Oculomics: A Crusade Against the Four Horsemen of Chronic Disease.

Chronic, non-communicable diseases present a major barrier to living a long and healthy life. In many cases, early diagnosis can facilitate prevention, monitoring, and treatment efforts, improving patient outcomes. There is therefore a critical need to make screening techniques as accessible, unintimidating, and cost-effective as possible. The association between ocular biomarkers and systemic health and disease (oculomics) presents an attractive opportunity for detection of systemic diseases, as ophthalmic techniques are often relatively low-cost, fast, and non-invasive. In this review, we highlight the key associations between structural biomarkers in the eye and the four globally leading causes of morbidity and mortality: cardiovascular disease, cancer, neurodegenerative disease, and metabolic disease. We observe that neurodegenerative disease is a particularly promising target for oculomics, with biomarkers detected in multiple ocular structures. Cardiovascular disease biomarkers are present in the choroid, retinal vasculature, and retinal nerve fiber layer, and metabolic disease biomarkers are present in the eyelid, tear fluid, lens, and retinal vasculature. In contrast, only the tear fluid emerged as a promising ocular target for the detection of cancer. The retina is a rich source of oculomics data, the analysis of which has been enhanced by artificial intelligence-based tools. Although not all biomarkers are disease-specific, limiting their current diagnostic utility, future oculomics research will likely benefit from combining data from various structures to improve specificity, as well as active design, development, and optimization of instruments that target specific disease signatures, thus facilitating differential diagnoses.

Long-term diseases can stop people living long and healthy lives. In many cases, early diagnosis can help to prevent, monitor, and treat disease, which can improve patients' health. In order to diagnose disease, we need tools that are easy for patients to access, painless, and low-cost. The eye may provide the solution. In this review, we discuss the link between changes in the eye and four types of long-term disease that, together, kill most of the population: (1) Cardiovascular disease (affecting the heart and/or blood). (2) Cancer (abnormal growth of cells). (3) Neurodegenerative disease (affecting the brain and/or nervous system). (4) Metabolic disease (problems storing, accessing, and using the body's fuel). We show that neurodegenerative disease leaves tell-tale signs in lots of different parts of the eye. Signs of cardiovascular and metabolic disease biomarkers are mostly found in the back of the eye, and signs of cancer can be found in the tear fluid. Although signs of disease can be seen in the eye, not all of them will tell us what the disease is. We believe that future research will help us to understand more about long-term disease and how to detect it if we combine information from different structures within the eye and develop new tools to target these specific structures.

Co-crystal of tramadol-celecoxib (CTC) for acute moderate-to-severe pain.

OBJECTIVE: This narrative review aims to provide a clinical perspective on the potential role of co-crystal of tramadol-celecoxib (CTC) in the management of acute moderate-to-severe pain by synthesizing the available preclinical and clinical data, with emphasis on phase 3 trials. METHODS: A non-systematic literature review was performed using a targeted PubMed search for articles published between January 1, 2000, and May 2, 2023; all publication types were permitted, and selected articles were limited to those published in English. Search results were manually reviewed to identify references based on their preclinical and clinical relevance to CTC and management of acute moderate-to-severe pain. RESULTS: The crystalline structure of CTC alters the physicochemical properties of tramadol and celecoxib, modifying their pharmacokinetics. If taken in a free combination, tramadol reduces absorption of celecoxib. Conversely, administration of CTC slows tramadol absorption and lowers its maximum plasma concentration, while increasing celecoxib plasma concentration through its enhanced release. In clinical studies across models of acute moderate-to-severe pain, CTC demonstrated an early onset of analgesia, with improved efficacy and lower rescue medication use, compared with either agent alone. CTC's safety profile was in line with that expected for the individual components; no additive effects were observed. CTC exhibited tramadol-sparing effects, with efficacy seen at lower daily/cumulative opioid doses vs. tramadol alone. CONCLUSIONS: Results from phase 3 trials suggest that the modified physicochemical properties of tramadol and celecoxib in CTC translate into an improved clinical benefit-risk profile, including fewer opioid-related adverse effects due to lower overall opioid dosing.

Co-crystal of Tramadol-Celecoxib Versus Tramadol or Placebo for Acute Moderate-to-Severe Pain After Oral Surgery: Randomized, Double-Blind, Phase 3 Trial (STARDOM1).

