Longitudinal analysis of the effect of water hardness on atopic eczema: evidence for gene-environment interaction.

BACKGROUND: Several studies have identified an association between water hardness and atopic eczema (AE); however, there is a paucity of longitudinal data in early life. OBJECTIVES: To examine whether water hardness is associated with an increased risk of AE and skin barrier dysfunction in infants and to assess effect modification by filaggrin (FLG) loss-of-function variants. METHODS: We performed a longitudinal analysis of data from infants in the Enquiring About Tolerance (EAT) study, who were enrolled at 3 months and followed up until 36 months of age. RESULTS: Of 1303 infants enrolled in the EAT study, 91·3% (n = 1189) attended the final clinic visit and 94·0% (n = 1225) of participants' families completed the 36-month questionnaire. In total, 761 (58·4%) developed AE by 36 months. There was no overall association between exposure to harder (> 257 mg L-1 CaCO3 ) vs. softer (≤ 257 mg L-1 CaCO3 ) water: adjusted hazard ratio (HR) 1·07, 95% confidence interval (CI) 0·92-1·24. However, there was an increased incidence of AE in infants with FLG mutations exposed to hard water (adjusted HR 2·72, 95% CI 2·03-3·66), and statistically significant interactions between hard water plus FLG and both risk of AE (HR 1·80, 95% CI 1·17-2·78) and transepidermal water loss (0·0081 g m-2 h-1 per mg L-1 CaCO3 , 95% CI 0·00028-0·016). CONCLUSIONS: There is evidence of an interaction between water hardness and FLG mutations in the development of infantile AE.

Overview of systematic reviews in allergy epidemiology.

BACKGROUND: There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta-analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research. METHODS: We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. RESULTS: The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. CONCLUSION: We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders.

Fruit, vegetable and vitamin C intakes and plasma vitamin C: cross-sectional associations with insulin resistance and glycaemia in 9-10 year-old children.

AIM: To examine whether low circulating vitamin C concentrations and low fruit and vegetable intakes were associated with insulin resistance and other Type 2 diabetes risk markers in childhood. METHODS: We conducted a cross-sectional, school-based study in 2025 UK children aged 9-10 years, predominantly of white European, South-Asian and black African origin. A 24-h dietary recall was used to assess fruit, vegetable and vitamin C intakes. Height, weight and fat mass were measured and a fasting blood sample collected to measure plasma vitamin C concentrations and Type 2 diabetes risk markers. RESULTS: In analyses adjusting for confounding variables (including socio-economic status), a one interquartile range higher plasma vitamin C concentration (30.9 µmol/l) was associated with a 9.6% (95% CI 6.5, 12.6%) lower homeostatic model assessment of insulin resistance value, 0.8% (95% CI 0.4, 1.2%) lower fasting glucose, 4.5% (95% CI 3.2, 5.9%) lower urate and 2.2% (95% CI 0.9, 3.4%) higher HDL cholesterol. HbA1c concentration was 0.6% (95% CI 0.2, 1.0%) higher. Dietary fruit, vegetable and total vitamin C intakes were not associated with any Type 2 diabetes risk markers. Lower plasma vitamin C concentrations in South-Asian and black African-Caribbean children could partly explain their higher insulin resistance. CONCLUSIONS: Lower plasma vitamin C concentrations are associated with insulin resistance and could partly explain ethnic differences in insulin resistance. Experimental studies are needed to establish whether increasing plasma vitamin C can help prevent Type 2 diabetes at an early stage.

Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial: a critical appraisal.

