]N/OFQ-NH2 (UFP-101; 60 and 150 nmol/kg iv), H1 and H2 antagonists pyrilamine (mepyramine, 1 mg/kg iv) and ranitidine (1 mg/kg iv), and mast cell stabilizer cromolyn (1 mg⅐kg Ϫ1 ⅐min Ϫ1) also abolished vasodilation and macromolecular leak to N/OFQ in vivo (P Ͻ 0.05), but did not affect hypotension. Isolated mesenteric arteries (ϳ200 m, n ϭ 25) preconstricted with U-46619 were also mounted on a pressure myograph (60 mmHg), and both intraluminally and extraluminally administered N/OFQ (10 Ϫ5 M) caused dilation, inhibited by pyrilamine in the extraluminal but not the intraluminal (control: Ϫ6.9 Ϯ 3.8%; N/OFQ: 32.6 Ϯ 8.4%; pyrilamine: 31.5 Ϯ 6.8%, n ϭ 18, P Ͻ 0.05) experiments. We conclude that, in vivo, mesenteric microvascular dilation and macromolecular leak occur via N/OFQ-NOP-mediated release of histamine from mast cells. Therefore, N/OFQ-NOP has an important role in microvascular inflammation, and this may be targeted during disease, particularly as we have proven that UFP-101 is an effective antagonist of microvascular responses in vivo.nociceptin/orphanin FQ; UFP-101; microcirculation; arteriole; nociceptin/orphanin FQ peptide receptor; ORL-1; permeability; vasodilatation; leukocyte NOCICEPTIN/ORPHANIN FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP), and NOP ligands can act centrally and peripherally to modulate several biological functions, including blood pressure, heart rate, and inflammation (18,20,23,26,28,37). N/OFQ displays ϳ60% homology with the classical opioid peptides (excluding endomorphins) but lacks the NH 2

Purpose: To identify the impact the COVID-19 lockdown had on the presentation and management of sight-threatening ocular trauma. Methods: A retrospective cohort analysis of all patients who presented to the Ophthalmology department of Royal Hallamshire Hospital Sheffield with serious ocular trauma during the COVID-19 lockdown period was performed. Data on mechanism of injury and date of injury, presentation, and surgical repair were collected. This process was repeated for the same dates in the previous 5 years for comparison. Results: During the COVID-19 lockdown period, we saw 10 cases of serious ocular trauma (4 globe ruptures, 4 full-thickness lid lacerations, and 2 intra-ocular foreign bodies). This is 3.33 times the average number of cases over the previous 5 years. The delay between injury and presentation rose to 1.1 days compared to 0.33 days pre-COVID; however, the time taken between presentation to surgery was only slightly affected (12 hours in 2020 compared to 11.38 hours pre-COVID). Conclusion:During the COVID-19 lockdown, the number of serious ocular trauma cases was more than three times the average of the previous 5 years. This increase is partially due to more DIY injuries as people stayed at home, but also surprisingly an increase in falls. There did appear to be a longer delay between injury and presentation, suggesting that patients were reluctant to come into hospital during the pandemic. Surgery was performed within 12 hours on average for both groups, reassuringly indicating that sight-saving surgery was not delayed despite extraordinary circumstances.

Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia).Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg-1; -2 h, 1 mg kg-1 i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography.200 nM kg-1 fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10-5M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg-1 i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg-1 UFP-101 (i.v., jugular vein).Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.

During the containment phase of the 2009 influenza A(H1N1) pandemic, mass treatment and prophylaxis with oseltamivir was used to control an outbreak of pandemic influenza in a primary school in Sheffield, United Kingdom, where ten cases of pandemic influenza had been laboratory confirmed over a three day period in June 2009. A subsequent cross-sectional survey showed that 51 of 297 (17%) pupils and 10 of 58 (17%) reported an influenza-like illness. The most common symptoms were headache, cough, fever, tiredness, sore throat and nausea. Fifty-three staff and 273 pupils took oseltamivir for treatment or prophylaxis. Of this group, 41% (113/273) of pupils and 47% (25/53) of staff reported adverse effects. Overall, 14% (37/273) of pupils and 20% (11/53) of staff did not complete the course of oseltamivir, primarily due to adverse effects. Nausea, vomiting and rash were statistically significantly associated with failing to complete the course of oseltamivir. Given the potential for side effects from oseltamivir, particularly among those without influenza who receive the drug for prophylaxis, our findings have two important implications. Firstly, the benefits of mass treatment in an outbreak setting must clearly be greater than the benefits of targeted treatment. Secondly, any large scale regional or state level system for distribution of antiviral drugs for treatment should ideally include a robust quantification of an individual’s probability of infection with influenza virus in order to avoid unnecessary treatment.