COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023;94:531-546.

Efficacy of direct pulp capping for management of cariously exposed pulps in permanent teeth: a systematic review and meta-analysis.

BACKGROUND: The outcome of vital pulp treatment after carious pulp exposure is multifactorial and related to the procedure, biomaterial and pre-operative pulpal diagnosis. OBJECTIVES: To conduct a systematic review and meta-analysis determining the outcome of direct pulp capping (DPC) in mature permanent teeth with a cariously exposed pulp and a clinical diagnosis of reversible pulpitis, and ascertain whether the capping material influences the outcome. METHODS: Sources: MEDLINE Ovid-SP, Cochrane Central Register of Controlled Trials (CENTRAL), International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, Embase and Web of Science until April 2020. Inclusion: Prospective, retrospective cohort studies and randomized trials investigating DPC outcome or comparing different capping materials after carious pulp exposure. Exclusion: Primary teeth, mechanical, traumatic or not specified pulp exposure, teeth with irreversible pulpitis or no pulpal diagnosis. Risk of bias assessed using Cochrane and modified Downs and Black quality assessment checklist. Meta-analysis on combined clinical/radiographic outcome was performed using a random effect model. Success was defined as absence of signs and symptoms of irreversible pulpitis, apical periodontitis or loss of pulp vitality. RESULTS: Quality assessment highlighted four non-randomized studies to be of fair and five of poor quality. Four randomized trials had a high risk of bias. The pooled success rate differed based on material and follow-up. Calcium hydroxide success rate was 74% at 6-months, 65% at 1-year, 59% at 2-3 years and 56% at 4-5 years. Mineral trioxide aggregate (MTA) success was 91%, 86%, 84% and 81% at the same time points. Biodentine success was 96% at 6-months, 86% at 1 year and 86% at 2-3 years. The meta-analysis revealed MTA had better success than calcium hydroxide at 1-year (OR 2.66, 95% CI; 1.46- 4.84, P = 0.001) and 2- to 3-year follow-up (OR 2.21, 95% CI; 1.42-3.44, P = 0.0004). There was no difference between MTA and Biodentine. DISCUSSION: These results were based on poor methodological quality studies. The effect size for of MTA vs Ca(OH)2, although modest, was consistent with narrow CI. CONCLUSIONS: Low-quality evidence suggests a high success rate for direct pulp capping in teeth with cariously exposed pulps with better long-term outcomes for MTA and Biodentine compared with calcium hydroxide.

Introduction of paediatric laparoscopic cholecystectomy in Scotland: a national review of incidence, outcomes and training implications.

BACKGROUND: We present a national data series to determine the incidence, outcomes and training opportunities for laparoscopic cholecystectomy among children <16yrs in Scotland as performed by paediatric surgeons. METHODS: A retrospective cohort study was performed reviewing laparoscopic cholecystectomy performed at the three children's hospitals in Scotland. Using the National Records Scotland Database mid-year population estimates; age and sex specific annual incidence rates of laparoscopic cholecystectomy were calculated between 1998-2015. Trends in the observed case mix were tested using univariate linear regression and students t-test. RESULTS: Between 1998-2015; 141 paediatric laparoscopic cholecystectomies were performed. The annual rate of cholecystectomy increased from 0.10/100,000 to 0.88/100,000 (p = 0.069). Sex specific incidences were identified; 0.00-0.90/100,000 (p = 0.098) in girls and 0.20-0.86/100,000 in boys (p = 0.28). Cholecystectomy was more frequent in girls (63%; p = 0.04). No major complications, defined as common bile duct injury or mortality were identified. Overall; 75% of cases were performed by consultants (n = 17 consultants, median = 5 cases, p < 0.05) and 25% by trainees. CONCLUSION: We have demonstrated that despite a low national case load (8 laparoscopic cholecystectomies per year) paediatric surgeons have been able to perform laparoscopic cholecystectomy safely without major morbidity.

Prenatal tobacco exposure and psychiatric outcomes in adolescence: is the effect mediated through birth weight?

