with dual comparative medial branch blocks (MBBs). We investigated long-term treatment outcomes of patients selected according to this paradigm. DESIGN: Cross-sectional cohort study. METHODS: The medical records of 111 consecutive patients were reviewed; 85 met inclusion criteria. A standardized telephone survey was used to capture current numerical rating scale (NRS) and Patient Global Impression of Change (PGIC) scores. The primary outcome was the proportion of patients reporting ≥50% reduction of index pain. Binary logistic regression analysis was performed to explore associations between the primary outcome and covariates, including age, duration of pain, presence of scoliosis, degenerative spondylolisthesis, and >75% disc height loss. RESULTS: At six to 12, 12-24, and >24 months, 63.2% (95% confidence interval [CI] = 41-85%), 65.6% (95% CI = 49-82%), and 44.1% (95% CI = 27-61%) of patients reported a ≥50% pain reduction (P = 0.170), respectively. At a minimum of six months, 70.6% of patients reported a pain reduction of two or more points (minimally clinically important change), and 54.1% reported a PGIC score consistent with "much improved" or better. Older age and a smaller Cobb angle were associated with a ≥50% pain reduction (P < 0.05). CONCLUSION: Lumbar medial branch RFA is an effective, durable treatment for a significant proportion of patients with recalcitrant lumbar z-joint pain when candidacy is determined by the guideline-concordant paradigm of ≥80% pain relief with dual comparative MBBs.

Interventions for medically unexplained symptoms in the emergency department: a critical literature review.

Medically unexplained symptoms, defined as physical symptoms for which no organic pathology can be found, represent 4% of all emergency department attendances annually. The standard management of these patients involves extensive investigation to rule out organic pathology, followed by simple reassurance. We conducted a literature review to determine if there was any intervention that could improve these patient's symptoms and reduce emergency department attendances. A search of MEDLINE, EMBASE and PsycINFO yielded 1612 unique citations, of which six studies met inclusion criteria. The studies were heterogeneous in terms of the participants involved, interventions tested and conclusions drawn. Three studies tested cognitive behavioural therapy, with two finding a reduction in emergency department attendance. Overall, evidence regarding interventions for patients with medically unexplained symptoms in the emergency department is limited and of a variable quality, despite comprising 4% of emergency department attendances. Further research is required to determine the best intervention for this challenging patient group.

A Novel Technical Protocol for Improved Capture of the Genicular Nerves by Radiofrequency Ablation.

BACKGROUND: Fluoroscopically guided cooled genicular nerve radiofrequency ablation (RFA) is an increasingly performed procedure for chronic, refractory knee pain due to osteoarthritis. Traditionally, partial sensory denervation has been accomplished through ablation of the superomedial, superolateral, and inferomedial genicular nerves. However, recent cadaveric studies have demonstrated additional sensory nerves and significant anatomic variation that impact current protocols. OBJECTIVE: We describe an updated cooled genicular nerve radiofrequency ablation protocol that accounts for varied nerve location of the superomedial, superolateral, and inferomedial genicular nerves, as well as capture of the terminal articular branches of the nerves to the vastus intermedius, vastus lateralis, and vastus medialis. Furthermore, we describe an adjusted technique for inferomedial genicular nerve capture that mitigates the risk of pes anserine tendon injury. DESIGN: Technical report and brief literature review. METHODS: Cadaveric studies relating to the sensory innervation of the anterior knee joint were reviewed, and a more accurate and comprehensive cooled genicular nerve radiofrequency ablation (CRFA) protocol is proposed. CONCLUSIONS: Based on recent, rigorous anatomic dissections of the knee, the proposed genicular nerve CRFA protocol will provide more complete sensory denervation and potentially improve clinical outcomes. Prospective studies will be needed to confirm the hypothesis that this protocol will result in improved effectiveness and safety of genicular nerve RFA.

Responsiveness of the Patient-Reported Outcomes Measurement Information System (PROMIS), Neck Disability Index (NDI) and Oswestry Disability Index (ODI) instruments in patients with spinal disorders.

