Optimal delineation of single C-tactile and C-nociceptive afferents in humans by latency slowing.

C-mechanoreceptors in humans comprise a population of unmyelinated afferents exhibiting a wide range of mechanical sensitivities. C-mechanoreceptors are putatively divided into those signaling gentle touch (C-tactile afferents, CTs) and nociception (C-mechanosensitive nociceptors, CMs), giving rise to positive and negative affect, respectively. We sought to distinguish, compare, and contrast the properties of a population of human C-mechanoreceptors to see how fundamental the divisions between these putative subpopulations are. We used microneurography to record from individual afferents in humans and applied electrical and mechanical stimulation to their receptive fields. We show that C-mechanoreceptors can be distinguished unequivocally into two putative populations, comprising CTs and CMs, by electrically evoked spike latency changes (slowing). After both natural mechanical stimulation and repetitive electrical stimulation there was markedly less latency slowing in CTs compared with CMs. Electrical receptive field stimulation, which bypasses the receptor end organ, was most effective in classifying C-mechanoreceptors, as responses to mechanical receptive field stimulation overlapped somewhat, which may lead to misclassification. Furthermore, we report a subclass of low-threshold CM responding to gentle mechanical stimulation and a potential subclass of CT afferent displaying burst firing. We show that substantial differences exist in the mechanisms governing axonal conduction between CTs and CMs. We provide clear electrophysiological "signatures" (extent of latency slowing) that can be used in unequivocally identifying populations of C-mechanoreceptors in single-unit and multiunit microneurography studies and in translational animal research into affective touch. Additionally, these differential mechanisms may be pharmacologically targetable for separate modulation of positive and negative affective touch information.NEW & NOTEWORTHY Human skin encodes a plethora of touch interactions, and affective tactile information is primarily signaled by slowly conducting C-mechanoreceptive afferents. We show that electrical stimulation of low-threshold C-tactile afferents produces markedly different patterns of activity compared with high-threshold C-mechanoreceptive nociceptors, although the populations overlap in their responses to mechanical stimulation. This fundamental distinction demonstrates a divergence in affective touch signaling from the first stage of sensory processing, having implications for the processing of interpersonal touch.

Small fibre pathology, small fibre symptoms and pain in fibromyalgia syndrome.

A proportion of people with fibromyalgia demonstrate small fibre pathology (SFP). However, it is unclear how SFP directly relates to pain phenomenology. Thirty-three individuals with FMS and ten healthy volunteers underwent assessment of SFP and sensory phenotyping using corneal confocal microscopy, validated questionnaires and quantitative sensory testing (QST). Corneal nerve fibre length was used to stratify participants with fibromyalgia into with SFP [SFP+] and without SFP [SFP-]. SFP was detected in 50% of the fibromyalgia cohort. Current pain score and QST parameters did not differ between SFP+ and SFP-. Mechanical pain sensitivity (MPS) demonstrated a significant gain-of-function in the SFP- cohort compared to healthy-volunteers (p = 0.014, F = 4.806, η2 = 0.22). Further stratification revealed a cohort without structural SFP but with symptoms compatible with small fibre neuropathy symptoms and a significant gain in function in MPS (p = 0.020 Chi-square). Additionally, this cohort reported higher scores for both depression (p = 0.039, H = 8.483, η2 = 0.312) and anxiety (p = 0.022, F = 3.587, η2 = 0.293). This study confirms that SFP is present in a proportion of people with fibromyalgia. We also show that in a proportion of people with fibromyalgia, small fibre neuropathy symptoms are present in the absence of structural SFP. Greater mechanical pain sensitivity, depression and anxiety are seen in these individuals.

odML-Tables as a Metadata Standard in Microneurography.

Metadata standards are well-established for many types of electrophysiological methods but are still lacking for microneurographic recordings of peripheral sensory nerve fibers in humans. Finding a solution for daily work in the laboratory is a complex process. We have designed templates based on odML and odML-tables to structure and capture metadata and provided an extension to the existing GUI to enable database searching.

odML-Tables as a Metadata Standard in Microneurography.