AIM: Anagnostou et al. investigated the efficacy of oral immunotherapy (OIT) in treating peanut allergy. SETTING AND DESIGN: An unmasked randomized controlled crossover trial of 7-16 year olds with double-blind placebo-controlled food challenge (DBPCFC)-proven peanut allergy. The first phase compared an active group undergoing 26 weeks of OIT with daily ingestion of peanut protein vs. a control group avoiding peanuts. Both groups underwent DBPCFC to peanut at 26 weeks. In the second phase the control group was then offered OIT for 26 weeks. STUDY EXPOSURE: Participants undergoing OIT attended hospital every 2 weeks to initiate and increase their daily peanut protein dose through nine stages (2, 5, 12·5, 25, 50, 100, 200, 400 and 800 mg - about five peanuts), subsequently maintaining consumption at the highest tolerated dose. Primary outcome The primary outcome compared the proportions of active- and control-group participants able to ingest a cumulative dose of 1400 mg of peanut protein (about 10 peanuts) during their DBPCFC at the end of the first phase without reacting. Secondary outcomes Further outcomes included the proportion of participants who tolerated the top maintenance dosage of 800 mg protein up to 26 weeks; the proportion of the control group who were desensitized or tolerated daily ingestion of 800 mg protein in the second phase; threshold changes in no observed adverse effect level after OIT (NOAEL: defined as the highest dose of peanut protein tolerated in milligrams of protein during challenge or immunotherapy); change in quality of life; number and type of adverse events; and immunological parameters (basophil reactivity, peanut-specific IgE, total IgE and skin-prick test). RESULTS: Primary outcome Twenty-four of 39 (62%) of the active group were able to tolerate the 1400 mg of peanut protein during their DBPCFC after 26 weeks of OIT, compared with none of the 46 control participants (P < 0·001). Secondary outcomes Twenty-five of 46 (54%) of the control group had a negative 1400-mg peanut protein challenge at the end of phase 2. Combining the two groups, 49 of 85 children (58%) were desensitized. Thirty-three of 39 (85%) active participants in phase one and 42 of 46 (91%) control participants in phase two tolerated 800 mg of OIT daily - a combined result of 75 of 85 (88%) trial participants. The median absolute change in NOAEL between baseline and 26 weeks was 1345 mg (P = 0·002), or a 25·5-fold increase (P < 0·001) for the active group. Both the active and control groups demonstrated a significant improvement (decrease) in Food Allergy Quality of Life scores after OIT in the under-13-year-old participants: -1·61 and -1·41, respectively (both P < 0·001). Mild side-effects predominated, with 54 (57%) reporting abdominal pain and 31 (33%) reporting vomiting. However, 21 (22%) also reported wheezing and one (1%) laryngeal oedema. One participant received adrenaline by self-administration on two occasions for wheezing. CONCLUSIONS: Anagnostou et al. concluded that OIT successfully induced desensitization in challenge-proven peanut-allergic children and resulted in a clinically and socially meaningful increase in tolerated peanut protein. Quality of life improved after intervention and there was a good safety profile.

The European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey.

BACKGROUND: There is a paucity of evidence for the use of systemic agents in children with atopic eczema refractory to conventional therapy, resulting in considerable variation in patient management. OBJECTIVES: The European TREatment of severe Atopic eczema in children Taskforce (TREAT) survey was established to collect data on current prescribing practice, to identify factors influencing the use of specific systemic agents, and to inform the design of a clinically relevant intervention study. METHODS: Consultant physician members of the paediatric dermatology societies and interest groups of eight European countries were invited to participate in a web-based survey. The multiple-response format questionnaire collated data on clinical practice in general, as well as detailed information on the use of systemic agents in refractory paediatric atopic eczema. RESULTS: In total, 343/765 members (44·8%) responded to the invitational emails; 89·2% were dermatologists and 71% initiate systemic immunosuppression for children with severe atopic eczema. The first-line drugs of choice were ciclosporin (43·0%), oral corticosteroids (30·7%) and azathioprine (21·7%). Ciclosporin was also the most commonly used second-line medication (33·6%), with methotrexate ranked as most popular third choice (26·2%). Around half of the respondents (53·7%) replied that they routinely test and treat reservoirs of cutaneous infection prior to starting systemic treatment. Across the eight countries, penicillins were the first-line antibiotic of choice (78·3%). CONCLUSIONS: In the absence of a clear evidence base, the European TREAT survey confirms the wide variation in prescribing practice of systemic immunosuppression in refractory paediatric atopic eczema. The results will be used to inform the design of a randomized controlled trial relevant to patient management across Europe.

Filaggrin loss-of-function mutations are associated with early-onset eczema, eczema severity and transepidermal water loss at 3 months of age.

