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Heleen Marynissen, Jan de Hoon Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, BelgiumCorrespondence: Heleen Marynissen, Center for Clinical Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, Leuven, 3000, Belgium, Tel +32 16 34 70 14, Email Heleen.marynissen@kuleuven.be

Background: Quantification of the vasodilation after topical application of capsaicin or cinnamaldehyde is often implemented to indirectly assess Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) or Ankyrin 1 (TRPA1) functionality respectively. This method has been well-established on the human forearm. However, to enable TRP functionality assessments in distal peripheral neuropathy, the vascular response upon TRP activation on dorsal finger skin was characterized., Methods: Two doses of cinnamaldehyde (3 % and 10 % v/v) and capsaicin (300 μg and 1000 μg) were topically applied (20 μL) on the skin of the mid three proximal phalanges in 17 healthy men. The dose-response, and inter-hand and inter-period reproducibility of the dermal blood flow (DBF) increase was assessed using Laser Speckle Contrast Imaging (LSCI) during 60 min post-application. Linear mixed models explored dose-driven differences, whereas the intra-class correlation coefficient (ICC) estimated the reproducibility of the vascular response., Results: Both doses of cinnamaldehyde and capsaicin induced a robust, dose-dependent increase in DBF. The vascular response to cinnamaldehyde 10 % on finger skin, expressed as area under the curve, correlated well over time (ICC = 0.66) and excellently between hands (ICC = 0.87). Similarly, the response to capsaicin 1000 μg correlated moderately over time (ICC = 0.50) and well between hands (ICC = 0.73)., Conclusion: The vascular response upon topical cinnamaldehyde and capsaicin application on finger skin is an alternative approach for measurements on forearm skin. Thereby, it is a promising vascular read-out to investigate the pathophysiology, and TRP involvement in particular, of specific peripheral neuropathic pain syndromes., Competing Interests: Declaration of competing interest “The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Transient receptor potential (TRP) channels are pivotal in modulating vascular functions. In fact, topical application of cinnamaldehyde or capsaicin (TRPA1 and TRPV1 channel agonists, respectively) induces "local" changes in blood flow by releasing vasodilator neuropeptides. We investigated TRP channels' contributions and the pharmacological mechanisms driving vasodilation in human isolated dermal arteries. Ex vivo studies assessed the vascular function of artery segments and analyzed the effects of different compounds. Concentration-response curves to cinnamaldehyde, pregnenolone sulfate (PregS, TRPM3 agonist), and capsaicin were constructed to evaluate the effect of the antagonists HC030031 (TRPA1); isosakuranetin (TRPM3); and capsazepine (TRPV1). Additionally, the antagonists/inhibitors olcegepant (CGRP receptor); L-NAME (nitric oxide synthase); indomethacin (cyclooxygenase); TRAM-34 plus apamin (K + channels); and MK-801 (NMDA receptors, only for PregS) were used. Moreover, CGRP release was assessed in the organ bath fluid post-agonist-exposure. In dermal arteries, cinnamaldehyde- and capsaicin-induced relaxation remained unchanged after the aforementioned antagonists, while PregS-induced relaxation was significantly inhibited by isosakuranetin, L-NAME and MK-801. Furthermore, there was a significant increase in CGRP levels post-agonist-exposure. In our experimental model, TRPA1 and TRPV1 channels seem not to be involved in cinnamaldehyde- or capsaicin-induced relaxation, respectively, whereas TRPM3 channels contribute to PregS-induced relaxation, possibly via CGRP-independent mechanisms.

Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans., (© 2023 Eli Lilly and Company and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: In preclinical research, etodolac, a non-steroidal anti-inflammatory drug, affected transient receptor potential ankyrin 1 (TRPA1) activation. Yet, whether the in vitro interaction between etodolac and TRPA1 translates to altered TRPA1 functionality in vivo in human remains to be investigated., Methods: A randomized, double-blinded, celecoxib-controlled study was conducted to assess the effect of etodolac on TRPA1-mediated dermal blood flow (DBF) changes on the forearm of 15 healthy, male volunteers aged between 18 and 45 years. Over four study visits, separated by at least five days wash-out, a single or four-fold dose of etodolac 200 mg or celecoxib 200 mg was administered orally. Two hours post-dose, TRPA1 functionality was evaluated by assessing cinnamaldehyde-induced DBF changes. DBF changes were quantified and expressed in Perfusion Units (PUs) using laser Doppler imaging during 60 min post-cinnamaldehyde application. The corresponding area under the curve (AUC 0-60min ) was calculated as summary measure. Statistical analysis was performed using Linear mixed models with post-hoc Dunnett., Results: Neither the single dose of etodolac nor celecoxib inhibited the cinnamaldehyde-induced DBF changes compared to no treatment (AUC 0-60min  ± SEM of 17,751 ± 1,514 PUs*min and 17,532 ± 1,706 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00). Similarly, also a four-fold dose of both compounds failed to inhibit the cinnamaldehyde-induced DBF changes (19,235 ± 1,260 PUs*min and 19,367 ± 1,085 PUs*min vs. 19,274 ± 1,031 PUs*min, respectively, both p=1.00)., Conclusions: Etodolac did not affect the cinnamaldehyde-induced DBF changes, suggesting that it does not alter TRPA1 functionality in vivo in human., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Maxadilan, a potent vasodilator peptide, selectively activates the PAC 1 receptor, a promising target for migraine therapy. Therefore, maxadilan has been suggested as a tool to study the pharmacodynamics (PDs) of PAC 1 receptor antagonists. The objectives of this first-in-human study were to: (1) determine the safety, tolerability, dose response, and time course of the dermal blood flow (DBF) changes after intradermal (i.d.) injections of maxadilan in the human forearm, and (2) assess the inter-arm and inter-period reproducibility of this response. This was a single-center, open-label study in healthy subjects, comprising three parts: (1) dose-response (n = 25), (2) response duration (n = 10), and (3) reproducibility (n = 15). DBF measurements were performed using laser Doppler imaging (LDI) up to 60 min postinjection, or up to 5 days for the response duration assessments. To assess reproducibility, the intraclass correlation coefficient (ICC) and sample sizes were calculated. The i.d. maxadilan (0.001, 0.01, 0.1, 0.9, 3, and 10 ng) produced a well-tolerated, dose-dependent increase in DBF, with a half-maximal effective concentration fitted at 0.0098 ng. The DBF response to 0.9 ng maxadilan was quantifiable with LDI up to 72 h postinjection. The inter-period reproducibility of the DBF response was better upon 0.9 ng (ICC > 0.6) compared to 0.01 ng (ICC < 0.4) maxadilan. However, irrespective of the study design or maxadilan dose, a sample size of 11 subjects is sufficient to detect a 30% difference in DBF response with 80% power. In conclusion, intradermal maxadilan provides a safe, well-tolerated, and reproducible PD biomarker for PAC 1 receptor antagonists in vivo in humans., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: This study aimed to provide recommendations for a personalized electronic informed consent interface that is adapted to research participants' needs and could enable a longitudinal interaction between the participants and the research team., Methods: The co-creation process consisted of three co-creation workshops, one focus group discussion, and four semi-structured interviews. In total, 24 participants, who had taken part in four disparate clinical studies in Belgium, were involved. Descriptive statistics and qualitative content analysis were applied to analyze the survey data and audio recordings., Results: Varying perceptions on the type and amount of information described in an informed consent form were reported. Other findings were related to the structure and presentation of information, setting preferences for data sharing, and electronically signing new informed consent versions. Regarding the long-term interaction, most of the participants wanted to receive progress updates, including the results, of the study in which they had taken part. They proposed to receive a notification, preferably via email, in case new information is made available on the electronic informed consent interface., Conclusions: To optimally support the design of an electronic informed consent interface, it is key to understand the research participants' needs. Study findings suggest that an electronic informed consent interface may be a promising technological application to interactively provide study-related information and to keep participants informed during and after the clinical study., Competing Interests: Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Aims: In search of noninvasive biomarkers to assess the pharmacodynamic effects of portal pressure-lowering drugs, the reproducibility of flow measurements in the superior mesenteric artery was evaluated using Doppler ultrasound., Methods: A reproducibility study was conducted in 15 healthy male volunteers (18-50 y). Eight ultrasound measurements were performed for each subject: 2 observers each conducted 2 measurements during 2 separate visits. The following flow parameters were captured: peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), volume flow (VF) and vessel diameter. Reproducibility was assessed by the intraclass correlation coefficient., Results: Results are presented as intraclass correlation coefficient [95% confidence interval]. The flow parameters PSV, EDV, PI and VF correlated excellently within observer during visit 1 (0.888 [0.748-0.953], 0.910 [0.793-0.962], 0.844 [0.656-0.933] and 0.916 [0.857-0.951], respectively) and visit 2 (0.925 [0.829-0.968], 0.942 [0.863-0.976], 0.883 [0.719-0.954] and 0.915 [0.855-0.951], respectively). Measurements conducted during 2 separate visits by 1 observer correlated well to excellently for PSV, EDV, PI and VF (0.756 [0.552-0.875], 0.836 [0.694-0.916], 0.807 [0.631-0.904] and 0.839 [0.783-0.882], respectively). Measurements conducted by 2 distinct observers correlated well to excellently for PSV, EDV and VF during visit 1 (0.813 [0.584-0.922], 0.884 [0.597-0.945] and 0.786 [0.575-0.899], respectively) and visit 2 (0.779 [0.498-0.912], 0.861 [0.672-0.945], 0.810 [0.553-0.926], respectively). Vessel diameter measurements were poorly reproducible., Conclusion: Doppler ultrasound is a reproducible method for flow measurements in the superior mesenteric artery in a standardized group of healthy volunteers. Therefore, it is a promising technique to assess pharmacodynamic effects of splanchnic vasoactive compounds in early clinical drug development., (© 2021 British Pharmacological Society.)

