A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

The role of fit testing N95/FFP2/FFP3 masks: a narrative review.

For healthcare workers performing aerosol-generating procedures during the COVID-19 pandemic, well fitted filtering facepiece respirators, for example, N95/FFP2 or N99/FFP3 masks, are recommended as part of personal protective equipment. In this review, we evaluate the role of fit checking and fit testing of respirators, in addition to airborne protection provided by respirators. Filtering facepiece respirators are made of material with sufficient high filter capacity to protect against airborne respiratory viruses. Adequate viral protection can only be provided by respirators that properly fit the wearer's facial characteristics. Initial fit pass rates vary between 40% and 90% and are especially low in female and in Asian healthcare workers. Fit testing is recommended to ensure a proper fit of respirators for the individual healthcare worker so that alternative respirators can be selected if required. Although fit testing is required to comply with respirator standards, it is not performed consistently within all healthcare settings. Fit checking (a self-test) is recommended every time a healthcare worker dons a respirator, but is unreliable in detecting proper fit or leak. Additionally, fit testing has a high educational value and as such is best performed as part of a hospital respiratory protection programme. Whether fit checking alone, as opposed to fit tested and fit checked respirators, provides adequate airborne protection against aerosols containing the SARS-CoV-2 virus and other respiratory viruses remains unknown. While fit testing undoubtedly incurs additional costs, it is still recommended, not only to protect healthcare workers but also as it may reduce overall healthcare cost when considering the potential costs of sickness leave and the associated legal costs of compensation.

Resilience strategies to manage psychological distress among healthcare workers during the COVID-19 pandemic: a narrative review.

The COVID-19 pandemic marks an extraordinary global public health crisis unseen in the last century, with its rapid spread worldwide and associated mortality burden. The longevity of the crisis and disruption to normality is unknown. With COVID-19 set to be a chronic health crisis, clinicians will be required to maintain a state of high alert for an extended period. The support received before and during an incident is likely to influence whether clinicians experience psychological growth or injury. An abundance of information is emerging on disease epidemiology, pathogenesis and infection control prevention. However, literature on interventions for supporting the psychological well-being of healthcare workers during disease outbreaks is limited. This article summarises the available management strategies to increase resilience in healthcare workers during the COVID-19 pandemic and beyond. It focuses on self-care and organisational justice. It highlights various individual as well as organisational strategies. With the success of slowing disease spread in many countries to date, and reduced work-load due to limitations on elective surgery in many institutions, there is more time and opportunity to be pro-active in implementing measures to mitigate or minimise potential adverse psychological effects and improve, restore and preserve the well-being of the workforce now and for years to come. The purpose of this review is to review available literature on strategies for minimising the psychological impact of the COVID-19 pandemic on clinicians and to identify pro-active holistic approaches which may be beneficial for healthcare workers both for the current crisis and into the future.

Propofol use in children with allergies to egg, peanut, soybean or other legumes.

Propofol is the most commonly administered intravenous agent for anaesthesia in children. However, there are concerns that the emulsified preparation may not be safe in children with an allergy to egg, peanut, soybean or other legumes. We conducted a retrospective study of children with immunologically confirmed egg, peanut, soybean or legume allergy and who underwent general anaesthesia at Princess Margaret Hospital for Children between 2005 and 2015. We extracted details regarding allergy diagnosis, each anaesthetic administered and any adverse events or signs of an allergic reaction in the peri-operative period. A convenience sample of patients without any known food allergies was identified from our prospective anaesthesia research database and acted as a control group. We identified 304 food-allergic children and 649 procedures where propofol was administered. Of these, 201 (66%) had an egg allergy, 226 (74%) had a peanut allergy, 28 (9%) had a soybean allergy and 12 (4%) had a legume allergy. These were compared with 892 allergy-free patients who were exposed to propofol. In 10 (3%) allergy patients and 124 (14%) allergy-free patients, criteria for a possible allergic reaction were met. In nine of the food-allergic children and in all the controls valid non-allergic explanations for the clinical symptoms were found. One likely mild allergic reaction was experienced by a child with a previous history of intralipid allergy. We conclude that genuine serious allergic reaction to propofol is rare and is not reliably predicted by a history of food allergy.

Multifocal fibrosclerosis: a new case report.

We describe the case of a gentleman who initially presented with isolated cranial diabetes insipidus and has subsequently developed progressive anterior pituitary failure. In addition, he has been found to have evidence of mesenteric fibrosis and primary sclerosing cholangitis. We suggest that his pituitary disease may also be caused by progressive fibrosis and that these separate pathological entities may be linked by the unifying diagnosis of progressive multifocal fibrosclerosis, a rare fibro-inflammatory process involving multiple organ systems.

Attentional functioning is impaired during acute hypoglycaemia in people with Type 1 diabetes.

