A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has claimed approximately 5 million lives and 257 million cases reported globally. This virus and disease have significantly affected people worldwide, whether directly and/or indirectly, with a virulent pathogen that continues to evolve as we race to learn how to prevent, control, or cure COVID-19. The focus of this review is on the SARS-CoV-2 virus' mechanism of infection and its proclivity at adapting and restructuring the intracellular environment to support viral replication. We highlight current knowledge and how scientific communities with expertize in viral, cellular, and clinical biology have contributed to increase our understanding of SARS-CoV-2, and how these findings may help explain the widely varied clinical observations of COVID-19 patients.

Multicenter study evaluating factors associated with treatment outcome for low back pain injections.

BACKGROUND: There has been a worldwide surge in interventional procedures for low back pain (LBP), with studies yielding mixed results. These data support the need for identifying outcome predictors based on unique characteristics in a pragmatic setting. METHODS: We prospectively evaluated the association between over two dozen demographic, clinical and technical factors on treatment outcomes for three procedures: epidural steroid injections (ESIs) for sciatica, and sacroiliac joint (SIJ) injections and facet interventions for axial LBP. The primary outcome was change in patient-reported average pain intensity on a numerical rating scale (average NRS-PI) using linear regression. For SIJ injections and facet radiofrequency ablation, this was average LBP score at 1 and 3 months postprocedure, respectively. For ESI, it was average leg pain 1- month postinjection. Secondary outcomes included a binary indicator of treatment response (success). RESULTS: 346 patients were enrolled at seven hospitals. All groups experienced a decrease in average NRS-PI (p<0.0001; mean 1.8±2.6). There were no differences in change in average NRS-PI among procedural groups (p=0.50). Lower baseline pain score (adjusted coefficient -0.32, 95% CI -0.48 to -0.16, p<0.0001), depressive symptomatology (adjusted coefficient 0.076, 95% CI 0.039 to 0.113, p<0.0001) and obesity (adjusted coefficient 0.62, 95% CI 0.038 to 1.21, p=0.037) were associated with smaller pain reductions. For procedural outcome, depression (adjusted OR 0.94, 95% CI 0.91, 0.97, p<0.0001) and poorer baseline function (adjusted OR 0.59, 95% CI 0.36, 0.96, p=0.034) were associated with failure. Smoking, sleep dysfunction and non-organic signs were associated with negative outcomes in univariate but not multivariate analyses. CONCLUSIONS: Identifying treatment responders is a critical endeavor for the viability of procedures in LBP. Patients with greater disease burden, depression and obesity are more likely to fail interventions. Steps to address these should be considered before or concurrent with procedures as considerations dictate. TRIAL REGISTRATION NUMBER: NCT02329951.

Biomechanical Comparison of Titanium Locking Fragment-Specific and Volar Locking Plates for AO B1 and B2 Fractures of the Distal Radius.

PURPOSE: This biomechanical study compared the stability of volar locking plates (VLPs) and locking fragment-specific (LFS) dorsal and radial styloid plates for the fixation of dorsal (AO 23-B2) and radial styloid (AO 23-B1) shear fractures of the distal radius, respectively. METHODS: Two groups of 6 composite radii were fixed with a VLP or an LFS dorsal plate over a simulated dorsal shear fracture. Two additional groups of 6 radii received the same VLP or an LFS radial plate to fix a radial styloid fracture. Each plated radius was tested under cyclic axial compression by a servohydraulic testing machine that recorded axial displacement per cycle. Construct stiffness was calculated from the slope of the force-displacement curve. RESULTS: In the dorsal shear fracture model, the dorsal LFS plate exhibited less displacement than the VLP (0.32 ± 0.04 vs 0.43 ± 0.07 mm, respectively) and showed greater average stiffness (645 ± 64 vs 433 ± 88 N/mm, respectively). Plate type was responsible for 53.1% of the variation in displacement and 68.6% of the variation in stiffness. In the radial styloid fracture model, variations due to number of cycles elapsed and plate type were similar for displacement and stiffness in both groups. The average stiffness during cyclical nondestructive testing was 566 ± 45 and 573 ± 60 N/mm for VLP and LFS radial plating groups, respectively. CONCLUSIONS: For AO 23-B2 (dorsal rim) fractures, the dorsal LFS plates exhibited significantly less displacement and greater stiffness in axial loading than VLPs. For AO 23-B1 (radial styloid) fractures, the VLP displayed similar displacement and stiffness to the radial LFS plates. CLINICAL RELEVANCE: All constructs tested could be expected to withstand axial compressive forces typical of early postoperative rehabilitation.

