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Background: Spatial acuity concerns the ability to localize and discriminate sensory input and is often tested using the two-point discrimination threshold (2PDT). Sensitization of the pain system can affect the spatial acuity, but it is unclear how 2PDTs of different testing modalities are affected. The aim was to investigate if the 2PDTs for mechanical and heat stimulation at different intensities were modulated by topical capsaicin sensitization., Methods: 30 healthy subjects were divided into either a capsaicin or a placebo group. The 2PDT was tested using two different modalities, mechanical and thermal (laser) delivered at innocuous and noxious intensities. The 2PDT were determined at baseline and re-assessed 48 h later. In the follow-up session, the subjects either had a capsaicin patch (8%) or placebo patch placed in the testing area for 30 min before re-testing the 2PDT., Results: The 2PDT was highly dependent on stimulation modality and intensity. The lowest 2PDT was found for innocuous mechanical stimuli (40.0 mm, 95% CI 38.1-41.9 mm), and the highest 2PDT was found for innocuous thermal stimuli (81.7 mm, 95% CI 73.9-89.5 mm). Topical capsaicin generally increased the 2PDT, but this was only significant for innocuous mechanical stimuli. The perceived intensity of the stimuli was increased following capsaicin and was generally higher for noxious stimuli than for innocuous stimuli (ANOVA, p < 0.001)., Conclusions: This study showed that capsaicin provoked pain sensitization increased the 2PDT. The 2PDT tested using innocuous mechanical stimuli showed less variable results indicating that this test is most suitable to detect this aspect of spatial acuity., Significance Statement: This study investigated how the two-point discrimination threshold (2PDT) can be modulated by topical capsaicin. The 2PDT was assessed for two different modalities (thermal and mechanical) and for two different intensities (innocuous and noxious) before and after capsaicin. The results showed that the 2PDT was generally impaired following capsaicin, but this was only significant for mechanical innocuous stimuli. Furthermore, it was shown that mechanical innocuous stimuli assessed the 2PDT with lower variability than other combinations., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Background: Commonly used models for eliciting muscle pain involve the injection of algesic substances or the induction of delayed onset muscle soreness. The former require invasive procedures, and the time frame for pain induction and subsidence in the latter can be inconvenient. This study presents a detailed spatiotemporal characterization of a new experimental model of muscle pain based on short-wave diathermy (SWD), developed to overcome the limitations of existing models., Methods: The shoulder was selected as target site and the effects of the model were tested in two sessions to assess its reliability. Pain intensity profiles were recorded during the application of SWD, and changes in pressure pain threshold (PPT) in the infraspinatus muscle, together with pain intensity, duration, and quality were assessed 30 min after induction., Results: SWD-induced pain intensity scores averaged 4 points on a visual analogue scale, whereas PPT showed a consistent decrease of about 25% relative to baseline values. Pain was localized in the shoulder area, and was described as continuous, dull, well-delimited, heavy, and bearable. Pain lasted for an average of 145 min without requiring reinduction and was reliably elicited in both experimental sessions., Conclusion: SWD can be used to elicit experimental muscle pain in a non-invasive, long-lasting, and reliable way and allows for repeated within- and between-session testing in the shoulder., Significance Statement: SWD produces deep heating in muscles by converting electromagnetic energy to thermal energy. It was previously shown that it can be used to elicit experimental pain in the forearm muscles, and the present study demonstrates that this can be reliably generalized to other body sites, such as the shoulder. Furthermore, SWD application is non-invasive and presents a convenient time frame for pain induction and subsidence, thus overcoming limitations associated with traditional muscle pain models., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Carbohydrates are critical for high-intensity exercise performance. However, the effects of carbohydrate supplementation on muscle metabolism and performance during short-duration high-intensity intermittent exercise remain inadequately explored. Our aim was to address this aspect in a randomized, counterbalanced, double-blinded crossover design. Eleven moderately-to-well-trained males performed high-intensity intermittent cycling receiving carbohydrate (CHO, ~55 g/h) or placebo (PLA) fluid supplementation. Three exercise periods (EX1-EX3) were completed comprising 10 × 45 s at ~105% W max interspersed with 135 s rest between bouts and ~20 min between periods. Repeated sprint ability (5 × 6 s sprints with 24 s recovery) was assessed at baseline and after each period. Thigh muscle biopsies were obtained at baseline and before and after EX3 to determine whole-muscle and fiber-type-specific glycogen depletion. No differences were found in muscle glycogen degradation at the whole-muscle (p = 0.683) or fiber-type-specific level (p = 0.763-0.854) with similar post-exercise whole-muscle glycogen concentrations (146 ± 20 and 122 ± 15 mmol·kg -1 dw in CHO and PLA, respectively). Repeated sprint ability declined by ~9% after EX3 with no between-condition differences (p = 0.971) and no overall differences in ratings of perceived exertion (p = 0.550). This was despite distinctions in blood glucose concentrations throughout exercise, reaching post-exercise levels of 5.3 ± 0.2 and 4.1 ± 0.2 mmol·L -1 (p < 0.001) in CHO and PLA, respectively, accompanied by fivefold higher plasma insulin levels in CHO (p < 0.001). In conclusion, we observed no effects of carbohydrate ingestion on net muscle glycogen breakdown or sprint performance during short-duration high-intensity intermittent exercise despite elevated blood glucose and insulin levels. These results therefore question the efficacy of carbohydrate supplementation strategies in high-intensity intermittent sports., (© 2024 The Author(s). Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Background: Cutaneous laser stimulation has commonly been employed to investigate the thermal properties of the nociceptive system. The aim of this study was to investigate how a temperature-controlled laser system improves the assessment of directional discrimination in the nociceptive system., Methods: In total, twenty healthy volunteers participated in this study. To determine the directional discrimination threshold (stimulation length 50% correct, expressed in mm), thermal stimuli were delivered using a diode laser and the laser beam was perpendicularly displaced across the skin to give a linear stimulation in four different directions (distal, proximal, lateral and medial) and displacement lengths (3 for lateral-medial and 5 for distal-proximal). Two temperature control modes were used in the stimulation system, open-loop and closed-loop control. The subjects had to report the perceived stimulus direction, the degree of certainty regarding the perceived direction and the intensity of the perceived stimulus (0-10 numerical rating scale, 3: pain threshold)., Results: During closed-loop control, the orientation of stimuli was discriminated significantly more accurately than during open-loop control. During closed-loop control, the directional discrimination threshold was 31.9 and 26.1 mm for distal-proximal and lateral-medial directed stimuli, respectively. A numerical rating scale was significantly higher for the lateral/medial directions. Moreover, the variability of the discrimination threshold is reduced in the closed-loop control system., Conclusions: The findings show that discrimination ability is better in the lateral-medial directions compared to the distal-proximal directions. This study indicates that using a system enabling closed-loop temperature control, allows more robust probing of the temporo-spatial mechanisms in the nociceptive system., Significance: This study shows that a newly developed temperature-controlled laser stimulation system enhances the possibilities to investigate the nociceptive temporo-spatial integration, as shown by a less variable directional discrimination threshold. The results also show that different orthogonal directions are discriminated differently. This new method allows a better investigation of the combined temporal and spatial mechanisms in the nociceptive system., (© 2024 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Objectives: To explore the antimicrobial potential of strontium (Sr)-functionalized wafers against multiple bacteria associated with per-implant infections, in both mono- and multispecies biofilms., Materials and Methods: The bactericidal and bacteriostatic effect of silicon wafers functionalized with a strontium titanium oxygen coating (Sr-Ti-O) or covered only with Ti (controls) against several bacteria, either grown as a mono-species or multispecies biofilms, was assessed using a bacterial viability assay and a plate counting method. Mono-species biofilms were assessed after 2 and 24 h, while the antimicrobial effect on multispecies biofilms was assessed at Days 1, 3, and 6. The impact of Sr functionalization on the total percentage of Porphyromonas gingivalis in the multispecies biofilm, using qPCR, and gingipain activity was also assessed., Results: Sr-functionalized wafers, compared to controls, were associated with statistically significant less viable cells in both mono- and multispecies tests. The number of colony forming units (CFUs) within the biofilm was significantly less in Sr-functionalized wafers, compared to control wafers, for Staphylococcus aureus at all time points of evaluation and for Escherichia coli at Day 1. Gingipain activity was less in Sr-functionalized wafers, compared to control wafers, and the qPCR showed that P. gingivalis remained below detection levels at Sr-functionalized wafers, while it consisted of 15% of the total biofilm on control wafers at Day 6., Conclusion: Sr functionalization displayed promising antimicrobial potential, possessing bactericidal and bacteriostatic ability against bacteria associated with peri-implantitis grown either as mono-species or mixed in a multispecies consortium with several common oral microorganisms., (© 2024 The Author(s). Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Aims: Salmonella infections are significant causes of foodborne outbreaks in the European Union. This study investigates a sudden increase in gastroenteritis patients in the hospital district of Central Finland in June 2021. The primary aim was to study the outbreak's magnitude and source of the outbreak., Methods and Results: Epidemiological, microbiological, environmental and traceback investigations were conducted. Over 700 persons fell ill during the outbreak caused by Salmonella Typhimurium associated with a daycare lunch. Similar S. Typhimurium was found in the patients and a vegetable mix containing iceberg lettuce, cucumber and peas served during lunch. The traceback investigation revealed that the batch information of vegetables from the wholesaler was not complete. The wholesaler had received quality complaints about the iceberg lettuce from the central kitchen. The manufacturer did not test the suspected batch for Salmonella since the production plant had given a certificate declaring it Salmonella negative., Conclusions: The most suspect ingredient was one batch of iceberg lettuce due to quality complaints. The lettuce had not been served in two daycare centres without cases. We recommend that in order to enable thorough microbiological investigation, institutional kitchens store the food samples separately as part of the internal quality control and that food items should always be tested when Salmonella contamination in an outbreak is suspected., (© 2024 The Author(s). Zoonoses and Public Health published by Wiley‐VCH GmbH.)