Metadata is essential for handling medical data according to FAIR principles. Standards are well-established for many types of electrophysiological methods but are still lacking for microneurographic recordings of peripheral sensory nerve fibers in humans. Developing a new concept to enhance laboratory workflows is a complex process. We propose a standard for structuring and storing microneurography metadata based on odML and odML-tables. Further, we present an extension to the odML-tables GUI that enables user-friendly search functionality of the database. With our open-source repository, we encourage other microneurography labs to incorporate odML-based metadata into their experimental routines.

Open-Source Real-Time Closed-Loop Electrical Threshold Tracking for Translational Pain Research.

Nociceptors are a class of primary afferent neurons that signal potentially harmful noxious stimuli. An increase in nociceptor excitability occurs in acute and chronic pain conditions. This produces abnormal ongoing activity or reduced activation thresholds to noxious stimuli. Identifying the cause of this increased excitability is required for the development and validation of mechanism-based treatments. Single-neuron electrical threshold tracking can quantify nociceptor excitability. Therefore, we have developed an application to allow such measurements and demonstrate its use in humans and rodents. APTrack provides real-time data visualization and action potential identification using a temporal raster plot. Algorithms detect action potentials by threshold crossing and monitor their latency after electrical stimulation. The plugin then modulates the electrical stimulation amplitude using an up-down method to estimate the electrical threshold of the nociceptors. The software was built upon the Open Ephys system (V0.54) and coded in C++ using the JUCE framework. It runs on Windows, Linux, and Mac operating systems. The open-source code is available (https://github.com/Microneurography/APTrack). The electrophysiological recordings were taken from nociceptors in both a mouse skin-nerve preparation using the teased fiber method in the saphenous nerve and in healthy human volunteers using microneurography in the superficial peroneal nerve. Nociceptors were classified by their response to thermal and mechanical stimuli, as well as by monitoring the activity-dependent slowing of the conduction velocity. The software facilitated the experiment by simplifying the action potential identification through the temporal raster plot. We demonstrate real-time closed-loop electrical threshold tracking of single-neuron action potentials during in vivo human microneurography, for the first time, and during ex vivo mouse electrophysiological recordings of C-fibers and Aδ-fibers. We establish proof of principle by showing that the electrical threshold of a human heat-sensitive C-fiber nociceptor is reduced by heating the receptive field. This plugin enables the electrical threshold tracking of single-neuron action potentials and allows the quantification of changes in nociceptor excitability.

Evaluating the association of TRPA1 gene polymorphisms with pain sensitivity: a protocol for an adaptive recall by genotype study.

BACKGROUND: Pain is a complex polygenic trait whose common genetic underpinnings are relatively ill-defined due in part to challenges in measuring pain as a phenotype. Pain sensitivity can be quantified, but this is difficult to perform at the scale required for genome wide association studies (GWAS). Existing GWAS of pain have identified surprisingly few loci involved in nociceptor function which contrasts strongly with rare monogenic pain states. This suggests a lack of resolution with current techniques. We propose an adaptive methodology within a recall-by-genotype (RbG) framework using detailed phenotyping to screen minor alleles in a candidate 'nociceptor' gene in an attempt to estimate their genetic contribution to pain. METHODS/DESIGN: Participants of the Avon Longitudinal Study of Parents and Children will be recalled on the basis of genotype at five common non-synonomous SNPs in the 'nociceptor' gene transient receptor potential ankylin 1 (TRPA1). Those homozygous for the common alleles at each of the five SNPs will represent a control group. Individuals homozygous for the minor alleles will then be recruited in a series of three sequential test groups. The outcome of a pre-planned early assessment (interim) of the current test group will determine whether to continue recruitment or switch to the next test group. Pain sensitivity will be assessed using quantitative sensory testing (QST) before and after topical application of 10% cinnamaldehyde (a TRPA1 agonist). DISCUSSION: The design of this adaptive RbG study offers efficiency in the assessment of associations between genetic variation at TRPA1 and detailed pain phenotypes. The possibility to change the test group in response to preliminary data increases the likelihood to observe smaller effect sizes relative to a conventional multi-armed design, as well as reducing futile testing of participants where an effect is unlikely to be observed. This specific adaptive RbG design aims to uncover the influence of common TRPA1 variants on pain sensation but can be applied to any hypothesis-led genotype study where costly and time intensive investigation is required and / or where there is large uncertainty around the expected effect size. TRIAL REGISTRATION: ISRCTN, ISRCTN16294731. Retrospectively registered 25th November 2021.