AIMS: To examine the effects of acute insulin-induced hypoglycaemia on different aspects of attention and on general non-verbal reasoning in people with Type 1 diabetes. METHODS: A hyperinsulinaemic glucose clamp was used to maintain euglycaemia (4.5 mmol/l) or induce hypoglycaemia (2.6 mmol/l) on separate occasions in 16 adults with Type 1 diabetes each of whom were studied on two occasions in a counterbalanced order. During each study condition, the subjects completed parallel tests of cognitive function assessed by the Test of Everyday Attention and the Raven's Progressive Matrices. RESULTS: Hypoglycaemia caused a significant deterioration in tests sensitive to visual and auditory selective attention. During hypoglycaemia, attentional flexibility deteriorated and speed of information processing was delayed. Sustained attention and intelligence scores were preserved during hypoglycaemia. CONCLUSIONS: In people with Type 1 diabetes, hypoglycaemia causes a significant deterioration in attentional abilities, while non-verbal reasoning is preserved. It is likely therefore that many complex cognitive tasks which involve attention will be impaired during moderate hypoglycaemia during everyday life.

Increased CD40 ligand and platelet-monocyte aggregates in patients with type 1 diabetes mellitus.

BACKGROUND: Diabetes mellitus is a major risk factor for cardiovascular disease and is associated with a proinflammatory and prothrombotic state. We investigated whether CD40 ligand (L) expression and platelet-monocyte aggregation are increased in patients with type 1 diabetes. METHODS: Serum C-reactive protein (CRP) and soluble (s) CD40L concentrations, platelet surface CD40L expression and platelet-monocyte aggregates were measured in 22 patients with uncomplicated type 1 diabetes and 22 age- and sex-matched non-diabetic control subjects. RESULTS: In comparison to controls, patients with type 1 diabetes had higher serum CRP concentrations (3.29 +/- 0.9 mg/L versus 0.99 +/- 0.2mg/L, P = 0.01), serum sCD40L concentrations (10.0 +/- 1.4 ng/mL versus 4.6 +/- 0.6 ng/mL, P = 0.006), and platelet surface expression of CD40L (13.8 +/- 0.9% versus 8.5 +/- 1.1%, P < 0.001). Platelet-monocyte aggregates were also significantly elevated in type 1 diabetes (35.9 +/- 3.3% versus 26.4 +/- 2.9%, P = 0.005; n = 10). We also observed a significant correlation between plasma glucose and serum CRP (r = 0.53, P = 0.01) as well as platelet-monocyte aggregates (r = 0.69, P = 0.03). CONCLUSIONS: Type 1 diabetes is associated with increased CD40L expression and platelet-monocyte aggregation, which may contribute to the proinflammatory and prothrombotic state as well as the accelerated atherogenesis associated with this disorder.

Hashimoto's encephalopathy presenting as an acute medical emergency.

Three cases are described of a reversible encephalopathy, all presenting with marked neurological disturbance. In all three, the diagnosis was not clear at the time of presentation but eventually it was felt all of the cases were consistent with Hashimoto's encephalopathy. The diagnosis of Hashimoto's encephalopathy should be considered in any case of unexplained encephalopathy. Common features are high anti-thyroid peroxidase antibody titres, an abnormal EEG and an elevated CSF protein concentration. The encephalopathy is independent of thyroid hormonal status. Treatment with corticosteroids leads to a prompt resolution of symptoms and long-term low dose steroid therapy prevents further neurological recurrence.

Peripheral T lymphocyte depletion by apoptosis after CD4 ligation in vivo: selective loss of CD44- and 'activating' memory T cells.

We have demonstrated that a single intravenous bolus of rat anti-CD4 MoAb caused a small but prolonged increase in apoptosis in murine lymph nodes. We have quantified this process using the novel Highly Optimized Microscope Environment (HOME) interactive images analysis system and shown that the increase in apoptosis was sufficient to account for the observed depletion of the peripheral CD4+ T cell subset. This occurred in the absence of any other exogenous signal. Furthermore, there was no evidence of an inflammatory or necrotic response in the tissues, indicating that this was unlikely to be Fc or complement-mediated antibody killing. The anti-CD4-induced depletion selectively removed CD44- T cells. Using mice previously immunized with yeast-derived HIV-1 p24 recombinant protein there was sparing of memory T cell function after in vivo anti-CD4 treatment, except during a window of less than 24 h duration, when simultaneous exposure to antigen and anti-CD4 antibody resulted in the depletion of specific memory T lymphocyte function. This indicated that a very minor alteration in the frequency of apoptosis had a marked effect on cell number over time, and suggested that opportunistic infection associated with CD4+ T cell depletion may be explained by loss of memory cells when there is antigenic stimulation at the same time as CD4 ligation. These results have implications for the pathology of HIV-associated disease which is associated with ligation of CD4 molecules in vivo.

A group II intron in the Neurospora mitochondrial coI gene: nucleotide sequence and implications for splicing and molecular evolution.

The temperature-sensitive Neurospora nuclear mutant cyt18-1 is deficient in splicing many Group I mitochondrial introns when grown at its non-permissive temperature; however, splicing of intron 1 in the coI gene of the Adiopodoume (formerly called North Africa) strain is unaffected (R.A. Collins and A.M. Lambowitz, J. Mol. Biol. 184: 413-428, 1985). Here we show that coI intron 1 is a typical Group II intron, the only one identified to date in Neurospora. The differential effect of the cyt18-1 mutation suggests that splicing of certain introns could be regulated independently of others by nuclear-encoded proteins. The intron contains a long open reading frame (ORF) resembling that of the Neurospora Mauriceville mitochondrial plasmid. The intron and plasmid ORFs share unusual features of codon usage that suggest both evolved outside of the Neurospora mitochondrial genetic system.