OBJECTIVE: This study aims to examine the associations between prenatal exposure to maternal smoking, birth weight and persistent offspring psychiatric symptoms. Additionally, we aim to examine whether the relationship between prenatal maternal smoking and persistent offspring psychiatric symptoms is mediated by offspring birth weight. METHODS: This study used the Growing Up in Ireland (GUI) longitudinal cohort. The GUI is a nationally representative longitudinal study of children which consisted of three data collection waves, at ages 9, 13, and 17 years. Logistic regression analysis was used to examine associations between prenatal tobacco exposure, and offspring psychiatric symptoms. Linear regression was used to examine associations between prenatal tobacco exposure and offspring birth weight. We conducted a mediation analysis examining potential etiological pathways linking maternal smoking during pregnancy, offspring birth weight, and later offspring psychiatric symptoms. All analyses were adjusted for confounders including household income, maternal level of education, and family psychiatric history. Additionally, examination of birth weight and subsequent psychiatric symptoms also was controlled for prematurity. RESULTS: We found that the association between prenatal tobacco exposure and later psychiatric symptoms is mediated by birth weight. CONCLUSIONS: This work provides further evidence that maternal smoking during pregnancy is an important modifiable lifestyle factor that has an impact not just on the physical health of offspring but also their mental wellbeing. Supporting women with structured smoking cessation programs at the earliest stages of pregnancy should be a public health priority.

The patient and clinician experience of informed consent for surgery: a systematic review of the qualitative evidence.

BACKGROUND: Informed consent is an integral component of good medical practice. Many researchers have investigated measures to improve the quality of informed consent, but it is not clear which techniques work best and why. To address this problem, we propose developing a core outcome set (COS) to evaluate interventions designed to improve the consent process for surgery in adult patients with capacity. Part of this process involves reviewing existing research that has reported what is important to patients and doctors in the informed consent process. METHODS: This qualitative synthesis comprises four phases: identification of published papers and determining their relevance; appraisal of the quality of the papers; identification and summary of the key findings from each paper while determining the definitiveness of each finding against the primary data; comparison of key themes between papers such that findings are linked across studies. RESULTS: Searches of bibliographic databases returned 11,073 titles. Of these, 16 studies met the inclusion criteria. Studies were published between 1996 and 2016 and included a total of 367 patients and 74 health care providers. Thirteen studies collected data using in-depth interviews and constant comparison was the most common means of qualitative analysis. A total of 94 findings were extracted from the primary papers and divided into 17 categories and ultimately 6 synthesised findings related to: patient characteristics, knowledge, communication, the model patient, trust and decision making. CONCLUSIONS: This qualitative meta-aggregation is the first to examine the issue of informed consent for surgery. It has revealed several outcomes deemed important to capture by patients and clinicians when evaluating the quality of a consent process. Some of these outcomes have not been examined previously in research comparing methods for informed consent. This review is an important step in the development of a COS to evaluate interventions designed to improve the consent process for surgery. REGISTRATION: The study protocol was registered on the international prospective register for systematic reviews (PROSPERO ID: CRD42017077101).

A review of the current public health practice for contact tracing in relation to laryngeal TB in England 2012-2016.

OBJECTIVES: Contact tracing following identification of tuberculosis (TB) is well established. However, evaluation of this activity, particularly for laryngeal TB, is limited. We compare contact tracing and outcomes in response to laryngeal TB with sputum-smear-positive pulmonary TB (ss + pTB) and consider the public health response in light of our findings. STUDY DESIGN: This study is a comparative secondary analysis of retrospective data, extracted from TB surveillance systems, to determine differences in contact tracing process and outcomes between two groups. METHODS: Cases of laryngeal TB (without ss + pTB) notified in England between 2012 and 2016 were selected and matched to ss + pTB controls. Number of contacts identified and screened, along with screening outcomes were gathered from local databases. RESULTS: There were 44 laryngeal TB cases who met inclusion criteria. The median number of contacts identified per case was 3 and 4 for controls (P = 0.04). Median number of contacts screened was 3 for cases and 4 for controls. The percentage of contacts with TB was 9.7 for cases and 20.3 for controls (P < 0.01). CONCLUSION: We observed a small difference, between case and control groups, in number of contacts identified but not number screened, indicative of a broadly similar approach to contact tracing. Conversely, the difference in screening outcomes between the groups was significant. These findings highlight a potential need to further understand infectivity of laryngeal TB; and consider possible implications for public health practice.