INTRODUCTION: Co-crystal of tramadol-celecoxib (CTC) is the first analgesic co-crystal for acute pain. This completed phase 3 multicenter, double-blind trial assessed the efficacy and safety/tolerability of CTC in comparison with that of tramadol in the setting of moderate-to-severe pain up to 72 h after elective third molar extraction requiring bone removal. METHODS: Adults (n = 726) were assigned randomly to five groups (2:2:2:2:1): orally administered twice-daily CTC 100 mg (44 mg rac-tramadol hydrochloride/56 mg celecoxib; n = 164), 150 mg (66/84 mg; n = 160) or 200 mg (88/112 mg; n = 160); tramadol 100 mg four times daily (n = 159); or placebo four times daily (n = 83). Participants in CTC groups also received twice-daily placebo. The full analysis set included all participants who underwent randomization. The primary endpoint was the sum of pain intensity differences over 0 to 4 h (SPID0-4; visual analog scale). Key secondary endpoints included 4-h 50% responder and rescue medication use rates. Safety endpoints included adverse events (AEs), laboratory measures, and Opioid-Related Symptom Distress Scale (OR-SDS) score. RESULTS: All CTC doses were superior to placebo (P < 0.001) for primary and key secondary endpoints. All were superior to tramadol for SPID0-4 (analysis of covariance least squares mean differences [95% confidence interval]: - 37.1 [- 56.5, - 17.6], - 40.2 [- 59.7, - 20.6], and - 41.7 [- 61.2, - 22.2] for 100, 150, and 200 mg CTC, respectively; P < 0.001) and 4-h 50% responder rate. Four-hour 50% responder rates were 32.9% (CTC 100 mg), 33.8% (CTC 150 mg), 40.6% (CTC 200 mg), 20.1% (tramadol), and 7.2% (placebo). Rescue medication use was lower in the 100-mg (P = 0.013) and 200-mg (P = 0.003) CTC groups versus tramadol group. AE incidence and OR-SDS scores were highest for tramadol alone. CONCLUSIONS: CTC demonstrated superior pain relief compared with tramadol or placebo, as well as an improved benefit/risk profile versus tramadol. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02982161; EudraCT number, 2016-000592-24.

The accumulation and growth of Pseudomonas aeruginosa on surfaces is modulated by surface mechanics via cyclic-di-GMP signaling.

Attachment of bacteria onto a surface, consequent signaling, and accumulation and growth of the surface-bound bacterial population are key initial steps in the formation of pathogenic biofilms. While recent reports have hinted that surface mechanics may affect the accumulation of bacteria on that surface, the processes that underlie bacterial perception of surface mechanics and modulation of accumulation in response to surface mechanics remain largely unknown. We use thin and thick hydrogels coated on glass to create composite materials with different mechanics (higher elasticity for thin composites; lower elasticity for thick composites) but with the same surface adhesivity and chemistry. The mechanical cue stemming from surface mechanics is elucidated using experiments with the opportunistic human pathogen Pseudomonas aeruginosa combined with finite-element modeling. Adhesion to thin composites results in greater changes in mechanical stress and strain in the bacterial envelope than does adhesion to thick composites with identical surface chemistry. Using quantitative microscopy, we find that adhesion to thin composites also results in higher cyclic-di-GMP levels, which in turn result in lower motility and less detachment, and thus greater accumulation of bacteria on the surface than does adhesion to thick composites. Mechanics-dependent c-di-GMP production is mediated by the cell-surface-exposed protein PilY1. The biofilm lag phase, which is longer for bacterial populations on thin composites than on thick composites, is also mediated by PilY1. This study shows clear evidence that bacteria actively regulate differential accumulation on surfaces of different stiffnesses via perceiving varied mechanical stress and strain upon surface engagement.

Bacterial mechanosensing of surface stiffness promotes signaling and growth leading to biofilm formation by Pseudomonas aeruginosa.

