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Background: This study aimed to get optimal sniffing position for successful intubation rate and measuring intubation time. The classical rationale for the sniffing position is that the alignment of the mandibular axis, pharyngeal axis, and laryngeal axis is facilitated, permitting successful direct laryngoscopy. Patients and Methods: A total of 100 patients without any anticipated difficult airway were enrolled after informed consent is given. After induction of anesthesia, patients were randomly divided into two groups. In Group PB, a deflated pressure infusion bag was put under the nape of the neck and occiput. The anesthetist performed laryngoscopy with the left hand while inflating the bag with the right hand up to the best glottic view without external pressure is achieved. The height of the bag was measured. In Group PI, 10-cm fixed-height noncompressible pillow was placed behind the head up to the shoulder. The best glottic view of the entire glottis without external pressure was noticed. Grading of glottic opening grade, SPO2, intubation time, and intubation trials were also noted. Results: Failure to intubate was noted in one patient in Group PB and two in Group PI. Intubations successful in 45 (90%) patients in Group PB as compared to 38 (76%) patients in Group PI (P < 0.05). Laryngoscopic view in Group PB was superior to that with Group PI (P < 0.05), with mean pressure bag height of 4.86 cm. Conclusion: The use of pressure infusion bag for adjustable-pillow height provides more success in intubation condition by head elevated position than the fixed height of 10 cm.

Introduction: Oxyntomodulin (Oxm) hormone peptide has a number of beneficial effects on nutrition and metabolism including increased energy expenditure and reduced body weight gain. Despite its many advantages as a potential therapeutic agent, Oxm is subjected to rapid renal clearance and protease degradation limiting its clinical application. Previously, we have shown that subcutaneous administration of a fibrillar Oxm formulation can significantly prolong its bioactivity in vivo from a few hours to a few days., Methods: We used a protease resistant analogue of Oxm, Aib2-Oxm, to form nanfibrils depot and improve serum stability of released peptide. The nanofibrils and monomeric peptide in solution were characterized by spectroscopic, microscopic techniques, potency assay, QCM-D and in vivo studies., Results: We show that in comparison to Oxm, Aib2-Oxm fibrils display a slower elongation rate requiring higher ionic strength solutions, and a higher propensity to dissociate. Upon subcutaneous administration of fibrillar Aib2-Oxm in rodents, a 5-fold increase in bioactivity relative to fibrillar Oxm and a significantly longer bioactivity than free Aib2-Oxm were characterized. Importantly, a decrease in food intake was observed up to 72-hour post-administration, which was not seen for free Aib2-Oxm., Conclusion: Our findings provides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced in vivo pharmacological response., Competing Interests: Authors AG, DH, DB, JN, LL and DC were employed by AstraZeneca. The remaining 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 Ouberai, Gomes Dos Santos, Kinna, Hornigold, Baker, Naylor, Liang, Corkill and Welland.)

The human peptide hormone Oxyntomodulin (Oxm) is known to induce satiety, increase energy expenditure, and control blood glucose in humans, making it a promising candidate for treatment of obesity and/or type 2 diabetes mellitus. However, a pharmaceutical exploitation has thus far been impeded by fast in vivo clearance and the molecule's sensitivity to half-life extending structural modifications. We recently showed that Oxm self-assembles into amyloid-like nanofibrils that continuously release active, soluble Oxm in a peptide-deprived environment. S.c. injected Oxm nanofibrils extended plasma exposure from a few hours to five days in rodents, compared to s.c. applied soluble Oxm. Here we show that Oxm fibril elongation kinetics and thermodynamics display a uniquely low temperature optimum compared to previously reported amyloid-like peptide and protein assemblies. Elongation rate is optimal at room temperature, with association rates 2-3 times higher at 25 °C than at ≥37 °C or ≤20 °C. We deduce from a combination of Cryo electron microscopy and spectroscopic methods that Oxm fibrils have a double-layered, triangular cross-section composed of arch-shaped monomers. We suggest a thermodynamic model that links the necessary molecular rearrangements during fibrillation and peptide release to the unique temperature effects in Oxm self-assembly and disassembly., (Copyright © 2021. Published by Elsevier B.V.)