Purpose: Short periods of reduced energy availability are commonly undertaken by athletes to decrease body mass, possibly improve the power-to-mass ratio, and enhance physical performance. Our primary aim was to investigate the impact of 10 d of low energy availability (LEA) followed by 2 d of optimal energy availability (OEA) on physical performance parameters in trained females. Second, physiological markers at the whole-body and molecular level related to performance were evaluated., Methods: Thirty young trained eumenorrheic females were matched in pairs based on training history and randomized to a 10-d intervention period of LEA (25 kcal·fat-free mass (FFM) -1 ·d -1 ) or OEA (50 kcal·FFM -1 ·d -1 ) along with supervised exercise training. Before the intervention, participants underwent a 5-d run-in period with OEA + supervised exercise training. After the LEA intervention, 2 d of recovery with OEA was completed. Participants underwent muscle biopsies, blood sampling, physical performance tests, body composition measurements, and resting metabolic rate measurements. A linear mixed model was used with group and time as fixed effects and subject as random effects., Results: Compared with OEA, LEA resulted in reduced body mass, muscle glycogen content, repeated sprint ability, 4-min time-trial performance, and rate of force development of the knee extensors (absolute values; P < 0.05). Two days of recovery restored 4-min time-trial performance and partly restored repeated sprint ability, but performance remained inferior to the OEA group. When the performance data were expressed relative to body mass, LEA did not enhance performance., Conclusions: Ten days of LEA resulted in impaired performance (absolute values), with concomitant reductions in muscle glycogen. Two days of recovery with OEA partially restored these impairments, although physical performance (absolute values) was still inferior to being in OEA. Our findings do not support the thesis that LEA giving rise to small reductions in body mass improves the power-to-mass ratio and thus increases physical performance., (Copyright © 2023 by the American College of Sports Medicine.)

Objectives: Background noise and linguistic violations have been shown to increase the listening effort. The present study aims to examine the effects of the interaction between background noise and linguistic violations on subjective listening effort and frontal theta oscillations during effortful listening., Design: Thirty-two normal-hearing listeners participated in this study. The linguistic violation was operationalized as sentences versus random words (strings). Behavioral and electroencephalography data were collected while participants listened to sentences and strings in background noise at different signal to noise ratios (SNRs) (-9, -6, -3, 0 dB), maintained them in memory for about 3 sec in the presence of background noise, and then chose the correct sequence of words from a base matrix of words., Results: Results showed the interaction effects of SNR and speech type on effort ratings. Although strings were inherently more effortful than sentences, decreasing SNR from 0 to -9 dB (in 3 dB steps), increased effort rating more for sentences than strings in each step, suggesting the more pronounced effect of noise on sentence processing that strings in low SNRs. Results also showed a significant interaction between SNR and speech type on frontal theta event-related synchronization during the retention interval. This interaction indicated that strings exhibited higher frontal theta event-related synchronization than sentences at SNR of 0 dB, suggesting increased verbal working memory demand for strings under challenging listening conditions., Conclusions: The study demonstrated that the interplay between linguistic violation and background noise shapes perceived effort and cognitive load during speech comprehension under challenging listening conditions. The differential impact of noise on processing sentences versus strings highlights the influential role of context and cognitive resource allocation in the processing of speech., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

In recent sea level studies, discrepancies have arisen in ocean mass observations obtained from the Gravity Recovery and Climate Experiment and its successor, GRACE Follow-On, with GRACE estimates consistently appearing lower than density-corrected ocean volume observations since 2015. These disparities have raised concerns about potential systematic biases in sea-level observations, with significant implications for our understanding of this essential climate variable. Here, we reconstruct the global and regional ocean mass change through models of ice and water mass changes on land and find that it closely aligns with both GRACE and density-corrected ocean volume observations after implementing recent adjustments to the wet troposphere correction and halosteric sea level. While natural variability in terrestrial water storage is important on interannual timescales, we find that the net increase in ocean mass over 20 years can be almost entirely attributed to ice wastage and human management of water resources., (© 2024. The Author(s).)

Objectives: To investigate the impact of a Ti-Sr-O technology, applied to either a turned surface or an SLA surface, on the mechanical robustness of osseointegration, benchmarked against the SLActive surface., Material and Methods: Ti discs (6.25-mm-diameter and 2-mm-thick) with three different surfaces were inserted on the proximal-anterior part of the tibial plateau of adult Swedish loop rabbits: (I) turned surface modified with Ti-Sr-O (turned + Ti-Sr-O), (II) SLA surface modified with Ti-Sr-O (SLA + Ti-Sr-O), and (III) SLActive surface (SLActive). Following a healing period of 2 weeks and 4 weeks, the pull-out (PO) force needed to detach the discs from the bone was assessed, as a surrogate of osseointegration., Results: The SLActive surface exhibited statistically significant higher median PO forces, compared with the SLA + Ti-Sr-O surfaces at both 2- and 4 weeks post-op (p > .05). In this study, no single turned + Ti-Sr-O surface disk was integrated., Conclusions: The tested Ti-Sr-O technology failed to enhance osseointegration; however, this finding may be related to the inappropriateness of the rabbit tibia plateau model for assessing third-generation implant surface technologies, due to the limited diffusion and clearance at the disk-bone interface., (© 2023 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Listening effort can be defined as a measure of cognitive resources used by listeners to perform a listening task. Various methods have been proposed to measure this effort, yet their reliability remains unestablished, a crucial step before their application in research or clinical settings. This study encompassed 32 participants undertaking speech-in-noise tasks across two sessions, approximately a week apart. They listened to sentences and word lists at varying signal-to-noise ratios (SNRs) (-9, -6, -3 and 0 dB), then retaining them for roughly 3 s. We evaluated the test-retest reliability of self-reported effort ratings, theta (4-7 Hz) and alpha (8-13 Hz) oscillatory power, suggested previously as neural markers of listening effort. Additionally, we examined the reliability of correct word percentages. Both relative and absolute reliability were assessed using intraclass correlation coefficients (ICC) and Bland-Altman analysis. We also computed the standard error of measurement (SEM) and smallest detectable change (SDC). Our findings indicated heightened frontal midline theta power for word lists compared to sentences during the retention phase under high SNRs (0 dB, -3 dB), likely indicating a greater memory load for word lists. We observed SNR's impact on alpha power in the right central region during the listening phase and frontal theta power during the retention phase in sentences. Overall, the reliability analysis demonstrated satisfactory between-session variability for correct words and effort ratings. However, neural measures (frontal midline theta power and right central alpha power) displayed substantial variability, even though group-level outcomes appeared consistent across sessions., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The purpose of this technical report is to present two novel experimental implant designs to boost data generation in preclinical in vivo research. Specifically, the report describes the rationale and the components of (1) a two-piece experimental implant suitable for a small animal platform (e.g., the rabbit femur/tibial epiphysis model), consisting of a threaded apical- and a coronal cylindrical piece, which is intended for collecting two types of biomechanical data, and (2) a three-piece experimental implant suitable for a large animal platform (e.g., the mini-pig mandible model), consisting of an apical "wound chamber", which allows the collection of histological/histomorphometrical data, and a middle threaded and coronal cylindrical piece, which also allow the collection of two types of biomechanical data. The increased volume of information generated from a single experiment in a small animal platform, using the proposed two-piece implant design, may assist in a more qualified decision-making process, on whether it is relevant to proceed to further assessment using a large animal platform. Furthermore, the increased volume of information generated in a single animal experiment either in a small or large animal platform, using the proposed two- and three-piece implants, respectively, likely decreases the number of animals otherwise needed for collecting the same information with standard one-piece implants and, thus, contributes to the reduction/refinement elements of the 3R principle., (© 2023 The Authors. Clinical and Experimental Dental Research published by John Wiley & Sons Ltd.)