BACKGROUND CONTEXT: The Patient-Reported Outcomes Information System (PROMIS) instruments are an important advancement in the use of PROs, but need to be evaluated with longitudinal data to determine whether they are responsive to change in specific clinical populations. PURPOSE: The purpose of this study was to assess the responsiveness of the PROMIS Physical Function (PF), PROMIS Pain Interference (PI), Neck Disability Index (NDI), and the Oswestry Disability Index (ODI). STUDY DESIGN/SETTING: This study entailed prospective data collection from consecutive patients aged 18 and older, visiting a university-based orthopaedic spine clinic between October 2013 and January 2017. PATIENT SAMPLE: A total of 763 participants in the sample had a mean age of 58 (SD = 15) years and the sample was 50.2% male and 92.8% Caucasian. OUTCOME MEASURES: The PROMIS PF and PROMIS PI Computerized Adaptive Tests along with either the NDI or ODI instruments were administered on tablet computers before clinic visits. Global rating of change questions relating to pain and function levels was also administered. METHODS: Baseline scores were compared with follow-up scores at four different time-points from 3-months to 6-months and beyond. Patient demographics, mean scores, paired-sample t tests, Standardized Response Mean (SRM), and Effect Size (ES) were analyzed to determine instrument responsiveness. This project was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number U01AR067138 and the authors have no conflicts of interest to disclose. RESULTS: The PROMIS instruments were strongly correlated with each other as well as with the NDI and ODI. Responsiveness was significant on all four instruments at every time-point assessed (paired sample t tests ranged from p < .001 to p = .049). SRM's were large and over 0.94 for every instrument at every time-point. Cohen's d ES were large and over 0.96 for all at all time-points, except for the NDI which had ES ranging from 0.74 to 0.83. This study showed large effect sizes and responsiveness of the PROMIS PF, PROMIS PI, NDI and ODI in a population of orthopaedic patients with spine pathologies. CONCLUSION: This study demonstrates strong responsiveness of the PROMIS PF and PROMIS PI in a spine clinic population.

What Are the MCIDs for PROMIS, NDI, and ODI Instruments Among Patients With Spinal Conditions?

BACKGROUND: As new Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are incorporated into clinical practice, determining how large a change on these instruments represents a clinically relevant difference is important; the metric that describes this is the minimum clinically important difference (MCID). Prior research on MCIDs of the Neck Disability Index (NDI) and Oswestry Disability Index (ODI) has produced values ranging from 5 to 10 points, but these measures have not been presented in relation to MCID values of PROMIS instruments. QUESTIONS/PURPOSES: To establish a comprehensive repository of MCID values calculated both with distribution-based and anchor-based methods for four outcomes instruments in spine care, we asked: (1) What are the MCIDs of the PROMIS Physical Function (PF); (2) the PROMIS Pain Interference (PI); (3) the NDI; and (4) the ODI among spine patients? METHODS: We conducted a prospective study of previously tested diagnostic measures on 1945 consecutive patients with a reference standard applied. All patients aged 18 years and older visiting an orthopaedic spine clinic between October 2013 and January 2017 completed the PROMIS PF and PI, NDI, and ODI on tablet computers before their clinic visits. Patients were grouped by change level (self-report of meaningful change versus slight or no change) using an anchor question in comparison to baseline. Descriptive statistics, two anchor-based MCID values (mean change and receiver operating characteristic curve), and five distribution-based values (SD at 1/2 and 1/3 values and minimum detectable change [MDC] at 90%, 95%, and 99%) were analyzed four different times between 3 months and > 6 months of followup. A total of 1945 included patients with a wide range of spine conditions and varying treatments had a mean age of 58 years (SD = 15.5), were 51% (988 of 1945) male, 90% (1754 of 1945) self-identified as white, and 5% (94 of 1945) as Hispanic with 1% to 2% of patients refusing participation. RESULTS: The PROMIS PF mean change scores in the changed group (much worse, worse, improved, or much improved) ranged between 7 and 8 points. MCID values ranged from 3 to 23 points depending on the method of calculation with a median of 8. For the PROMIS PI, mean change scores ranged from 8 to 9 points and MCID values from 1 to 24 points with a median of 8. For the NDI, mean change scores ranged from 13 to 18 points and MCID values ranged from 6 to 43 points with a median of 18. For the ODI, mean change ranged from 17 to 19 points and MCID values ranged from 7 to 51 points with a median of 24. For each instrument, distribution-based SD yielded the smallest values, followed by anchor-based methods, with MDC yielding the largest MCID values. CONCLUSIONS: This study uses a range of methods for determining MCIDs of the PROMIS PF and PI, NDI, and ODI from anchor-based to distribution-based methods. MCIDs do not have a static value for a given outcome measure, but have a range of values and are dependent on the method calculated. The lowest MCIDs identified for the NDI and ODI are consistent with prior studies, but those at the upper range are much higher. Anchor-based methods are thought to be most relevant in the clinical setting and are more easily understood by clinicians, whereas the distribution-based MCIDs are useful in understanding population breadth. Lower MCID values may be most appropriate for screening purposes or low-risk effects, and the median or higher MCID values should be used for high-risk effects or outcomes. LEVEL OF EVIDENCE: Level I, diagnostic study.

