EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Determining an Upper Reference Value for the Urinary Fluoride-Creatinine Ratio in Healthy Children Younger than 7 Years.

The urinary fluoride/creatinine ratio (UF/Cr) in a spot urine sample could be a useful systemic F exposure monitoring tool. No reference value for UF/Cr currently exists, therefore this study aimed to establish an upper reference value for a UF/Cr, corresponding to excessive systemic F exposure, i.e., >0.07 mg F/kg body weight (b.w.)/day, in children. Subsidiary aims were to examine the relationship between (i) total daily F intake (TDFI) and 24-h urinary F excretion (DUFE); (ii) DUFE and UF/Cr, and (iii) TDFI and UF/Cr. Simultaneously collected TDFI, DUFE, and urinary creatinine (UCr) data in children <7 years were taken from UK studies conducted from 2002 to 2014 in order to calculate UF/Cr (mg/g) for each child. For the 158 children (mean age 5.8 years) included in the data analysis, mean TDFI and DUFE were 0.049 (SD 0.033) and 0.016 (SD 0.008) mg/kg b.w./day, respectively, and the mean UF/Cr was 1.21 (SD 0.61) mg/g. Significant (p < 0.001) positive linear correlations were found between TDFI and DUFE, DUFE and UF/Cr, and TDFI and UF/Cr. The estimated upper reference value for UF/Cr was 1.69 mg/g; this was significantly (p = 0.019) higher than the UF/Cr (1.29) associated with optimal F exposure (0.05-0.07 mg/kg b.w./day). In conclusion, the strong positive correlation between TDFI and UF/Cr confirms the strong association of these 2 F exposure variables and the value of a spot urine sample for prediction of TDFI (i.e., the most important risk factor in determining fluorosis occurrence and severity) in young children. Establishing an estimation of an upper reference value of 1.69 mg/g for UF/Cr in spot urine samples could simplify and facilitate their use as a valuable tool in large epidemiological studies.

Using Normalisation Process Theory to investigate the implementation of school-based oral health promotion.

Despite the considerable improvement in oral health of children in the UK over the last forty years, a significant burden of dental caries remains prevalent in some groups of children, indicating the need for more effective oral health promotion intervention (OHPI) strategies in this population. OBJECTIVE: To explore the implementation process of a community-based OHPI, in the North East of England, using Normalisation Process Theory (NPT) to provide insights on how effectiveness could be maximised. METHODS: Utilising a generic qualitative research approach, 19 participants were recruited into the study. In-depth interviews were conducted with relevant National Health Service (NHS) staff and primary school teachers while focus group discussions were conducted with reception teachers and teaching assistants. Analyses were conducted using thematic analysis with emergent themes mapped onto NPT constructs. RESULTS: Participants highlighted the benefits of OHPI and the need for evidence in practice. However, implementation of 'best evidence' was hampered by lack of adequate synthesis of evidence from available clinical studies on effectiveness of OHPI as these generally have insufficient information on the dynamics of implementation and how effectiveness obtained in clinical studies could be achieved in 'real life'. This impacted on the decision-making process, levels of commitment, collaboration among OHP teams, resource allocation and evaluation of OHPI. CONCLUSIONS: A large gap exists between available research evidence and translation of evidence in OHPI in community settings. Effectiveness of OHPI requires not only an awareness of evidence of clinical effectiveness but also synthesised information about change mechanisms and implementation protocols.

Group O low titre only emergency donor panels for small combat teams.