Adult stem cells play key roles in tissue homeostasis and regeneration. Recent evidence suggests that dietary interventions can significantly impact adult stem cell function. Some of these effects depend on ketone bodies. Adult stem cells could therefore potentially be manipulated through dietary regimens or exogenous ketone body supplementation, a possibility with significant implications for regenerative medicine. In this review we discuss recent findings of the mechanisms by which ketone bodies could influence adult stem cells, including ketogenesis in adult stem cells, uptake and transport of circulating ketone bodies, receptor-mediated signaling, and changes to cellular metabolism. We also discuss the potential effects of ketone bodies on intracellular processes such as protein acetylation and post-transcriptional control of gene expression. The exploration of mechanisms underlying the effects of ketone bodies on stem cell function reveals potential therapeutic targets for tissue regeneration and age-related diseases and suggests future research directions in the field of ketone bodies and stem cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Andersen, Poulsen, Farup and de Morree.)

Low energy availability (LEA) describes a state where the energy intake is insufficient to cover the energy costs of both exercise energy expenditure and basal physiological body functions. LEA has been associated with various physiological consequences, such as reproductive dysfunction. However, the effect of LEA on skeletal muscle protein synthesis in females performing exercise training is still poorly understood. We conducted a randomized controlled trial to investigate the impact of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in trained females. Thirty eumenorrheic females were matched based on training history and randomized to undergo 10 days of LEA (25 kcal · kg fat-free mass (FFM) -1  · day -1 ) or optimal energy availability (OEA, 50 kcal · kg FFM -1  · day -1 ). Before the intervention, both groups underwent a 5-day 'run-in' period with OEA. All foods were provided throughout the experimental period with a protein content of 2.2 g kg lean mass -1  · day -1 . A standardized, supervised combined resistance and cardiovascular exercise training programme was performed over the experimental period. Daily integrated muscle protein synthesis was measured by deuterium oxide (D 2 O) consumption along with changes in body composition, resting metabolic rate, blood biomarkers and 24 h nitrogen balance. We found that LEA reduced daily integrated myofibrillar and sarcoplasmic muscle protein synthesis compared with OEA. Concomitant reductions were observed in lean mass, urinary nitrogen balance, free androgen index, thyroid hormone concentrations and resting metabolic rate following LEA. These results highlight that LEA may negatively affect skeletal muscle adaptations in females performing exercise training. KEY POINTS: Low energy availability (LEA) with potential health and performance impairments is widespread among female athletes. We investigated the impact of 10 days of LEA on daily integrated myofibrillar and sarcoplasmic muscle protein synthesis in young, trained females. We show that LEA impairs myofibrillar and sarcoplasmic muscle protein synthesis in trained females performing exercise training. These findings suggest that LEA may have negative consequences for skeletal muscle adaptations and highlight the importance of ensuring adequate energy availability in female athletes., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The envelope of a speech signal is tracked by neural activity in the cerebral cortex. The cortical tracking occurs mainly in two frequency bands, theta (4-8 Hz) and delta (1-4 Hz). Tracking in the faster theta band has been mostly associated with lower-level acoustic processing, such as the parsing of syllables, whereas the slower tracking in the delta band relates to higher-level linguistic information of words and word sequences. However, much regarding the more specific association between cortical tracking and acoustic as well as linguistic processing remains to be uncovered. Here, we recorded EEG responses to both meaningful sentences and random word lists in different levels of signal-to-noise ratios (SNRs) that lead to different levels of speech comprehension as well as listening effort. We then related the neural signals to the acoustic stimuli by computing the phase-locking value (PLV) between the EEG recordings and the speech envelope. We found that the PLV in the delta band increases with increasing SNR for sentences but not for the random word lists, showing that the PLV in this frequency band reflects linguistic information. When attempting to disentangle the effects of SNR, speech comprehension, and listening effort, we observed a trend that the PLV in the delta band might reflect listening effort rather than the other two variables, although the effect was not statistically significant. In summary, our study shows that the PLV in the delta band reflects linguistic information and might be related to listening effort., (© 2023 Massachusetts Institute of Technology.)

Deep neural networks are complex machine learning models that have shown promising results in analyzing high-dimensional data such as those collected from medical examinations. Such models have the potential to provide fast and accurate medical diagnoses. However, the high complexity makes deep neural networks and their predictions difficult to understand. Providing model explanations can be a way of increasing the understanding of "black box" models and building trust. In this work, we applied transfer learning to develop a deep neural network to predict sex from electrocardiograms. Using the visual explanation method Grad-CAM, heat maps were generated from the model in order to understand how it makes predictions. To evaluate the usefulness of the heat maps and determine if the heat maps identified electrocardiogram features that could be recognized to discriminate sex, medical doctors provided feedback. Based on the feedback, we concluded that, in our setting, this mode of explainable artificial intelligence does not provide meaningful information to medical doctors and is not useful in the clinic. Our results indicate that improved explanation techniques that are tailored to medical data should be developed before deep neural networks can be applied in the clinic for diagnostic purposes.

Performance in short-duration sports is highly dependent on muscle glycogen, but the total degradation is only moderate and considering the water-binding property of glycogen, unnecessary storing of glycogen may cause an unfavorable increase in body mass. To investigate this, we determined the effect of manipulating dietary carbohydrates (CHO) on muscle glycogen content, body mass, and short-term exercise performance. In a randomized and counterbalanced cross-over design, twenty-two men completed two maximal cycle tests of either 1-min (n = 10) or 15-min (n = 12) duration with different pre-exercise muscle glycogen levels. Glycogen manipulation was initiated three days prior to the tests by exercise-induced glycogen depletion followed by ingestion of a moderate (M-CHO) or high (H-CHO) CHO-diet. Subjects were weighed before each test, and muscle glycogen content was determined in biopsies from m. vastus lateralis before and after each test. Pre-exercise muscle glycogen content was lower following M-CHO than H-CHO (367 mmol · kg -1 DW vs. 525 mmol · kg -1 DW, p < 0.00001), accompanied by a 0.7 kg lower body mass (p < 0.00001). No differences were observed in performance between diets in neither the 1-min (p = 0.33) nor the 15-min (p = 0.99) test. In conclusion, pre-exercise muscle glycogen content and body mass were lower after ingesting moderate compared with high amounts of CHO, while short-term exercise performance was unaffected. This demonstrates that adjusting pre-exercise glycogen levels to the requirements of competition may provide an attractive weight management strategy in weight-bearing sports, particularly in athletes with high resting glycogen levels., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Objectives: To examine factors influencing the primary stability of dental implants when stabilized in over-sized osteotomies using a calcium phosphate-based adhesive cement was the objective., Methods: Using implant removal torque measurements as a surrogate for primary stability, we examined the influence of implant design features (diameter, surface area, and thread design), along with cement gap size and curing time, on the resulting primary implant stability., Results: Removal torque values scaled with implant surface area and increasing implant diameters. Cement gap size did not alter the median removal torque values; however, larger gaps were associated with an increased spread of the measured values. Among the removal torque values measured, all were found to be above 32 Ncm which is an insertion torque threshold value commonly recommended for immediate loading protocols., Conclusion: The adhesive cement show potential for offering primary implant stability for different dental implant designs. In this study, the primary parameters influencing the measured removal torque values were the implant surface area and diameter. As the liquid cement prevents the use of insertion torque, considering the relationship between insertion and removal torque, removal torque can be considered a reliable surrogate for primary implant stability for bench and pre-clinical settings., Clinical Relevance: At present, the primary stability of dental implants is linked to the quality of the host bone, the drill protocol, and the specific implant design. The adhesive cement might find applications in future clinical settings for enhancing primary stability of implants under circumstances where this cannot be achieved conventionally., (© 2023. The Author(s).)

