Adipose microenvironment promotes hypersialylation of ovarian cancer cells.

Sialylation, the addition of negatively charged sialic acid sugars to terminal ends of glycans, is upregulated in most cancers. Hypersialylation supports multiple pro-tumor mechanisms such as enhanced migration and invasion, resistance to apoptosis and immune evasion. A current gap in knowledge is the lack of understanding on how the tumor microenvironment regulates cancer cell sialylation. The adipose niche is a main component of most peritoneal cancers' microenvironment. This includes ovarian cancer (OC), which causes most deaths from all gynecologic cancers. In this report, we demonstrate that the adipose microenvironment is a critical regulator of OC cell sialylation. In vitro adipose conditioning led to an increase in both ⍺2,3- and ⍺2,6-linked cell surface sialic acids in both human and mouse models of OC. Adipose-induced sialylation reprogramming was also observed in vivo from intra-peritoneal OC tumors seeded in the adipose-rich omentum. Mechanistically, we observed upregulation of at least three sialyltransferases, ST3GAL1, ST6GAL1 and ST3GALNAC3. Hypersialylated OC cells consistently formed intra-peritoneal tumors in both immune-competent mice and immune-compromised athymic nude mice. In contrast, hyposiaylated OC cells persistently formed tumors only in athymic nude mice demonstrating that sialylation impacts OC tumor formation in an immune dependent manner. To our knowledge, this is the first demonstration of the effect of adipose microenvironment on OC tumor sialylation. Our results set the stage for translational applications targeting sialic acid pathways in OC and other peritoneal cancers.

Prolonged remission followed by low insulin requirements in a patient with type 1 diabetes on a very low-carbohydrate diet.

Summary: The use of a low-carbohydrate diet (LCD) reduces insulin requirements in insulinopenic states such as type 1 diabetes mellitus (T1DM). However, the use of potentially ketogenic diets in this clinical setting is contentious and the mechanisms underlying their impact on glycaemic control are poorly understood. We report a case of a patient with a late-onset classic presentation of T1DM who adopted a very low-carbohydrate diet and completely avoided insulin therapy for 18 months, followed by tight glycaemic control on minimal insulin doses. The observations suggest that adherence to an LCD in T1DM, implemented soon after diagnosis, can facilitate an improved and less variable glycaemic profile in conjunction with temporary remission in some individuals. Importantly, these changes occurred in a manner that did not lead to a significant increase in blood ketone (beta-hydroxybutyrate) concentrations. This case highlights the need for further research in the form of randomised controlled trials to assess the long-term safety and sustainability of carbohydrate-reduced diets in T1DM. Learning points: This case highlights the potential of low-carbohydrate diets (LCDs) in type 1 diabetes mellitus (T1DM) to mediate improved diabetes control and possible remission soon after diagnosis. Could carbohydrate-reduced diets implemented early in the course of T1DM delay the decline in endogenous insulin production? Adherence to an LCD in T1DM can facilitate an improved and less variable glycaemic profile. This case suggests that LCDs in T1DM may not be associated with a concerning supraphysiological ketonaemia.

Tools for investigating O-GlcNAc in signaling and other fundamental biological pathways.

Cells continuously fine-tune signaling pathway proteins to match nutrient and stress levels in their local environment by modifying intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) sugars, an essential process for cell survival and growth. The small size of these monosaccharide modifications poses a challenge for functional determination, but the chemistry and biology communities have together created a collection of precision tools to study these dynamic sugars. This review presents the major themes by which O-GlcNAc influences signaling pathway proteins, including G-protein coupled receptors, growth factor signaling, mitogen-activated protein kinase (MAPK) pathways, lipid sensing, and cytokine signaling pathways. Along the way, we describe in detail key chemical biology tools that have been developed and applied to determine specific O-GlcNAc roles in these pathways. These tools include metabolic labeling, O-GlcNAc-enhancing RNA aptamers, fluorescent biosensors, proximity labeling tools, nanobody targeting tools, O-GlcNAc cycling inhibitors, light-activated systems, chemoenzymatic labeling, and nutrient reporter assays. An emergent feature of this signaling pathway meta-analysis is the intricate interplay between O-GlcNAc modifications across different signaling systems, underscoring the importance of O-GlcNAc in regulating cellular processes. We highlight the significance of O-GlcNAc in signaling and the role of chemical and biochemical tools in unraveling distinct glycobiological regulatory mechanisms. Collectively, our field has determined effective strategies to probe O-GlcNAc roles in biology. At the same time, this survey of what we do not yet know presents a clear roadmap for the field to use these powerful chemical tools to explore cross-pathway O-GlcNAc interactions in signaling and other major biological pathways.