The attachment of bacteria onto a surface, consequent signaling, and the accumulation and growth of the surface-bound bacterial population are key initial steps in the formation of pathogenic biofilms. While recent reports have hinted that the stiffness of a surface may affect the accumulation of bacteria on that surface, the processes that underlie bacterial perception of and response to surface stiffness are unknown. Furthermore, whether, and how, the surface stiffness impacts biofilm development, after initial accumulation, is not known. We use thin and thick hydrogels to create stiff and soft composite materials, respectively, with the same surface chemistry. Using quantitative microscopy, we find that the accumulation, motility, and growth of the opportunistic human pathogen Pseudomonas aeruginosa respond to surface stiffness, and that these are linked through cyclic-di-GMP signaling that depends on surface stiffness. The mechanical cue stemming from surface stiffness is elucidated using finite-element modeling combined with experiments - adhesion to stiffer surfaces results in greater changes in mechanical stress and strain in the bacterial envelope than does adhesion to softer surfaces with identical surface chemistry. The cell-surface-exposed protein PilY1 acts as a mechanosensor, that upon surface engagement, results in higher cyclic-di-GMP levels, lower motility, and greater accumulation on stiffer surfaces. PilY1 impacts the biofilm lag phase, which is extended for bacteria attaching to stiffer surfaces. This study shows clear evidence that bacteria actively respond to different stiffness of surfaces where they adhere via perceiving varied mechanical stress and strain upon surface engagement.

Efficacy and safety of co-crystal of tramadol-celecoxib (CTC) in acute moderate-to-severe pain after abdominal hysterectomy: A randomized, double-blind, phase 3 trial (STARDOM2).

BACKGROUND: STARDOM2 is a randomized, double-blind, phase 3 trial evaluating the efficacy and safety of co-crystal of tramadol-celecoxib (CTC)-a first-in-class analgesic co-crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties-for the management of acute postoperative pain (NCT03062644; EudraCT:2016-000593-38). METHODS: Patients with moderate-to-severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac-tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate-release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0-4 h (SPID0-4 ). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability. RESULTS: Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPID0-4 , CTC 200 mg was not superior to tramadol but showed non-inferior efficacy (p < 0.001) that was sustained throughout the 120-h period, despite a 5-day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment-emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol. Treatment-related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol. CONCLUSIONS: Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure. SIGNIFICANCE: In the randomized, double-blind, phase 3 STARDOM2 trial-in acute moderate-to-severe pain after abdominal hysterectomy-the novel co-crystal of tramadol-celecoxib (CTC) 200 mg BID was superior to placebo and non-inferior to tramadol 100 mg QID. Although superiority to tramadol was not reached, CTC 200 mg BID exposed patients to lower cumulative opioid (tramadol) doses than tramadol (100 mg QID) alone, with fewer treatment-emergent adverse events. CTC 200 mg thus has a clinically relevant improved benefit/risk profile compared with tramadol alone.

Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study.

INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation. METHODS: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM). RESULTS: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not. CONCLUSION: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

Subcutaneous tanezumab for osteoarthritis: Is the early improvement in pain and function meaningful and sustained?

BACKGROUND: To evaluate if early improvements in pain and function with subcutaneous tanezumab are meaningful and sustained over 24 weeks. METHODS: Patients with moderate-to-severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16). Outcomes included: average daily index joint pain score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales, rescue medication use, WOMAC responders (within-patient ≥30% reduction in WOMAC Pain or Physical Function), Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders (within-patient) and Patient-reported Treatment Impact Assessment-Modified questionnaire. RESULTS: Patients received placebo (n = 282), tanezumab 2.5 mg (n = 283) or tanezumab 5 mg (n = 284). Changes from baseline in average daily index joint pain (within the first week) and WOMAC subscales (Week 2 through Week 24) were greater for each tanezumab group versus placebo (least squares [LS] mean, unadjusted p ≤ .05). Rescue medication use (days/week) was lower for each tanezumab group versus placebo from Week 2 through Week 12 (LS mean, unadjusted p ≤ .05) but not at Week 16 or 24. A higher proportion of each tanezumab group than placebo achieved ≥30% reduction from baseline in WOMAC Pain or Physical Function, or OMERACT-OARSI response (Week 2 through Week 24, unadjusted p ≤ .05), or were satisfied with treatment at Week 24 (unadjusted p ≤ .05). CONCLUSIONS: Subcutaneous tanezumab, compared with placebo, reduced pain within the first week, and pain and function were improved throughout 24 weeks. The proportions of responders and patients satisfied were higher with tanezumab than placebo. ClinicalTrials.gov:NCT02709486. SIGNIFICANCE: This exploratory analysis of data from a placebo-controlled, Phase 3 study of patients with moderate-to-severe osteoarthritis of the hip or knee for whom standard analgesics were not effective or could not be taken, found that onset of efficacy of subcutaneous tanezumab was within the first week, and efficacy was maintained through the 24-week treatment period. Tanezumab was effective in those patients with the most radiologically severe osteoarthritis.