INTRODUCTION: Military elements increasingly operate in small teams in remote areas with no immediate blood product support. Planners and operators may endorse collection of fresh whole blood from pretested donors in emergency situations. The biggest risk of transfusion is the accidental use of ABO incompatible blood which can be fatal. The risk may be mitigated by using only group O LOw (OLO) titre donors with plasma containing low levels of the naturally occurring antibody to group A and B red cells. This paper reviews the ABO blood group distribution in potential blood donors from a high readiness UK medical regiment and explores the feasibility of using only group OLO donors in small teams. METHODS: A retrospective review of routine volunteer blood donor samples was undertaken at 6 monthly intervals during a 2-year period. Personnel were tested in groups when available during training to create multiple donor panels to simulate small teams. RESULTS: 206 donation samples were collected from 157 potential donors. All donors were acceptable based on the lifestyle questionnaire, serology and microbiology screen. Of the 206 samples reviewed, 85 (41%) were group O (D pos and D neg). 14 group O (16.5%) were shown to have high titre of anti-A or B. Therefore, 71, that is, 34% overall were suitable as OLO donors. The donor panel size varied from 15 to 44. The absolute number of OLO donors in each panel ranged from 4 to 17 and the number of O neg donors was 0-3. CONCLUSION: A third of samples were suitable as OLO donors; however, there were insufficient 'universal' donors within smaller subgroups (<10). In this situation, we recommend the careful use of both group O and group A donors or the use of a buddy-buddy blood group matrix.

Spatial variation of the colonic microbiota in patients with ulcerative colitis and control volunteers.

OBJECTIVES: The relevance of spatial composition in the microbial changes associated with UC is unclear. We coupled luminal brush samples, mucosal biopsies and laser capture microdissection with deep sequencing of the gut microbiota to develop an integrated spatial assessment of the microbial community in controls and UC. DESIGN: A total of 98 samples were sequenced to a mean depth of 31,642 reads from nine individuals, four control volunteers undergoing routine colonoscopy and five patients undergoing surgical colectomy for medically-refractory UC. Samples were retrieved at four colorectal locations, incorporating the luminal microbiota, mucus gel layer and whole mucosal biopsies. RESULTS: Interpersonal variability accounted for approximately half of the total variance. Surprisingly, within individuals, asymmetric Eigenvector map analysis demonstrated differentiation between the luminal and mucus gel microbiota, in both controls and UC, with no differentiation between colorectal regions. At a taxonomic level, differentiation was evident between both cohorts, as well as between the luminal and mucosal compartments, with a small group of taxa uniquely discriminating the luminal and mucosal microbiota in colitis. There was no correlation between regional inflammation and a breakdown in this spatial differentiation or bacterial diversity. CONCLUSIONS: Our study demonstrates a conserved spatial structure to the colonic microbiota, differentiating the luminal and mucosal communities, within the context of marked interpersonal variability. While elements of this structure overlap between UC and control volunteers, there are differences between the two groups, both in terms of the overall taxonomic composition and how spatial structure is ascribable to distinct taxa.

Estimation of daily dietary fluoride intake: 3-d food diary v. 2-d duplicate plate.

The 3-d food diary method (3-d FD) or the 2-d duplicate plate (2-d DP) method have been used to measure dietary fluoride (F) intake by many studies. This study aimed to compare daily dietary F intake (DDFI) estimated by the 3-d FD and 2-d DP methods at group and individual levels. Dietary data for sixty-one healthy children aged 4-6 years were collected using 3-d FD and 2-d DP methods with a 1-week gap between each collection. Food diary data were analysed for F using the Weighed Intake Analysis Software Package, whereas duplicate diets were analysed by an acid diffusion method using an F ion-selective electrode. Paired t test and linear regression were used to compare dietary data at the group and individual levels, respectively. At the group level, mean DDFI was 0·025 (sd 0·016) and 0·028 (sd 0·013) mg/kg body weight (bw) per d estimated by 3-d FD and 2-d DP, respectively. No statistically significant difference (P=0·10) was observed in estimated DDFI by each method at the group level. At an individual level, the agreement in estimating F intake (mg/kg bw per d) using the 3-d FD method compared with the 2-d DP method was within ±0·011 (95 % CI 0·009, 0·013) mg/kg bw per d. At the group level, DDFI data obtained by either the 2-d DP method or the 3-d FD method can be replaced. At an individual level, the typical error and the narrow margin between optimal and excessive F intake suggested that the DDFI data obtained by one method cannot replace the dietary data estimated from the other method.

Cellular discrimination using in vitro Raman micro spectroscopy: the role of the nucleolus.