Developing and exploring the validity of a patient reported experience measure for adult inpatient diabetes care.

AIM: To develop and explore the validity of a Patient Reported Experience Measure (PREM) for adult inpatient diabetes care. METHOD: 27 in-depth interviews were conducted to inform the development of the 42-item PREM which was cognitively tested with 10 people. A refined 38-item PREM was piloted with 228 respondents completing a paper (n = 198) or online (n = 30) version. The performance of the PREM was evaluated by exploring (i) uptake/number of responses and (ii) survey validity by investigating whether the PREM data were of adequate quality and delivered useful information. RESULTS: The PREM had low drop-out or missing data rates suggesting it was appropriately constructed. Analysis of item frequencies and variances, and problem score calculations concluded that questions provided sufficient score differentiation. CONCLUSIONS: This new PREM allows for experiences of inpatient diabetes care to be measured, understood and reported on to help identify priority areas for improving care quality.

Type 1 diabetes and low carbohydrate diets-Defining the degree of nutritional ketosis.

AIMS: Adopting a low- or very low-carbohydrate (LCD or VLCD) diet in type 1 diabetes mellitus (T1D) is a controversial intervention. The main fear is that these diets may increase the risk of diabetic ketoacidosis. However, there is little data about the ketoacidosis risk and the level of physiological nutritional ketosis in individuals following these diets. We aimed to define the level of ketosis in those with T1D following carbohydrate restricted diets in a real-world observational study. METHODS: Patients with T1D who had self-selected dietary carbohydrate restriction were enrolled from local clinics and were compared to those following an unrestricted regular carbohydrate control diet (RCCD). Participants completed a 3-day diary, documenting food intake, ketones, and blood/interstitial glucose concentrations. RESULTS: Participants were divided into three groups according to mean carbohydrate intake: VLCD (<50 g carbohydrates/day) n = 6, LCD (50-130 g carbohydrates/day) n = 6, and RCCD (>130 g carbohydrates/day) n = 3. Mean beta-hydroxybutyrate (BOHB) concentrations were 1.2 mmol/l (SD 0.14), 0.3 mmol/l (SD 0.12) and 0.1mmol/l (SD 0.05) in the VLCD, LCD and RCCD groups, respectively (p = 0.02). Post hoc Dunn test demonstrated this reached statistical significance between the VLCD and RCCD groups (p = 0.02). CONCLUSION: Carbohydrate restricted diets, in particular VLCDs, are associated with a higher BOHB level. However, the degree of ketosis seen is much lower than we expected, and significantly lower than the level typically associated with diabetic ketoacidosis. This may suggest the risk of ketoacidosis is lower than feared, although safety will need to be evaluated further in large scale randomised trials.

Bringing the Nature Futures Framework to life: creating a set of illustrative narratives of nature futures.

To halt further destruction of the biosphere, most people and societies around the globe need to transform their relationships with nature. The internationally agreed vision under the Convention of Biological Diversity-Living in harmony with nature-is that "By 2050, biodiversity is valued, conserved, restored and wisely used, maintaining ecosystem services, sustaining a healthy planet and delivering benefits essential for all people". In this context, there are a variety of debates between alternative perspectives on how to achieve this vision. Yet, scenarios and models that are able to explore these debates in the context of "living in harmony with nature" have not been widely developed. To address this gap, the Nature Futures Framework has been developed to catalyse the development of new scenarios and models that embrace a plurality of perspectives on desirable futures for nature and people. In this paper, members of the IPBES task force on scenarios and models provide an example of how the Nature Futures Framework can be implemented for the development of illustrative narratives representing a diversity of desirable nature futures: information that can be used to assess and develop scenarios and models whilst acknowledging the underpinning value perspectives on nature. Here, the term illustrative reflects the multiple ways in which desired nature futures can be captured by these narratives. In addition, to explore the interdependence between narratives, and therefore their potential to be translated into scenarios and models, the six narratives developed here were assessed around three areas of the transformative change debate, specifically, (1) land sparing vs. land sharing, (2) Half Earth vs. Whole Earth conservation, and (3) green growth vs. post-growth economic development. The paper concludes with an assessment of how the Nature Futures Framework could be used to assist in developing and articulating transformative pathways towards desirable nature futures. Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-023-01316-1.

Research priorities for the sustainability of coral-rich western Pacific seascapes.

