Embracing the positive: an examination of how well resilience factors at age 14 can predict distress at age 17.

One-in-two people suffering from mental health problems develop such distress before or during adolescence. Research has shown that distress can predict itself well over time. Yet, little is known about how well resilience factors (RFs), i.e. those factors that decrease mental health problems, predict subsequent distress. Therefore, we investigated which RFs are the best indicators for subsequent distress and with what accuracy RFs predict subsequent distress. We examined three interpersonal (e.g. friendships) and seven intrapersonal RFs (e.g. self-esteem) and distress in 1130 adolescents, at age 14 and 17. We estimated the RFs and a continuous distress-index using factor analyses, and ordinal distress-classes using factor mixture models. We then examined how well age-14 RFs and age-14 distress predict age-17 distress, using stepwise linear regressions, relative importance analyses, as well as ordinal and linear prediction models. Low brooding, low negative and high positive self-esteem RFs were the most important indicators for age-17 distress. RFs and age-14 distress predicted age-17 distress similarly. The accuracy was acceptable for ordinal (low/moderate/high age-17 distress-classes: 62-64%), but low for linear models (37-41%). Crucially, the accuracy remained similar when only self-esteem and brooding RFs were used instead of all ten RFs (ordinal = 62%; linear = 37%); correctly predicting for about two-in-three adolescents whether they have low, moderate or high distress 3 years later. RFs, and particularly brooding and self-esteem, seem to predict subsequent distress similarly well as distress can predict itself. As assessing brooding and self-esteem can be strength-focussed and is time-efficient, those RFs may be promising for risk-detection and translational intervention research.

Cognitive behavioral therapy may have a rehabilitative, not normalizing, effect on functional connectivity in adolescent depression.

BACKGROUND: Whether the differences in brain structure and function, characteristic of adult major depressive disorder (MDD1), are present in adolescent MDD is still unclear, but it has been shown that cognitive behavioral therapy (CBT2) affects resting-state functional connectivity in both adult and adolescent MDD patients, with the claim that CBT has a normalizing effect on MDD-related functional disruption, but this has not been directly tested. METHODS: 128 adolescent MDD patients and 40 adolescent controls were enrolled in the study. We investigated pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity. We also investigated the longitudinal effects of CBT on resting-state functional connectivity, and the relationship between pre-treatment functional disruption and CBT-related changes to resting-state functional connectivity was assessed by the correlation of pre-treatment cross-sectional effects and longitudinal CBT-related effects across multiple brain regions. RESULTS: Patients had greater cortical thickness and white matter volume within fronto-limbic regions of the brain. Patients had greater pre-treatment resting-state functional connectivity within the default-mode, fronto-limbic, central-executive, and salience networks. CBT increased resting-state functional connectivity of the subgenual anterior cingulate and amygdala seeds with predominantly frontal regions. Regions showing the greatest pre-treatment functional disruption showed the weakest CBT-related changes. LIMITATIONS: For ethical reasons, there was no placebo group. CONCLUSIONS: Adolescent MDD is associated with structural and functional differences also seen in adult patients. CBT-related changes in resting-state functional connectivity do not appear to show a normalizing effect, but instead indicate rehabilitative effects on resting-state functional connectivity.

Unravelling the complex nature of resilience factors and their changes between early and later adolescence.

BACKGROUND: Childhood adversity (CA) is strongly associated with mental health problems. Resilience factors (RFs) reduce mental health problems following CA. Yet, knowledge on the nature of RFs is scarce. Therefore, we examined RF mean levels, RF interrelations, RF-distress pathways, and their changes between early (age 14) and later adolescence (age 17). METHODS: We studied 10 empirically supported RFs in adolescents with (CA+; n = 631) and without CA (CA-; n = 499), using network psychometrics. RESULTS: All inter-personal RFs (e.g. friendships) showed stable mean levels between age 14 and 17, and three of seven intra-personal RFs (e.g. distress tolerance) changed in a similar manner in the two groups. The CA+ group had lower RFs and higher distress at both ages. Thus, CA does not seem to inhibit RF changes, but to increase the risk of persistently lower RFs. At age 14, but not 17, the RF network of the CA+ group was less positively connected, suggesting that RFs are less likely to enhance each other than in the CA- group. Those findings underpin the notion that CA has a predominantly strong proximal effect. RF-distress pathways did not differ in strength between the CA+ and the CA- group, which suggests that RFs have a similarly protective strength in the two groups. Yet, as RFs are lower and distress is higher, RF-distress pathways may overall be less advantageous in the CA+ group. Most RF interrelations and RF-distress pathways were stable between age 14 and 17, which may help explain why exposure to CA is frequently found to have a lasting impact on mental health. CONCLUSIONS: Our findings not only shed light on the nature and changes of RFs between early and later adolescence, but also offer some accounts for why exposure to CA has stronger proximal effects and is often found to have a lasting impact on mental health.