In this article, the authors describe and illustrate what they call a "network of networks" perspective and map the development of a lead network for the Antwerp Port Authority that governed organizations and networks in the port community before and during the COVID-19 pandemic. They find that setting a collective focus and selective integration are crucial in the creation and reproduction of an effective system to adequately deal with a wicked problem like the COVID-19 pandemic. The findings on crisis management and network governance are used to engage practitioners and public policy planners to revisit the current design and governance of organizational networks within organizational fields that have been hit by the COVID-19 pandemic., (© 2020 by The American Society for Public Administration.)

Background: Neonatal hypoxic ischaemic encephalopathy due to perinatal asphyxia, can result in severe neurodevelopmental disability or mortality. Hypothermia is at present the only proven neuroprotective intervention. During hypothermia, the neonate may need a variety of drugs with their specific pharmacokinetic profile. The aim of this paper is to determine the effect that hypothermia for neonates suffering from hypoxic ischaemic encephalopathy has on the pharmacokinetics and to what extent dosing regimens need adjustments., Method: A systematic search was performed on PubMed, Embase and Cochrane Library of literature (2000-2020) using a combination of the following search terms: therapeutic hypothermia, neonate, hypoxic ischemic encephalopathy and pharmacokinetics. Titles and abstracts were screened, and inclusion/exclusion criteria were applied. Finally, relevant full texts were read, and secondary inclusion was applied on the identified articles., Results: A total of 380 articles were retrieved, and 34 articles included after application of inclusion/exclusion criteria and duplicate removal, two additional papers were included as suggested by the reviewers. Twelve out of 36 studies on 15 compounds demonstrated a significant decrease in clearance, be it that the extent differs between routes of elimination and compounds, most pronounced for renal elimination (phenobarbital no difference, midazolam metabolite -21%, lidocaine -24%; morphine -21% to -47%, gentamicin -25% to -35%, amikacin -40%) during hypothermia. The data as retrieved in literature were subsequent compared with the dosing regimen as stated in the Dutch paediatric formulary., Conclusion: Depending on the drug-specific disposition characteristics, therapeutic hypothermia in neonates with hypoxic ischaemic encephalopathy affects pharmacokinetics., Competing Interests: Competing interests: This paper is an adapted version of the master's thesis written by ICL., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Design: A retrospective cross-sectional analysis., Objective: The aim of this study was to describe the provision of a spinal service using an electronic platform to direct management from an external spinal unit, and to quantify the time taken to obtain definitive management plans while under prescribed spinal immobilization., Summary of Background Data: Most attending district general hospitals following spinal trauma will have stable injuries and normal neurology, with only a small proportion requiring urgent transfer to a specialist center., Methods: A retrospective review of 104 patients admitted following vertebral trauma during a 12-month period. The British Orthopaedic Association Standards for Trauma consensus that "spinal immobilisation is not recommended for more than 48 hours" was the standard of care measured against., Results: One hundred patients occupied a total of 975 hospital inpatient bed days. One hundred and seventeen radiological investigations were requested after the point of external referral [47 computed tomography (CT)-scans, 37 magnetic resonance imaging (MRI)-scans, and 33 weight-bearing radiographs]. The period between initial referral to the regional spinal service and then receiving a definitive final management plan had a median value of 72 hours and a range of 0 and 33 days. Patients will have been under some form of prescribed spinal immobilization until the definitive management plan was communicated. Thirty-four patients (34% of the overall cohort) had a definitive management plan in place within 48 hours. Eighty patients had vertebral injuries (73 stable, six unstable), three patients had prolapsed intervertebral disks, one had metastatic disease, and 17 did not have evidence of an acute injury following evaluation., Conclusion: Patients are being placed under prescribed immobilization for longer than is recommended. Delays in obtaining radiological imaging were an important factor, together with the time taken to receive a definitive management plan. Limitations in social care provision and delays in arranging this were additional barriers to hospital discharge following the final management plan., Level of Evidence: 4.