The association between subjective maternal stress during pregnancy and offspring clinically diagnosed psychiatric disorders.

OBJECTIVE: Exposure to prenatal stress is a ubiquitous and non-specific risk factor for adverse outcomes in adulthood. In this study, we examined associations between exposure to subjective maternal stress during pregnancy and subsequent diagnosis of psychiatric disorders in offspring. METHOD: This study used the Helsinki Longitudinal Temperament Cohort, a prospective birth cohort of individuals born between 1 July 1975 and 30 June 1976 in Helsinki, Finland. The sample for this study comprised 3626 infants whose mothers had completed health and well-being assessments during pregnancy which included a measure of self-reported stress. We ran logistic regressions to assess potential associations between prenatal stress and offspring psychiatric disorder in adulthood, identified through the Finnish Hospital Discharge Register. RESULTS: Individuals whose mothers reported stress during pregnancy had significantly greater odds of developing a psychiatric disorder (OR = 1.41, 95% CI = 1.10-1.81) particularly a mood disorder (OR = 1.67, 95% CI = 1.10-2.54). These associations remained after adjusting for parental psychiatric history, and other prenatal factors. CONCLUSIONS: Individuals exposed to prenatal stress had significantly increased risk of developing psychiatric disorders later in life. This finding highlights the importance of supporting the mental health and emotional well-being of women during pregnancy.

Development of a Core Outcome Set for studies evaluating the effects of anaesthesia on perioperative morbidity and mortality following hip fracture surgery.

BACKGROUND: Perioperative studies of patients following hip fracture have large heterogeneity within their reported outcomes. This study aimed to develop a core outcome set for use in perioperative studies comparing the types of anaesthesia for hip fracture surgery. METHODS: The consensus process consisted of a systematic review of the literature, three rounds of a Delphi survey, two consensus webinars, and face-to-face patient meetings. RESULTS: The Delphi participants represented nine stakeholder groups. The numbers of participants completing Rounds 1-3 were 242, 186, and 169, respectively. Seventeen outcomes that met the predefined consensus criteria were considered at two consensus meetings. A final set of 10 core outcomes was agreed: mortality, time from injury to surgery, acute coronary syndrome, hypotension, acute kidney injury, delirium, pneumonia, orthogeriatric input, being out of bed at day 1, and pain. CONCLUSIONS: We generated a consensus-based set of core outcomes recommended for use in all perioperative trials evaluating the effects of anaesthesia for hip fracture surgery. An important next step is developing consensus-based consistency on how they should be measured. CLINICAL TRIAL REGISTRATION: http://www.comet-initiative.org/studies/details/757.

Giri-nya-la-nha (talk together) to explore acceptability of targeted smoking cessation resources with Australian Aboriginal women.

OBJECTIVES: To engage with health providers and Aboriginal women to understand what educational resources they want and need to support quit smoking attempts during pregnancy in order to develop a comprehensive evidence-based intervention. STUDY DESIGN: Resources were developed in partnership with Aboriginal people, communities and academics with the aim to be inclusive of diverse communities. We then recruited Aboriginal women of various ages for yarning circles (focus groups) held in three Australian states to explore the acceptability of the resources and seeking further guidance as to the needs of Aboriginal women to support smoking cessation during pregnancy. METHODS: Yarning circles were recorded and transcribed, and data were analysed independently by two researchers. Responses were coded using predetermined themes and further general inductive analysis for emergent themes. RESULTS: Twenty-four Aboriginal women reflected on the resources they included: one pregnant woman, 15 mothers and eight elders. Predetermined themes of attraction, comprehension, cultural acceptability, graphics and layout, persuasion and self-efficacy were explored. Women suggested the following: resources need to be visually attractive and interactive to enhance self-efficacy; additional scientific content on health consequences of smoking and combining with non-pharmacological approaches to quitting. CONCLUSION: Indigenous peoples prefer culturally targeted messages. However, developing effective Aboriginal health promotion requires more than a 'culturally appropriate' adaptation of mainstream resources. Consideration needs to be given to the diversity of Aboriginal communities when developing effective, evidence-based interventions. Aboriginal women are calling for innovative and interactive resources that enhance self-efficacy; the use of videos to explain medical and informational brochure content is well received. Requests for non-pharmacological cessation options were reported in New South Wales and Queensland and should be further explored.