Postactivation potentiation refers to an acute enhancement of contractile properties following muscle activity. Previously, the effects of prior muscle activation on eccentric force at tetanic activation frequencies have only been sparsely reported. This paper aimed to study acute activity-induced effects on eccentric force of slow and fast-twitch muscles and characterize them in relation to postactivation potentiation. We elicited eccentric contractions in isolated rat extensor digitorum longus and soleus muscles by actively lengthening muscles at a constant velocity. We assessed contractile properties by measuring force over shortly interspaced, identical eccentric, and isometric contractions. We then analyzed stretch force, isometric peak force, rate of force development, and relaxation times. Finally, we compared the time courses for the development and cessation of changes in stretch force to known features of postactivation potentiation. In extensor digitorum longus, muscles stretch force consistently increased in a contraction-to-contraction manner by up to 49% [95% confidence interval (CI): 35-64%] whereas isometric peak force simultaneously showed minor declines (8%, 95% CI: 5-10%). The development and cessation of eccentric force potentiation coincided with the development of twitch potentiation and increases in rate of force development. In soleus muscles we found no consistent eccentric potentiation. Characterization of the increase in eccentric force revealed that force only increased in the very beginning of an active stretch. Eccentric force at tetanic activation frequencies potentiates substantially in extensor digitorum longus muscles over consecutive contractions with a time course coinciding with postactivation potentiation. Such eccentric potentiation may be important in sport performance. NEW & NOTEWORTHY Force during eccentric contractions can increase to a magnitude that may have profound consequences for our understanding of skeletal muscle locomotion. This increase in eccentric force occurs over consecutive, shortly interspaced, tetanic contractions in rat extensor digitorum longus muscles-not in rat soleus muscles-and coincides with well-known traits of postactivation potentiation. Eccentric force potentiation may significantly enhance muscle performance in activities involving stretch-shortening cycles.

Objective . Laser stimulators have been widely used in pain studies to selectively activate A δ and C nociceptors without coactivation of mechanoreceptors. Temperature-controlled laser systems have been implemented with low-temperature variations during stimulations, however, these systems purely enabled stationary stimulation. This study aimed to implement, test and validate a new laser stimulation system that controls skin temperature by continuously adjusting laser output during stimulus movement to allow accurate investigation of tempo-spatial mechanisms in the nociceptive system. Approach . For validation, laser stimuli were delivered to the right forearm of eight healthy subjects using a diode laser. The laser beam was displaced across the skin to deliver a moving thermal stimulation to the skin surface. To test the function and feasibility of the system, different stimulation parameters were investigated involving two control modes (open-loop and closed-loop), three displacement velocities (5, 10 and 12 mm s -1 ), two intensities (high 46 °C and low 42 °C), two stimulus lengths (20 and 100 mm) and two directions (distal and proximal). Main results . During closed-loop control, the stimulation error and variation of stimulation temperatures were significantly smaller than during open-loop control. The standard deviation of stimulation temperatures increased significantly with stimulation intensity and displacement length. Significance . This study showed that more accurate, less variable laser stimulations were delivered to the skin using closed-loop control during a movable stimulus. The more uniform skin temperature during stimuli is likely to ensure a more uniform nociceptor activation., (© 2023 IOP Publishing Ltd.)

Purpose: We investigated the coupling between muscle glycogen content and localization and high-intensity exercise performance using a randomized, placebo-controlled, parallel-group design with emphasis on single-fiber subcellular glycogen concentrations and sarcoplasmic reticulum Ca 2+ kinetics., Methods: Eighteen well-trained participants performed high-intensity intermittent glycogen-depleting exercise, followed by randomization to a high- (CHO; ~1 g CHO·kg -1 ·h -1 ; n = 9) or low-carbohydrate placebo diet (PLA, <0.1 g CHO·kg -1 ·h -1 ; n = 9) for a 5-h recovery period. At baseline, after exercise, and after the carbohydrate manipulation assessments of repeated sprint ability (5 × 6-s maximal cycling sprints with 24 s of rest), neuromuscular function and ratings of perceived exertion during standardized high-intensity cycling (~90% Wmax ) were performed, while muscle and blood samples were collected., Results: The exercise and carbohydrate manipulations led to distinct muscle glycogen concentrations in CHO and PLA at the whole-muscle (291 ± 78 vs 175 ± 100 mmol·kg -1 dry weight (dw), P = 0.020) and subcellular level in each of three local regions ( P = 0.001-0.046). This was coupled with near-depleted glycogen concentrations in single fibers of both main fiber types in PLA, especially in the intramyofibrillar region (within the myofibrils). Furthermore, increased ratings of perceived exertion and impaired repeated sprint ability (~8% loss, P < 0.001) were present in PLA, with the latter correlating moderately to very strongly ( r = 0.47-0.71, P = 0.001-0.049) with whole-muscle glycogen and subcellular glycogen fractions. Finally, sarcoplasmic reticulum Ca 2+ uptake, but not release, was superior in CHO, whereas neuromuscular function, including prolonged low-frequency force depression, was unaffected by dietary manipulation., Conclusions: Together, these results support an important role of muscle glycogen availability for high-intensity exercise performance, which may be mediated by reductions in single-fiber levels, particularly in distinct subcellular regions, despite only moderately lowered whole-muscle glycogen concentrations., (Copyright © 2022 by the American College of Sports Medicine.)

Glycogen particles are situated in key areas of the muscle cell in the vicinity of the main energy-consumption sites and may be utilised heterogeneously dependent on the nature of the metabolic demands. The present study aimed to investigate the time course of fibre type-specific utilisation of muscle glycogen in three distinct subcellular fractions (intermyofibrillar, IMF; intramyofibrillar, Intra; and subsarcolemmal, SS) during repeated high-intensity intermittent exercise. Eighteen moderately to well-trained male participants performed three periods of 10 × 45 s cycling at ∼105% watt max (EX1-EX3) coupled with 5 × 6 s maximal sprints at baseline and after each period. Muscle biopsies were sampled at baseline and after EX1 and EX3. A higher glycogen breakdown rate in type 2 compared to type 1 fibres was found during EX1 for the Intra (-72 vs. -45%) and IMF (-59 vs. -35%) glycogen fractions (P < 0.001) but with no differences for SS glycogen (-52 vs. -40%). In contrast, no fibre type differences were observed during EX2-EX3, where the utilisation of Intra and IMF glycogen in type 2 fibres was reduced, resulting in depletion of all three subcellular fractions to very low levels post-exercise within both fibre types. Importantly, large heterogeneity in single-fibre glycogen utilisation was present with an early depletion of especially Intra glycogen in individual type 2 fibres. In conclusion, there is a clear fibre type- and localisation-specific glycogen utilisation during high-intensity intermittent exercise, which varies with time course of exercise and is characterised by exacerbated pool-specific glycogen depletion at the single-fibre level. KEY POINTS: Muscle glycogen is the major fuel during high-intensity exercise and is stored in distinct subcellular areas of the muscle cell in close vicinity to the main energy consumption sites. In the present study quantitative electron microscopy imaging was used to investigate the utilisation pattern of three distinct subcellular muscle glycogen fractions during repeated high-intensity intermittent exercise. It is shown that the utilisation differs dependent on fibre type, subcellular localisation and time course of exercise and with large single-fibre heterogeneity. These findings expand on our understanding of subcellular muscle glycogen metabolism during exercise and may help us explain how reductions in muscle glycogen can attenuate muscle function even at only moderately lowered whole-muscle glycogen concentrations., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Several models have been developed to analyse cortical activity in response to salient events constituted by multiple sensory modalities. In particular, additive models compare event-related potentials (ERPs) in response to stimuli from two or more concomitant sensory modalities with the ERPs evoked by unimodal stimuli, in order to study sensory interactions. In this approach, components that are not specific to a sensory modality are commonly disregarded, although they likely carry information about stimulus expectation and evaluation, attentional orientation and other cognitive processes. In this study, we present an analytical method to assess the contribution of modality-specific and nonspecific components to the ERP. We developed an experimental setup that recorded ERPs in response to four stimulus types (visual, auditory, and two somatosensory modalities to test for stimulus specificity) in three different conditions (unimodal, bimodal and trimodal stimulation) and recorded the saliency of these stimuli relative to the sensory background. Stimuli were delivered in pairs, in order to study the effects of habituation. To this end, spatiotemporal features (peak amplitudes and latencies at different scalp locations) were analysed using linear mixed models. Results showed that saliency relative to the sensory background increased with the number of concomitant stimuli. We also observed that the spatiotemporal features of modality-specific components derived from this method likely reflect the amount and type of sensory input. Furthermore, the nonspecific component reflected habituation occurring for the second stimulus in the pair. In conclusion, this method provides an alternative to study neural mechanisms of responses to multisensory stimulation., (© 2022 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The nociceptive withdrawal reflex (NWR) is a behavioral response to protect the body from noxious stimuli. The spatial characteristics of the stimulus modulate the reflex response to prevent damage to the affected tissue. Interneurons in the deep dorsal horn in the spinal cord encode the relationship between stimulus characteristics and the magnitude of the NWR and are also likely integrating spatial information of the nociceptive stimulus. The aim of this study was to use the NWR to investigate whether the spinal spatial integration of a simultaneous stimulus is modulated by shifting the attention of the participant towards (attention) or away from (distraction) the stimulus. We hypothesized that the descending activity shapes the receptive fields of the spinal neurons encoding spatial integration of nociception. Twenty healthy volunteers participated in the study. Single and simultaneous stimuli were delivered through two stimulating electrodes located in the arch and on the lateral side in the sole of the foot. The NWR was quantified by electromyography from the Tibialis Anterior and Biceps Femoris muscles during baseline and active tasks (attention and distraction). During the baseline task, spatial summation of the NWR was evoked during simultaneous stimulation. During the distraction task, the NWR was significantly larger compared to baseline, regardless of the sites being stimulated (single and simultaneous stimuli). In contrast, the NWR recorded during the attention task did not differ from baseline. These results further support that the spinal NWR pathway is under descending control which can be modulated by cognitive processes. The NWRs recorded over both proximal and distal muscles were similarly affected by the tasks, suggesting that the descending control affects the lower leg spinal system, with no discrimination between spinal segments., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Heat/capsaicin sensitization and electrical high-frequency stimulation (HFS) are well-known models of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45°C heat stimulation for 5 min followed by a topical capsaicin patch (4 × 4 cm) for 30 min on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1 s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS + HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS), and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pin-prick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pin-prick stimulation (difference from baseline and control area) was observed in the HFS + HEAT/CAPS session than in the HFS session 20 and 30 min after HFS. Furthermore, sensitivity was increased after HFS + HEAT/CAPS compared with after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS. NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) and heat/capsaicin sensitization are well-known models of secondary hyperalgesia. The results from the current study indicate that increased sensitivity to 128 mN pin-prick stimulation can be obtained when HFS is delivered following an already established heightened central hyperexcitability provoked by heat/capsaicin sensitization.