Purpose: The suture anchor technique for medial capsular plication has been previously described. We present our technique and its medium-term results., Methods: A single surgeon's experience (senior author) of the suture anchor technique for medial capsular plication was reviewed in 14 knees in 14 patients. All patients underwent arthroscopic stabilisation for patello-femoral instability. The method used was the suture anchor technique for medial capsular plication (full technique described in paper). The primary outcome measure used was further dislocation or instability. The validated Kujala score was used pre- and post-op to assess functional outcome., Results: There were nine male and five female patients (M:F, 64%:34%). Median age was 25 (range 16-65). Mean follow-up was 52 months (95% CI 44-56 range 24-72). The mean pre-op Kujala score was 54.6 (SD 24.4). The mean post-op Kujala score was 78.2 (SD 20.5). The mean increase in Kujala score was 23.6 (95% CI 7.9-39.4). There was a statistically significant increase in Kujala score, P=0.006. Only 1 of 14 patients had a further dislocation (7%), and there were no further episodes of instability., Conclusion: This is the first paper to describe the results of this technique in the literature. There was a statistically significant improvement in the patients' functional outcome and 13/14 patients did not re-dislocate or experience instability. It was concluded that this technique is a successful mode of treatment for patello-femoral instability., Level of Evidence: Case series, Level IV.

Unicompartmental knee replacements have become increasingly popular with improved survivorship and clinical results. This has been combined with minimally invasive surgery to further improve patient recovery and rehabilitation. Despite improved instrumentation, it remains a technically demanding procedure. We present a previously unreported case of tibial nerve impingement as a consequence of posterior cement extrusion after a unicompartmental knee replacement., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Ankle arthroscopy is believed to have the least vascular complications compared with other types of arthroscopies. We present a case of traumatic pseudoaneurysm of the anterior tibial artery after ankle arthroscopy, an extremely rare complication that was treated surgically and had an uneventful recovery.

Arthroscopic transglenoid suture of Bankart lesions was performed in 31 patients from 1988 to 1992. The diagnosis in all patients was recurrent traumatic anterior luxation, and a Bankart lesion was found in all cases. Mean time for clinical follow-up was 43 months (ranging from 25 to 76 months). A telephone review of all cases was obtained two years later. Five patients experienced postoperative wound problems posteriorly, where the sutures were tied over the fascia of the infraspinatus. One transient suprascapular nerve palsy was seen. There was a recurrence of complete dislocation in eight patients, while six patients had had repeated subluxations (total failure rate of 45.1%). Sixteen patients (51.6%) were assessed as having good to excellent results according to the Rowe scoring system. A slight loss of external rotation was found in six cases. Seventeen patients (54.8%) were able to return to their pre-injury level of athletic activity. Due to the high failure rate, we do not recommend arthroscopic transglenoid suture of Bankart lesions in patients with recurrent traumatic anterior dislocations.