Compounded Topical Pain Creams to Treat Localized Chronic Pain: A Randomized Controlled Trial.

Background: The use of compounded topical pain creams has increased dramatically, yet their effectiveness has not been well evaluated. Objective: To determine the efficacy of compounded creams for chronic pain. Design: Randomized controlled trials of 3 interventions. (ClinicalTrials.gov: NCT02497066). Setting: Military treatment facility. Participants: 399 patients with localized pain classified by each patient's treating physician as neuropathic (n = 133), nociceptive (n = 133), or mixed (n = 133). Intervention: Pain creams compounded for neuropathic pain (ketamine, gabapentin, clonidine, and lidocaine), nociceptive pain (ketoprofen, baclofen, cyclobenzaprine, and lidocaine), or mixed pain (ketamine, gabapentin, diclofenac, baclofen, cyclobenzaprine, and lidocaine), or placebo. Measurements: The primary outcome measure was average pain score 1 month after treatment. A positive categorical response was a reduction in pain score of 2 or more points coupled with a score above 3 on a 5-point satisfaction scale. Secondary outcomes included Short Form-36 Health Survey scores, satisfaction, and categorical response. Participants with a positive outcome were followed through 3 months. Results: For the primary outcome, no differences were found in the mean reduction in average pain scores between the treatment and control groups for patients with neuropathic pain (-0.1 points [95% CI, -0.8 to 0.5 points]), nociceptive pain (-0.3 points [CI, -0.9 to 0.2 points]), or mixed pain (-0.3 points [CI, -0.9 to 0.2 points]), or for all patients (-0.3 points [CI, -0.6 to 0.1 points]). At 1 month, 72 participants (36%) in the treatment groups and 54 (28%) in the control group had a positive outcome (risk difference, 8% [CI, -1% to 17%]). Limitations: Generalizability is limited by heterogeneity among pain conditions and formulations of the study interventions. Randomized follow-up was only 1 month. Conclusion: Compounded pain creams were not better than placebo creams, and their higher costs compared with approved compounds should curtail routine use. Primary Funding Source: Centers for Rehabilitation Sciences Research, Defense Health Agency, U.S. Department of Defense.

Radiofrequency techniques to treat chronic knee pain: a comprehensive review of anatomy, effectiveness, treatment parameters, and patient selection.

BACKGROUND: The use of radiofrequency ablation (RFA) procedures to treat chronic knee pain has surged in the past decade, though many questions remain regarding anatomical targets, selection criteria, and evidence for effectiveness. METHODS: A comprehensive literature review was performed on anatomy, selection criteria, technical parameters, results of clinical studies, and complications. Databases searched included MEDLINE and Google Scholar, with all types of clinical and preclinical studies considered. RESULTS: We identified nine relevant clinical trials, which included 592 patients, evaluating knee RFA for osteoarthritis and persistent postsurgical pain. These included one randomized, placebo-controlled trial, one randomized controlled trial evaluating RFA as add-on therapy, four comparative-effectiveness studies, two randomized trials comparing different techniques and treatment paradigms, and one non-randomized, controlled trial. The results of these studies demonstrate significant benefit for both reduction and functional improvement lasting between 3 and 12 months, with questionable utility for prognostic blocks. There was considerable variation in the described neuroanatomy, neural targets, radiofrequency technique, and selection criteria. CONCLUSION: RFA of the knee appears to be a viable and effective treatment option, providing significant benefit to well-selected patients lasting at least 3 months. More research is needed to better identify neural targets, refine selection criteria to include the use of prognostic blocks, optimize treatment parameters, and better elucidate relative effectiveness compared to other treatments.