American election results at the precinct level.

We describe the creation and quality assurance of a dataset containing nearly all available precinct-level election results from the 2016, 2018, and 2020 American elections. Precincts are the smallest level of election administration, and election results at this granularity are needed to address many important questions. However, election results are individually reported by each state with little standardization or data quality assurance. We have collected, cleaned, and standardized precinct-level election results from every available race above the very local level in almost every state across the last three national election years. Our data include nearly every candidate for president, US Congress, governor, or state legislator, and hundreds of thousands of precinct-level results for judicial races, other statewide races, and even local races and ballot initiatives. In this article we describe the process of finding this information and standardizing it. Then we aggregate the precinct-level results up to geographies that have official totals, and show that our totals never differ from the official nationwide data by more than 0.457%.

Inflammation reduces mechanical thresholds in a population of transient receptor potential channel A1-expressing nociceptors in the rat.

Inflammatory hypersensitivity is characterized by behavioural reductions in withdrawal thresholds to noxious stimuli. Although cutaneous primary afferent neurones are known to have lowered thermal thresholds in inflammation, whether their mechanical thresholds are altered remains controversial. The transient receptor potential channel A1 (TRPA1) is a receptor localized to putative nociceptive neurones and is implicated in mechanical and thermal nociception. Herein, we examined changes in the properties of single primary afferents in normal and acutely inflamed rats and determined whether specific nociceptive properties, particularly mechanical thresholds, are altered in the subpopulation of afferents that responded to the TRPA1 agonist cinnamaldehyde (TRPA1-positive afferents). TRPA1-positive afferents in normal animals belonged to the mechanonociceptive populations, many of which also responded to heat or capsaicin but only a few of which responded to cold. In acute inflammation, a greater proportion of afferents responded to cinnamaldehyde and an increased proportion of dorsal root ganglion neurones expressed TRPA1 protein. Functionally, in inflammation, TRPA1-positive afferents showed significantly reduced mechanical thresholds and enhanced activity to agonist stimulation. Inflammation altered thermal thresholds in both TRPA1-positive and TRPA1-negative afferents. Our data show that a subset of afferents is sensitized to mechanical stimulation by inflammation and that these afferents are defined by expression of TRPA1.

Ultrasound-guided, open-source microneurography: Approaches to improve recordings from peripheral nerves in man.

OBJECTIVE: Microneurography is the only method for recording from single neurons in intact human nerves. It is challenging - requiring technical expertise, investment in specialised equipment and has sparse data yields. METHODS: We assessed whether ultrasound guidance in combination with an 'open access' amplifier and data capture system (Open-Ephys) would simplify and expand the scope of microneurographic recordings in humans. RESULTS: In 32 healthy consenting volunteers, ultrasound-guidance improved success rates for obtaining cutaneous C-fibres and reduced "Skin to Nerve" times from 28.5 min to 4.5 min for recordings of the peroneal nerve (P < 0.0001). We illustrate the potential utility of ultrasound-guided microneurography for difficult to access nerves with phrenic nerve recording during a Valsalva manoeuvre. We show that Open Ephys is a viable alternative to commercially available recording systems and offers advantages in terms of cost and software customisability. CONCLUSIONS: Ultrasound guidance for microneurography with Open Ephys facilitates cutaneous C nociceptor recordings and allows recordings to be made from nerves previously considered inaccessible. SIGNIFICANCE: We anticipate that the adoption of these techniques will improve microneurography experimental efficiency, adds an important visual learning aid and increases the generalisability of the approach.

Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Care Excellence Single Technology Appraisal.