Feasibility of Videophone-Assisted Neuropsychological Testing For Intensive Care Unit Survivors.

BACKGROUND: Most hospitals lack neuropsychologists, and this lack has hampered the conduct of large-scale, multicenter clinical trials to evaluate the effect of interventions on long-term cognition in patients in intensive care units (ICUs). OBJECTIVE: To evaluate the feasibility of videophone-assisted neuropsychological testing administered by using an inexpensive high-definition web camera and a laptop. METHODS: This prospective, single-center observational study, conducted at a tertiary care academic hospital, included ICU survivors aged 18 years or older. Participants were seated in a quiet room with a proctor who provided neuropsychological testing forms and addressed technical difficulties. The neuropsychological rater was in a room 100 yd (90 m) from the participant. Skype was used for videoconferencing via a wireless connection. After the testing session was completed, participants completed surveys. RESULTS: In April 2017, 10 ICU survivors (median age, 63 years; range, 51-73 years) were enrolled. All indicated that "Videophone-assisted neuropsychological testing is reasonable to use in research studies." When asked "What made the videophone-assisted cognitive testing difficult?" 1 participant (10%) reported occasionally becoming frustrated with the testing because the wireless internet speed was slower than usual and reduced the resolution of visual stimuli. Three participants (30%) reported difficulty with the line orientation task because the lines were "shaky" and the images were "hard to see." CONCLUSION: Videophone-assisted neuropsychological testing is feasible for evaluating cognition in multicenter studies of ICU patients. Feedback provided will be used to refine this telemedicine approach to neuropsychological testing.

CareConekta: study protocol for a randomized controlled trial of a mobile health intervention to improve engagement in postpartum HIV care in South Africa.

BACKGROUND: South Africa is home to the world's largest antiretroviral therapy program but sustaining engagement along the HIV care continuum has proven challenging in the country and throughout the wider region. Population mobility is common in South Africa, but there are important research gaps in describing this mobility and its impact on engagement in HIV care. Postpartum women and their infants in South Africa are known to be at high risk of dropping out of HIV care after delivery and are frequently mobile. METHODS: In 2017, we developed a beta version of a smartphone application (app) - CareConekta - that detects a user's smartphone location to allow for prospective characterization of mobility. Now we will adapt and test CareConekta to conduct essential formative work on mobility and evaluate an intervention - the CareConekta app plus text notifications and phone calls and/or WhatsApp messages - to facilitate engagement in HIV care during times of mobility. During the 3-year project period, our first objective is to evaluate the feasibility, acceptability, and initial efficacy of using CareConekta as an intervention to improve engagement in HIV care. Our second objective is to characterize mobility among South African women during the peripartum period and its impact on engagement in HIV care. We will enroll 200 eligible pregnant women living with HIV and receiving care at the Gugulethu Midwife Obstetric Unit in Cape Town, South Africa. DISCUSSION: This work will provide critical information about mobility during the peripartum period and the impact on engagement in HIV care. Simultaneously, we will pilot test an intervention to improve engagement with rigorously assessed outcomes. If successful, CareConekta offers tremendous potential as a research and service tool that can be adapted and evaluated in multiple geographic regions, study contexts, and patient populations. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03836625. Registered on 8 February 2019.

A randomized pilot study to investigate the effect of opioids on immunomarkers using gene expression profiling during surgery.