Background: Transfer learning is a form of machine learning where a pre-trained model trained on a specific task is reused as a starting point and tailored to another task in a different dataset. While transfer learning has garnered considerable attention in medical image analysis, its use for clinical non-image data is not well studied. Therefore, the objective of this scoping review was to explore the use of transfer learning for non-image data in the clinical literature., Methods and Findings: We systematically searched medical databases (PubMed, EMBASE, CINAHL) for peer-reviewed clinical studies that used transfer learning on human non-image data. We included 83 studies in the review. More than half of the studies (63%) were published within 12 months of the search. Transfer learning was most often applied to time series data (61%), followed by tabular data (18%), audio (12%) and text (8%). Thirty-three (40%) studies applied an image-based model to non-image data after transforming data into images (e.g. spectrograms). Twenty-nine (35%) studies did not have any authors with a health-related affiliation. Many studies used publicly available datasets (66%) and models (49%), but fewer shared their code (27%)., Conclusions: In this scoping review, we have described current trends in the use of transfer learning for non-image data in the clinical literature. We found that the use of transfer learning has grown rapidly within the last few years. We have identified studies and demonstrated the potential of transfer learning in clinical research in a wide range of medical specialties. More interdisciplinary collaborations and the wider adaption of reproducible research principles are needed to increase the impact of transfer learning in clinical research., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Ebbehoj et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It is well known that strontium (Sr) has a significant effect on peri-implant bone healing when administered systemically. Due to the risk of adverse effects of such treatments, new routes focusing on the local, sustained release of Sr from bone-implant contact surfaces have been explored, with success in in vivo experiments. However, the increase of Sr concentrations in the peri-implant bone has not been described in depth yet. Here, we show that a local, sustained Sr release from Ti-Sr-O physical vapor deposition (PVD) coatings by magnetron sputter coating increases the Sr/Ca ratio close to the implant in a rabbit model and that the Sr/Ca background level is reached approximately 500 μm from the implant.

Objective. Small area electrodes enable preferential activation of nociceptive fibers. It is debated, however, whether co-activation of large fibers still occurs for the existing electrode designs. Moreover, existing electrodes are limited to low stimulation intensities, for which behavioral and physiological responses may be considered less reliable. A recent optimization study showed that there is a potential for improving electrode performance and increase the range of possible stimulation intensities. Based on those results, the present study introduces and tests a novel planar concentric array electrode design for small fiber activation in healthy volunteers. Approach. Volunteers received electrical stimulation with the planar concentric array electrode and a regular patch electrode. Perception thresholds (PT) were estimated at the beginning and the end of the experiment. Evoked cortical potentials were recorded in blocks of 30 stimuli. For the patch, stimulation current intensity was set to two times PT, while three intensities, two, five, and ten times PT, were applied with the planar concentric array electrode. Sensation quality, numerical-rating scores, and reaction times were obtained for each PT estimation and during each block of evoked potential recordings. Main results. Stimulation with the patch electrode was characterized as dull, while stimulation with the planar concentric array electrode was characterized as sharp, with increased sharpness for increasing stimulus current intensity. Likewise, scores of the numerical rating scale were higher for the planar concentric array electrode compared to the patch and increased with increasing stimulation current intensity. Reaction times and ERP latencies were longer for the planar concentric array electrode compared to the patch. Significance. The presented novel planar concentric array electrode is a small, non-invasive, and single-use electrode that has the potential to investigate small fiber neuropathy and pain mechanisms, as it is small fiber preferential for a wide range of stimulation intensities., (© 2022 IOP Publishing Ltd.)

This study describes a novel series of UDP- N -acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC 50 ) <5 nM) and cellular activity against P. aeruginosa (best minimal inhibitory concentration (MIC) of 4 μg/mL). Lack of activity against E. coli was maintained (IC 50 > 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa .

Spatial information of nociceptive stimuli applied in the skin of healthy humans is integrated in the spinal cord to determine the appropriate withdrawal reflex response. Double-simultaneous stimulus applied in different skin sites are integrated, eliciting a larger reflex response. The temporal characteristics of the stimuli also modulate the reflex, e.g., by temporal summation. The primary aim of this study was to investigate how the combined tempo-spatial aspects of two stimuli are integrated in the nociceptive system. This was investigated by delivering single- and double-simultaneous stimulation and sequential stimulation with different interstimulus intervals (ISIs ranging 30-500 ms) to the sole of the foot of 15 healthy subjects. The primary outcome measure was the size of the nociceptive withdrawal reflex (NWR) recorded from the tibialis anterior (TA) and biceps femoris (BF) muscles. Pain intensity was measured using a numerical rating scale (NRS) scale. Results showed spatial summation in both TA and BF when delivering simultaneous stimulation. Simultaneous stimulation provoked larger reflexes than sequential stimulation in TA, but not in BF. Larger ISIs elicited significantly larger reflexes in TA, whereas the opposite pattern occurred in BF. This differential modulation between proximal and distal muscles suggests the presence of spinal circuits eliciting a functional reflex response based on the specific tempo-spatial characteristics of a noxious stimulus. No modulation was observed in pain intensity ratings across ISIs. Absence of modulation in the pain intensity ratings argues for an integrative mechanism located within the spinal cord governed by a need for efficient withdrawal from a potentially harmful stimulus. NEW & NOTEWORTHY Tempo-spatial integration of electrical noxious stimuli was studied using the nociceptive withdrawal reflex and a perceived intensity. Tibialis anterior and biceps femoris muscles were differentially modulated by the temporal characteristics of the stimuli and stimulated sites. These findings suggest that spinal neurons are playing an important role in the tempo-spatial integration of nociceptive information, leading to a reflex response that is distributed across multiple spinal cord segments and governed by an efficient defensive withdrawal strategy.

Background: There is little knowledge about rest-activity cycles (RAC) in patients with severe-acquired brain injury (sABI) during early in-hospital rehabilitation. This study aimed to investigate if patients with sABI displayed unconsolidated RACs at the beginning of in-hospital rehabilitation, and how these changed over time., Methods: This study was a prospective observational study. All patients consecutively admitted to one ward were screened for eligibility. We recorded accelerometric activity for 20 days. The Daytime Activity Ratio (DAR) of activity between daytime (7-22) and the total activity during the entire day was calculated and used to estimate consolidation., Results: Fifty-five patients were screened and 20 patients were included. Complete day 1 & 2 data was obtained on 18 patients. Fifty-six percentage of these had a consolidated RAC at the beginning of rehabilitation. On day 19 & 20, complete data could be obtained from 15 patients, 80% of these had consolidation of RAC. When comparing these a significant mean increase of 5.8% 95%CI(0.52; 11.01) in DAR was found p < .05, and the model of all data also showed a significant increase in median DAR over time p < .01., Conclusion: RAC consolidation improves over time in patients admitted for in-hospital early neurorehabilitation.