The manufacturer of olaratumab (Lartruvo®), Eli Lilly & Company Limited, submitted evidence for the clinical and cost effectiveness of this drug, in combination with doxorubicin, for untreated advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy, as part of the National Institute for Health and Care Excellence (NICE) Single Technology Appraisal process. The Peninsula Technology Assessment Group, commissioned to act as the Evidence Review Group (ERG), critically reviewed the company's submission. Clinical effectiveness evidence for the company's analysis was derived from an open-label, randomised controlled trial, JGDG. The analysis was based on a partitioned survival model with a time horizon of 25 years, and the perspective was of the UK National Health Service (NHS) and Personal Social Services. Costs and benefits were discounted at 3.5% per year. Given the available evidence, olaratumab is likely to meet NICE's end-of-life criteria. To improve the cost effectiveness of olaratumab, the company offered a discount through a Commercial Access Agreement (CAA) with the NHS England. When the discount was applied, the mean base-case and probabilistic incremental cost-effectiveness ratios (ICERs) for olaratumab plus doxorubicin versus the standard-of-care doxorubicin were £46,076 and £47,127 per quality-adjusted life-year (QALY) gained, respectively; the probability of this treatment being cost effective at the willingness-to-pay threshold of £50,000 per QALY gained, applicable to end-of-life treatments, was 0.54. The respective ICERs from the ERG's analysis were approximately £60,000/QALY gained, and the probability of the treatment being cost effective was 0.21. In August 2017, the NICE Appraisal Committee recommended olaratumab in combination with doxorubicin for this indication for use via the UK Cancer Drugs Fund under the agreed CAA until further evidence being collected in the ongoing phase III trial-ANNOUNCE-becomes available in December 2020.

Correction to: Olaratumab in Combination with Doxorubicin for the Treatment of Advanced Soft Tissue Sarcoma: An Evidence Review Group Perspective of a National Institute for Health and Clinical Excellence Single Technology Appraisal.

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A novel method for delivering ramped cooling reveals rat behaviours at innocuous and noxious temperatures: A comparative study of human psychophysics and rat behaviour.

BACKGROUND: Thermal sensory testing in rodents informs human pain research. There are important differences in the methodology for delivering thermal stimuli to humans and rodents. This is particularly true in cold pain research. These differences confound extrapolation and de-value nociceptive tests in rodents. NEW METHOD: We investigated cooling-induced behaviours in rats and psychophysical thresholds in humans using ramped cooling stimulation protocols. A Peltier device mounted upon force transducers simultaneously applied a ramped cooling stimulus whilst measuring contact with rat hind paw or human finger pad. Rat withdrawals and human detection, discomfort and pain thresholds were measured. RESULTS: Ramped cooling of a rat hind paw revealed two distinct responses: Brief paw removal followed by paw replacement, usually with more weight borne than prior to the removal (temperature inter-quartile range: 19.1 °C to 2.8 °C). Full withdrawal was evoked at colder temperatures (inter quartile range: -11.3 °C to -11.8 °C). The profile of human cool detection threshold and cold pain threshold were remarkably similar to that of the rat withdrawals behaviours. COMPARISON: Previous rat cold evoked behaviours utilise static temperature stimuli. By utilising ramped cold stimuli this novel methodology better reflects thermal testing in patients. CONCLUSION: Brief paw removal in the rat is driven by non-nociceptive afferents, as is the perception of cooling in humans. This is in contrast to the nociceptor-driven withdrawal from colder temperatures. These findings have important implications for the interpretation of data generated in older cold pain models and consequently our understanding of cold perception and pain.

Facets and mechanisms of adaptive pain behavior: predictive regulation and action.

Neural mechanisms underlying nociception and pain perception are considered to serve the ultimate goal of limiting tissue damage. However, since pain usually occurs in complex environments and situations that call for elaborate control over behavior, simple avoidance is insufficient to explain a range of mammalian pain responses, especially in the presence of competing goals. In this integrative review we propose a Predictive Regulation and Action (PRA) model of acute pain processing. It emphasizes evidence that the nervous system is organized to anticipate potential pain and to adjust behavior before the risk of tissue damage becomes critical. Regulatory processes occur on many levels, and can be dynamically influenced by local interactions or by modulation from other brain areas in the network. The PRA model centers on neural substrates supporting the predictive nature of pain processing, as well as on finely-calibrated yet versatile regulatory processes that ultimately affect behavior. We outline several operational categories of pain behavior, from spinally-mediated reflexes to adaptive voluntary action, situated at various neural levels. An implication is that neural processes that track potential tissue damage in terms of behavioral consequences are an integral part of pain perception.

Sensory nerves have altered function contralateral to a monoarthritis and may contribute to the symmetrical spread of inflammation.