Raman micro spectroscopy has attracted considerable attention over the last few years to explore its possible clinical applications as a non-invasive powerful label-free in vitro screening tool in cancer diagnosis and monitoring, subcellular analysis of biochemical processes, drug uptake, mode of action and mechanisms of interaction as well as toxicity of, for example, chemotherapeutic agents. However, in order to evaluate accurately the potential of Raman micro spectroscopy for such applications it is essential to optimise measurement and data processing protocols associated with subcellular analysis. To this end, in vitro differentiation of cell lines is a basic proof of concept for the potential of the technique, and although many studies have indicated successful differentiation based on Raman micro spectroscopy, it is important, as the measurement and processing techniques are improved, to establish the biochemical and subcellular basis of that discrimination. In this study, Raman micro spectroscopy is used to compare and differentiate normal and cancer cells from human lung origin, A549 adenocarcinoma cell line, Calu-1 epidermoid non-small-cell and BEAS-2B normal immortalized bronchial epithelium cell line. Spectra were taken from the three subcellular compartments, cytoplasm, nucleus and nucleolus and Principal Components Analysis was used to compare the spectral profiles between the cell lines and, coupled to Linear Discriminant Analysis, to explore the optimum sensitivity and specificity of discrimination. To support the analysis, Raman micro spectroscopy was coupled with Flow Cytometry, Confocal Laser Scanning Microscopy and Atomic Force Microscopy. While all subcellular regions can be employed to differentiate the normal and cancer cell lines, optimum discrimination sensitivity and specificity is achieved using the spectra from the nucleolar region alone. Notably, only the nucleolar spectral profiles differentiate the two cancer cell lines. The results point to the importance of the nucleolar regions in diagnostic applications of Raman microscopy as well as further applications in subcellular analysis of cytological processes.

Competitive evaluation of data mining algorithms for use in classification of leukocyte subtypes with Raman microspectroscopy.

Raman microspectroscopy has been investigated for some time for use in label-free cell sorting devices. These approaches require coupling of the Raman spectrometer to complex data mining algorithms for identification of cellular subtypes such as the leukocyte subpopulations of lymphocytes and monocytes. In this study, three distinct multivariate classification approaches, (PCA-LDA, SVMs and Random Forests) are developed and tested on their ability to classify the cellular subtype in extracted peripheral blood mononuclear cells (T-cell lymphocytes from myeloid cells), and are evaluated in terms of their respective classification performance. A strategy for optimisation of each of the classification algorithm is presented with emphasis on reduction of model complexity in each of the algorithms. The relative classification performance and performance characteristics are highlighted, overall suggesting the radial basis function SVM as a robust option for classification of leukocytes with Raman microspectroscopy.

Aspects of structural health and condition monitoring of offshore wind turbines.

Wind power has expanded significantly over the past years, although reliability of wind turbine systems, especially of offshore wind turbines, has been many times unsatisfactory in the past. Wind turbine failures are equivalent to crucial financial losses. Therefore, creating and applying strategies that improve the reliability of their components is important for a successful implementation of such systems. Structural health monitoring (SHM) addresses these problems through the monitoring of parameters indicative of the state of the structure examined. Condition monitoring (CM), on the other hand, can be seen as a specialized area of the SHM community that aims at damage detection of, particularly, rotating machinery. The paper is divided into two parts: in the first part, advanced signal processing and machine learning methods are discussed for SHM and CM on wind turbine gearbox and blade damage detection examples. In the second part, an initial exploration of supervisor control and data acquisition systems data of an offshore wind farm is presented, and data-driven approaches are proposed for detecting abnormal behaviour of wind turbines. It is shown that the advanced signal processing methods discussed are effective and that it is important to adopt these SHM strategies in the wind energy sector.

Fractional Urinary Fluoride Excretion (FUFE) of 3-4 year children in the Gaza Strip.