Household air pollution in Nairobi's slums: A long-term policy evaluation using participatory system dynamics.

58% of Nairobi's population live in informal settlements in extremely poor conditions. Household air pollution is one of the leading causes of premature death and disease in these settlements. Regulatory frameworks and government budgets for household air pollution do not exist and humanitarian organisations remain largely inattentive and inactive on this issue. The purpose of this paper is to evaluate the effectiveness of potential indoor-air related policies, as identified together with various stakeholders, in lowering household air pollution in Nairobi's slums. Applying a novel approach in this context, we used participatory system dynamics within a series of stakeholder workshops in Nairobi, to map and model the complex dynamics surrounding household air pollution and draw up possible policy options. Workshop participants included community members, local and national policy-makers, representatives from parastatals, NGOs and academics. Simulation modelling demonstrates that under business-as-usual, the current trend of slowly improving indoor air quality will soon come to a halt. If we aim to continue to substantially reduce household PM2.5 levels, a drastic acceleration in the uptake of clean stoves is needed. We identified the potentially high impact of redirecting investment towards household air quality monitoring and health impact assessment studies, therefore raising the public's and the government's awareness and concern about this issue and its health consequences. Such investments, due to their self-reinforcing nature, can entail high returns on investment, but are likely to give 'worse-before-better' results due to the time lags involved. We also discuss the usefulness of the participatory process within similar multi-stakeholder contexts. With important implications for such settings this work advances our understanding of the efficacy of high-level policy options for reducing household air pollution. It makes a case for the usefulness of participatory system dynamics for such complex, multi-stakeholder, environmental issues.

A Network Model of Resilience Factors for Adolescents with and without Exposure to Childhood Adversity.

Resilience factors (RFs) help prevent mental health problems after childhood adversity (CA). RFs are known to be related, but it is currently unknown how their interrelations facilitate mental health. Here, we used network analysis to examine the interrelations between ten RFs in 14-year-old adolescents exposed ('CA'; n = 638) and not exposed to CA ('no-CA'; n = 501). We found that the degree to which RFs are assumed to enhance each other is higher in the no-CA compared to the CA group. Upon correction for general distress levels, the global RF connectivity also differed between the two groups. More specifically, in the no-CA network almost all RFs were positively interrelated and thus may enhance each other, whereas in the CA network some RFs were negatively interrelated and thus may hamper each other. Moreover, the CA group showed more direct connections between the RFs and current distress. Therefore, CA seems to influence how RFs relate to each other and to current distress, potentially leading to a dysfunctional RF system. Translational research could explore whether intervening on negative RF interrelations so that they turn positive and RFs can enhance each other, may alter 'RF-mental distress' relations, resulting in a lower risk for subsequent mental health problems.

Technical note: Evaluating nuclear magnetic resonance spectroscopy for determining body composition in Holstein dairy calves using deuterium oxide dilution methods.