Effectiveness of Lumbar Facet Joint Blocks and Predictive Value before Radiofrequency Denervation: The Facet Treatment Study (FACTS), a Randomized, Controlled Clinical Trial.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: With facet interventions under scrutiny, the authors' objectives were to determine the effectiveness of different lumbar facet blocks and their ability to predict radiofrequency ablation outcomes. METHODS: A total of 229 participants were randomized in a 2:2:1 ratio to receive intraarticular facet injections with bupivacaine and steroid, medial branch blocks, or saline. Those with a positive 1-month outcome (a 2-point or more reduction in average pain score) and score higher than 3 (positive satisfaction) on a 5-point satisfaction scale were followed up to 6 months. Participants in the intraarticular and medial branch block groups with a positive diagnostic block (50% or more relief) who experienced a negative outcome proceeded to the second phase and underwent radiofrequency ablation, while all saline group individuals underwent ablation. Coprimary outcome measures were average reduction in numerical rating scale pain score 1 month after the facet or saline blocks, and average numerical rating scale pain score 3 months after ablation. RESULTS: Mean reduction in average numerical rating scale pain score at 1 month was 0.7 ± 1.6 in the intraarticular group, 0.7 ± 1.8 in the medial branch block group, and 0.7 ± 1.5 in the placebo group; P = 0.993. The proportions of positive blocks were higher in the intraarticular (54%) and medial branch (55%) groups than in the placebo group (30%; P = 0.01). Radiofrequency ablation was performed on 135 patients (45, 48, and 42 patients from the intraarticular, medial branch, and saline groups, respectively). The average numerical rating scale pain score at 3 months was 3.0 ± 2.0 in the intraarticular, 3.2 ± 2.5 in the medial branch, and 3.5 ± 1.9 in the control group (P = 0.493). At 3 months, the proportions of positive responders in the intraarticular, medial branch block, and placebo groups were 51%, 56%, and 24% for the intraarticular, medial branch, and placebo groups, respectively (P = 0.005). CONCLUSIONS: This study establishes that facet blocks are not therapeutic. The higher responder rates in the treatment groups suggest a hypothesis that facet blocks might provide prognostic value before radiofrequency ablation.

Predictive factors associated with success and failure for Calmare (Scrambler) therapy: a multicenter analysis.

OBJECTIVE: Calmare (Scrambler) therapy is a novel therapeutic modality that purports to provide pain relief by "scrambling" afferent pain signals and replacing them with "non-pain" information through conventional lines of neural transmission. The goal of this study is to identify which factors are associated with treatment outcome for Calmare therapy. METHODS: Data were garnered from 3 medical centers on 147 patients with various pain conditions who underwent a minimum of either 3 Calmare therapies on consecutive days or 5 therapies overall. A successful outcome was predefined as ≥50% pain relief on a 0 to 10 numerical rating scale that persisted for longer than 1 month after the last treatment. Variables evaluated for their association with outcome included age, sex, study site, baseline pain score, etiology, type of pain, diagnosis, treatment compliance, coexisting psychopathology, opioid use, antidepressant use, and membrane stabilizer use. RESULTS: Overall, the success rate was 38.1%. Variables found to be associated with a positive outcome in multivariate logistic regression included the presence of neuropathic (OR=24.78; 95% CI, 2.47-248.97; P=0.006) or mixed (OR=10.52; 95% CI, 1.09-101.28; P=0.042) pain, and treatment at either Walter Reed (OR=6.87; 95% CI, 1.60-29.51; P=0.010) or Seoul National University (OR=12.29; 95% CI, 1.73-87.43; P=0.012). Factors that correlated with treatment failure were disease (OR=0.04; 95% CI, 0.002-0.59; P=0.020) or traumatic/surgical etiologies (OR=0.05; 95% CI, 0.005-0.56; P=0.015) and antidepressant use (OR=0.47; 95% CI, 0.18-1.02; P=0.056). CONCLUSIONS: A neuropathic or mixed neuropathic-nociceptive pain condition was associated with a positive treatment outcome. Investigators should consider these findings when developing selection criteria in clinical trials designed to determine the efficacy of Calmare therapy.