UNLABELLED: A positive association between dental fluorosis prevalence and fluoride (F) concentration in drinking waters has been detected in Gaza Strip. Total Daily Fluoride Retention (TDFR), and Fractional Urinary Fluoride Excretion (FUFE) indicate F body burden; important in assessing fluorosis risk in susceptible age groups. OBJECTIVE: 1, To determine and compare Daily Urinary Fluoride Excretion (DUFE) and FUFE of 3-4-year-olds living in lower (< 0.7), moderate (0.7-1.2) or higher (> 1.2 ) ppm F tap water areas; 2, To determine any relationship between i, DUFE and tap water F; ii, DUFE and Total Daily Fluoride Intake (TDFI); iii, TDFI and TDFR. METHODS: 24-hour urine and tap water samples were collected from 216 children exposed to lower (n = 81), moderate (n = 72), or higher (n = 63) tap water F. ANOVA with Tukey's Test and Pearson's correlation were used to examine differences in mean DUFE and FUFE and relationships between variables. RESULTS: Mean drinking water F was 0.11(sd 0.17), 0.14 (sd 0.28) and 0.38 (sd 0.63) ppmF respectively. Differences (p < 0.0001) in mean DUFEs (0.17 (sd 0.13), 0.25 (sd 0.15) and 0.38 (sd 0.23) mg/day respectively) and mean FUFEs (48 (sd 39)%, 47 (sd 31)% and 63(sd 76)%) were found (p < 0.05). Significant (p < 0.0001) positive correlations were found between DUFE and tap water F; DUFE and TDFI, and; TDFI and TDFR. CONCLUSION: DUFEs of children drinking waters with 0.11 and 0.14ppm F, represented low F usage. The group drinking 0.38ppm F water represented optimal F usage. The weak significant positive association of DUFE with home tap water F suggests low validity for tap water F in estimating F exposure.

Correlations between colonic crypt mucin chemotype, inflammatory grade and Desulfovibrio species in ulcerative colitis.

AIM: The colonic mucus gel layer is composed of mucins that may be sulphated or sialyated. Sulphated mucins predominate in health while in ulcerative colitis (UC) sulphation is reduced. These differences result directly from inflammatory events. It may also be hypothesized that they arise in part from alterations in the colonic microbiota, particularly changes in the burden of sulphated mucin-metabolizing species, such as Desulfovibrio (DSV) bacteria. The aim of this study was to correlate colonic mucin chemotypes and inflammatory scores in health and UC and relate these changes to changes in the colonization of colonic crypts by DSV. METHOD: Paired colonic biopsies from 34 healthy controls (HC) and 19 patients with active UC were collected for the purpose of parallel histological and microbiological assessment. High-iron diamine and Alcian blue staining and haematoxylin and eosin of mucosal biopsy specimens were used to assess histological changes within the clinical spectrum of UC. Quantitative real-time polymerase chain reaction analysis was employed to determine the total and DSV copy number within the colonic crypts. RESULTS: Compared with HC, the mucin chemotype in UC was less sulphated and inversely correlated with the degree of mucosal inflammation. A weak but significant negative correlation was found between the abundance of sulphated mucins and DSV burden. CONCLUSION: Mucin composition strongly correlates with the degree of mucosal inflammation, and to a lesser extent with DSV burden. These data suggest that mucin chemotype and DSV burden are linked phenomena and highlight the need to consider changes in mucin chemotype in the setting of microbial dysbiosis occurring within the colitic colon. What does this paper add to the literature? Decreased sulphation of mucins has been associated with inflammation in ulcerative colitis. Currently there are few data describing the relationship between microbial species and changes in mucin chemotype. This study validates previous findings and presents evidence of changes in mucin chemotype occurring in tandem with coherent changes in the microbiota within crypt niches.

Rates and risk of hospitalisation among patients with type 2 diabetes: retrospective cohort study using the UK General Practice Research Database linked to English Hospital Episode Statistics.