Endogenous opioid peptides and exogenous opioids modulate immune function, and animal and human studies have shown that some have a depressant immunomodulatory effect. This is potentially of high clinical significance, eg, in cancer patients and surgery. The primary objective of this pilot study was to evaluate the effect of morphine and oxycodone on immune pathways associated with immunosuppression in gynecological laparotomy patients. Gene expression was analyzed in CD4, CD8, and natural killer (NK) cells using the 3' Affymetrix microarray. Patients were randomized to receive morphine, oxycodone, or nonopioid "control" analgesia during and after surgery. Genes demonstrating differential expression were those with a ≥±2-fold difference and P-value ≤0.05 after analysis of variance. Cytometric bead array and NK cell degranulation assay were used to investigate changes in serum cytokine concentration and in NK cell cytotoxicity, respectively. Forty patients had satisfactory RNA which was hybridized to gene chips. Genes were identified (Partek Genomics Suite 6.6) at baseline, 2, 6, and 24 hours and were either ≥2-fold upregulated or downregulated from baseline. At 2 hours, a large number of genes were downregulated with morphine but not with control analgesia or oxycodone. Statistically significant increases in IL-6 concentrations were induced by morphine only; NK cell activity was suppressed with morphine, but maintained with oxycodone and epidural analgesia. Gene expression profiles suggest that at 2 hours, post incision morphine appeared to be immunosuppressive as compared to oxycodone and nonopioid control analgesia.

Prolonged Perioperative Use of Pregabalin and Ketamine to Prevent Persistent Pain after Cardiac Surgery.

BACKGROUND: Persistent postsurgical pain is common and affects quality of life. The hypothesis was that use of pregabalin and ketamine would prevent persistent pain after cardiac surgery. METHODS: This randomized, double-blind, placebo-controlled trial was undertaken at two cardiac surgery centers in the United Kingdom. Adults without chronic pain and undergoing any elective cardiac surgery patients via sternotomy were randomly assigned to receive either usual care, pregabalin (150 mg preoperatively and twice daily for 14 postoperative days) alone, or pregabalin in combination with a 48-h postoperative infusion of intravenous ketamine at 0.1 mg · kg · h. The primary endpoints were prevalence of clinically significant pain at 3 and 6 months after surgery, defined as a pain score on the numeric rating scale of 4 or higher (out of 10) after a functional assessment of three maximal coughs. The secondary outcomes included acute pain, opioid use, and safety measures, as well as long-term neuropathic pain, analgesic requirement, and quality of life. RESULTS: In total, 150 patients were randomized, with 17 withdrawals from treatment and 2 losses to follow-up but with data analyzed for all participants on an intention-to-treat basis. The prevalence of pain was lower at 3 postoperative months for pregabalin alone (6% [3 of 50]) and in combination with ketamine (2% [1 of 50]) compared to the control group (34% [17 of 50]; odds ratio = 0.126 [0.022 to 0.5], P = 0.0008; and 0.041 [0.0009 to 0.28], P < 0.0001, respectively) and at 6 months for pregabalin alone (6% [3 of 50]) and in combination with ketamine 0% (0 of 5) compared to the control group (28% [14 of 50]; odds ratio = 0.167 [0.029 to 0.7], P = 0.006; and 0.000 [0 to 0.24], P < 0.0001). Diplopia was more common in both active arms. CONCLUSIONS: Preoperative administration of 150 mg of pregabalin and postoperative continuation twice daily for 14 days significantly lowered the prevalence of persistent pain after cardiac surgery.

Persistent Postsurgical Pain Following Thoracotomy: A Comparison of Thoracic Epidural and Paravertebral Blockade as Preventive Analgesia.

OBJECTIVE: Persistent postsurgical pain (PPP) is common following thoracotomy. Thoracic epidural (TEB) and paravertebral blockade (PVB) are both established forms of perioperative analgesia for thoracotomy. There is currently a lack of data on their influence on PPP; this study aims to evaluate both techniques on PPP. DESIGN: Observational study, prospectively collected data. METHODS: Adults who underwent thoracotomy had either TEB or PVB for analgesia and were prospectively interviewed at six months. A numerical rating scale, the short form of the Leeds Assessment of Neuropathic Symptoms and Signs, and the EuroQol-5 dimension (EQ-5D) index were used to assess pain, neuropathic pain, and quality of life. RESULTS: Eighty-two patients who underwent a thoracotomy were recruited (TEB N = 36, PVB N = 46). Pain scores had a median (interquartile range [IQR]) of 1 (0 to 4.5) and 1.5 (0 to 4, P = 0.89), presence of PPP was 58.3% (95% confidence interval [CI] = 40.0-74.5%) and 60.9% (95% CI = 45.4-74.9%, P = 0.81), and presence of neuropathic pain was 30.6% (95% CI = 16.3-48.1%) and 28.2% (95% CI = 16.0-43.5%, P = 0.85). Reported quality of life was 0.71 (0.14-0.85) and 0.80 (0.19-0.91, P = 0.21). Patients who had PPP reported worse quality of life measures compared with those who were pain free, with a median (IQR) EQ-5D index of 0.69 (-0.15 to 0.85) and 0.85 (0.72 to 1, P = 0.0007); quality of life was worst when there was a neuropathic component (median = 0.39, IQR = -0.24 to 0.75). CONCLUSIONS: There was no statistical difference in the development of persistent postsurgical pain between patients who received a TEB or a PVB; however, patients who developed PPP had a significantly lower quality of life, which was worse with a neuropathic component.