Pain arises from the integration of sensory and cognitive processes in the brain, resulting in specific patterns of neural oscillations that can be characterized by measuring electrical brain activity. Current source density (CSD) estimation from low-resolution brain electromagnetic tomography (LORETA) and its standardized (sLORETA) and exact (eLORETA) variants, is a common approach to identify the spatiotemporal dynamics of the brain sources in physiological and pathological pain-related conditions. However, there is no consensus on the magnitude and variability of clinically or experimentally relevant effects for CSD estimations. Here, we systematically examined reports of sample size calculations and effect size estimations in all studies that included the keywords pain, and LORETA, sLORETA, or eLORETA in Scopus and PubMed. We also assessed the reliability of LORETA CSD estimations during non-painful and painful conditions to estimate hypothetical sample sizes for future experiments using CSD estimations. We found that none of the studies included in the systematic review reported sample size calculations, and less than 20% reported measures of central tendency and dispersion, which are necessary to estimate effect sizes. Based on these data and our experimental results, we determined that sample sizes commonly used in pain studies using CSD estimations are suitable to detect medium and large effect sizes in crossover designs and only large effects in parallel designs. These results provide a comprehensive summary of the effect sizes observed using LORETA in pain research, and this information can be used by clinicians and researchers to improve settings and designs of future pain studies., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals. PERSPECTIVE: This article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception., (Copyright © 2021. Published by Elsevier Inc.)

Musculoskeletal pain is a clinical condition that is characterized by ongoing pain and discomfort in the deep tissues such as muscle, bones, ligaments, nerves, and tendons. In the last decades, it was subject to extensive research due to its high prevalence. Still, a quantitative description of the electrical brain activity during musculoskeletal pain is lacking. This study aimed to characterize intracranial current source density (CSD) estimations during sustained deep-tissue experimental pain. Twenty-three healthy volunteers received three types of tonic stimuli for three minutes each: computer-controlled cuff pressure (1) below pain threshold (sustained deep-tissue no-pain, SDTnP), (2) above pain threshold (sustained deep-tissue pain, SDTP) and (3) vibrotactile stimulation (VT). The CSD in response to these stimuli was calculated in seven regions of interest (ROIs) likely involved in pain processing: contralateral anterior cingulate cortex, contralateral primary somatosensory cortex, bilateral anterior insula, contralateral dorsolateral prefrontal cortex, posterior parietal cortex and contralateral premotor cortex. Results showed that participants exhibited an overall increase in spectral power during SDTP in all seven ROIs compared to both SDTnP and VT, likely reflecting the differences in the salience of these stimuli. Moreover, we observed a difference is CSD due to the type of stimulus, likely reflecting somatosensory discrimination of stimulus intensity. These results describe the different contributions of neural oscillations within these brain regions in the processing of sustained deep-tissue pain.

Objective. Electrical preferential activation of small nociceptive fibers may be achieved with the use of specialized small area electrodes, however, the existing electrodes are limited to low stimulation intensities. As existing electrodes have been developed empirically, the present study aimed to use computational modeling and optimization techniques to investigate if changes in electrode design parameters could improve the preferential activation of small fibers. Approach. Two finite element models; one of a planar concentric and one of an intra-epidermal electrode were combined with two multi-compartmental nerve fiber models of an Aδ-fiber and an Aβ-fiber. These two-step hybrid models were used for the optimization of four electrode parameters; anode area, anode-cathode distance, cathode area, and cathode protrusion. Optimization was performed using a gradient-free bounded Nelder-Mead algorithm, to maximize the current activation threshold ratio between the Aβ-fiber model and the Aδ-fiber model. Main results. All electrode parameters were optimal at their lower bound, except the cathode protrusion, which was optimal a few micrometers above the location of the Aδ-fiber model. A small cathode area is essential for producing a high current density in the epidermal skin layer enabling activation of small fibers, while a small anode area and anode-cathode distance are important for the minimization of current spread to deeper tissues, making it less likely to activate large fibers. Combining each of the optimized electrode parameters improved the preferential activation of small fibers in comparison to existing electrodes, by increasing the activation threshold ratio between the two nerve fiber types. The maximum increase in the activation threshold ratio was 289% and 595% for the intra-epidermal and planar concentric design, respectively. Significance. The present study showed that electrical preferential small fiber activation can be improved by electrode design. Additionally, the results may be used for the production of an electrode that could potentially be used for clinical assessment of small fiber neuropathy., (© 2021 IOP Publishing Ltd.)

Improving the ability to predict persistent pain after spine surgery would allow identification of patients at risk and guide treatment decisions. Quantitative sensory tests (QST) are measures of altered pain processes, but in our previous study, preoperative QST did not predict pain and disability at single time-points. Trajectory analysis accounts for time-dependent patterns. We hypothesized that QST predict trajectories of pain and disability during 1 year after low back surgery. We performed a trajectory analysis on the cohort of our previous study (n = 141). Baseline QST included electrical, pressure, heat, and cold stimulation of the low back and lower extremity, temporal summation, and conditioned pain modulation. Pain intensity and Oswestry Disability Index were measured before, and 2, 6, and 12 months after surgery. Bivariate trajectories for pain and disability were computed using group-based trajectory models. Multivariable regressions were used to identify QST as predictors of trajectory groups, with sociodemographic, psychological, and clinical characteristics as covariates. Cold pain hypersensitivity at the leg, not being married, and long pain duration independently predicted worse recovery (complete-to-incomplete, incomplete-to-no recovery). Cold pain hypersensitivity increased the odds for worse recovery by 3.8 (95% confidence intervals 1.8-8.0, P < 0.001) and 3.0 (1.3-7.0, P = 0.012) in the univariable and multivariable analyses, respectively. Trajectory analysis, but not analysis at single time-points, identified cold pain hypersensitivity as strong predictor of worse recovery, supporting altered pain processes as predisposing factor for persisting pain and disability, and a broader use of trajectory analysis. Assessment of cold pain sensitivity may be a clinically applicable, prognostic test.

Although most of the harmful radionuclides are of anthropogenic origin and released from military or industrial processes, radioactive substances, such as uranium, also occur naturally in the environment. Low standards of care at nuclear facilities can lead to the contamination of employees with radionuclides due to inhalation of gases or dust or contamination of skin or wounds. Various sources for radionuclide exposure may present concerns for radioactive polonium or plutonium exposure, for instance, terrorist actions on the infrastructure, such as on drinking water basins. Early health effects after extensive radiation exposure may be vomiting, headaches, and fatigue, followed by bone marrow depression, fever, and diarrhea. The main purpose of radionuclide mobilization is to minimize the radiation dose. Since some of the important radionuclides, such as polonium and plutonium, have very long biological half-times after their deposition in bone, liver or kidneys, rapid initiation of chelation treatment is usually imperative after a contamination event. The antidote DMPS (dimercapto-propanesulfonate) is considered the drug of choice for polonium decorporation. DTPA (diethylenetriamine pentaacetate) is a potent chelator especially approved for radionuclide mobilization, including polonium and other actinides. Other chelators and drugs are under investigation as potential chelators of transuranic elements., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Telerehabilitation programs can be employed to establish communication between patients and healthcare professionals and empower patients performing their training remotely. This study aimed to identify patients' requirements after a total knee replacement following a self-training rehabilitation program, leading to the design and development of a telerehabilitation program that can meet the stakeholders' actual needs. System design, development, and testing were conducted in five iterations based on a participatory design approach. Data collection was performed using interviews, observations, prototyping, and questionnaires. It was found that the main barriers facing the existing rehabilitation program were a lack of clear communication, lack of relevant information, and healthcare professional's feedback. The participants emphasized the main themes of communication, information, training, and motivation in the process of design and development. In using the telerehabilitation program, the patients reported a high level of user-friendliness, flexibility, and a sense of security. This study has identified obstacles in the current rehabilitation program and revealed the potential effectiveness of using asynchronous communication and sensor-based technologies by employing participatory design and development. A higher level of portability and flexibility were observed. However, future studies and development are required to investigate the overall usability and reliability of the telerehabilitation program.