AIMS: To investigate the rates and risk of hospitalisations in patients with type 2 diabetes (T2D) mellitus in England. METHODS: This retrospective population-based cohort study used computerised records from the General Practice Research Database linked to Hospital Episode Statistics data in England. Patients with T2D from January 2006 to December 2010 were selected. Primary outcome measures were all-cause, non-diabetes-related, diabetes-related and hypoglycaemia-related hospitalisations. Factors associated with all-cause and diabetes-related hospitalisations were investigated with Cox's proportional hazards models. RESULTS: Amongst 97,689 patients with T2D, approximately 60% had at least one hospitalisation during the 4-year study period. Rates of hospitalisation were as follows: all-cause, 33.9 per 100 patient-years (pt-yrs); non-diabetes-related, 29.1 per 100 pt-yrs; diabetes-related, 18.8 per 100 pt-yrs and hypoglycaemia, 0.3 per 100 pt-yrs. The risk of all-cause hospitalisation increased with hospitalisation in the previous year, insulin use and the presence of major comorbidities. The risk of a diabetes-related hospitalisation increased with age, female gender, insulin use, chronic renal insufficiency, hypoglycaemia (as diagnosed by a general practitioner) and diabetes-related hospitalisation in the previous year. CONCLUSIONS: Patients with T2D are hospitalised at a considerably high rate for causes directly related with diabetes complications and stay longer in hospital. History of hospitalisation and complications of diabetes were found to be predictive of inpatient hospitalisations suggesting previous hospitalisation episodes could serve as points of intervention. This study highlights important areas for healthcare intervention and provides a reminder for vigilance when risk factors for hospitalisation in patients with T2D are present.

ADAM-17: a novel therapeutic target for triple negative breast cancer.

BACKGROUND: Validated targeted therapy is currently unavailable for patients with invasive breast cancer negative for oestrogen receptors, progesterone receptors and HER2 [i.e., those with triple-negative (TN) disease]. ADAM-17 is a protease involved in the activations of several ligands that bind to and promotes intracellular signalling from the EGFR/HER family of receptors. PATIENTS AND METHODS: Expression of ADAM-17 was measured in 86 triple-negative and 96 non-triple-negative breast cancers. The ADAM-17 specific inhibitor, PF-5480090 (TMI-002, Pfizer) was tested in a panel of breast cancer cell lines for effects on functional outputs. RESULTS: In this study we show using both Western blotting and immunohistochemistry that ADAM-17 is expressed at significantly higher levels in TN than non-TN breast cancers. Using a panel of breast cancer cell lines in culture, PF-5480090 was found to decrease release of the EGFR ligand, TGF-alpha, decrease levels of phosphorylated EGFR and block cell proliferation in a cell-type-dependent manner. Potentially important was the finding of a significant and moderately strong correlation between ADAM-17 activity and extent of proliferation inhibition by PF-5480090 (r = 0.809; p = 0.003; n = 11). Pretreatment of cell lines with PF-5480090 enhanced response to several different cytotoxic and anti-EGFR/HER agents. CONCLUSION: It is concluded that inhibition of ADAM-17, especially in combination with chemotherapy or anti-EGFR/HER inhibitors, may be a new approach for treating breast cancer, including patients with TN disease.

Fractional urinary fluoride excretion of 6-7-year-old children attending schools in low-fluoride and naturally fluoridated areas in the UK.

F is an important trace element for bones and teeth. The protective effect of F against dental caries is well established. Urine is the prime vehicle for the excretion of F from the body; however, the relationship between F intake and excretion is complex: the derived fractional urinary F excretion (FUFE) aids understanding of this in different age groups. The present study aimed to investigate the relationships between (1) total daily F intake (TDFI) and daily urinary F excretion (DUFE), and (2) TDFI and FUFE in 6-7-year-olds, recruited in low-F and naturally fluoridated (natural-F) areas in north-east England. TDFI from diet and toothbrushing and DUFE were assessed through F analysis of duplicate dietary plate, toothbrushing expectorate and urine samples using a F-ion-selective electrode. FUFE was calculated as the ratio between DUFE and TDFI. Pearson's correlation and regression analysis were used to investigate the relationship between TDFI and FUFE. A group of thirty-three children completed the study; twenty-one receiving low-F water (0·30 mg F/l) and twelve receiving natural-F water (1·06 mg F/l) at school. The mean TDFI was 0·076 (SD 0·038) and 0·038 (SD 0·027) mg/kg per d for the natural-F and low-F groups, respectively. The mean DUFE was 0·017 (SD 0·007) and 0·012 (SD 0·006) mg/kg per d for the natural-F and low-F groups, respectively. FUFE was lower in the natural-F group (30 %) compared with the low-F group (40 %). Pearson's correlation coefficient for (1) TDFI and DUFE was +0·22 (P= 0·22) and for (2) TDFI and FUFE was − 0·63 (P< 0·001). In conclusion, there was no correlation between TDFI and DUFE. However, there was a statistically significant negative correlation between FUFE and TDFI.