BACKGROUND: Filaggrin loss-of-function (FLG) mutations are associated with eczema and skin barrier impairment, but it is unclear whether skin barrier impairment precedes phenotypic eczema in FLG mutation carriers. OBJECTIVES: To study the association between FLG mutations, skin barrier impairment and clinical eczema at 3 months of age. METHODS: A total of 88 infants were examined for eczema. Disease severity was determined by the SCORAD eczema severity score. Transepidermal water loss (TEWL) was measured on unaffected forearm skin. Venous blood samples were screened for the four most common FLG mutations found in the U.K. white population (R501X, 2282del4, R2447X and S3247X). Median SCORAD and TEWL measurements in children with and without eczema and FLG mutations were compared. RESULTS: Thirty-three per cent (29/88) of children had clinical eczema. Median SCORAD was 10·6 (range 3·5-31·0). TEWL (g m⁻² h⁻¹) was higher in children with eczema compared with unaffected infants (median TEWL 14·24 vs. 11·24, P < 0·001). Higher TEWL was associated with more severe disease (r = 0·59, P < 0·001, median TEWL, SCORAD < 15, 13·1 vs. 29·6, SCORAD ≥ 15, P = 0·029). Clinically dry skin was associated with higher TEWL, even in the absence of eczema (median TEWL 17·55 vs. 11·08, P = 0·008). Seventeen per cent (15/88) of children carried at least one FLG mutation. FLG mutation carriers were significantly more likely to have clinically dry skin, even in the absence of eczema [odds ratio (OR) 8·50, 95% confidence interval (CI) 1·09-66·58, P = 0·042]. FLG mutation carriers were also more likely to have eczema by 3 months of age (OR 4·26, 95% CI 1·34-13·57, P = 0·014). FLG mutations were significantly associated with higher median TEWL (all children, FLG 'yes' 21·59 vs. FLG 'no' 11·24, P < 0·001), even without clinical eczema (FLG 'yes' 15·99 vs. FLG 'no' 10·82, P = 0·01). CONCLUSIONS: By the age of 3 months, FLG mutations are associated with an eczema phenotype, dry skin and TEWL. The observation that TEWL is elevated in unaffected FLG mutation carriers suggests that skin barrier impairment precedes clinical eczema.

Do junior doctors take sick leave?

Nosocomial infections place a heavy burden on overstretched health services. An audit of junior doctors' sick leave behaviour was undertaken in 1993 and again in 2001. The object was to ascertain the level of common infectious illness and to investigate whether junior doctors were remaining at work inappropriately. The doctors were asked if any factors had influenced their decision to take sick leave or not. Between the two audits several initiatives have been introduced to improve the working conditions of junior doctors, including the New Deal to reduce hours of work. Eighty one junior doctors in a large teaching hospital participated in 1993 and 110 in 2001. The number reporting an infectious illness in the previous six months was similar (61.7% in 1993, 68.2% in 2001). There had been a significant increase in the percentage of infectious illness episodes for which the doctors took sick leave (15.1% in 1993, 36.8% in 2001, p < 0.001). The most common reason for taking less sick leave than was felt necessary was concern about colleagues having to do extra work (72% in 1993, 68% in 2001). Consultant pressure was cited by 26% (1993) and 20% (2001). Use of the staff occupational health unit was minimal, with none of the ill doctors contacting the department in 1993 and only three in 2001. Overall, despite the reduction in the number of infectious doctors not taking sick leave, the majority remained at work. Fundamental changes are needed if potentially infected doctors are not to present a risk of iatrogenic infection.

A comparison of the attitudes shown by general practitioners, hospital doctors and medical students towards alternative medicine.

The aim of this study was to compare and contrast the views of general practitioners (GPs), hospital doctors and medical students to alternative medicine. A questionnaire was sent to a random sample of 100 GPs and 100 hospital doctors in the South West Thames Regional Health Authority (SWTRHA). A convenience sample of 237 pre-clinical medical students at St George's Hospital Medical School was also given a questionnaire. Eighty-seven GPs and 81 hospital doctors replied. Five therapies were investigated: acupuncture; chiropractice; homeopathy; naturopathy; and osteopathy. All respondents were asked about their attitude towards and knowledge of these therapies. Doctors were asked how often they referred patients for such treatment and whether they practised it themselves. GPs and hospital doctors had similar levels of knowledge of the therapies. Medical students were the least informed but the most enthusiastic respondents. Seventy per cent of hospital doctors and 93% of GPs had, on at least one occasion, suggested a referral for alternative treatment. GPs were making these referrals more frequently and earlier. Twelve per cent of hospital doctors and 20% of GPs were practising alternative medicine. The majority of the respondents felt that alternative medicine should be available on the National Health Service (NHS) and that medical students should receive some tuition about alternative therapies. A considerable proportion of those doctors referring patients to alternative practitioners were ignorant of their official qualifications.