Childhood psychotic experiences are associated with poorer global functioning throughout adolescence and into early adulthood.

BACKGROUND: Psychotic experiences (PEs) are common in childhood and have been associated with concurrent mental disorder and poorer global functioning. Little is known about the effects of childhood PEs on future functioning. We investigated the effects of childhood PEs on global functioning from childhood into early adulthood. METHOD: Fifty-six participants from a community sample completed all three waves of the Adolescent Brain Development study (T1x¯ Age: 11.69, T2x¯ Age: 15.80 T3x¯Age: 18.80). At each phase, participants completed a clinical interview assessing for PEs, mental disorder and global function. Repeated measures models, adjusted for mental disorder and gender, were used to compare current (C-GAF) and most severe past (MSP-GAF) functioning in participants who had reported PEs in childhood and controls. RESULTS: Participants with a history of PEs had significantly poorer C-GAF (P < 0.001) and MSP-GAF scores (P < 0.001). Poorer functioning was evident in childhood (C-GAF: P = 0.001; MSP-GAF: P < 0.001), adolescence (C-GAF: P < 0.001; MSP-GAF: P = 0.004) and early adulthood (C-GAF: P = 0.001; MSP-GAF: P = 0.076). DISCUSSION: Children who report PEs have persistently poorer functioning through to early adulthood. The longitudinal association between childhood PEs and global functioning highlights the underlying global vulnerability in children reporting PEs, beyond what can be explained by mental disorder.

Perioperative outcomes in the context of mode of anaesthesia for patients undergoing hip fracture surgery: systematic review and meta-analysis.

BACKGROUND: Previous meta-analyses on the anaesthetic management of patients undergoing surgery for hip fracture have focused on randomized trials. Furthermore, heterogeneity in outcome reporting across the studies has made it difficult to inform best practice guidelines for patient care. METHODS: This systematic review examined how perioperative outcomes were reported and defined in the context of comparing modes of anaesthesia for hip fracture surgery. Outcomes were included from randomised and non-randomised studies published between January 2000 and July 2017. Meta-analyses were performed for regional versus general anaesthesia, with sensitivity analyses performed for spinal versus general anaesthesia. RESULTS: By including data from 15 large observational studies in this meta-analysis, we have increased the number of patients for whom outcomes were assessed from approximately 3000 to 202 000. There was no significant difference in 30-day mortality (OR 1.02; 95% CI 0.96, 1.07, I2 31%; n=200 616), prevalence of pneumonia (OR 1.07; 95% CI 0.94, 1.23, I2 34%; n=65 011), acute myocardial infarction (OR 0.96; 95% CI 0.88, 1.04, I2 0%, n=64 904), delirium (OR 1.07; 95% CI 0.72, 1.58, I2 93%, n=19 923), or renal failure (OR 0.94; 95% CI 0.54, 1.64, I2 0%, n=27 873) for regional compared with general anaesthesia [corrected]. There was a small statistically significant difference for length of stay (standardized mean difference -0.03; 95% CI -0.05, -0.02; I2 0%; n=78 711) favouring regional anaesthesia, which is unlikely to be clinically significant. Sensitivity analyses for the same outcomes examining spinal only vs general anaesthesia showed minor statistical significance for length of stay favouring spinal. We also present data highlighting the scale of the inconsistencies in reported outcomes across 32 studies, making evaluation in a standardized manner very difficult. As an example, mortality was reported in nine different ways throughout the studies. CONCLUSIONS: We highlight the need for agreement on outcome definitions and for a minimum core outcome set to be measured and reported in hip fracture studies. This would strengthen the evidence-based approach to delivering optimal care.

Vitamin D insufficiency in the first 6 months of infancy and challenge-proven IgE-mediated food allergy at 1 year of age: a case-cohort study.

BACKGROUND: Ecological evidence suggests vitamin D insufficiency (VDI) due to lower ambient ultraviolet radiation (UVR) exposure may be a risk factor for IgE-mediated food allergy. However, there are no studies relating directly measured VDI during early infancy to subsequent challenge-proven food allergy. OBJECTIVE: To prospectively investigate the association between VDI during infancy and challenge-proven food allergy at 1 year. METHODS: In a birth cohort (n = 1074), we used a case-cohort design to compare 25-hydroxyvitamin D3 (25(OH)D3 ) levels among infants with food allergy vs a random subcohort (n = 274). The primary exposures were VDI (25(OH)D3 <50 nM) at birth and 6 months of age. Ambient UVR and time in the sun were combined to estimate UVR exposure dose. IgE-mediated food allergy status at 1 year was determined by formal challenge. Binomial regression was used to examine associations between VDI, UVR exposure dose and food allergy and investigate potential confounding. RESULTS: Within the random subcohort, VDI was present in 45% (105/233) of newborns and 24% (55/227) of infants at 6 months. Food allergy prevalence at 1 year was 7.7% (61/786), and 6.5% (53/808) were egg-allergic. There was no evidence of an association between VDI at either birth (aRR 1.25, 95% CI 0.70-2.22) or 6 months (aRR 0.93, 95% CI 0.41-2.14) and food allergy at 1 year. CONCLUSIONS: There was no evidence that VDI during the first 6 months of infancy is a risk factor for food allergy at 1 year of age. These findings primarily relate to egg allergy, and larger studies are required.

Structure-function relationship of phenolic antioxidants in topical skin health products.

OBJECTIVES: The present work analysed the antioxidative activity of phenol-based antioxidants using an electron spin resonance method to predict the activity and stability of these antioxidants in cosmetic products. METHODS: The antioxidative power (AP) method was chosen to measure both the capacity and kinetics of an antioxidative reaction by detecting the DPPH (diphenylpicrylhydrazyl) radical. The antioxidative capacity (wc ) relates to the amount of free radicals that can be reduced, whereas the antioxidative reactivity (tr ) relates to the reaction speed and offers a fingerprinting of the redox state of the antioxidant molecules. Fifteen phenolic molecules have been analysed. They differed in the position of the hydroxyl groups and substituents on the aromatic ring. The AP of two distinct formulations containing hydroxytyrosol is presented as well as three phenol-based antioxidants within the same formulation vehicle. RESULTS: The rate at which phenol (ArOH) reacts with DPPH radicals, defined by the term reactivity (tr ) in this paper, was dependent upon the bond dissociation enthalpy (BDE) of the OH bond. Molecules having weak OH bonds and consequently low BDE values showed high antioxidant reactivity. On the other hand, the capacity factor (wc ), which is the concentration of phenol required to reduce a fixed concentration of DPPH radical, depends on the number and position of hydroxyl groups. The results showed that ortho and para positions of the two hydroxyl groups are important for higher capacity. If one of the two hydroxyl groups is blocked by methylation, both the antioxidative capacity and reactivity are reduced, mainly for ortho disubstituted compounds. The presence of a vinylic side chain improved reactivity and capacity tremendously. AP values may be useful in formulation design when identifying antioxidants that are likely to be physically and chemically stable. The importance of optimization of the formulation vehicle itself for a given antioxidant is also illustrated. CONCLUSION: Based on the presented findings, it is possible to predict the antioxidative performance of a phenol-based molecule and its stability and oxidation resistance within a cosmetic formulation. This is essential for antioxidant containing dermal formulations designed to combat skin ageing.

The rational design of biomimetic skin barrier lipid formulations using biophysical methods.

OBJECTIVE: The focus of this communication was to study phospholipid-structured emulsions whose phase behaviour is modified with monoalkyl fatty amphiphiles. Ideally, these systems would mimic key physical and structural attributes observed in human stratum corneum (SC) so that they better alleviate xerotic skin conditions. METHODS: Phosphatidylcholine-structured emulsions were prepared, and their phase behaviour modified with monoalkyl fatty amphiphiles. The effect of molecular volume, acyl chain length and head-group interactions was studied using a combination of physical methods. Water vapour transmission rate (WVTR) was used as a primary test to assess occlusive character. Changes in the vibrational modes observed in Fourier transform infrared (FTIR) spectroscopy and bilayer spacing measured by X-ray diffraction (XRD) were then applied to elucidate the lateral and lamellar microstructural characteristics in the systems. RESULTS: Water vapour transmission rate demonstrated that as the phosphatidylcholine acyl chain length increased from C14, to C18, to C22, there was a corresponding increase in occlusive character. The addition of monoalkyl fatty amphiphiles such as behenic acid, behenyl alcohol or cetostearyl alcohol to a base formulation incorporating dipalmitoyl and distearoylphosphatidylcholine (C18) was seen to further increase barrier characteristics of the emulsions. FTIR methods used to probe lipid-chain conformational ordering demonstrated that as phosphatidylcholine acyl chain lengths increased, there was a corresponding improvement in acyl chain ordering, with an increase in thermal transition temperatures. The addition of a monoalkyl fatty amphiphile resulted in conformational order and thermal transition temperature improvements trending towards those observed in stratum corneum. FTIR also demonstrated that systems containing behenic acid or behenyl alcohol exhibited features associated with orthorhombic character. X-ray diffraction data showed that addition of monoalkyl fatty amphiphile also resulted in thicker lamellar structures than when those agents are not present. CONCLUSION: The generalized approach described herein is shown to mechanistically describe the occlusive character of phospholipid-structured formulations in the presence of long-chain fatty acids or alcohols and that they exhibit characteristics mimicking those found in human SC lipids.

Fractionated aliphatic alcohols as synthetic precursors of ultra long-chain monoacylglycerols for cosmetic applications.

BACKGROUND: Xerosis is an abnormally dry and flaky skin condition that is associated with a change in the packing behaviour of the lipid matrix in the stratum corneum (SC), the outermost layer of the skin. This skin condition can lead to an increase in transepidermal water loss (TEWL). As ultralong-chain fatty acids have a positive effect on maintaining the packing behaviour of the SC lipid matrix, a moisturizer which contains glycerides of ultralong-chain fatty acids could act as a semi-occlusive layer on the surface of the skin. This will lower the rate of water evaporation through the epidermis and consequently help prevent or improve skin xerosis. OBJECTIVE: To identify a novel source of ultralong-chain lipids and develop monoacylglycerols with mixed fatty acyl chain lengths that have occlusive properties superior to petrolatum. METHODS: Initially, Performacol 425, a mixture of very long-chain fatty alcohols, was fractionated using short path distillation to yield a fraction enriched with C22:0-C26:0 fatty alcohols. The fatty alcohol fraction was then oxidized using Jones reagent, and the resulting fatty acids were esterified with glycerol to yield the corresponding monoglycerides using Novozym 435. These were then evaluated using Fourier transform infrared spectroscopy, differential scanning calorimetry and water vapour transmission rate measurements. RESULTS: The monoacylglycerols enriched with C22:0-C26:0 displayed a melting point of 80°C and orthorhombic packing; packing behaviour mainly present in healthy SC. In addition, a phospholipid-structured emulsion containing 3% of the monoglycerides displayed occlusive properties superior to the vehicle containing 3% petrolatum jelly. CONCLUSIONS: Performacol 425 can be a potential source of fatty alcohols to synthesize monoacylglycerols that can improve the occlusive behaviour of phospholipid-structured emulsions.

Neighbourhood characteristics and the incidence of first-episode psychosis and duration of untreated psychosis.

