Human assumed central sensitisation (HACS) in patients with chronic low back pain radiating to the leg (CLaSSICO study)

INTRODUCTION: Patients with chronic low back pain radiating to the leg (CLBPr) are sometimes referred to a specialised pain clinic for a precise diagnosis based, for example, on a diagnostic selective nerve root block. Possible interventions are therapeutic selective nerve root block or pulsed radiofrequency. Central pain sensitisation is not directly assessable in humans and therefore the term ‘human assumed central sensitisation’ (HACS) is proposed. The possible existence and degree of sensitisation associated with pain mechanisms assumed present in the human central nervous system, its role in the chronification of pain and its interaction with diagnostic and therapeutic interventions are largely unknown in patients with CLBPr. The aim of quantitative sensory testing (QST) is to estimate quantitatively the presence of HACS and accumulating evidence suggest that a subset of patients with CLBPr have facilitated responses to a range of QST tests. The aims of this study are to identify HACS in patients with CLBPr, to determine associations with the effect of selective nerve root blocks and compare outcomes of HACS in patients to healthy volunteers. METHODS AND ANALYSIS: A prospective observational study including 50 patients with CLBPr. Measurements are performed before diagnostic and therapeutic nerve root block interventions and at 4 weeks follow-up. Data from patients will be compared with those of 50 sex-matched and age-matched healthy volunteers. The primary study parameters are the outcomes of QST and the Central Sensitisation Inventory. Statistical analyses to be performed will be analysis of variance. ETHICS AND DISSEMINATION: The Medical Research Ethics Committee of the University Medical Center Groningen, Groningen, the Netherlands, approved this study (dossier NL60439.042.17). The results will be disseminated via publications in peer-reviewed journals and at conferences. TRIAL REGISTRATION NUMBER: NTR NL6765

Music and low-frequency vibrations for the treatment of chronic musculoskeletal pain in elderly:A pilot study

BACKGROUND: Transcutaneous vagal nerve stimulation has analgesic potential and might be elicited by abdominally administered low-frequency vibrations. The objective was to study the safety and effect of a combination of music and abdominally administered low-frequency vibrations on pain intensity in elderly patients with chronic musculoskeletal pain. METHODS: This trial was an international multicenter, randomized controlled pilot study. Patients at age ≥ 65 years with musculoskeletal pain for ≥ 3 months and a daily pain score ≥ 4 out of 10 were recruited at three centers. They were randomized to receive either a combination of music and low-frequency (20–100 Hz) vibrations administered to the abdomen, or a combination with the same music but with higher frequency (200–300 Hz) vibrations administered to the abdomen. Low-frequency vibrations were expected to result in pain reduction measured with a numeric pain rating scale (NRS). Patients in both groups received eight treatments of the music combined with the vibrations in three weeks. Primary outcomes were safety (Serious Adverse Events) and pain intensity measured at baseline, after the last treatment and at six weeks follow-up. Multilevel linear model analyses were performed to study group and time effects. RESULTS: A total of 45 patients were analyzed according to intention-to-treat principle. After 344 treatments, 1 Adverse Event was found related to the intervention, while 13 Adverse Events were possibly related. A multilevel linear model showed that the interaction effect of group by time did not predict pain intensity (F[1, 45.93] = 0.002, p = 0.97) when comparing pain intensity at baseline, after the last treatment and at follow-up. CONCLUSIONS: The combination of music and abdominally administered vibrations was found to be safe and well tolerated by the elderly patients. However, over time, neither the low-frequency treatment group nor the high-frequency treatment group provided clinically meaningful pain relief. There is no evidence that the low-frequency treatment elicited vagal nerve stimulation. TRIAL REGISTRATION: The trial was prospectively registered in the Netherlands Trial Register (NTR: NL7606) on 21-03-2019

Health Outcomes for Clients of Needle and Syringe Programs in Prisons

High levels of drug dependence have been observed in the prison population globally, and the sharing of injecting drug equipment in prisons has contributed to higher prevalence of bloodborne diseases in prisoners than in the general population. Few prison needle and syringe programs (PNSPs) exist. We conducted a systematic review to assess evidence regarding health outcomes of PNSPs. We searched peer-reviewed databases for data relating to needle and syringe programs in prisons. The search methodology was conducted in accordance with accepted guidelines. Five studies met review inclusion criteria, and all presented evidence associating PNSPs with one or more health benefits, but the strength of the evidence was low. The outcomes for which the studies collectively demonstrated the strongest evidence were prevention of human immunodeficiency virus and viral hepatitis. Few negative consequences from PNSPs were observed, consistent with previous evidence assessments. More research is needed on PNSP effectiveness, and innovative study designs are needed to overcome methodological limitations of previous research. Until stronger evidence becomes available, policymakers are urged to recognize that not implementing PNSPs has the potential to cause considerable harm, in light of what is currently known about the risks and benefits of needle and syringe programs and PNSPs and about the high prevalence of human immunodeficiency virus and viral hepatitis in prisons

Quantum Monte Carlo Loop Algorithm for the t-J Model

We propose a generalization of the Quantum Monte Carlo loop algorithm to the t-J model by a mapping to three coupled six-vertex models. The autocorrelation times are reduced by orders of magnitude compared to the conventional local algorithms. The method is completely ergodic and can be formulated directly in continuous time. We introduce improved estimators for simulations with a local sign problem. Some first results of finite temperature simulations are presented for a t-J chain, a frustrated Heisenberg chain, and t-J ladder models.Comment: 22 pages, including 12 figures. RevTex v3.0, uses psf.te

Avoiding Catch-22:Validating the PainDETECT in a in a population of patients with chronic pain