Animal studies have previously shown that deep dorsal horn neurons play a role in the processing of spatial characteristics of nociceptive information in mammals. Human studies have supported the role of the spinal neurons; however, the mechanisms involved, and its significance, remain to be clarified. The aim of this study was to investigate spatial aspects of the spinal integration of concurrent nociceptive electrical stimuli in healthy humans using the Nociceptive Withdrawal Reflex (NWR) as an objective indication of spinal nociceptive processing. Fifteen healthy volunteers participated in the study. Electrical stimuli were delivered, using five electrodes located across the sole of the foot in a mediolateral disposition, as a single or double simultaneous stimuli with varying Inter-Electrode Distances (IEDs). The stimulation intensity was set at 1.5× NWR threshold (TA muscle). The size of the NWR was quantified in the 60-180 ms poststimulus window as a primary outcome measure. Psychophysical measures were secondary outcomes. Single stimulation elicited significantly smaller NWRs and perceived intensity than double stimulation (p < .01), suggesting the presence of spatial summation occurring within the spinal processing. During double stimulation, increasing the inter-electrode distance produced significantly smaller NWR sizes (p < .05) but larger pain intensity ratings (p < .05). By the NWR, spatial summation was shown to affect the nociceptive processing within the spinal cord. The inhibited motor response obtained when simultaneously stimulating the medial and lateral side of the sole of the foot suggests the presence of an inhibitory mechanism with a functional, behaviorally oriented function., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Fecal occult blood test (FOBT) screening for colorectal cancer (CRC) is implemented in several countries. Approximately half of all FOBT-positive persons have screen-detected adenomas. Despite removal of these, patients with large/multiple adenomas have increased risk of later developing new advanced adenomas and CRC. International guidelines exist for colonoscopic surveillance following adenoma removal. These divide patients into low-, intermediate- and high-risk groups. We followed 711 FOBT-positive patients with screening adenoma identified during population-based CRC screening in two Danish counties in 2005-2006. As reference population, we included 1,240,348 persons in the same age group from the rest of Denmark not included in the screening. We estimated the long-term CRC risk stratified by adenoma findings during screening and compared to the reference group. After 12 years follow-up, the CRC incidence among all adenoma patients was 322 cases per 100,000 person-years (95% confidence interval [CI]: 212-489) ranging from 251 (95% CI: 94-671) to 542 (95% CI: 300-978) cases per 100,000 person-years in the low- and high-risk groups, respectively. In the reference population, the CRC incidence was 244 (95% CI: 242-247) per 100,000. Patients with screen-detected high-risk adenomas after a positive FOBT had an almost doubled risk of CRC compared to the reference population (adjusted hazard ratio [aHR] 1.95, 95% CI: 1.08-3.51), and the incidence in those with no follow-up visits was over 3.6 (aHR 3.64, 95% CI: 1.82-7.29) times the incidence in the reference population. The increased CRC risk could be controlled if high-risk patients underwent follow-up colonoscopy (aHR 0.87, 95% CI: 0.28-2.69)., (© 2020 UICC.)

Introduction: The Danish Cancer Registry (DCR) and the Danish Lung Cancer Registry (DLCR) are nation-wide registries recording Danish patients with lung cancer (LC). The aim of this study was to assess data agreement and possible consequences hereof on estimation of survival between patients in the two registries., Methods: Descriptive statistics were used for comparison of registered patients in 2013-2014 in the DCR and the DLCR. Furthermore, the one-year relative survival (1y-RS) and Cox proportional mortality hazard rates (MRR) were calculated., Results: In 2013-2014, a total of 9,111 Danish residents were identified with LC in the DCR and 9,316 were found in the DLCR. Merging the two registries showed an agreement of 87%, whereas 6% were included only in the DCR and 8% only in the DLCR. Including patients only registered in one registry, but who seemed to meet the inclusion criteria of both registries, would increase the agreement to 95%. No differences were seen for 1y-RS. However, MRR for patients in the DLCR was significantly lower than for patients in the DCR: 0.94 (95% confidence interval: 0.91-0.98)., Conclusions: Surprisingly, the DCR registered fewer patients in 2013-2014 than the DLCR, even though they employ the same primary data source. The agreement between the DCR and the DLCR was 87%; this may be increased to 95% if patients who seemed to meet the inclusion criteria of the other register were also included. The discrepancies found were mainly due to different definitions of dates of diagnosis, registrations probably missed by the algorithms and possible registration errors. Discrepancies resulted in a significant difference in MRR, but not in 1y-RS., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: The Danish multidisciplinary renal cancer group (DaRenCa) established the nationwide database DaRenCaData in 2010. The Danish Cancer Registry (DCR) has been considered the golden standard. In contrast to DCR, DaRenCaData required the diagnosis to be histologically or cytologically verified. DaRenCaData and DCR have not previously been compared., Patients and Methods: We included patients with renal cell carcinoma registered in DaRenCaData and/or DCR from August 1st 2010 to December 31st 2015. We computed completeness and positive predictive value (PPV) of a diagnosis in DaRenCaData compared with DCR, 1-year, 3-year and 5-year mortality rate ratios, and relative survival., Results: We identified 4890 patients in the two registries. Of these, 4326 were registered in DaRenCaData and 4714 in DCR. Completeness of DaRenCaData was 88% [95% CI, 87-89%] and increased during the period from 82% to 94%. The PPV was 96% [95% CI, 95-97%]. A total of 4150 patients (85%) were found in both registries, 4% (176 patients) in DaRenCaData only, and 12% (564 patients) in DCR only. The relative survival was higher for patients in DaRenCaData vs DCR; the 1-year and 5-year relative survival was 85% vs 81% and 65% vs 59%, respectively. Compared with patients registered in both registries, the mortality rates were higher in patients registered in DaRenCaData only (1-year hazard ratio (HR)=2.84 [95% CI, 2.20-3.68]) or DCR only (1-year HR=4.29 [95% CI, 3.72-4.93]). Observed in both registries, survival improved over time with a 7% yearly reduction in death based on estimations of 1-year mortality rate ratios., Conclusion: DaRenCaData had high and increasing completeness and high PPV, establishing it as a high-quality research database. Observed in both registries, renal cell carcinoma mortality declined over time; patients only registered in DCR or DaRenCaData had poorer outcomes. This study points to the importance of assessing the inclusion criteria when interpreting registry-based studies., Competing Interests: Professor Frede Donskov reports grants from the Danish Cancer Society (R94-A6063-B271) and grants from the Health Research Foundation of Central Denmark Region, during the conduct of the study. The authors report no other possible conflicts of interest in this work., (© 2020 Danckert et al.)

Objective: Over the recent years, several small area electrodes have been introduced as tools for preferential stimulation of small cutaneous nerve fibers. However, the performance of the electrodes is highly debated and have not previously been systematically compared. The electrodes have been developed empirically and little is known about the electrical potential they produce in the skin, and how this influences the nerve fiber activation. The objective of the present study was to develop and validate a computational model to compare the preferential stimulation of small fibers for electrodes of different designs., Approach: A finite element model of the skin was developed and coupled with an Aβ-fiber and an Aδ-fiber multi-compartmental nerve fiber model, to describe the current spread and consequent nerve fiber activation produced by five different surface electrodes; intra-epidermal, planar concentric, pin, planar array, and patch. The model was validated through experimental assessments of the strength-duration relationship, impedance, and reaction times., Main Results: The computational model predicted the intra-epidermal electrode to be the most preferential for small fiber activation. The intra-epidermal electrode was, however, also found to be the most sensitive to positioning relative to nerve fiber location, which may limit the practical use of the electrode., Significance: The present study highlights the influence of different electrode design features on the current spread and resulting activation of cutaneous nerve fibers. Additionally, the computational model may be used for the optimization of electrode design towards even better preferential stimulation of small fibers.

Nociceptive withdrawal reflex (NWR) is a protective reaction to a noxious stimulus, resulting in withdrawal of the affected area and thus preventing potential tissue damage. This involuntary reaction consists of neural circuits, biomechanical strategies, and muscle activity that ensure an optimal withdrawal. Studies of lower limb NWR indicate that the amplitude of the NWR is highly modulated by extrinsic and intrinsic factors, such as stimulation site, intensity, frequency, and supraspinal activity, among others. Whether the predictability of the stimulus has an effect on the biomechanical strategies is still unclear. This study aimed to evaluate how the predictability of impending noxious stimuli modulate the NWR reaction in the lower limb. NWR was evoked on fifteen healthy participants by trains of electrical stimuli on the sole of the foot and was measured in one distal (tibialis anterior) and one proximal (biceps femoris) muscle. The predictability was manipulated by giving participants prior information about the onset of the stimulus trains and the number of delivered stimuli per train. Results showed that the predictability of the incoming stimuli differentially modulates the muscle activity involved in the NWR reaction. For the most unpredictable stimulus train, larger NWR at distal muscles were evoked. Furthermore, the stereotyped temporal summation profile to repeated stimulation was observed when the stimulus train was completely predictable, while it was disrupted in proximal muscles in unpredictable conditions. It is inferred that the reflex response is shaped by descending control, which dynamically tunes the activity of the muscles involved in the resulting reaction. NEW & NOTEWORTHY Innate defensive behaviors such as reflexes are found across all species, constituting preprogrammed responses to external threats that are not anticipated. Previous studies indicated that the excitability of the reflex arcs like spinal nociceptive withdrawal reflex (NWR) pathways in humans are modulated by several cognitive factors. This study assesses how the predictability of a threat affects the biomechanical pattern of the withdrawal response, showing that distal and proximal muscles are differentially modulated by descending control.

Background: The Danish Cancer Registry (DCR) and the Danish Colorectal Cancer Group (DCCG) database are population-based registries collecting information on Danish patients with colorectal cancer (CRC). DCR registers all patients with incident CRC whereas DCCG records patients with first time CRC. The registries use different inclusion criteria. The consequencenses of this are unknown and not previously evaluated. The aim of this study was to examine the agreement between patients registered in DCR and DCCG and to evaluate its influence on estimated survival and mortality. Material and methods: Patients registered in DCR and DCCG with CRC in 2014-2015 were included. Because of different inclusion criteria, DCCG's inclusion criteria were applied to DCR. Descriptive statistics were used for comparisons. One-year relative survival (1-year RS) was calculated, and the Cox proportional hazard model used for calculating 1-year mortality rate ratios (1-year MRR). Results: In 2014-2015, DCR registered 9678 Danish residents with CRC that fulfilled DCCG's inclusion criteria, while DCCG registered 10,312 Danish residents with CRC. Allowing ±180 days between dates of diagnosis, 10,688 patients were registered with CRC in the merger of the two registries. Of these, 86% were included in both registers, 4% only in DCR, and 10% only in DCCG. No difference was found in 1-year RS between patients in DCR 86% (95% CI: 85-87) and DCCG 85% (95% CI: 84-86). However, patients registered in DCCG had a 1-year MRR of 1.09 (95% CI: 1.01-1.17) compared to DCR. Conclusion: An agreement of 86% of patients was found between the two registries. The discrepancy did not influence 1-year RS. DCCG registered more patients than DCR, and 1-year MRR of patients in DCCG was increased compared to patients in DCR. Regular linkage of the registries is recommended to improve data quality of both registries.

Follow-up studies after the Chernobyl and Fukushima accidents have shown that 137 Cs and 131 I made up the major amount of harmful contaminants in the atmospheric dispersion and fallout. Other potential sources for such radionuclide exposure may be terrorist attacks, e.g., via contamination of drinking water reservoirs. A primary purpose of radionuclide mobilization is to minimize the radiation dose. Rapid initiation of treatment of poisoned patients is imperative after a contaminating event. Internal contamination with radioactive material can expose patients to prolonged radiation, thus leading to short- and long-term clinical consequences. After the patient's emergency conditions are addressed, the treating physicians and assisting experts should assess the amount of radioactive material that has been internalized. This evaluation should include estimation of the radiation dose that is delivered and the specific radionuclides inside the body. These complex assessments warrant the reliance on a multidisciplinary approach that incorporates regional experts in radiation medicine and emergencies. Regional hospitals should have elaborated strategies for the handling of radiation emergencies. If radioactive cesium is a significant pollutant, Prussian blue is the approved antidote for internal detoxification. Upon risks of radioiodine exposure, prophylactic or immediate treatment with potassium iodide tablets is recommended. Chelators developed from calcium salts have been studied for gastrointestinal trapping and enhanced mobilization after strontium exposure.

Phasic pain stimuli are inhibited when they are applied concomitantly with a conditioning tonic stimulus at another body location (heterotopic noxious conditioning stimulation, HNCS). While the effects of HNCS are thought to rely on a spino-bulbo-spinal mechanism in animals (termed diffuse noxious inhibitory controls, DNIC), the underlying neurophysiology in humans may involve other pathways. In this study, we investigated the role of concomitant supraspinal mechanisms during HNCS by presenting auditory stimuli during a conditioning tonic painful stimulus (the cold pressor test, CPT). Considering that auditory stimuli are not conveyed through the spinal cord, any changes in brain responses to auditory stimuli during HNCS can be ascribed entirely to supraspinal mechanisms. Electroencephalography (EEG) was recorded during HNCS, and auditory stimuli were administered in three blocks, before, during and after HNCS. Nociceptive withdrawal reflexes (NWRs) were recorded at the same time points to investigate spinal processing. Our results showed that AEPs were significantly reduced during HNCS. Moreover, the amplitude of the NWR was significantly diminished during HNCS in most participants. Given that spinal and supraspinal mechanisms operate concomitantly during HNCS, the possibility of isolating their individual contributions in humans is questionable. We conclude that the net effects of HCNS are not independent from attentional/cognitive influences., (© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Assessing conditioning pain modulation (CPM) with spinal reflex measures may produce more objective and stable CPM effects than using psychophysical measures. The aim of the study was to compare the CPM effect and test-retest reliability between a psychophysical protocol with thermal test-stimulus and a spinal reflex protocol with electrical test-stimulus., Methods: Twenty-five healthy volunteers participated in two identical experiments separated by minimum 1 week. The thermal test-stimulus was a constant heat stimulation of 120 s on the subjects' forearm with continuous ratings of pain intensity on a 10 cm visual analogue scale. The electrical test-stimulus was repeated electrical stimulation on the arch of the foot for 120 s, which elicited a nociceptive withdrawal reflex recorded from the anterior tibial muscle. Conditioning stimulus was a 7°C water bath. Differences in the magnitude and test-retest reliability were investigated with repeated-measures analysis of variance and by relative and absolute reliability indices., Results: The CPM effect was -46% and 4.5% during the thermal and electrical test-stimulus (p < 0.001) respectively. Intraclass correlation coefficient of 0.5 and 0.4 was found with the electrical and thermal test-stimulus respectively. Wide limits of agreement were found for both the electrical (-3.4 to 3.8 mA) and the thermal test-stimulus (-3.2 to 3.6 cm)., Conclusions: More pronounced CPM effect was demonstrated when using a psychophysical protocol with thermal test-stimulus compared to a spinal reflex protocol with electrical test-stimulus. Fair relative reliability and poor absolute reliability (due to high intraindividual variability) was found in both protocols., Significance: The large difference in CPM effect between the two protocols suggests that the CPM effect relates to pain perception rather than nociception on the spinal level. Due to poor absolute intrarater reliability, we recommend caution and further research before using any of the investigated CPM protocols in clinical decision making on an individual level., (© 2019 European Pain Federation - EFIC®.)

Background: Experimental models of pain in humans are crucial for understanding pain mechanisms. The most often used muscle pain models involve the injection of algesic substances, such as hypertonic saline solution or nerve growth factor or the induction of delayed onset muscle soreness (DOMS) by an unaccustomed exercise routine. However, these models are either invasive or take substantial time to develop, and the elicited level of pain/soreness is difficult to control. To overcome these shortcomings, we propose to elicit muscle pain by a localized application of short-wave diathermy (SWD)., Methods: In this crossover study, SWD was administered to 18 healthy volunteers to the wrist extensor muscle group, with a constant stimulation intensity and up to 4 min. Pressure pain threshold (PPT), pinprick sensitivity (PPS) and self-reported muscle soreness were assessed at baseline and at 0, 30 and 60 min after application of SWD., Results: SWD evoked localized muscle pain/soreness in the wrist extensor muscle group and a decrease of PPT in the treated arm compared with the control arm that lasted for at least 60 min, reflecting ongoing hyperalgesia after SWD application. PPS was not significantly altered 30-60 min following SWD, suggesting a minimal contribution from skin tissue to sustained hyperalgesia., Conclusions: SWD was able to elicit muscle soreness and hyperalgesia up to 60 min after its application. Thus, this new model represents a promising tool for investigating muscle pain in humans., Significance: This study presents an experimental model to elicit sustained muscle pain based on short-wave diathermy. The main advantages of the model are its noninvasiveness, the possibility to control stimulation parameters in a reliable way and the convenience of the time frame in which pain and hyperalgesia are developed., (© 2019 European Pain Federation - EFIC®.)

Electrical stimulation is widely used in pain research and profiling, but current technologies lack selectivity toward small sensory fibers. Pin electrodes deliver high current density in upper skin layers, and it has been proposed that slowly rising exponential pulses can elevate large-fiber activation threshold and thereby increase preferential small-fiber activation. Optimal stimulation parameters for the combined pin electrode and exponential pulse stimulation have so far not been established, which is the aim of this study. Perception thresholds were compared between pin and patch electrodes using single 1- to 100-ms exponential and rectangular pulses. Stimulus-response functions were evaluated for both pulse shapes delivered as single pulses and pulse trains of 10 Hz using intensities from 0.1 to 20 times perception threshold. Perception thresholds (mA) decreased when duration was increased for both electrodes with rectangular pulses and the pin electrode with exponential pulses. For the patch electrode, perception thresholds for exponential pulses decreased for durations ≤10 ms but increased for durations ≥15 ms, indicating accommodation of large fibers. Stimulus-response curves for single pulses were similar for the two pulse shapes. For pulse trains, the slope of the curve was higher for rectangular pulses. Maximal large-fiber accommodation to exponential pulses was observed for 100-ms pulses, indicating that 100-ms exponential pulses should be applied for preferential small-fiber activation. Intensity of 10 times perception threshold was sufficient to cause maximal pain ratings. The developed methodology may open new opportunities for using electrical stimulation paradigms for small-fiber stimulation and diagnostics. NEW & NOTEWORTHY Selective activation of small cutaneous nerve fibers is pivotal for investigations of the pain system. The present study demonstrated that patch electrode perception thresholds increase with increased duration of exponential currents from 20 to 100 ms. This is likely caused by large-fiber accommodation, which can be utilized to activate small fibers preferentially through small-diameter pin electrodes. This finding may be utilized in studies of fundamental pain mechanisms and, for example, in small-fiber neuropathy.