Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1β response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1β released into the supernatant was measured with ELISA. Significantly increased IL-1β expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F (6, 277) = 15, P<0.0001), TLR4 (F (8, 263) = 3, P = 0.002) and TLR7 (F (2,201) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The contribution of (S)-warfarin to the clinical effect of rac-warfarin is well understood. The extent to which (R)-warfarin contributes to the clinical effect of rac-warfarin is unclear. WHAT THIS STUDY ADDS• Using unequivocally pure (R)-and (S)-warfarin we have demonstrated that (R)-warfarin contributes to the hypoprothrombinaemic effect of single large doses of warfarin.• The extent of the interaction is dependent on VKORC1 genotype. AIMS1) To determine the pharmacokinetics and pharmacodynamics of (R)-and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)-and (S)-warfarin is dependent on VKORC1 genotype. METHODSA three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)-and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTSPharmacokinetic parameters for (R)-and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUCPT (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUCPT (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)-and (S)-warfarin (AUCPT((R)-warfarin) : AUCPT((S)-warfarin)) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS(R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

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In response to the COVID-19 pandemic, there has been a rapid growth in research focused on developing vaccines and therapies. In this context, the need for speed is taken for granted, and the scientific process has adapted to accommodate this. On the surface, attempts to speed up the research enterprise appear to be a good thing. It is, however, important to consider what, if anything, might be lost when biomedical innovation is sped up. In this article we use the case of a study recently retracted from the Lancet to illustrate the potential risks and harms associated with speeding up science. We then argue that, with appropriate governance mechanisms in place (and adequately resourced), it should be quite possible to both speed up science and remain attentive to scientific quality and integrity. Keywords COVID-19. Pandemic. Research quality. Research governance. Research integrity. Biomedical publication The COVID-19 pandemic has changed the world in profound ways and led to significant shifts in our social, political, economic, and scientific priorities. Among these has been a major shift in both public and private research funding towards COVID-19-related projects, with the aim of mapping the pandemic and its effects and developing vaccines and therapies (London and Kimmelman 2020). In this context, the need for speed is taken for granted, and the scientific process has adapted to accommodate this. Rather than going through the usual research-dissemination-translation pathway, existing drugs are being "repurposed," usual preclinical testing regimes are being bypassed or shortened, study sizes are being reduced, and timeconsuming randomized controlled trials are being replaced or supplemented with observational studies. The results of research are already being reported mere months after the epidemic's onset-often prior to formal peer review or after so-called "rapid" review. And regulators are "fast tracking" their review of potentially promising drugs and vaccines (

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The intradermal capsaicin model of neuropathic pain has been previously developed and used in healthy volunteers.• Few previous studies have used this model in pain patients. WHAT THIS STUDY ADDS• We have compared the response to intradermal capsaicin in the painful and nonpainful legs of patients with unilateral sciatica and compared these with healthy, pain-free control subjects. Pain and hyperalgesia responses were enhanced in both legs of patients with unilateral sciatica compared with healthy controls. The time course of hyperalgesia was different in sciatica patients, demonstrating a slower and larger evolution.• Qualitative and quantitative differences between pain patients and healthy controls suggest that the use of a neuropathic pain model such as intradermal capsaicin to screen for novel antineuropathic agents might be superior in patients with pre-existing neuropathic pain syndromes. AIMThis study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin. METHODSFourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 mg and 10 mg capsaicin, into each calf. For each dose, spontaneous pain (10 cm VAS), area of flare (cm 2 ) and the sum of allodynia and hyperalgesia radii across eight axes (cm) were recorded pre-injection and at 5, 15, 30, 45 and 60 min post injection. RESULTSSciatica subjects experienced higher spontaneous pain and hyperalgesia responses in both legs compared with pain-free volunteers. The largest mean difference in spontaneous pain was 2.8 cm (95% CI 1.6, 3.9) at 5 min in the unaffected leg following 10 mg. The largest mean difference in hyperalgesia was 19.7 cm (95% CI 12.4, 27.0) at 60 min in the unaffected leg following 10 mg. Allodynia was greater in patients than in controls with the largest mean difference of 2.9 cm (95% CI 1, 4.8) at 5 min following 10 mg in the affected leg. Allodynia was also higher in the affected leg compared with the unaffected leg in sciatica patients with the highest mean difference of 3.0 cm (95% CI 1.2, 4.7) at 5 min following 10 mg. CONCLUSIONSThe responses to intradermal capsaicin are quantitatively and qualitatively different in unilateral sciatica patients compared with pain-free controls.