Deuterium oxide (D2O) dilution methods have been used to assess body composition in live animals. Estimated body water content can be used to predict body fat and protein, and thus, the amount of energy reserves. It is an alternative method to direct chemical analysis and considered a noninvasive technique that is economical and repeatable. Deuterium oxide use is considered easy, safe, and accurate; however, the traditional methods of analyzing D2O are expensive, tedious, and time consuming. The objective of this study was to evaluate the potential for using nuclear magnetic resonance spectroscopy (NMR) to determine body composition in Holstein dairy heifers. Nuclear magnetic resonance is less expensive and requires minutes to calculate the percentage of D2O in the blood. This study used 24 newborn dairy heifer calves blocked by birth and randomly assigned to 1 of 3 treatments: (1) 446 g dry matter (DM) of a conventional milk replacer (MR) [CON; 20% crude protein (CP), 20% fat], (2) 669 g DM of a moderately high protein MR (MOD; 26% CP, 18% fat), or (3) 892 g DM of a moderately high protein MR (aggressive, AGG; 26% CP, 18% fat). All calves had free-choice access to starter and water. Both MR and starter were medicated with decoquinate. During weaning (d 43 to 49), the morning MR feeding ceased. On d 50, all MR feedings ended but starter and water intakes were continuously recorded until d 56. When calves were 50 d of age, a baseline blood sample was taken followed by injection of 300 mg of D2O/kg of body weight in sterile physiological saline (0.9%). The syringes containing the D2O in physiological saline were weighed before and after administration to record the actual dose of D2O injected gravimetrically. After injection, the D2O was allowed to equilibrate with body water for 1 h. Six blood samples were taken over 6 d (1/d) at 1630 h to estimate the dilution of the tracer. The plasma was aspirated and stored at -20°C until further D2O analysis. This new method was validated using 4 calf plasma samples that were sent to an outside laboratory for measurement using an independent validation method. We detected no differences in total body water, protein, fat, or mineral content in calves fed CON, MOD, or AGG; however, results demonstrated that the D2O dilution technique and analysis by NMR is an appropriate and easy method to estimate water, protein, ash, and fat in young heifers.

Carbapenemase-producing Enterobacteriaceae in hospital wastewater: a reservoir that may be unrelated to clinical isolates.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) are an emerging infection control problem in hospitals worldwide. Identifying carriers may help reduce potential spread and infections. AIM: To assess whether testing hospital wastewater for CPE can supplement patient-based screening for infection prevention purposes in a hospital without a recognized endemic CPE problem. METHODS: Wastewater collected from hospital pipework on 16 occasions during February to March 2014 was screened for CPE using chromID(®) CARBA agar and chromID(®) CPS agar with a 10µg ertapenem disc and combination disc testing. Minimum inhibitory concentrations were determined using British Society for Antimicrobial Chemotherapy methodology and carbapenemase genes detected by polymerase chain reaction or whole-genome sequencing. Selected isolates were typed by pulsed-field gel electrophoresis. FINDINGS: Suspected CPE were recovered from all 16 wastewater samples. Of 17 isolates sent to the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, six (four Citrobacter freundii and two Enterobacter cloacae complex) were New Delhi metallo-ß-lactamase (NDM) producers and the remaining 11 (six Klebsiella oxytoca and five Enterobacter cloacae complex) were Guiana-Extended-Spectrum-5 (GES-5) producers, the first to be described among Enterobacteriaceae in the UK. The four NDM-producing C. freundii, two NDM-producing E. cloacae complex, and four out of five GES-5-producing E. cloacae complex were each indistinguishable isolates of the same three strains, whereas the six GES-5-producing K. oxytoca overall shared 79% similarity. CONCLUSION: CPE are readily isolated from hospital wastewater using simple culture methods. There are either undetected carriers of CPE excreting into the wastewater, or these CPE represent colonization of the pipework from other sources. Surveillance of hospital wastewater for CPE does not appear helpful for infection control purposes within acute hospitals.

Prevention of SHIV transmission by topical IFN-ß treatment.

Understanding vaginal and rectal HIV transmission and protective cellular and molecular mechanisms is critical for designing new prevention strategies, including those required for an effective vaccine. The determinants of protection against HIV infection are, however, poorly understood. Increasing evidence suggest that innate immune defenses may help protect mucosal surfaces from HIV transmission in highly exposed, uninfected subjects. More recent studies suggest that systemically administered type 1 interferon protects against simian immunodeficiency virus infection of macaques. Here we hypothesized that topically applied type 1 interferons might stimulate vaginal innate responses that could protect against HIV transmission. We therefore applied a recombinant human type 1 interferon (IFN-ß) to the vagina of rhesus macaques and vaginally challenged them with pathogenic simian/human immunodeficiency virus (SHIV). Vaginal administration of IFN-ß resulted in marked local changes in immune cell phenotype, increasing immune activation and HIV co-receptor expression, yet provided significant protection from SHIV acquisition as interferon response genes were also upregulated. These data suggest that protection from vaginal HIV acquisition may be achieved by activating innate mucosal defenses.