BACKGROUND: The incidence of psychotic disorders varies between geographical areas and it has been hypothesized that neighbourhood-level factors may influence this variation. It is also plausible that the duration of untreated psychosis (DUP) is associated with neighbourhood characteristics. The aims of this study were to determine whether the incidence of first-episode psychosis (FEP) and the DUP are associated with the level of social deprivation, fragmentation, social capital and population density. METHOD: All individuals with a FEP from a geographical defined catchment area over a 5-year period were included. Age-standardized incidence rates were calculated for each neighbourhood factor. RESULTS: A total of 292 cases of FEP were included in the study and 45% had a diagnosis of a schizophrenia-spectrum disorder. The age standardized incidence rate of FEP in the most deprived area was 72.4 [95% confidence interval (CI) 26.4-162.7] per 100 000 person-years compared with 21.5 (95% CI 17.6-26.0) per 100 000 person-years in the most affluent areas. This represents a 3.4-fold increase in FEP incidence in the most deprived areas. The incidence of FEP was also increased in neighbourhoods that were more socially fragmented [incidence rate ratio (IRR) = 2.40, 95% CI 1.05-5.51, p = 0.04] and there was a trend for the incidence to be increased in neighbourhoods with lower social capital (IRR = 1.43, 95% CI 0.99-2.06, p = 0.05). The median DUP was 4 months and was higher in more socially fragmented neighbourhoods. CONCLUSIONS: The incidence of psychotic disorders is related to neighbourhood factors and it may be useful to consider neighbourhood factors when allocating resources for early intervention services.

A tertiary hospital audit of opioids and sedatives administered in the last 24 h of life.

BACKGROUND/AIM: To audit the doses of opioids and sedatives administered to patients in the last 24 h of life in an Australian tertiary hospital and compare results with doses published in New Zealand (NZ) benchmarking studies and to examine the effect of caring for dying patients using a modified version of the Liverpool Care Pathway (mLCP) in respect to doses of opioids and sedatives. METHODS: A retrospective chart audit of 102 patients who died in a tertiary hospital was carried out over a 3-month period in 2011. Diagnosis, demographic patient characteristics, use of the mLCP, use of subcutaneous infusions and key symptoms were identified. Chi-squared and the non-parametric Mann-Whitney tests were applied to compare the group differences for categorical and continuous variables as appropriate. Parenteral morphine-equivalent daily dose (pMEDD) was calculated. A t-test assessed the variable mean doses of medication and patient characteristics. RESULTS: Of the audited patients, 76.5% died of non-malignant disease. The overall mean dose of midazolam was significantly lower compared with that of the NZ study pMEDD (6.0 vs 20.7 mg). The overall mean dose of morphine benchmarked closely with the NZ study (56.5 mg Australian study vs 47.8 mg NZ study). A total of 83% of patients with a malignant diagnosis was supported with the mLCP compared with 51% of patients with a non-malignant diagnosis. CONCLUSION: The significance of the lower midazolam doses was postulated, including the possibility of inadequate symptom control for patients with a non-malignant diagnosis. The use of the mLCP did not lead to the provision of higher doses of medications.

How should individual participant data (IPD) from publicly funded clinical trials be shared?

BACKGROUND: Individual participant data (IPD) from completed clinical trials should be responsibly shared to support efficient clinical research, generate new knowledge and bring benefit to patients. The Medical Research Council (MRC) Hubs for Trials Methodology Research (HTMR) has developed guidance to facilitate the sharing of IPD from publicly funded clinical trials. METHODS: Development of the guidance was completed over four phases which included a focussed review of policy documents, a web-based survey of the UK Clinical Research Collaboration (CRC) Registered Clinical Trials Units (CTU) Network, participation of an expert committee and an open consultation with the UKCRC Registered CTU Network. The project was funded by the MRC HTMR (MR/L004933/1-R39). RESULTS: Good practice principles include: (i) the use of a controlled access approach, using a transparent and robust system to review requests and provide secure data access; (ii) seeking consent for sharing IPD from trial participants in all future clinical trials with adequate assurance that patient privacy and confidentiality can be maintained; and (iii) establishing an approach to resource the sharing of IPD which would include support from trial funders, sponsor organisations and users of IPD. The guidance has been endorsed by Cancer Research UK, MRC Methodology Research Programme Advisory Group, Wellcome Trust and the Executive Group of the UKCRC Registered CTU Network. The National Institute for Health Research (NIHR) has confirmed it is supportive of the application of this guidance. CONCLUSIONS: Implementation of these principles will improve transparency, increase the coherent sharing of IPD from publicly funded trials, and help publicly funded trials to adhere to trial funder and journal requirements for data sharing.