Mycobacterium tuberculosis (Mtb) remains a major challenge to global health, made worse by the spread of multi-drug resistance. Currently, the efficacy and safety of treatment is limited by difficulties in achieving and sustaining adequate tissue antibiotic concentrations while limiting systemic drug exposure to tolerable levels. Here we show that nanoparticles generated from a polymer-antibiotic conjugate ('nanobiotics') deliver sustained release of active drug upon hydrolysis in acidic environments, found within Mtb-infected macrophages and granulomas, and can, by encapsulation of a second antibiotic, provide a mechanism of synchronous drug delivery. Nanobiotics are avidly taken up by infected macrophages, enhance killing of intracellular Mtb, and are efficiently delivered to granulomas and extracellular mycobacterial cords in vivo in an infected zebrafish model. We demonstrate that isoniazid (INH)-derived nanobiotics, alone or with additional encapsulation of clofazimine (CFZ), enhance killing of mycobacteria in vitro and in infected zebrafish, supporting the use of nanobiotics for Mtb therapy and indicating that nanoparticles generated from polymer-small molecule conjugates might provide a more general solution to delivering co-ordinated combination chemotherapy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Cutaneous mechanical hyperalgesia can be induced in healthy volunteers in early phase analgesic studies to model central sensitization, a key mechanism of persistent pain. However, such hyperalgesia is short-lived (a matter of hours), and is used only for assessing only single drug doses. In contrast, postsurgical peri-incisional hyperalgesia may be more persistent and hence be a more useful model for the assessment of the efficacy of new analgesics. We undertook quantitative sensory testing in 18 patients at peri-incisional and nonoperated sites before open inguinal hernia repair and up to the 24th postsurgical week. The spatial extent of punctate hyperalgesia and brush allodynia at the peri-incisional site were greatest at weeks 2 and 4, but had resolved by week 24. Heat allodynia, suggestive of local inflammation or peripheral sensitization, was not observed; instead, there were deficits in cold and heat sensory detection that persisted until week 24. The findings suggest that central sensitization contributes significantly to mechanical hyperalgesia at the peri-incisional site. The prolonged duration of hyperalgesia would be advantageous as a pain model, but there was considerable variability of mechanical hyperalgesia in the cohort; the challenges of recruitment may limit its use to small, early phase analgesic studies. PERSPECTIVE: Peri-incisional mechanical hyperalgesia persists for ≥4 weeks after open inguinal hernia repair and reflects central sensitization; this may have usefulness as a model of chronic pain to assess the potential of antineuropathic analgesics., (Copyright © 2019 the American Pain Society. Published by Elsevier Inc. All rights reserved.)

The use of peptides as therapeutic agents is undergoing a renaissance with the expectation of new drugs with enhanced levels of efficacy and safety. Their clinical potential will be only fully realised once their physicochemical and pharmacokinetic properties have been precisely controlled. Here we demonstrate a reversible peptide self-assembly strategy to control and prolong the bioactivity of a native peptide hormone in vivo. We show that oxyntomodulin, a peptide with potential to treat obesity and diabetes, self-assembles into a stable nanofibril formulation which subsequently dissociates to release active peptide and produces a pharmacological effect in vivo. The subcutaneous administration of the nanofibrils in rats results in greatly prolonged exposure, with a constant oxyntomodulin bioactivity detectable in serum for at least 5 days as compared to free oxyntomodulin which is undetectable after only 4 h. Such an approach is simple, cost-efficient and generic in addressing the limitations of peptide therapeutics.