Public health vulnerability to wintertime weather: time-series regression and episode analyses of national mortality and morbidity databases to inform the Cold Weather Plan for England.

OBJECTIVES: To inform development of Public Health England's Cold Weather Plan (CWP) by characterizing pre-existing relationships between wintertime weather and mortality and morbidity outcomes, and identification of groups most at risk. STUDY DESIGN: Time-series regression analysis and episode analysis of daily mortality, emergency hospital admissions, and accident and emergency visits for each region of England. METHODS: Seasonally-adjusted Poisson regression models estimating the percent change in daily health events per 1 °C fall in temperature or during individual episodes of extreme weather. RESULTS: Adverse cold effects were observed in all regions, with the North East, North West and London having the greatest risk of cold-related mortality. Nationally, there was a 3.44% (95% CI: 3.01, 3.87) increase in all-cause deaths and 0.78% (95% CI: 0.53, 1.04) increase in all-cause emergency admissions for every 1 °C drop in temperature below identified thresholds. The very elderly and people with COPD were most at risk from low temperatures. A&E visits for fractures were elevated during heavy snowfall periods, with adults (16-64 years) being the most sensitive age-group. Since even moderately cold days are associated with adverse health effects, by far the greatest health burdens of cold weather fell outside of the alert periods currently used in the CWP. CONCLUSIONS: Our findings indicate that levels 0 ('year round planning') and 1 ('winter preparedness and action') are crucial components of the CWP in comparison to the alerts. Those most vulnerable during winter may vary depending on the type of weather conditions being experienced. Recommendations are made for the CWP.

Estimated cost per HIV infection diagnosed through routine HIV testing offered in acute general medical admission units and general practice settings in England.

OBJECTIVES: Following national guidelines to expand HIV testing in high-prevalence areas in England, a number of pilot studies were conducted in acute general medical admission units (ACUs) and general practices (GPs) to assess the feasibility and acceptability of testing in these settings. The aim of this study was to estimate the cost per HIV infection diagnosed through routine HIV testing in these settings. METHODS: Resource use data from four 2009/2010 Department of Health pilot studies (two ACUs; two GPs) were analysed. Data from the pilots were validated and supplemented with information from other sources. We constructed possible scenarios to estimate the cost per test carried out through expanded HIV testing in ACUs and GPs, and the cost per diagnosis. RESULTS: In the pilots, cost per test ranged from £8.55 to £13.50, and offer time and patient uptake were 2 minutes and 90% in ACUs, and 5 minutes and 60% in GPs, respectively. In scenario analyses we fixed offer time, diagnostic test cost and uptake rate at 2 minutes, £6 and 80% for ACUs, and 5 minutes, £9.60 and 40% for GPs, respectively. The cost per new HIV diagnosis at a positivity of 2/1000 tests conducted was £3230 in ACUs and £7930 in GPs for tests performed by a Band 3 staff member, and £5940 in ACUs and £18 800 in GPs for tests performed by either hospital consultants or GPs. CONCLUSIONS: Expanded HIV testing may be more cost-efficient in ACUs than in GPs as a consequence of a shorter offer time, higher patient uptake, higher HIV positivity and lower diagnostic test costs. As cost per new HIV diagnosis reduces at higher HIV positivity, expanded HIV testing should be promoted in high HIV prevalence areas.

Evaluation of the cold weather plan for England: modelling of cost-effectiveness.

OBJECTIVE: To determine the conditions under which the Cold Weather Plan (CWP) for England is likely to prove cost-effective in order to inform the development of the CWP in the short term before direct data on costs and benefits can be collected. STUDY DESIGN: Mathematical modelling study undertaken in the absence of direct epidemiological evidence on the effect of the CWP in reducing cold-related mortality and morbidity, and limited data or on its costs. METHODS: The model comprised a simulated temperature time series based on historical data; epidemiologically-derived relationships between temperature, and mortality and morbidity; and information on baseline unit costs of contacts with health care and community care services. Cost-effectiveness was assessed assuming varying levels of protection against cold-related burdens, coverage of the vulnerable population and willingness-to-pay criteria. RESULTS: Simulations showed that the CWP is likely to be cost effective under some scenarios at the high end of the willingness to pay threshold used by National Institute for Health and Care Excellence (NICE) in England, but these results are sensitive to assumptions about the extent of implementation of the CWP at local level, and its assumed effectiveness when implemented. The incremental cost-effectiveness ratio varied from £29,754 to £75,875 per Quality Adjusted Life Year (QALY) gained. Conventional cost-effectiveness (<£30,000/QALY) was reached only when effective targeting of at-risk groups was assumed (i.e. need for low coverage (∼5%) of the population for targeted actions) and relatively high assumed effectiveness (>15%) in avoiding deaths and hospital admissions. CONCLUSIONS: Although the modelling relied on a large number of assumptions, this type of modelling is useful for understanding whether, and in what circumstances, untested plans are likely to be cost-effective before they are implemented and in the early period of implementation before direct data on cost-effectiveness have accrued. Steps can then be taken to optimize the relevant parameters as far as practicable during the early implementation period.

The relationship between meteorological variables and sporadic cases of Legionnaires' disease in residents of England and Wales.

We studied the timing of occurrence of 1676 sporadic, community-acquired cases of Legionnaires' disease in England and Wales between 1993 and 2008, in relation to temperature, relative humidity, rainfall, windspeed and ultraviolet light using a fixed-stratum case-crossover approach. The analysis was conducted using conditional logistic regression, with consideration of appropriate lag periods. There was evidence of an association between the risk of Legionnaires' disease and temperature with an apparently long time lag of 1-9 weeks [odds of disease at 95th vs. 75th centiles: 3·91, 95% confidence interval (CI) 2·06-7·40], and with rainfall at short time lags (of 2-10 days) (odds of disease at 75th vs. 50th centiles: 1·78, 95% CI 1·50-2·13). There was some evidence that the risk of disease in relation to high temperatures was greater at high relative humidities. A higher risk of Legionnaires' disease may be indicated by preceding periods of warmer wetter weather.

The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study).

BACKGROUND: The association between testosterone deficiency and insulin resistance in men with type 2 diabetes is well established. Current Endocrine Society and European Association of Urology guidelines recommend the measurement of testosterone levels in all men with type 2 diabetes and in men suffering from erectile dysfunction. It is recognised that a range of physical symptoms appear as the testosterone level falls but few studies have addressed the threshold at which symptoms improve with physiological replacement. We report the first double-blind placebo-controlled study conducted exclusively in a male type 2 diabetes population to assess the metabolic changes with testosterone replacement. METHODS: The type 2 diabetes registers of seven general practices were screened to establish the prevalence of low testosterone and the associations with diabetes control. Of 550 eligible patients approached, 488 men (mean age 62.6) consented to take part in screening with a morning testosterone level, assessed between 8 and 11 am. This identified 211 patients for a double-blind placebo-controlled study of long acting testosterone undecanoate (TU) 1000 mg lasting 30 weeks followed by 52 weeks of open label use. The population was divided into a SEVERE group with either total testosterone (TT) of 8 nmol/l or less or free testosterone (FT) 180 pmol/l or less or a MILD group with TT 8.1-12 nmol/l or FT 181-250 pmol/l. RESULTS: Men in the SEVERE group increased mean through TT from 7.73 nmol/l at baseline to 9.93 at 30 weeks and the MILD group from 10.47 to 11.94. The SEVERE group showed marked improvement in sexual function, but no significant improvement in metabolic parameters. The MILD group showed no improvement in sexual function, but significant improvement in weight, body mass index, waist circumference and Hospital Anxiety and Depression Scale. Improvement was seen in all parameters during 52 weeks open label treatment where trough TT levels approached 15 nmol/l. Baseline prostate-specific antigen (PSA) was lower in the SEVERE group and increased with TU for 30 weeks and then stabilised. There was no increase in PSA with treatment in the MILD group. CONCLUSIONS: Testosterone undecanoate significantly improves sexual parameters and Ageing Male Symptom Score, but not metabolic factors at 30 weeks in men with SEVERE testosterone deficiency syndrome (TDS). In men with MILD TDS, significant improvements in metabolic but not sexual parameters were seen, suggesting that there are threshold levels for response to testosterone replacement therapy and that trials of therapy need to achieve sustained therapeutic levels to be effective. PSA showed minor rises, but only for 30 weeks in the SEVERE group.

Cytochrome P450-encoding genes from the Heliconius genome as candidates for cyanogenesis.

Cytochrome P450s are important both in the metabolism of xenobiotics and the production of compounds such as cyanogenic glucosides, which insects use in their defence. In the present study, we use transcriptomic and genomic information to isolate and name P450-encoding genes from the butterfly Heliconius melpomene. We classify each of the putative genes into its appropriate superfamily and compare the distribution of P450s across sequenced insects. We also identify homologues of two P450s known to be involved in cyanogenesis in the six-spot Burnet moth, Zygaena filipendulae. Classification of Heliconius P450s should be an important step in the dissection of their role in the exploitation of their host plant, the passion vine Passiflora.

Involvement in research activities and factors influencing research capacity among dietitians.

BACKGROUND: A healthcare professional's aptitude to develop research skills and actively engage in research is necessary to optimise healthcare efficacy. The present study investigated the factors that contribute to research capacity within the Australian dietetic workforce. METHODS: Queensland-based dietitians scored their department and individual skill or success in research on a 10-point scale using an anonymous online survey that incorporated the validated Research Capacity in Context tool. Descriptive statistics were assessed against geographical setting, dietetic experience and the proportion of role (Full Time Equivalent; FTE) designated to research. Research activities were defined by the number of items currently involved in or completed in the past 6 months (n = 11). Factors associated with research activities were assessed by multivariable linear regression. RESULTS: Dietitians (n = 130) identified having a moderate skill or success in 14 research items [mean (SD) 5.1 (1.7)] and perceived that their departments provided a moderate level of research support in 19 research items [mean (SD) 6.1 (2.5)]. Geographical setting, the proportion of role designated to research (FTE) and participation in research activities were associated with individual and department ratings of research skill or success. Research involvement was predicted by the proportion of role (FTE) designated to research (ß = 0.34, t = 4.16, P < 0.001) and years of experience in dietetics (ß = 0.32, t = 2.67, P < 0.009). CONCLUSIONS: A dietitian's capacity for research is related to professional experience and the designation of research in the role description. The findings of the present study will provide a baseline of research capacity and expertise among dietitians, and also inform the strategic development of building research capacity.

Ambient temperature and activation of implantable cardioverter defibrillators.

The degree to which weather influences the occurrence of serious cardiac arrhythmias is not fully understood. To investigate, we studied the timing of activation of implanted cardiac defibrillators (ICDs) in relation to daily outdoor temperatures using a fixed stratum case-crossover approach. All patients attending ICD clinics in London between 1995 and 2003 were recruited onto the study. Temperature exposure for each ICD patient was determined by linking each patient's postcode of residence to their nearest temperature monitoring station in London and the South of England. There were 5,038 activations during the study period. Graphical inspection of ICD activation against temperature suggested increased risk at lower but not higher temperatures. For every 1 °C decrease in ambient temperature, risk of ventricular arrhythmias up to 7 days later increased by 1.2 % (95 % CI -0.6 %, 2.9 %). In threshold models, risk of ventricular arrhythmias increased by 11.2 % (0.5 %, 23.1 %) for every 1° decrease in temperature below 2 °C. Patients over the age of 65 exhibited the highest risk. This large study suggests an inverse relationship between ambient outdoor temperature and risk of ventricular arrhythmias. The highest risk was found for patients over the age of 65. This provides evidence about a mechanism for some cases of low-temperature cardiac death, and suggests a possible strategy for reducing risk among selected cardiac patients by encouraging behaviour modification to minimise cold exposure.

