Daval International (United Kingdom)

AimEffective treatment for neuropathic pain remains an unmet clinical need. The therapeutic benefits of the Cannabis plant are well known, especially for pain relief. Here, we have assessed ten “minor” cannabinoids for their analgesic effects in an established model of neuronal hypersensitivity, a key mechanism which underlies neuropathic pain.MethodsAdult rat DRG neurons were cultured in medium containing 100 ng/mL nerve growth factor (NGF) and 50 ng/mL glial cell-line derived neurotrophic factor (GDNF) for 48 hours to sensitize the neurons. Ca2+ imaging was used to measure the responses to pain stimulation using capsaicin, and to determine the modulatory effects of the cannabinoids, in individual neurons.ResultsControl neurons (nociceptors) showed robust responses of Ca2+ influx to capsaicin application, while neurons treated with ten minor cannabinoids tetrahydrocannabiorcol (THCC), cannabitriol (CBT), cannabidivarin (CBDV), cannabinol (CBN), cannabichromene (CBC), cannabichromevarin (CBCV), cannabicitran (CBCT), cannabigerol monomethyl ether (CBGM), tetrahydrocannabutol (THCB) or tetrahydrocannabiphorol (THCP), at concentrations of 0.001–100 μM, showed differential dose-related effects on the responses to capsaicin. Ca2+ influx in response to capsaicin application was completely inhibited for each compound in 35–78% capsaicin-sensitive neurons, while other neurons showed reduced responses. The opioid receptor agonist morphine and α2δ1- Ca2+ channel inhibitor gabapentin were also tested for comparison and showed similar results. All the cannabinoids tested here inhibited calcium influx in response to capsaicin, and two, namely, CBN and THCC elicited calcium influx at higher doses. Inhibition of Ca2+ influx due to cannabichromene (CBC) was reversed by the potassium channel inhibitor Tertiapin Q.ConclusionAll the cannabinoids tested here inhibited TRPV1 signalling. CBC targeted K+ channels to block TRPV1 mediated Ca2+ influx, demonstrating potential analgesic effects in vitro.

Abstract Introduction The burden of morbidity and mortality from severe pneumonia remains high among children under five, particularly in resource-limited countries such as Burkina Faso. Targeted hospital-based interventions are essential to achieve Sustainable Development Goal 3.2, which aims to reduce under-five mortality to 25 deaths per 1,000 live births by 2030. Methods A prospective cohort study was conducted in the pediatrics department of Regional Referral Hospital of Banfora, including 1,406 children aged 2–59 months hospitalized for severe pneumonia between August 2021 and January 2024. Predictors of mortality were identified using the Fine and Gray competing risk model. Results A total of 1,406 children were included in the analysis. The median age was 18 months (interquartile range: 9–32 months), and 53% were male. During hospitalization, 8.96% (126/1,406; 95% CI: 7.58–10.57) died, corresponding to a mortality rate of 1.93 per 100 person-days. Age < 12 months doubled the instantaneous risk of death. Additionally, hypoxemia (SaO₂ < 90%) (adjusted subdistribution hazard ratio [aSHR]: 1.54; 95% CI: 1.02–2.32), hospitalization during the rainy season (aSHR: 1.73; 95% CI: 1.18–2.54), convulsions (aSHR: 2.93; 95% CI: 1.92–4.47), the presence of stridor (aSHR: 2.17; 95% CI: 1.46–3.22), and hypoglycemia (aSHR: 2.37; 95% CI: 1.45–3.88) increased the risk of death. However, the risk of death was significantly lower in children with moderate or severe anaemia (respectively aSHR = 0.45; 95% CI: 0.24 - 0.84 and aSHR = 0.26; 95% CI: 0.13 - 0.52) and having received antibiotic therapy (ceftriaxone alone [SHRa = 0.52; 95% CI: 0.30 - 0.90] or combined with gentamicin (SHRa = 0.45; 95% CI: 0.30-0.69); ampicillin [aSHR = 0,35; IC95%: 0,13-0,97] and ampicillin combined with gentamicin (SHRa = 0.43; CI: 0.20 - 0.95). Conclusion The incidence and in-hospital mortality of severe pneumonia are a cause for concern at the Regional Referral Hospital of Banfora and in Burkina Faso. Targeted interventions in hospital settings are necessary and can help achieve Sustainable Development Goal 3.2 on reducing under-five mortality to 25 deaths per 1,000 live births by 2030.

<div class="section abstract"><div class="htmlview paragraph">In pursuit of safety validation of automated driving functions, efforts are being made to accompany real world test drives by test drives in virtual environments. To be able to transfer highly automated driving functions into a simulation, models of the vehicle’s perception sensors such as lidar, radar and camera are required. In addition to the classic pulsed time-of-flight (ToF) lidars, the growing availability of commercial frequency modulated continuous wave (FMCW) lidars sparks interest in the field of environment perception. This is due to advanced capabilities such as directly measuring the target’s relative radial velocity based on the Doppler effect. In this work, an FMCW lidar sensor simulation model is introduced, which is divided into the components of signal propagation and signal processing. The signal propagation is modeled by a ray tracing approach simulating the interaction of light waves with the environment. For this purpose, an ASAM Open Simulation Interface (OSI) object list referencing virtual 3D objects provides the input for the ray tracer. The divergence of the continuous laser beam is approximated by super-sampling the beam with multiple rays, the calculation of the received power is supported by the future ASAM OpenMATERIAL standard. Subsequently, the output of the ray tracer serves as the input of the signal processing that adapts the so-called Fourier tracing from the field of radar sensor simulation. This approach uses the range and velocity information of the individual rays to estimate the frequency spectrum of the intermediate frequency signal. A subsequent peak detection algorithm determines the output of the model, which is provided in the form of OSI lidar detections. Verification scenarios are tested to check the plausibility of the output and the source code of the signal processing is made available as open source.</div></div>