BACKGROUND: Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system and is a major therapeutic challenge. Several screening tools have been developed to help physicians detect patients with neuropathic pain. These have typically been validated in populations pre-stratified for neuropathic pain, leading to a so called "Catch-22 situation:" "a problematic situation for which the only solution is denied by a circumstance inherent in the problem or by a rule". The validity of screening tools needs to be proven in patients with pain who were not pre-stratified on basis of the target outcome: neuropathic pain or non-neuropathic pain. This study aims to assess the validity of the Dutch PainDETECT (PainDETECT-Dlv) in a large population of patients with chronic pain. METHODS: A cross-sectional multicentre design was used to assess PainDETECT-Dlv validity. Included where patients with low back pain radiating into the leg(s), patients with neck-shoulder-arm pain and patients with pain due to a suspected peripheral nerve damage. Patients' pain was classified as having a neuropathic pain component (yes/no) by two experienced physicians ("gold standard"). Physician opinion based on the Grading System was a secondary comparison. RESULTS: In total, 291 patients were included. Primary analysis was done on patients where both physicians agreed upon the pain classification (n = 228). Compared to the physician's classification, PainDETECT-Dlv had a sensitivity of 80% and specificity of 55%, versus the Grading System it achieved 74 and 46%. CONCLUSION: Despite its internal consistency and test-retest reliability the PainDETECT-Dlv is not an effective screening tool for a neuropathic pain component in a population of patients with chronic pain because of its moderate sensitivity and low specificity. Moreover, the indiscriminate use of the PainDETECT-Dlv as a surrogate for clinical assessment should be avoided in daily clinical practice as well as in (clinical-) research. Catch-22 situations in the validation of screening tools can be prevented by not pre-stratifying the patients on basis of the target outcome before inclusion in a validation study for screening instruments. TRIAL REGISTRATION: The protocol was registered prospectively in the Dutch National Trial Register: NTR 3030

Critical dynamics in the 2d classical XY-model: a spin dynamics study

Using spin-dynamics techniques we have performed large-scale computer simulations of the dynamic behavior of the classical three component XY-model (i.e. the anisotropic limit of an easy-plane Heisenberg ferromagnet), on square lattices of size up to 192^2, for several temperatures below, at, and above T_KT. The temporal evolution of spin configurations was determined numerically from coupled equations of motion for individual spins by a fourth order predictor-corrector method, with initial spin configurations generated by a hybrid Monte Carlo algorithm. The neutron scattering function S(q,omega) was calculated from the resultant space-time displaced spin-spin correlation function. Pronounced spin-wave peaks were found both in the in-plane and the out-of-plane scattering function over a wide range of temperatures. The in-plane scattering function S^xx also has a large number of clear but weak additional peaks, which we interpret to come from two-spin-wave scattering. In addition, we observed a small central peak in S^xx, even at temperatures well below the phase transition. We used dynamic finite size scaling theory to extract the dynamic critical exponent z. We find z=1.00(4) for all T <= T_KT, in excellent agreement with theoretical predictions, although the shape of S(q,omega) is not well described by current theory.Comment: 31 pages, LaTex, 13 figures (38 subfigures) included as eps-files, needs psfig, 260 K

Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors

Investigating the validity of the DN4 in a consecutive population of patients with chronic pain

Neuropathic pain is clinically described as pain caused by a lesion or disease of the somatosensory nervous system. The aim of this study was to assess the validity of the Dutch version of the DN4, in a cross-sectional multicentre design, as a screening tool for detecting a neuropathic pain component in a large consecutive, not pre-stratified on basis of the target outcome, population of patients with chronic pain. Patients’ pain was classified by two independent (pain-)physicians as the gold standard. The analysis was initially performed on the outcomes of those patients (n = 228 out of 291) in whom both physicians agreed in their pain classification. Compared to the gold standard the DN4 had a sensitivity of 75% and specificity of 76%. The DN4-symptoms (seven interview items) solely resulted in a sensitivity of 70% and a specificity of 67%. For the DN4-signs (three examination items) it was respectively 75% and 75%. In conclusion, because it seems that the DN4 helps to identify a neuropathic pain component in a consecutive population of patients with chronic pain in a moderate way, a comprehensive (physical-) examination by the physician is still obligate

Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism

Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and poly-brominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T(4)) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T(4) was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose–response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED(30)), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs

Time-variability in the Interstellar Boundary Conditions of the Heliosphere: Effect of the Solar Journey on the Galactic Cosmic Ray Flux at Earth

During the solar journey through galactic space, variations in the physical properties of the surrounding interstellar medium (ISM) modify the heliosphere and modulate the flux of galactic cosmic rays (GCR) at the surface of the Earth, with consequences for the terrestrial record of cosmogenic radionuclides. One phenomenon that needs studying is the effect on cosmogenic isotope production of changing anomalous cosmic ray fluxes at Earth due to variable interstellar ionizations. The possible range of interstellar ram pressures and ionization levels in the low density solar environment generate dramatically different possible heliosphere configurations, with a wide range of particle fluxes of interstellar neutrals, their secondary products, and GCRs arriving at Earth. Simple models of the distribution and densities of ISM in the downwind direction give cloud transition timescales that can be directly compared with cosmogenic radionuclide geologic records. Both the interstellar data and cosmogenic radionuclide data are consistent with cloud transitions during the Holocene, with large and assumption-dependent uncertainties. The geomagnetic timeline derived from cosmic ray fluxes at Earth may require adjustment to account for the disappearance of anomalous cosmic rays when the Sun is immersed in ionized gas.Comment: Submitted to Space Sciences Review