Certainty in ascending sensory signals - The unexplored driver of analgesic placebo response.

Previous frameworks have failed to adequately explain the observed correlation between within-subject variability in pain reporting and analgesic placebo response. These relationships have been observed in both clinical and experimental setups. Within-subject variability of clinical pain scores is traditionally assessed based on daily pain diaries collected during the pre-intervention stage. Experimental variability can be assessed by the Focused Analgesia Selection Test (FAST), which calculates the relationship between noxious stimuli administrated at various intensities and pain reports. The variability, either clinical or experimental, has been shown to predict the placebo response. In explaining the placebo response, Bayesian Brain Hypothesis (BBH) posits that pain perception (posterior), is composed of certainty (precision) of expectations (priors due to belief or conditioning) and incoming sensory information (likelihood), with the bulk of research focused on the precision of priors. Virtually all placebo analgesia research has focused on the priors and their certainty, rather than on the certainty of the likelihood, mainly because it cannot be assessed directly. We propose that the within-subject variability, as encapsulated by the FAST, is a proxy for certainty in (or, precision of) ascending sensory signals, and our results suggest that it could not only be assessed, but also manipulated. If true, our hypothesis will facilitate new lines of research and could potentially promote precision analgesic medicine by use of variability of pain scores as a diagnostic method to identify pain patients who will benefit from specific treatments

Effects of a Single Intra-Articular Injection of a Microsphere-Formulation of Triamcinolone Acetonide on Knee Osteoarthritis Pain: A Double-Blinded, Randomized, Placebo-Controlled, Multinational Study

Background: Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs. Methods: In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit. Results: The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: −3.12 versus −2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments. Conclusions: FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point)

Improved Treatment Effect of Triamcinolone Acetonide Extended-Release in Patients with Concordant Baseline Pain Scores on the Average Daily Pain and Western Ontario and McMaster Universities Osteoarthritis Index Pain Scales

Introduction A phase 3 randomized controlled study comparing triamcinolone acetonide extended-release (TA-ER) to conventional TA crystalline suspension (TAcs) reported variable efficacy results. Enrollment criteria may have contributed to this discrepancy, as moderate-to-severe average daily pain (ADP) was required at baseline, whereas no limitations were placed on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A) pain severity. We conducted a post hoc sensitivity analysis to compare treatment effects in patients reporting moderate-to-severe osteoarthritis (OA) pain on both scales. Methods Participants > 40 years old with symptomatic knee OA were randomly assigned to a single intra-articular injection of TA-ER 32 mg, TAcs 40 mg, or saline-placebo and followed for 24 weeks. Patient-reported ADP, WOMAC-A, rescue medication usage, and adverse events (AEs) were assessed. Participants who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥ 5 to ≤ 9, maximum 10 and WOMAC-A ≥ 2, maximum 4) were categorized as “concordant” pain reporters; patients with baseline moderate-to-severe OA on ADP only were termed “discordant” pain reporters. Results Two-hundred-ninety-two concordant pain reporters of 484 total subjects received TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or saline-placebo (n = 97). Baseline characteristics and AE profiles of the concordant and discordant pain responders were consistent with the full analysis population. Among concordant pain reporters, TA-ER significantly (p < 0.05) improved ADP scores vs. TAcs (weeks 5–19; area-under-the-effect [AUE]weeks1–12; AUEweeks1–24) and saline-placebo (weeks 1–20; AUEweeks1–12; AUEweeks1–24). At week 12, a higher proportion reported no knee pain (ADP = 0) with TA-ER (~ 28%) vs. TAcs (~ 8%). TA-ER significantly improved WOMAC-A vs. TAcs at weeks 4, 8, and 12, with significant reduction in rescue medication usage observed with TA-ER from weeks 2 to 20 vs. TAcs. Conclusions In patients reporting moderate-to-severe knee OA pain at baseline based on concordant ADP and WOMAC-A scores, TA-ER provided statistically significant pain relief for ≥ 12 weeks compared with conventional TAcs. Trial Registration ClinicalTrials.gov Identifier: NCT02357459