The effect of sedation on the accuracy and treatment outcomes for diagnostic injections: a randomized, controlled, crossover study.

BACKGROUND AND OBJECTIVE: Diagnostic injections are used to diagnose myriad pain conditions, but are characterized by a high false-positive rate. One potential cause of inaccurate diagnostic blocks is the use of sedation. We sought to determine the effect of sedation on the validity of diagnostic injections. DESIGN: Randomized, crossover study in which 73 patients were allocated to receive a diagnostic sacroiliac joint or sympathetic nerve block performed either with or without sedation using midazolam and fentanyl. Those who obtained equivocal relief, good relief lasting less than 3 months, or who were otherwise deemed good candidates for a repeat injection, received a subsequent crossover injection within 3 months (N = 46). SETTING AND PATIENTS: A tertiary care teaching hospital and a military treatment facility. RESULTS: In the primary crossover analysis, blocks performed with sedation resulted in a larger mean reduction in pain diary score than those done without sedation (1.2 [2.6]; P = 0.006), less procedure-related pain (difference in means 2.3 [2.5]; P < 0.0001), and a higher proportion of patients who obtained > 50% pain relief on their pain diaries (70% vs. 54%; P = 0.039). The increased pain reduction was not accompanied by increased satisfaction (sedation mean 3.9 [1.1] vs. 3.7 [1.3]; P = 0.26). Similar findings were observed for the parallel group (N = 73) and omnibus (all sedation vs. no sedation blocks, N = 110) analyses. No differences in outcomes were noted between the use and non-use of sedation at 1-month. CONCLUSIONS: The use of sedation during diagnostic injections may increase the rate of false-positive blocks and lead to misdiagnoses and unnecessary procedures, but has no effect on satisfaction or outcomes at 1-month.

Epidural lysis of adhesions.

As our population ages and the rate of spine surgery continues to rise, the use epidural lysis of adhesions (LOA) has emerged as a popular treatment to treat spinal stenosis and failed back surgery syndrome. There is moderate evidence that percutaneous LOA is more effective than conventional ESI for both failed back surgery syndrome, spinal stenosis, and lumbar radiculopathy. For cervical HNP, cervical stenosis and mechanical pain not associated with nerve root involvement, the evidence is anecdotal. The benefits of LOA stem from a combination of factors to include the high volumes administered and the use of hypertonic saline. Hyaluronidase has been shown in most, but not all studies to improve treatment outcomes. Although infrequent, complications are more likely to occur after epidural LOA than after conventional epidural steroid injections.

The effect of creep on human lumbar intervertebral disk impact mechanics.