The effect of anxiety and depression during pregnancy on obstetric complications.

OBJECTIVE: To investigate the effects of anxiety and depression during pregnancy on obstetric complications using the data collected from the St George's Birthweight Study. DESIGN: Prospective population study. SETTING: District general hospital in inner London. SUBJECTS: A consecutive series of 1860 white women booking for delivery were approached. Of these, 136 refused and 209 failed to complete the study for other reasons, leaving a sample of 1515. MAIN OUTCOME MEASURE: Data were obtained by research interviewers at booking, 17, 28, and 36 weeks gestation and from the structured antenatal and obstetric record. The predictor variables were the anxiety and depression scores measured using the General Health Questionnaire. The outcome variables were five obstetric complications: preterm delivery; nonspontaneous onset of labour; major analgesia in the first and second stages of labour; and nonspontaneous vaginal deliveries. The possible confounding effects of 35 socio-economic, psychological and personal variables were investigated using logistic regression. RESULTS: The factors that had the strongest relation with the outcomes were parity and maternal age. Depression during pregnancy was unrelated to the obstetric complications. Anxiety was weakly related to analgesia/anaesthesia in the second stage of labour (P = 0.04). However, anxiety accounted for only 0.1% of the variance in use of major analgesia/anaesthesia. The most effective model, that for analgesia/anaesthesia in the first stage of labour, accounted for only 7.3% of the variance. CONCLUSIONS: In the general population of pregnant women, anxiety and depression during pregnancy, while undesirable in themselves, are of little importance in the evolution of obstetric complications.

A comparative study on the effects of diethyl ether and thiopentone sodium on plasma catecholamine levels in the rat.

1. The primary aim of this investigation was to ascertain the effects of thiopentone sodium and diethyl ether as anaesthetics on plasma catecholamine levels of Sprague-Dawley and Long-Evans rats. A secondary aim was to investigate the effect of norepinephrine on susceptibility to electrically induced arrhythmia in the Langendorff perfused isolated rat heart. 2. Thiopentone sodium anaesthesia resulted in significantly lower plasma norepinephrine and epinephrine levels when compared with diethyl ether anaesthesia. 3. Long-Evans rats exhibited significantly higher epinephrine levels regarding both anaesthetics in comparison with their Sprague-Dawley counterparts. 4. If plasma catecholamines are an indicator of the level of induced stress then diethyl ether anaesthesia resulted in more stress both of a psychological and physiological origin when compared with thiopentone sodium anaesthesia. 5. Long-Evans rats seem to be more prone to the physiologically-induced component of stress than Sprague-Dawley rats. 6. In isolated hearts, norepinephrine increased susceptibility (P less than 0.002) to electrically induced arrhythmia. This occurred at a concentration corresponding to measured upper levels of total catecholamines in diethyl ether anaesthetised animals.

Lack of early antitoxin response to tetanus booster.

Tetanus immune globulin (TIG) continues to be recommended in persons with tetanus-prone wounds who have incomplete or unknown tetanus immunization status. The aim of this study was to determine whether, following a booster dose of tetanus toxoid in adults who had not been immunized in the previous 10 years, there was an antitoxin response to tetanus toxoid booster within 4 days. Thirty-one adults were investigated, baseline levels for tetanus antitoxin assayed using an ELISA technique, and an injection of adsorbed tetanus toxoid (0.5 ml) given. Blood samples for tetanus antitoxin levels were taken at daily intervals for the 4 days following immunization. Tetanus boosters following the primary course but before the present study did not significantly increase the levels of pre-study tetanus antitoxin and following the study booster there was no difference between the preboost levels and the levels on days 1 to 4. This finding indicates that the present recommendations for the use of TIG in tetanus-prone wounds are appropriate.