Genetic analysis of NR0B1 in congenital adrenal hypoplasia patients: identification of a rare regulatory variant resulting in congenital adrenal hypoplasia and hypogonadal hypogonadism without testicular carcinoma in situ.

There have been few testicular histology reports of adult patients with congenital adrenal hypoplasia/hypogonadal hypogonadism (AHC/HH), but Leydig cell hyperplasia has been observed, an indicator of the possibility of malignant transformation. We aimed to define the basis of AHC/HH in 4 pedigrees of different ethnic backgrounds. One patient was elected to have testicular biopsy which was examined for evidence of carcinoma in situ (CIS). NR0B1 mutation analysis was performed by sequence analysis. NR0B1 expression was investigated by RT-PCR. Testicular biopsy sections were stained with HE or immunostained for OCT3/4, an established marker of CIS. We identified NR0B1 variants in the 4 AHC pedigrees: pedigree 1 (United Arab Emirates), c.1130A>G predicting p.(Glu377Gly); pedigree 2 (English Caucasian), c.327C>A predicting p.(Cys109*); pedigree 3 (Oman), a 6-bp deletion of a direct repeat, c.857_862delTGGTGC predicting p.(Leu286_Val287del); pedigree 4 (English Caucasian), c.1168+1G>A, a regulatory variant within the NR0B1 splice donor site. This last male patient, aged 30 years, presented with evidence of HH but incomplete gonadotrophin deficiency, following an earlier diagnosis of Addison's disease at 3 years. Hormonal therapy induced virilisation. Testicular biopsy was performed. The c.1168+1G>A variant abrogated normal splicing of testicular mRNA. Histological examination showed poorly organised testicular architecture and absence of spermatozoa. Morphological analyses and the absence of immunohistochemical staining for OCT3/4 excluded the presence of malignant germ cell cancer and its precursor lesion, CIS. These studies add to the knowledge of the types and ethnic diversity of NR0B1 mutations and their associated phenotypes, and provide insight into the assessment and interpretation of testicular histology in AHC and HH.

Impact of a blood culture collection kit on the quality of blood culture sampling: fear and the law of unintended consequences.

Blood culture is a vital investigation and can be the first step in obtaining a definitive diagnosis in a patient with presumed sepsis, but can also have serious adverse consequences for the patient. The aim of this study was to evaluate the extent of the blood culture contamination problem at the Lancashire Teaching Hospitals (LTH) and to assess the impact of the introduction of a new blood culture collection kit on the contamination rate. Blood culture contamination rate at the LTH before the introduction of the blood culture collection kit was 9.2%. A fall in contamination rate was observed after kit introduction, to 3.8%, a proportion approaching the American Society of Microbiologists' recommended standard of ≤3%. The reduction in contamination was associated with an unintended, yet sustained, reduction in the total number of blood culture sets collected and an unwanted reduction in the number of genuine Gram-negative bacteraemias. This reduction may reflect education and training issues at the time of the introduction. In the era of 'route cause analyses', it may also reflect fears by junior colleagues of the consequences of being found responsible for a blood culture contaminant. The study recommended continuing with the blood culture kit, but ensuring regular training and education sessions, carried out in a non-blame manner.

Using dynamical barriers to control the transmission of light through slowly varying photonic crystals.

We use semiclassical Hamiltonian optics to investigate the propagation of light rays through two-dimensional photonic crystals when slow spatial modulation of the lattice parameters induces mixed stable-chaotic ray dynamics. This modulation changes both the shape and frequency range of the allowed frequency bands, thereby bending the resulting semiclassical ray trajectories and confining them within particular regions of the crystal. The curved boundaries of these regions, combined with the bending of the orbits themselves, creates a hierarchy of stable and unstable chaotic trajectories in phase space. For certain lattice parameters and electromagnetic wave frequencies, islands of stable orbits act as a dynamical barrier, which separates the chaotic trajectories into two distinct regions of the crystal, thereby preventing the rays propagating through the structure. We show that changing the frequency of the electromagnetic wave strongly affects the distribution of stable and unstable orbits in both real and phase space. This switches the dynamical barriers on and off and thus modulates the transmission of rays through the crystal. We propose microwave analogs of the photonic crystals as a route to the experimental study of the transport effects that we predict.