BackgroundHyperimmune caprine serum (HICS) is a novel biological therapy with potential benefit for skin in established diffuse cutaneous systemic sclerosis. Here we report multiplex protein analysis of blood samples from a placebo-controlled phase II clinical trial and explore mechanisms of action and markers of response.MethodsPatients were treated with HICS (n = 10) or placebo (n = 10) over 26 weeks, with follow-up open-label treatment to 52 weeks in 14 patients. Serum or plasma samples at baseline, 26 and 52 weeks were analysed using multiplex or individual immunoassays for 41 proteins. Patterns of change were analysed by clustering using Netwalker 1.0, Pearson coefficient and significance analysis of microarrays (SAM) correction.ResultsCluster analysis, SAM multiplex testing and paired comparison of individual analytes identified proteins that were upregulated or downregulated during treatment with HICS. There was upregulation of the hypothalamo-pituitary-adrenal axis after HICS treatment evidenced by increases in α-MSH and ACTH in cases treated with HICS. Interestingly, significant increase in PIIINP was associated with HICS treatment and improved MRSS suggesting that this may be a marker of extracellular matrix turnover. Other relevant factors reduced in HICS-treated patients compared with controls, although not reaching statistical significance included COMP, CCL2, IL6, TIMP2, Fractalkine and TGFβ1 levels.ConclusionsOur results suggest mechanisms of action for HICS, including upregulation of α-MSH, that has been shown to be anti-fibrotic in preclinical models, and possible markers to be included in future trials targeting skin in diffuse cutaneous systemic sclerosis.Trial registrationEudract, No. 2007-003122-24. ClinTrials.gov, No. NCT00769028. Registered 7 October 2008.

BACKGROUND A phase II trial to explore the efficacy, safety and tolerability of a stabilised neuropeptide - SR-CRH-01 in Secondary Progressive MS (SPMS) DESIGN AND METHODS A phase II double-blind placebo controlled (DBPC) crossover clinical trial was performed with n=20 SPMS patients who received SR-CRH-01 [known as AIMSPRO®] (n=10), or placebo (n=10) by s.c. injection with 1 mL (4.5 mg/mL) twice weekly for 4-weeks, followed by a 6-week washout, and then a crossover to the other treatment for 4-weeks. Post-DBPC phase, SR-CRH-01 was given in an open-label phase (OL) for an additional 38 weeks. RESULTS Primary endpoints; in the DBPC phase SR-CRH-01 did not show significantly altered bladder function. The therapy was safe and well tolerated throughout the trial period. In the OL phase, SR-CRH-01 significantly decreased the mean voiding frequency (p<0.0001) and mean urinary incontinence (p=0.0009). Secondary endpoints; in the DBPC phase, SR-CRH-01 significantly increased the total MS Functional Composite (MSFC) versus placebo (p=0.0215); the 25-foot walk (p=0.049) and mean 9-hole peg test [9-HPT] (p=0.046). Analysis of the mean PASAT 3 in the OL phase showed that SR-CRH-01 also significantly increased the mean score from baseline to 26 weeks (p<0.0001). SR-CRH-01 significantly decreased the mean MS Impact (physical) scale in the DBPC phase (p=0.007), which continued through to week 26 (p<0.0001). The visual acuity (LogMar - both eyes combined) by treatment in the DBPC phase was significantly improved by SR-CRH-01 versus placebo (p=0.026). This effect persisted to the OL phase (p=0.005). The mean colour vision score also showed a strong trend towards improvement in the DBPC phase (p=0.06). SR-CRH-01 significantly increased the overall I-QOL during the OL phase (p=0.007). CONCLUSION The medication SR-CRH-01 was well tolerated. Although bladder function in the short DBPC phase was not significantly altered, the trial results implied that longer term administration had a therapeutic effect on bladder instability. The multiple significant secondary outcome results support future development of larger, longer-term studies.

ObjectiveThe primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum (AIMSPRO) in established diffuse cutaneous systemic sclerosis (SSc). Secondary objectives included assessment of potential efficacy and biological activity and exploration of candidate biomarkers.MethodsThis was a double-blind parallel group randomised placebo-controlled clinical trial. After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were randomised to receive either active (n=10) or placebo formulation (n=10) by subcutaneous twice weekly injection over 26 weeks. Clinical assessments were evaluated over 26 weeks.ResultsThere were no safety concerns during this study. Frequency of adverse events was not different between active and placebo groups. Mean modified Rodnan Skin Score (mRSS) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinically meaningful improvement in mRSS at 26 weeks in 5 (50%) of actively treated patients compared with 1 (10%) in the control group (p=0.062). PIIINP (µg/L) showed a comparatively larger increase in the treatment group compared with the placebo group, (p=0.0118).ConclusionsThese results confirm tolerability and safety of this novel biological agent in established diffuse SSc. The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed. Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation.