Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.

Measles virus causes immunogenic cell death in human melanoma.

Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.

Plastic physicians: The surgical salamanders of the COVID-19 pandemic.

At the time of writing, coronavirus disease-2019 (COVID-19) has affected 6.42 million people globally and over 380,000 deaths, with the United Kingdom now having the highest death rate in Europe. The plastic surgery department at Leeds Teaching Hospitals put necessary steps in place to maintain an excellent urgent elective and acute service whilst also managing COVID-positive medical patients in the ward. We describe the structures and pathways implemented together with complex decision-making, which has allowed us to respond early and effectively. We hope these lessons will prove a useful tool as we look to open conversations around the recovery of normal activity.

Melanoma sentinel node biopsy and prediction models for relapse and overall survival.

BACKGROUND: To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas. METHODS: A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illumina's DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced. RESULTS: Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 × 10⁻7), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%). CONCLUSION: Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients.

Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement.

Sentinel node biopsy (SNB) has been at the forefront of the surgical staging of melanoma patients for the past 15 years. The high accuracy of this prognostic staging procedure is now recognised in all international guidelines for melanoma. However during this period there have been a number of important changes in the management of melanoma, many occurring within the past five years. The outcomes of five recent randomised Phase 3 trials have established the role of adjuvant targeted therapy and immunotherapy in resected Stage 3 and Stage 4 disease and have potentially changed the role of SNB. Two landmark international prospective studies have examined the benefit of performing a completion lymph node dissection (CLND) following the detection of microscopicallyinvolved sentinel nodes. Finally, the marked increase in the incidence of melanoma and the role of SNB in potentially guiding therapy has resulted in a significant increase in the pathological workload of the dermatopathology services. To address these issues a multi-disciplinary consensus meeting involving many melanoma experts from the UK was convened in May 2018. Three main areas were considered: oncology, surgery and pathology. This report is a summary of the conclusions reached, which were agreed by the clinicians attending the meeting and then externally peer reviewed. The recommendations summarised in this Consensus Statement.

Evaluation of a new course to teach the principles and clinical applications of epidemiology to medical students.

A new short course to teach clinical medical students the principles of epidemiology and their applications to clinical practice was introduced at St. Thomas's Hospital Medical School. During the first year one half of the students took the new course. All the students also received the previous epidemiological teaching which was performed on the wards in the context of individual patients with a particular disease. In the next year all students were given only the new course. One year after attending these courses, students completed a questionnaire designed to test how well the course objectives had been met. A comparison was made between those who had received the new course and those who had received only ward round teaching. Students exposed to both the ward rounds and the course were more satisfied with the latter and had a greater appreciation of the importance of epidemiology to clinical practice than students receiving only ward rounds. This improvement was maintained in the subsequent year when the ward rounds were dropped. Students who had the new course also performed relatively better than the others in the Community Medicine multiple choice questions in the Medicine Finals examination, and the marks improved in the subsequent year. This evaluation was also useful in identifying those aspects of the course that need further development.

Helicobacter pylori infection and fasting plasma glucose concentration.

BACKGROUND: Helicobacter pylori infection raises basal and meal stimulated serum gastrin concentrations and lowers iron stores, which may in turn reduce fasting plasma glucose concentrations in the population. AIM: To determine whether H pylori infection leads to lower fasting plasma glucose concentrations in the population. METHODS: One hundred and seventy three women and 165 men, randomly selected from the electoral rolls of an Australian city, participated in a cardiovascular risk factor survey. Plasma glucose concentrations and H pylori IgG antibody titres were measured. Non-fasting subjects and pregnant women were excluded, as were known diabetics, whose plasma glucose concentrations would be affected by diet and/or medications. Fasting plasma glucose concentrations were logarithmically transformed and the relation with H pylori infection, adjusting for age and other confounding factors, was determined for men and women separately by analyses of variance. RESULTS: Helicobacter pylori infection was significantly associated with fasting plasma glucose concentration among women. Infected women had a lower mean fasting plasma glucose concentration (5.2 mmol/litre; range, 3.9-8.2) than did non-infected women (5.4 mmol/litre; range, 3.9-11.1). CONCLUSIONS: Helicobacter pylori infection may lead to lower fasting plasma glucose concentrations among women and should be considered when interpreting concentrations bordering on diabetes.

Post-test probability that men in the community with raised plasma ferritin concentrations are hazardous drinkers.

BACKGROUND: Raised plasma ferritin concentrations occur unexpectedly during iron studies done by primary care physicians. Plasma ferritin concentration has been positively associated with alcohol use among men. AIM: To determine the post-test probability that men in the community with raised plasma ferritin concentrations are hazardous drinkers. METHODS: The subjects were 152 men, randomly selected from a city's electoral roll. Nineteen (12.5 (2.7)%, mean (SEM)) admitted to drinking hazardously. The pretest probability of a man being a hazardous drinker was 0.125. This was converted to pretest odds of 0.14. The likelihood ratio (the ratio of the probability of obtaining a raised plasma ferritin concentration in a hazardous drinker (sensitivity) to the probability of obtaining a raised plasma ferritin concentration in a non-hazardous drinker (1-specificity)) was calculated for different plasma ferritin cut off points. RESULTS: A plasma ferritin level of > 652 micrograms/l gave the largest likelihood ratio, 4.16. Post-test odds were obtained by multiplying the pretest odds (0.14) by the likelihood ratio (4.16). A plasma ferritin level of > 652 micrograms/l had a post-test odds for a man being a hazardous drinker of 0.58. This was converted to a post-test probability of 0.37. CONCLUSIONS: Inquiries could usefully be made into the alcohol consumption of men with a plasma ferritin concentration > 652 micrograms/l, as approximately one in three would admit to drinking hazardously.

Helicobacter pylori antibody titres in serum, plasma and successively thawed specimens: implications for epidemiological and clinical studies.

Agreement between Helicobacter pylori IgG antibodies measured using the Pylori-set EIA-G kit in serum, plasma and successively thawed specimens was studied and the implications for epidemiological and clinical studies assessed. Plasma titres may differ from serum titres by -6% to +8% and therefore may be substituted for serum. The change in titre around the cut off value was -0.31 (se = 5.7, p = 0.96) per thaw. The estimated maximum drop after three thawings, 34.5, would result in only a small decrease in sensitivity (1.3%). For qualitative epidemiological studies, this additional misclassification rate is relatively small. However, positive titres did reduce over successive thawings, with the estimated maximum drop being 11.4% per thaw. Therefore, thawing does need to be considered as a contributing factor when interpreting titre drops in eradication trials. Baseline and follow up specimens from clinical studies should be thawed once only and tested concurrently.

Value of plasma calcium, phosphate, and alkaline phosphatase measurements in the diagnosis of histological osteomalacia.

Plasma calcium and phosphate concentrations and alkaline phosphatase activities were examined retrospectively in 50 patients with histologically proven osteomalacia and 50 age- and sex-matched control subjects with normal bone histology. An abnormal plasma alkaline phosphatase activity was more useful than an abnormal plasma calcium or phosphate concentration in distinguishing between normal and osteomalacic subjects, producing a false-negative rate of 14% and a false-positive rate of 8%. False-negative and false-positive rates of 10% and 8% respectively were obtained when the presence of an abnormality in any one of the three biochemical measurements was used as a predictor of histological osteomalacia. When discriminant analysis was applied to plasma calcium, phosphate and alkaline phosphatase together a false-negative rate of 12% and a false-positive rate of 0% was obtained.Sixty-two patients in whom a diagnosis of osteomalacia was suspected were investigated prospectively, using both single biochemical abnormalities and the classification functions derived from the discriminant analysis of all three biochemical measurements to predict the presence or absence of histological osteomalacia. Plasma alkaline phosphatase activity gave false-negative and false-positive rates of 10% and 32% respectively but was a more reliable predictor of abnormal bone histology than were plasma calcium or plasma phosphate concentrations or the presence of an abnormality in any one of the three measurements. Discriminant analysis using plasma calcium, phosphate and alkaline phosphatase together produced a false-negative rate of 16% and a false-positive rate of 10%. We conclude that plasma alkaline phosphatase activity is the best single routine biochemical screening test for osteomalacia, although a high false-positive rate may occur. Direct discriminant analysis of plasma calcium, phosphate and alkaline phosphatase together provides a more sensitive method of detecting histological osteomalacia which should be useful in determining the prevalence of osteomalacia within high-risk populations.

Illness, disability, and drugs among 25 to 75 year olds living at home.

A survey in a London borough showed that 15% of adults living at home were restricted in one or more areas of their lives because of illness. A sample of these adults aged 25 to 75 years was interviewed using a validated medical questionnaire, and the severity of their restrictions was also assessed using a separate instrument. Many symptoms were found which had not been reported to a doctor and many were not being treated. When the disability scores were regressed on symptoms classified as reported to a doctor, unreported, or absent, with a few exceptions it was the reported symptoms that were significantly associated with disability. Similarly, when symptoms were classified as treated (by doctor or respondent), untreated, or absent, treated symptoms were associated with disability. Some disabling symptoms were similar to the effects, mainly adverse, of commonly prescribed drugs, and these symptoms were reported more frequently by respondents taking the possible offending drug than by those not taking the drug. It appears that making general practitioners aware of unreported and untreated symptoms among their 25 to 75 year old patients will not reduce the overall level of disability in the community. However, the iatrogenic component of disability needs to be studied further.

Use of multivariate measures of disability in health surveys.

It has been claimed that the aggregation of information from several areas of life into a small set of global measures has certain advantages for describing disability. Global measures of disability were constructed from a modified version of an existing health survey instrument and the sickness impact profile (SIP) and their properties were tested. The disability items grouped satisfactorily into five global measures (physical, psychosocial, eating, communication, and work). All disability measures (global and original category scores) were poor predictors of service use by individuals but were related as expected to age and number of medical conditions. The global measures generally had lower standard errors and better repeatability. All scores exhibit J-shaped distributions for cross sectional data but the change in global measures over time was consistent with the normal distribution. Preferably, both global and category measures should be used for comparing changes over time between groups of individuals.

Phlegm production and lung function among cigarette smokers changing tar groups during the 1970s.

In 1971-3 data on smoking habits, cigarette brand smoked, morning phlegm production, and lung function were recorded for factory workers as part of the Heart Disease Prevention Project. These men were reassessed in 1984 and those who had always smoked cigarettes from the same tar group were compared with those who had dropped one tar group (mean decreases of 6.6 mg tar, 0.1 mg nicotine) and two tar groups (mean decreases of 11.9 mg tar, 0.5 mg nicotine). Over the 13 years, men who had dropped one tar group were significantly more likely (p less than 0.05) to stop producing phlegm, but the effect was less marked for those who had dropped two tar groups. The mean fall in FEV1 was similar in all three groups, but 95% confidence limits showed that although dropping one tar group could be associated with at most a saving of 84 ml over the follow up period, there could be little extra benefit from dropping two tar groups. In 1984, all three groups of smokers excreted similar amounts of nicotine metabolites in the urine, suggesting that men who had dropped two tar groups compensated for the reduced nicotine yield of their cigarettes. This could account for the lack of a dose response relationship between reduction in the tar yield of cigarettes and cessation of phlegm and fall in FEV1.

The establishment of an industry-based education program in public health.

Commonwealth reforms have led to staff of the Department of Health and Aged Care needing a greater knowledge of public health, to more effectively evaluate evidence and to quickly acquire competence in new emerging areas. The department's requirements of a training program could not be met by existing university-based public health courses. A consortium of five universities and the department worked together to develop an industry-based course that would meet the Commonwealth's needs. The course was constituted within university regulations; had an incremental and articulated structure with exit points at certificate, diploma and Masters levels; was relevant to the work of staff; offered subjects which complemented the staff's existing skills, training and career aspirations; drew upon expertise across the universities; and was flexible in its delivery. The Commonwealth's and universities' experience has been sufficiently positive to conclude that a corporate public health postgraduate program has a place alongside university-based programs.

Comparison of unsafe drinking between a rural and metropolitan area.

Factors associated with unsafe drinking in a rural area were identified and the prevalence of unsafe drinking and alcohol related mortality compared with a metropolitan area. Alcohol consumption data were collected from a random sample of adults in Greater Ballarat. Odds ratios of demographic factors associated with unsafe drinking were estimated by logistic regression. Compared with males and 20-29-year-olds, females and 30-59-year-olds had a significantly lower prevalence of 'intermediate' or higher risk drinking and binge-only drinking. Rural-metropolitan ratios for the prevalence of unsafe drinking and alcohol related mortality were also greatest in young adults. Young adults must adopt safer drinking habits if the rural excess in mortality is to be reduced.

Information about strokes lost between post-mortem and reported cause of death.

Pathologists' opinions of cause of death given at the end of post-mortem (PM) reports have often been used to validate clinicians' death certificates. Information about strokes, common coincident conditions and complications in 120 full PM reports was compared with the pathologists' opinions of cause of death given at the end of the reports. Intracranial haemorrhage and myocardial infarction were mentioned as frequently in the cause of death as in the full PM report. On the other hand, cerebral infarction, precerebral artery occlusion, severe cerebral atheroma, coronary artery occlusion, bronchopneumonia and pulmonary embolism were all under-cited in the causes of death. Whether a pathological condition mentioned in the full PM report also appeared in the cause of death varied with the decedent's age, the extent of the condition and type of stroke. Consideration should be given to using all the information in PM reports rather than just pathologists' opinions of cause of death given at the end of PM reports when studying the validity of clinicians' death certificates.

Australia's university courses: are they meeting the educational expectations of the National Environmental Health Strategy?

Australia has developed a national strategy to encourage an intersectoral approach to environmental health and the creation of an environment that promotes good health and prevents problems. This strategy has implications for the education and training of the workforce. Therefore, the authors conducted a survey of courses in environmental health and other courses highly relevant to the environment offered by Australian universities in 2000. The purpose was to determine the extent to which those courses meet the educational expectations of the National Environmental Health Strategy. Results of the survey showed that Australia's universities are not meeting all the educational expectations of the national strategy. These findings might prompt other countries that agree with the thrust of the strategy to review their own educational offerings.

Death certification by doctors in non-metropolitan Victoria.

OBJECTIVE: To examine the completeness and accuracy of death certification by general practitioners, specialists and resident medical officers (RMOs) in non-metropolitan Victoria. DESIGN: An examination of the death certificates written by a representative sample of community and hospital doctors and comparison with the clinical history. SETTING: The Ballarat statistical district. RESULTS: Eighteen percent of the death certificates at initial assessment, were unsatisfactory (the percentage for those written by RMOs were significantly higher). After review of the clinical record, 27% of certificates were found to inaccurately represent the cause of death, (again the percentage for RMOs was higher) Eighteen percent of certificates required a change of code. CONCLUSION: Monitoring the health of the public relies in part on information gained from death certificates. It is thus of concern that such a high percentage of death certificates are inaccurate to the extent that they are incorrectly coded. Consideration should be given to new educational initiatives and to the promotion of the existing toll free telephone advice service to doctors.