Surgical management of great saphenous vein varicose veins: A meta-analysis.

PURPOSE: The purpose of this systematic review and meta-analysis is to synthesise the available evidence of randomised controlled trials comparing endovenous laser therapy to traditional open surgery, high ligation and stripping, for the treatment of great saphenous vein varicose veins in terms of clinical effectiveness, patient satisfaction and peri-operative complications. METHODS: MEDLINE, CINAHL, EMBASE and the Cochrane library were searched to identify eligible studies. All randomised controlled trials comparing endovenous laser therapy to high ligation and stripping that used ultrasound examination as an outcome measure and had follow up of one year or more were included. The Cochrane Collaboration's tool for assessing risk of bias was also used to assess the methodological quality of the included studies. Pooled risk ratios with 95% confidence intervals were used as the measure of effect for each dichotomous outcome. FINDINGS: Nine eligible publications relating to six randomised controlled trials were identified. The total enrolment of the studies was 1289 limbs. The clinical efficacy of endovenous laser therapy is comparable to that of surgery in the relatively short follow up period described in the studies. Meta-analysis revealed a trend towards a higher risk of ultrasound recurrence after endovenous laser therapy at 12 months. Quality of life questionnaires reveal similar outcomes for endovenous laser therapy and surgery. There is low quality evidence to suggest surgery is associated with more pain, sensory complications and infection. CONCLUSION: Endovenous laser therapy is a safe alternative to traditional open surgery. There is some weak evidence to suggest that endovenous laser therapy has a higher risk of ultrasound-detected recurrence at 12 months following treatment compared to open surgery. However, it may be associated with less sensory complications, pigmentation and infection.

Construct validation of judgement-based assessments of medical trainees' competency in the workplace using a "Kanesian" approach to validation.

BACKGROUND: Evaluations of clinical assessments that use judgement-based methods have frequently shown them to have sub-optimal reliability and internal validity evidence for their interpretation and intended use. The aim of this study was to enhance that validity evidence by an evaluation of the internal validity and reliability of competency constructs from supervisors' end-of-term summative assessments for prevocational medical trainees. METHODS: The populations were medical trainees preparing for full registration as a medical practitioner (74) and supervisors who undertook ≥2 end-of-term summative assessments (n = 349) from a single institution. Confirmatory Factor Analysis was used to evaluate assessment internal construct validity. The hypothesised competency construct model to be tested, identified by exploratory factor analysis, had a theoretical basis established in workplace-psychology literature. Comparisons were made with competing models of potential competency constructs including the competency construct model of the original assessment. The optimal model for the competency constructs was identified using model fit and measurement invariance analysis. Construct homogeneity was assessed by Cronbach's α. Reliability measures were variance components of individual competency items and the identified competency constructs, and the number of assessments needed to achieve adequate reliability of R > 0.80. RESULTS: The hypothesised competency constructs of "general professional job performance", "clinical skills" and "professional abilities" provides a good model-fit to the data, and a better fit than all alternative models. Model fit indices were χ2/df = 2.8; RMSEA = 0.073 (CI 0.057-0.088); CFI = 0.93; TLI = 0.95; SRMR = 0.039; WRMR = 0.93; AIC = 3879; and BIC = 4018). The optimal model had adequate measurement invariance with nested analysis of important population subgroups supporting the presence of full metric invariance. Reliability estimates for the competency construct "general professional job performance" indicated a resource efficient and reliable assessment for such a construct (6 assessments for an R > 0.80). Item homogeneity was good (Cronbach's alpha = 0.899). Other competency constructs are resource intensive requiring ≥11 assessments for a reliable assessment score. CONCLUSION: Internal validity and reliability of clinical competence assessments using judgement-based methods are acceptable when actual competency constructs used by assessors are adequately identified. Validation for interpretation and use of supervisors' assessment in local training schemes is feasible using standard methods for gathering validity evidence.