Rheumatoid arthritis (RA) and rat models of RA exhibit symmetrical mirror-image spread. Many studies have sought to understand the underlying mechanisms and have reported contralateral effects that are manifested in many different forms. It is now well accepted that neurogenic mechanisms contribute to the symmetrical spread of inflammation. However, very few investigators have directly assessed changes in contralateral nerve function and there is a paucity of data. In the present study our aim was to investigate whether there are changes, in particular in the nervous system but also in the vascular system contralateral to an inflamed rat knee joint, that might precede overt inflammation and symmetrical spread. Three to five days following Complete Freund's Adjuvant (CFA) injection we found spontaneous antidromic (away from the CNS) activity in the homologous sensory nerve contralateral to the inflamed joint. Antidromic activity of this nature is known to result in the peripheral release of pro-inflammatory and vasoactive neuropeptides. Importantly, this activity was modulated by systemic analgesic treatment. Furthermore, levels of Evans blue dye extravasation were significantly increased in the joint contralateral to inflammation, indicating altered vascular function. These data suggest that contralateral increases in sensory neural activity and vascular function may account for the symmetrical spread of RA, and that early analgesic treatment may prevent or delay the spread of this debilitating disease.

Molecular mechanism of voltage sensor movements in a potassium channel.

Voltage-gated potassium channels are six-transmembrane (S1-S6) proteins that form a central pore domain (4 x S5-S6) surrounded by four voltage sensor domains (S1-S4), which detect changes in membrane voltage and control pore opening. Upon depolarization, the S4 segments move outward carrying charged residues across the membrane field, thereby leading to the opening of the pore. The mechanism of S4 motion is controversial. We have investigated how S4 moves relative to the pore domain in the prototypical Shaker potassium channel. We introduced pairs of cysteines, one in S4 and the other in S5, and examined proximity changes between each pair of cysteines during activation, using Cd2+ and copper-phenanthroline, which crosslink the cysteines with metal and disulphide bridges, respectively. Modelling of the results suggests a novel mechanism: in the resting state, the top of the S3b-S4 voltage sensor paddle lies close to the top of S5 of the adjacent subunit, but moves towards the top of S5 of its own subunit during depolarization--this motion is accompanied by a reorientation of S4 charges to the extracellular phase.

Las organizaciones inteligentes en la toma de decisiones en salud: el caso del dengue / Intelligent organizations for decision making in health: the case of dengue fever

Las Organizaciones Inteligentes (OI) son un instrumento de gran ayuda para organizar y conducir acciones de vigilancia, prevención y control. Son tecnología de punta en la administración; permiten generar esquemas del comportamiento de estructuras y políticas de organizaciones, describen sistématicamente problemas e integran modelos computalizados. Con esto se desarrollan pensamientos sistématicos; producen una visión compartida; crean modelos mentales de aprendizaje y superación continuos; se aprende en equipo; y se mejora el dominio personal. El avance científico-tecnológico ha producido una información impresionante en medicina, concomitante crecimiento de sus organizaciones y dificultad en las respuestas debido a cambios e innovaciones repentinos y constantes por ello se justifican las OI. Este trabajo está orientado a probar la utilidad de la tecnología de OI en el ordenamiento y sistematización de la información sobre los acontecimientos de las ciencias médicas. Se seleccionó el dengue para ejemplificar la aplicación de dicha tecnología porque representa un problema de crecimiento, importancia en el continente y en México, es complejo, puede evolucionar a formas de mayor gravedad en la población y es factible de analizarse en forma sistémica

Intelligent organizations (IO) represent a valuable tool to organize and guide dengue fever surveillance, prevention and control interventions. IO entail state of the art technology in managerial science to generate behavioral frameworks of organizational structures and policies. They present a systematic description of problems and construct computerized models to develop systemic thinking; they produce a shared vision and build progressive mental learning and advancement models. Also, IO promote team building and personal control skills. Scientific-technological advances have produced a wealth of information in medicine, with the corresponding growth of organizations and difficulty of responses because of sudden and incessant change. This new environment calls for the application of IO know-how. This article is oriented to prove the usefulness of the IO technology in the ordering and systematization of the reports about the medical sciences facts. Dengue was chosen to exemplify the use of IO technology as it represents an increasing health problem in America, as well as in Mexico; it is so complex that it can evolve to a more serious problem, besides it can be analized within a systemic method.