Total fluoride intake and excretion in children up to 4 years of age living in fluoridated and non-fluoridated areas.

Fractional fluoride retention is important during the early years of life when considering the risk of development of dental fluorosis. This study aimed to measure fractional fluoride retention in young children. The objectives were to investigate the relationships between fractional fluoride retention and total daily fluoride intake, age, and body mass index (BMI). Twenty-nine healthy children, up to 4 yr of age, participated; 14 lived in a fluoridated area (0.64 µg ml(-1) of fluoride in drinking water) and 15 lived in a non-fluoridated area (0.04 µg ml(-1) of fluoride in drinking water). The total daily fluoride intake of each child was calculated from the daily dietary fluoride intake and toothpaste ingestion (if fluoride toothpaste was used). Total daily fluoride excretion was measured by collecting voided urine and faeces over a 24-h period, and fractional fluoride retention was calculated by dividing the amount of fluoride retained in the body (total daily fluoride intake minus total daily fluoride excretion) by the total daily fluoride intake. Nine children were excluded from data analysis because of suspected invalid samples. Mean (range) fractional fluoride retention for the remaining 20 children was 0.61 (0.06-0.98). There were no statistically significant correlations between fractional fluoride retention and either age or BMI. However, fractional fluoride retention was correlated with total daily fluoride intake: fractional fluoride retention = 1 - exp (-C × total daily fluoride intake), where C = 28.75 (95% CI = 19.75-37.75). The wide variation in fluoride retention in young children could have important implications when recommendations for fluoride use are being considered.

Urinary fluoride excretion in 6- to 7-year-olds ingesting milk containing 0.5 or 0.9 mg fluoride.

Effectiveness of 0.5 mg fluoride (F) milk ingestion in preventing caries has been termed only 'moderate'. In this 3-arm partial cross-over intervention, 32 children aged 6-7 years in a non-F area were recruited and urinary F excretion (UFE) measured before and after ingestion of 0.5 or 0.9 mg F milk. Maintaining customary dietary and oral hygiene habits, children underwent a 2-week 'wash-in' with non-F milk, providing a 24-hour urine sample on day 4 of non-F (baseline) and F milk ingestion containing either (i) 0.5 mg or (ii) 0.9 mg F (intervention). A comparative group of thirteen 6- to 7-year-olds living in fluoridated areas provided a 24-hour urine sample on day 4 of daily non-F milk ingestion, following a 2-week non-F milk wash-in. Valid urine samples were analysed for F and UFE estimated from corrected 24-hour urine volume and F concentration. For the 24 test children providing 2 valid urine samples, mean (95% CI) change in corrected 24-hour UFE was 0.130 (0.049, 0.211) and 0.153 (0.062, 0.245) mg/day for 0.5 mg (p < 0.007) and 0.9 mg F (p < 0.001) groups, respectively. Post-intervention, mean (SD) corrected 24-hour UFE was 0.437 (0.153) mg/day and 0.420 (0.188) mg/day for the 0.5 and 0.9 mg F groups, respectively, which were lower than the WHO provisional standards (0.48-0.60 mg F/day). F milk consumption significantly increased UFE; however, the F content of 0.5 and 0.9 mg F milk may be too low to achieve WHO provisional UFE standards concomitant with optimal F exposure in children aged ≥6 years.