Stable Isotopic Evidence for Methane Seeps in Neoproterozoic Postglacial Cap Carbonates

The Earth's most severe glaciations are thought to have occurred about 600 million years ago, in the late Neoproterozoic era. A puzzling feature of glacial deposits from this interval is that they are overlain by 1–5-m-thick 'cap carbonates' (particulate deep-water marine carbonate rocks) associated with a prominent negative carbon isotope excursion. Cap carbonates have been controversially ascribed to the aftermath of almost complete shutdown of the ocean ecosystems for millions of years during such ice ages—the 'snowball Earth' hypothesis. Conversely, it has also been suggested that these carbonate rocks were the result of destabilization of methane hydrates during deglaciation and concomitant flooding of continental shelves and interior basins. The most compelling criticism of the latter 'methane hydrate' hypothesis has been the apparent lack of extreme isotopic variation in cap carbonates inferred locally to be associated with methane seeps. Here we report carbon isotopic and petrographic data from a Neoproterozoic postglacial cap carbonate in south China that provide direct evidence for methane-influenced processes during deglaciation. This evidence lends strong support to the hypothesis that methane hydrate destabilization contributed to the enigmatic cap carbonate deposition and strongly negative carbon isotopic anomalies following Neoproterozoic ice ages. This explanation requires less extreme environmental disturbance than that implied by the snowball Earth hypothesis

Long-Term Opioid Contract Use for Chronic Pain Management in Primary Care Practice. A Five Year Experience

BACKGROUND: The use of opioid medications to manage chronic pain is complex and challenging, especially in primary care settings. Medication contracts are increasingly being used to monitor patient adherence, but little is known about the long-term outcomes of such contracts. OBJECTIVE: To describe the long-term outcomes of a medication contract agreement for patients receiving opioid medications in a primary care setting. DESIGN: Retrospective cohort study. SUBJECTS: All patients placed on a contract for opioid medication between 1998 and 2003 in an academic General Internal Medicine teaching clinic. MEASUREMENTS: Demographics, diagnoses, opiates prescribed, urine drug screens, and reasons for contract cancellation were recorded. The association of physician contract cancellation with patient factors and medication types were examined using the Chi-square test and multivariate logistic regression. RESULTS: A total of 330 patients constituting 4% of the clinic population were placed on contracts during the study period. Seventy percent were on indigent care programs. The majority had low back pain (38%) or fibromyalgia (23%). Contracts were discontinued in 37%. Only 17% were cancelled for substance abuse and noncompliance. Twenty percent discontinued contract voluntarily. Urine toxicology screens were obtained in 42% of patients of whom 38% were positive for illicit substances. CONCLUSIONS: Over 60% of patients adhered to the contract agreement for opioids with a median follow-up of 22.5 months. Our experience provides insight into establishing a systematic approach to opioid administration and monitoring in primary care practices. A more structured drug testing strategy is needed to identify nonadherent patients

Unilateral aplasia of both cruciate ligaments

Aplasia of both cruciate ligaments is a rare congenital disorder. A 28-year-old male presented with pain and the feeling of instability of his right knee after trauma. The provided MRI and previous arthroscopy reports did not indicate any abnormalities except cruciate ligament tears. He was referred to us for reconstruction of both cruciate ligaments. The patient again underwent arthroscopy which revealed a hypoplasia of the medial trochlea and an extremely narrow intercondylar notch. The tibia revealed a missing anterior cruciate ligament (ACL) footprint and a single bump with a complete coverage with articular cartilage. There was no room for an ACL graft. A posterior cruciate ligament could not be identified. The procedure was ended since a ligament reconstruction did not appear reasonable. A significant notch plasty if not a partial resection of the condyles would have been necessary to implant a ligament graft. It is most likely that this would not lead to good knee stability. If the surgeon would have retrieved the contralateral hamstrings at the beginning of the planned ligament reconstruction a significant damage would have occurred to the patient. Even in seemingly clear diagnostic findings the arthroscopic surgeon should take this rare abdnormality into consideration and be familiar with the respective radiological findings. We refer the abnormal finding of only one tibial spine to as the "dromedar-sign" as opposed to the two (medial and a lateral) tibial spines in a normal knee. This may be used as a hint for aplasia of the cruciate ligaments

Population-Based Rates of Revision of Primary Total Hip Arthroplasty: A Systematic Review

Background: Most research on failure leading to revision total hip arthroplasty (THA) is reported from single centers. We searched PubMed between January 2000 and August 2010 to identify population- or community-based studies evaluating ten-year revision risks. We report ten-year revision risk using the Kaplan-Meier method, stratifying by age and fixation technique. Results: Thirteen papers met the inclusion criteria. Cemented prostheses had Kaplan-Meier estimates of revision-free implant survival of ten years ranging from 88 % to 95%; uncemented prostheses had Kaplan-Meier estimates from 80 % to 85%. Estimates ranged from 72 % to 86 % in patients less than 60 years old and from 90 to 96 % in older patients. Conclusion: Data reported from national registries suggest revision risks of 5 to 20 % ten years following primary THA. Revision risks are lower in older THA recipients. Uncemented implants may have higher ten-year rates of revision, regardless of age

Strong interface-induced spin-orbit coupling in graphene on WS2

Interfacial interactions allow the electronic properties of graphene to be modified, as recently demonstrated by the appearance of satellite Dirac cones in the band structure of graphene on hexagonal boron nitride (hBN) substrates. Ongoing research strives to explore interfacial interactions in a broader class of materials in order to engineer targeted electronic properties. Here we show that at an interface with a tungsten disulfide (WS2) substrate, the strength of the spin-orbit interaction (SOI) in graphene is very strongly enhanced. The induced SOI leads to a pronounced low-temperature weak anti-localization (WAL) effect, from which we determine the spin-relaxation time. We find that spin-relaxation time in graphene is two-to-three orders of magnitude smaller on WS2 than on SiO2 or hBN, and that it is comparable to the intervalley scattering time. To interpret our findings we have performed first-principle electronic structure calculations, which both confirm that carriers in graphene-on-WS2 experience a strong SOI and allow us to extract a spin-dependent low-energy effective Hamiltonian. Our analysis further shows that the use of WS2 substrates opens a possible new route to access topological states of matter in graphene-based systems.Comment: Originally submitted version in compliance with editorial guidelines. Final version with expanded discussion of the relation between theory and experiments to be published in Nature Communication

Isogenic Pairs of Wild Type and Mutant Induced Pluripotent Stem Cell (iPSC) Lines from Rett Syndrome Patients as In Vitro Disease Model

Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5–6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology

Rapid Sampling of Molecules via Skin for Diagnostic and Forensic Applications

Skin provides an excellent portal for diagnostic monitoring of a variety of entities; however, there is a dearth of reliable methods for patient-friendly sampling of skin constituents. This study describes the use of low-frequency ultrasound as a one-step methodology for rapid sampling of molecules from the skin. Sampling was performed using a brief exposure of 20 kHz ultrasound to skin in the presence of a sampling fluid. In vitro sampling from porcine skin was performed to assess the effectiveness of the method and its ability to sample drugs and endogenous epidermal biomolecules from the skin. Dermal presence of an antifungal drug—fluconazole and an abused substance, cocaine—was assessed in rats. Ultrasonic sampling captured the native profile of various naturally occurring moisturizing factors in skin. A high sampling efficiency (79 ± 13%) of topically delivered drug was achieved. Ultrasound consistently sampled greater amounts of drug from the skin compared to tape stripping. Ultrasonic sampling also detected sustained presence of cocaine in rat skin for up to 7 days as compared to its rapid disappearance from the urine. Ultrasonic sampling provides significant advantages including enhanced sampling from deeper layers of skin and high temporal sampling sensitivity