Background and Aims: Hospitalization as a result of acute exacerbation of complex chronic pain is a largely hidden problem, as patients are often admitted to hospital under a variety of specialities, and there is frequently no overarching inpatient chronic pain service dedicated to their management. Our institution had established an inpatient acute pain service overseen by pain physicians and staffed by specialist nurses that was intended to focus on the management of perioperative pain. We soon observed an increasing number of nurse-to-nurse referrals of non-surgical inpatients admitted with chronic pain. Some of these patients had seemingly intractable and highly complex pain problems, and consequently we initiated twice-weekly attending physician-led inpatient pain rounds to coordinate their management. From these referrals, we identified a cohort of 20 patients who were frequently hospitalized for long periods with exacerbations of chronic pain. We sought to establish whether the introduction of the physician-led inpatient pain ward round reduced the number and duration of hospitalizations, and costs of treatment., Methods: We undertook a retrospective, observational, intervention cohort study. We recorded acute Emergency Department (ED) attendances, hospital admissions, and duration and costs of hospitalization of the cohort of 20 patients in the year before and year after introduction of the inpatient pain service., Results: The patients' mean age was 38.2 years (±standard deviation 13.8 years, range 18-68 years); 13 were women (65.0%). The mode number of ED attendances was 4 (range 2-15) pre-intervention, and 3 (range 0-9) afterwards (p=0.116). The mode bed occupancy was 32 days (range 9-170 days) pre-intervention and 19 days (range 0-115 days) afterwards (p=0.215). The total cost of treating the cohort over the 2-year study period was £733,010 (US$1.12m), comprising £429,479 (US$656,291) of bed costs and £303,531 (US$463,828) of investigation costs. The intervention did not achieve significant improvements in the total costs, bed costs or investigation costs., Conclusions: Despite our attending physician-led intervention, the frequency, duration and very substantial costs of hospitalization of the cohort were not significantly reduced, suggesting that other strategies need to be identified to help these complex and vulnerable patients., Implications: Frequent hospitalization with acute exacerbation of chronic pain is a largely hidden problem that has very substantial implications for patients, their carers and healthcare providers. Chronic pain services tend to focus on outpatient management. Breaking the cycle of frequent and recurrent hospitalization using multidisciplinary chronic pain management techniques has the potential to improve patients' quality of life and reduce hospital costs. Nonetheless, the complexity of these patients' chronic pain problems should not be underestimated and in some cases are very challenging to treat., (Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objectives: Transmucosal fentanyl is used to treat transient exacerbations of cancer pain. Several immediate release products are available, presented as intranasal sprays, sublingual and buccal tablets, or lozenges. These are not interchangeable, creating potential for medication errors. We compared the incidence of medication errors in a simulated scenario using handwritten drug charts and charts labelled with preprinted self-adhesive stickers with full pictorial fentanyl prescriptions., Methods: 54 nurses were shown 5 handwritten drug charts and 5 with self-adhesive pictorial labels. Nurses indicated which preparation and dose they would administer from boxes of Instanyl, Abstral, Effentora and Actiq (Nycomed, ProStrakan, Cephalon and Teva, respectively). We measured the frequency of drug administration errors and asked them to rate the prescriptions for clarity on four-point Likert items., Results: The use of pictorial self-adhesive prescriptions significantly reduced errors in choice of preparation, from 20 with traditional handwritten charts to 6 with self-adhesive labels (OR 3.52, 95% CI 1.39 to 8.90, p=0.006), but the incidence of dose error was not significantly different (OR 1.47, 95% CI 0.80 to 2.70, p=0.281). Analysis of Likert items showed using pictorial printed labels significantly improved nurses' understanding of choice of preparation, dose and maximum four hourly dose (p<0.0001, p=0.006 and p=0.028, respectively)., Conclusions: The use of pictorial prescribing appears to be a promising strategy that could reduce medication errors in choice of fentanyl preparations. There may be a wider use for pictorial prescribing where non-interchangeable preparations of the same drug exist., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)