Gene therapy restores vision in a canine model of childhood blindness.

The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65-/- dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness.

Emergency department presentations with suicide and self-harm ideation: a missed opportunity for intervention?

AIMS: Suicidal ideation constitutes a central element of most theories of suicide and is the defining facet separating suicide from other causes of death such as accidents. However, despite a high worldwide prevalence, most research has focused on suicidal behaviours, such as completed suicide and suicide attempts, while the greater proportion who experienced ideation, which frequently precedes suicidal behaviour, have received much less attention. This study aims to examine the characteristics of those presenting to EDs with suicidal ideation and quantify the associated risk of suicide and other causes of death. METHODS: Retrospective cohort study was performed based on population-wide health administration data linked to data from the Northern Ireland Registry of Self-Harm and centrally held mortality records from April 2012 to December 2019. Mortality data, coded as suicide, all-external causes and all-cause mortality were analysed using Cox proportional hazards. Additional cause-specific analyses included accidental deaths, deaths from natural causes and drug and alcohol-related causes. RESULTS: There were 1,662,118 individuals aged over 10 years, of whom 15,267 presented to the ED with ideation during the study period. Individuals with ideation had a 10-fold increased risk of death from suicide (hazard ratio [HRadj] = 10.84, 95% confidence interval [CI] 9.18, 12.80) and from all-external causes (HRadj = 10.65, 95% CI 9.66, 11.74) and a threefold risk of death from all-causes (HRadj = 3.01, 95% CI 2.84, 3.20). Further cause-specific analyses indicated that risk of accidental death (HRadj = 8.24, 95% CI 6.29, 10.81), drug-related (HRadj = 15.17, 95% CI 11.36, 20.26) and alcohol-related (HRadj = 10.57, 95% CI 9.07, 12.31) has also significantly increased. There were few socio-demographic and economic characteristics that would identify which of these patients are most at risk of suicide or other causes of death. CONCLUSIONS: Identifying people with suicidal ideation is recognized to be both important but difficult in practice; this study shows that presentations to EDs with self-harm or suicide ideation represent an important potential intervention point for this hard-to-reach vulnerable population. However, and unlike individuals presenting with self-harm, clinical guidelines for the management and recommended best practice and care of these individuals are lacking. Whilst suicide prevention may be the primary focus of interventions aimed at those experiencing self-harm and suicide ideation, death from other preventable causes, especially substance misuse, should also be a cause of concern.

A retrospective database study of insulin initiation in patients with Type 2 diabetes in UK primary care.

AIMS: This study characterized UK primary care patients with Type 2 diabetes who initiated insulin treatment, and described the initial insulin regimens used, overall metabolic changes and health-care resource usage. METHODS: A retrospective cohort study was performed using quality-checked patient data from The Health Improvement Network database. Eligible patients who initiated insulin for the first time between 2004 and 2006 were grouped into four cohorts according to the type of insulin regimen initiated. Data on patient characteristics, metabolic and clinical outcomes and health-care resource use were collected at baseline and during 6 months of follow-up. RESULTS: In total, 4045 eligible adults [2269 male, 1776 female; mean age 62.6 ± 13.3 years; mean baseline HbA(1c) 82 ± 22 mmol/mol (9.6% ± 2.0%)] initiated insulin. Approximately half (52.4%) initiated insulin as basal insulin only, 41.6% as premixed only, 4.0% as basal-bolus and 2.1% as prandial insulin only. Among patients with ≥ 180 days follow-up (n=3815), the initial insulin regimen was not changed during follow-up in 75.1% of patients, while 13.7% discontinued, 7.0% switched and 4.7% intensified insulin therapy. The mean change in HbA(1c) was -14 mmol/mol (-1.3%, n=2881), with 17.3% of patients achieving an HbA(1c) of <53 mmol/mol (7%, n=3024). The mean weight change was +0.9 kg (n=2345). CONCLUSIONS: Basal and premixed insulin were the most common types of insulin initiated and in most patients no changes were made to the initial regimen over 6 months. However, few patients achieved glycemic control targets.