Characterizing the Somatosensory Profile of Patients With Failed Back Surgery Syndrome With Unilateral Lumbar Radiculopathy Undergoing Spinal Cord Stimulation: A Single Center Prospective Pilot Study.

OBJECTIVES: Currently little objective evidence exists regarding the phenotype or somato-sensory profile of patients with Failed Back Surgery Syndrome (FBSS). The aim of this study is to characterize the somato-sensory profile of the patients with FBSS undergoing spinal cord stimulation (SCS). METHODS: A combined quantitative sensory test and questionnaire approach was used to characterize the somatosensory profiles of patients undergoing SCS. RESULTS: Baseline somatosensory profiles were obtained from 23 patients and full three-month data was obtained from 19 patients. At baseline, there was a high prevalence (>50% prevalence of moderate to severe sensation) of burning, tingling, electric shock, numbness, and pressure pain sensitivity. None of the sensory symptoms were present at significant levels at three months following SCS. At baseline, 65% of patients had an inefficient conditioned pain modulation (CPM). Three months post-SCS, 95% of patients had an efficient CPM. All the patients who had an inefficient CPM at baseline had a successful implant at three months and their CPM became efficient in all but one patient. Only 50% of the patients with an efficient CPM at baseline, had a successful implant at three months post-SCS. CONCLUSION: Although very low numbers, we could demonstrate the somatosensory profiles of patients with FBSS undergoing SCS. Early indication may associate an efficient CPM profile having a higher chance of an unsuccessful implant at three months.

The Effects of Radiofrequency Neurotomy Using a Strip-Lesioning Device on Patients with Sacroiliac Joint Pain: Results from a Single-Center, Randomized, Sham-Controlled Trial.

BACKGROUND: Radiofrequency neurotomy (RFN) is a therapy aimed at providing lasting back pain relief for sacroiliac joint (SIJ) pain. A recent advancement in RFN is a strip lesioning technique that involves placement of a single curved electrode and a 3-pole design that facilitates the creation of 5 overlapping lesions. These lesions form one long strip lesion accessible through a single entry point, without the need for multiple punctures. Although the early case series data looks promising, there is lack of long-term, randomized, controlled study evaluating the strip-lesioning system for SIJ pain. OBJECTIVES: The purpose of this study was to examine the safety and effectiveness of RFN using a strip lesioning device for reduction of SIJ pain. STUDY DESIGN: Prospective, double-blind, randomized, sham-controlled trial with 6-month follow-upSETTING: A tertiary care interventional pain management center in the UK METHODS: Patients with SIJ pain with positive diagnostic local anesthetic blocks were randomly assigned (2:1) to either the sham (no RF lesions performed) or the active group (RF lesions performed). The primary endpoint was improvement of pain using the Numeric Rating Scale (NRS-11) at 3 months. Results were analyzed using nonparametric tests. Safety, secondary, and long-term outcome data were also collected. RESULTS: Seventeen of 30 enrolled patients were randomly assigned to active treatment (n = 11) or sham treatment (n = 6). At 3 months, the mean NRS-11 score for the active group had decreased significantly, from 8.1 (± 0.8) at baseline to 3.4 (± 2.0) (P < 0.001). The sham group did not experience a statistically or clinically meaningful decrease in mean NRS-11 score from baseline (7.3 ± 0.8) to 3 months (7.0 ± 1.7). On average, patients in the active group moved from borderline anxiety at baseline (9.4 ± 5.9) to no anxiety (6.6 ± 6.3) at 3 months. Results were similar at 6 months. LIMITATIONS: Recruitment was stopped at 30 enrolled patients, only 17 of whom were randomly assigned to active or sham treatment, after the interim analysis indicated a statistically significant (P < 0.001) difference in the pain outcome between the treatment and the sham groups. CONCLUSIONS: This study demonstrated that radiofrequency neurotomy using a strip lesioning device is an appropriate therapy to treat SIJ pain. KEY WORDS: Radiofrequency, sacroiliac joint pain, low back pain, neurotomy, randomized controlled trial, simplicity.

Evolutionary-Optimized Photonic Network Structure in White Beetle Wing Scales.

Most studies of structural color in nature concern periodic arrays, which through the interference of light create color. The "color" white however relies on the multiple scattering of light within a randomly structured medium, which randomizes the direction and phase of incident light. Opaque white materials therefore must be much thicker than periodic structures. It is known that flying insects create "white" in extremely thin layers. This raises the question, whether evolution has optimized the wing scale morphology for white reflection at a minimum material use. This hypothesis is difficult to prove, since this requires the detailed knowledge of the scattering morphology combined with a suitable theoretical model. Here, a cryoptychographic X-ray tomography method is employed to obtain a full 3D structural dataset of the network morphology within a white beetle wing scale. By digitally manipulating this 3D representation, this study demonstrates that this morphology indeed provides the highest white retroreflection at the minimum use of material, and hence weight for the organism. Changing any of the network parameters (within the parameter space accessible by biological materials) either increases the weight, increases the thickness, or reduces reflectivity, providing clear evidence for the evolutionary optimization of this morphology.

Facet-joint injections for non-specific low back pain: a feasibility RCT.

BACKGROUND: Pain of lumbar facet-joint origin is a common cause of low back pain in adults and may lead to chronic pain and disability, with associated health and socioeconomic implications. The socioeconomic burden includes an inability to return to work resulting in loss of productivity in addition to direct and indirect health-care utilisation costs. Lumbar facet-joints are paired synovial joints between the superior and inferior articular processes of consecutive lumbar vertebrae and between the fifth lumbar vertebra and the sacrum. Facet-joint pain is defined as pain that arises from any structure that is part of the facet-joints, including the fibrous capsule, synovial membrane, hyaline cartilage and bone. This pain may be treated by intra-articular injections with local anaesthetic and steroid, although this treatment is not standardised. At present, there is no definitive research to support the use of targeted lumbar facet-joint injections to manage this pain. Because of the lack of high-quality, robust clinical evidence, the National Institute for Health and Care Excellence (NICE) guidelines on the management of chronic low back pain [NICE. Low Back Pain in Adults: Early Management. Clinical guideline (CG88). London: NICE; 2009] did not recommend the use of spinal injections despite their perceived potential to reduce pain intensity and improve rehabilitation, with NICE calling for further research to be undertaken. The updated guidelines [NICE. Low Back Pain and Sciatica in Over 16s: Assessment and Management. NICE guideline (NG59). London: NICE; 2016] again do not recommend the use of spinal injections. OBJECTIVES: To assess the feasibility of carrying out a definitive study to evaluate the clinical effectiveness and cost-effectiveness of lumbar facet-joint injections compared with a sham procedure in patients with non-specific low back pain of > 3 months' duration. DESIGN: Blinded parallel two-arm pilot randomised controlled trial. SETTING: Initially planned as a multicentre study involving three NHS trusts in the UK, recruitment took place in the pain and spinal orthopaedic clinics at Barts Health NHS Trust only. PARTICIPANTS: Adult patients referred by their GP to the specialist clinics with non-specific low back pain of at least 3 months' duration despite NICE-recommended best non-invasive care (education and one of a physical exercise programme, acupuncture or manual therapy). Patients who had already received lumbar facet-joint injections or who had had previous back surgery were excluded. INTERVENTIONS: Participants who had a positive result following a diagnostic test (single medial branch nerve blocks) were randomised and blinded to receive either intra-articular lumbar facet-joint injections with steroids (intervention group) or a sham procedure (control group). All participants were invited to attend a group-based combined physical and psychological (CPP) programme. MAIN OUTCOME MEASURES: In addition to the primary outcome of feasibility, questionnaires were used to assess a range of pain-related (including the Brief Pain Inventory and Short-Form McGill Pain Questionnaire version 2) and disability-related (including the EuroQol-5 Dimensions five-level version and Oswestry Low Back Pain Questionnaire) issues. Health-care utilisation and cost data were also assessed. The questionnaire visits took place at baseline and at 6 weeks, 3 months and 6 months post randomisation. The outcome assessors were blinded to the allocation groups. RESULTS: Of 628 participants screened for eligibility, nine were randomised to receive the study intervention (intervention group, n = 5; sham group, n = 4), six completed the CPP programme and eight completed the study. LIMITATIONS: Failure to achieve our expected recruitment targets led to early closure of the study by the funder. CONCLUSIONS: Because of the small number of participants recruited to the study, we were unable to draw any conclusions about the clinical effectiveness or cost-effectiveness of intra-articular lumbar facet-joint injections in the management of non-specific low back pain. Although we did not achieve the target recruitment rate from the pain clinics, we demonstrated our ability to develop a robust study protocol and deliver the intended interventions safely to all nine randomised participants, thus addressing many of the feasibility objectives. FUTURE WORK: Stronger collaborations with primary care may improve the recruitment of patients earlier in their pain trajectory who are suitable for inclusion in a future trial. TRIAL REGISTRATION: EudraCT 2014-003187-20 and Current Controlled Trials ISRCTN12191542. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 74. See the NIHR Journals Library website for further project information.