Median Nerve Symptoms, Signs, and Electrodiagnostic Abnormalities Among Working Adults.

INTRODUCTION: Diagnostic screening tests for carpal tunnel syndrome (CTS) have not been rigorously assessed in large populations. METHODS: This study is a cross-sectional analysis from a prospective cohort study. Participants' (n = 1,194) symptoms and disease prevalence were measured. Sensitivity, specificity, and positive and negative predictive values (NPVs) were calculated. RESULTS: When defining CTS as tingling/numbness in at least two median nerve-served digits and an abnormal median nerve conduction study, the prevalence was 8.9%. The sensitivity of paresthesias with nocturnal awakening was 77.4%. The sensitivity of the Phalen sign was 52.8% and that of the Hoffman-Tinel sign was only 37.7%. DISCUSSION: The highest sensitivity (77.4%) for a case definition of CTS in this population of workers was for nocturnal tingling/numbness in a median nerve distribution, and the highest specificity (97.5%) was for continuous tingling/numbness. The Phalen sign has a sensitivity of 52.8% and NPV of 95%, suggesting that the NPV is of particular diagnostic value. Hoffman-Tinel signs seem primarily helpful for the NPV (93.7%). LEVEL OF EVIDENCE: Level II diagnostic study.

The Relationship of PROMIS Pain Interference and Physical Function Scales.

Objectives: To examine the relationship between the Patient Reported Outcome Measurement Information System (PROMIS) Pain Interference (PI) and PROMIS Physical Function (PF) scales in patients with spinal pain at a university spine center. Design: Retrospective analysis of prospectively collected patient-reported outcome data at a university spine clinic. Pearson correlation was done to examine the relationship of the PROMIS PF and PROMIS PI scores. Age, gender, and race were analyzed by subgroups on the PROMIS Physical Function and Pain Interference score. Linear regression analyzed predictive relationships. Statistical significance was set at P < 0.05. Results: A total of 1,992 participants completed an assessment, with 1,923 completing the PF CAT and 1,927 the PI CAT. Participants' mean age was 52.8 years (range = 18-94 years, SD = 6.5 years). Correlation analysis of the PROMIS PF with the PROMIS PI showed a Pearson correlation value of -0.717 (P < 0.05). There was a strong linear relationship with a high negative correlation between PF CAT and PI CAT. The PI CAT predicted PF CAT scores (ß = -0.707, P < 0.001). Conclusions: For patients with pain from spinal origin, there is a strong negative correlation between self-reported physical function and pain interference related to physical, social, and mental health. The predictive relationship of function from pain scores supports the PROMIS PI being used as an important adjunct measure of physical function in patients with spinal pain.