The intervertebral disk (IVD) is a highly hydrated tissue, with interstitial fluid making up 80% of the wet weight of the nucleus pulposus (NP), and 70% of the annulus fibrosus (AF). It has often been modeled as a biphasic material, consisting of both a solid and fluid phase. The inherent porosity and osmotic potential of the disk causes an efflux of fluid while under constant load, which leads to a continuous displacement phenomenon known as creep. IVD compressive stiffness increases and NP pressure decreases as a result of creep displacement. Though the effects of creep on disk mechanics have been studied extensively, it has been limited to nonimpact loading conditions. The goal of this study is to better understand the influence of creep and fluid loss on IVD impact mechanics. Twenty-four human lumbar disk samples were divided into six groups according to the length of time they underwent creep (tcreep = 0, 3, 6, 9, 12, 15 h) under a constant compressive load of 400 N. At the end of tcreep, each disk was subjected to a sequence of impact loads of varying durations (timp = 80, 160, 320, 400, 600, 800, 1000 ms). Energy dissipation (ΔE), stiffness in the toe (ktoe) and linear (klin) regions, and neutral zone (NZ) were measured. Analyzing correlations with tcreep, there was a positive correlation with ΔE and NZ, along with a negative correlation with ktoe. There was no strong correlation between tcreep and klin. The data suggest that the IVD mechanical response to impact loading conditions is altered by fluid content and may result in a disk that exhibits less clinical stability and transfers more load to the AF. This could have implications for risk of diskogenic pain as a function of time of day or tissue hydration.

A comparison of the human lumbar intervertebral disc mechanical response to normal and impact loading conditions.

Thirty-four percent of U.S. Navy high speed craft (HSC) personnel suffer from lower back injury and low back pain, compared with 15 to 20% of the general population. Many of these injuries are specifically related to the intervertebral disc, including discogenic pain and accelerated disc degeneration. Numerous studies have characterized the mechanical behavior of the disc under normal physiological loads, while several have also analyzed dynamic loading conditions. However, the effect of impact loads on the lumbar disc--and their contribution to the high incidence of low back pain among HSC personnel--is still not well understood. An ex-vivo study on human lumbar anterior column units was performed in order to investigate disc biomechanical response to impact loading conditions. Samples were subjected to a sequence of impact events of varying duration (Δt = 80, 160, 320, 400, 600, 800, and 1000 ms) and the level of displacement (0.2, 0.5, and 0.8 mm), stiffness k, and energy dissipation ΔE were measured. Impacts of Δt = 80 ms saw an 18-21% rise in k and a 3-7% drop in ΔE compared to the 1000 ms baseline, signaling an abrupt change in disc mechanics. The altered disc mechanical response during impact likely causes more load to be transferred directly to the endplates, vertebral bodies, and surrounding soft tissues and can help begin to explain the high incidence of low back pain among HSC operators and other individuals who typically experience similar loading environments. The determination of a "safety range" for impacts could result in a refinement of design criteria for shock mitigating systems on high-speed craft, thus addressing the low back injury problem among HSC personnel.

Epidural steroids: a comprehensive, evidence-based review.

Epidural steroid injections (ESIs) are the most widely utilized pain management procedure in the world, their use supported by more than 45 placebo-controlled studies and dozens of systematic reviews. Despite the extensive literature on the subject, there continues to be considerable controversy surrounding their safety and efficacy. The results of clinical trials and review articles are heavily influenced by specialty, with those done by interventional pain physicians more likely to yield positive findings. Overall, more than half of controlled studies have demonstrated positive findings, suggesting a modest effect size lasting less than 3 months in well-selected individuals. Transforaminal injections are more likely to yield positive results than interlaminar or caudal injections, and subgroup analyses indicate a slightly greater likelihood for a positive response for lumbar herniated disk, compared with spinal stenosis or axial spinal pain. Other factors that may increase the likelihood of a positive outcome in clinical trials include the use of a nonepidural (eg, intramuscular) control group, higher volumes in the treatment group, and the use of depo-steroid. Serious complications are rare following ESIs, provided proper precautions are taken. Although there are no clinical trials comparing different numbers of injections, guidelines suggest that the number of injections should be tailored to individual response, rather than a set series. Most subgroup analyses of controlled studies show no difference in surgical rates between ESI and control patients; however, randomized studies conducted by spine surgeons, in surgically amenable patients with standardized operative criteria, indicate that in some patients the strategic use of ESI may prevent surgery.