Comparison of fentanyl iontophoretic transdermal system and routine care with morphine intravenous patient-controlled analgesia in the management of early postoperative mobilisation: results from a randomised study.

INTRODUCTION: Fentanyl iontophoretic transdermal system (ITS) (IONSYS®, The Medicines Company, Parsippany, NJ, USA) and morphine intravenous (IV) patient-controlled analgesia (PCA) have demonstrated equivalent pain control in several published studies. The primary objective of the current study was to compare fentanyl ITS with morphine IV PCA with regard to the patient's ability to mobilise with acute postoperative pain. METHODS: In this multicentre, open-label, randomised, active-controlled, prospective phase IV study, postoperative patients initially received IV morphine and were titrated to pain score ⩽ 4out of 10 on a Numeric Rating Scale (NRS) and then received fentanyl ITS (up to 240 µg (6 doses)/hour; up to a maximum of 3.2 mg (80 doses)/24 hours) or morphine IV PCA (doses up to 20 mg morphine/2 hours, up to 240 mg/24 hours). The primary efficacy measure was ability to mobilise, assessed using patient responses to three validated questions regarding mobility on a 6-point Likert scale (0 = no difficulty to mobilise to 5 = a very great deal of difficulty to mobilise). The study was originally planned to include ~200 patients. However, following the early suspension and termination of the study, a total of 108 patients were randomised to study treatment. RESULTS: One hundred and eight patients were recruited prior to undergoing surgical procedures (orthopaedic surgical procedures (72%) or underwent major abdominal procedures (28%)). Postoperatively, 58 were randomised to receive fentanyl ITS, and 50 to morphine IV PCA. Fentanyl ITS patients had a greater ability to mobilise at the time of stopping study drug, with an adjusted mean ability to mobilise score (95% confidence interval (CI)) of 0.14 (-0.19, 0.47) for fentanyl ITS patients and 2.37 (1.98, 2.76) for morphine IV PCA patients (p < 0.001). CONCLUSION: Patients treated with fentanyl ITS reported that they were better able to mobilise than patients treated with morphine IV PCA, at all time-points following surgery out to 24 hours.

Is tapentadol different from classical opioids? A review of the evidence.

Tapentadol is a single molecule able to deliver analgesia by two distinct mechanisms, a feature which differentiates it from many other analgesics. Pre-clinical data demonstrate two mechanisms of action: mu-opioid receptor agonist activity and noradrenaline re-uptake inhibition. From these, one may predict that tapentadol would be applicable across a broad spectrum of pain from nociceptive to neuropathic. The evidence in animal models suggests that norepinephrine re-uptake inhibition (NRI) is a key mechanism and may even predominate over opioid actions in chronic (and especially neuropathic) pain states, reinforcing that tapentadol is different to classical opioids and may, therefore, be an a priori choice for the treatment of neuropathic and mixed pain. The clinical studies and subsequent practice experience and surveillance support the concept of opioid and non-opioid mechanisms of action. The reduced incidence of some of the typical opioid-induced side effects, compared to equianalgesic doses of classical opioids, supports the hypothesis that tapentadol analgesia is only partially mediated by opioid agonist mechanisms. Both the pre-clinical and clinical profiles appear to be differentiated from those of classical opioids.