Nearly a billion people depend on tropical seascapes. The need to ensure sustainable use of these vital areas is recognised, as one of 17 policy commitments made by world leaders, in Sustainable Development Goal (SDG) 14 ('Life below Water') of the United Nations. SDG 14 seeks to secure marine sustainability by 2030. In a time of increasing social-ecological unpredictability and risk, scientists and policymakers working towards SDG 14 in the Asia-Pacific region need to know: (1) How are seascapes changing? (2) What can global society do about these changes? and (3) How can science and society together achieve sustainable seascape futures? Through a horizon scan, we identified nine emerging research priorities that clarify potential research contributions to marine sustainability in locations with high coral reef abundance. They include research on seascape geological and biological evolution and adaptation; elucidating drivers and mechanisms of change; understanding how seascape functions and services are produced, and how people depend on them; costs, benefits, and trade-offs to people in changing seascapes; improving seascape technologies and practices; learning to govern and manage seascapes for all; sustainable use, justice, and human well-being; bridging communities and epistemologies for innovative, equitable, and scale-crossing solutions; and informing resilient seascape futures through modelling and synthesis. Researchers can contribute to the sustainability of tropical seascapes by co-developing transdisciplinary understandings of people and ecosystems, emphasising the importance of equity and justice, and improving knowledge of key cross-scale and cross-level processes, feedbacks, and thresholds.

Dietary Approaches to the Management Of type 2 Diabetes (DIAMOND) in primary care: A protocol for a cluster randomised trial.

INTRODUCTION: There is strong evidence that type 2 diabetes (T2D) remission can be achieved by adopting a low-energy diet achieved through total dietary replacement products. There is promising evidence that low-carbohydrate diets can achieve remission of T2D. The Dietary Approaches to the Management of type 2 Diabetes (DIAMOND) programme combines both approaches in a behaviourally informed low-energy, low-carbohydrate diet for people with T2D, delivered by nurses in primary care. This trial compares the effectiveness of the DIAMOND programme to usual care in inducing remission of T2D and in reducing risk of cardiovascular disease. METHODS AND ANALYSIS: We aim to recruit 508 people in 56 practices with T2D diagnosed within 6 years, who are demographically representative of the UK population. We will allocate general practices, based on ethnicity and socioeconomic status, to provide usual care for diabetes or offer the DIAMOND programme. Participants in practices offering DIAMOND will see the nurse seven times over 6 months. At baseline, 6 months, and 1 year we will measure weight, blood pressure, HbA1c, lipid profile and risk of fatty liver disease. The primary outcome is diabetes remission at 1 year, defined as HbA1c < 48 mmol/mol and off glucose-lowering medication for at least 6 months. Thereafter, we will assess whether people resume treatment for diabetes and the incidence of microvascular and macrovascular disease through the National Diabetes Audit. Data will be analysed using mixed-effects generalised linear models. This study has been approved by the National Health Service Health Research Authority Research Ethics Committee (Ref: 22/EM/0074). TRIAL REGISTRATION NUMBER: ISRCTN46961767.

Improved glycaemic control in patients with type 2 diabetes has a beneficial impact on NAFLD, independent of change in BMI or glucose lowering agent.

BACKGROUND AND AIM: The current focus of the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) is lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with type 2 diabetes (T2D) and obesity. In patients with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. METHODS AND RESULTS: In a retrospective analysis of data from 637 people with T2D, we examined the longitudinal impact of optimizing glycaemic control with DPP-IV inhibitors, GLP-1RAs and SGLT2 inhibitors on Fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Multiple linear regression analysis demonstrated a significant correlation between the change in glycated haemoglobin and change in FLI after adjustment for change in BMI, age, sex, and drug class (R = 0.467, p = 0.031). The greatest reduction in FLI was observed in patients with the largest reduction in glycated haemoglobin (p < 0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. CONCLUSIONS: Improvements in glucose control that are independent of weight loss are associated with improvement in NAFLD and should form an integral part of the management patients with co-existent NAFLD and T2D.

Synthesis and mammalian cell compatibility of light-released glycan precursors for controlled metabolic engineering.

Sugar additions to biomolecules, or glycans, are some of the most abundant biomolecule modifications in biology because they enable cells to adapt to changing nutrient and stress conditions. An unmet challenge for the field of glycobiology is the study of glycan biosynthetic pathways with chemical control, especially in live cell settings. The objective of this study was to create biocompatible glycan precursors with controlled release properties. Here, we report eleven "caged" sugar probes that release glycan biosynthetic precursor molecules upon light exposure. The specific sugar pathways we target with our probes regulate the addition of the N-acetyl sugars GlcNAc, GalNAc, and sialic acid onto biomolecules in cells, each of which has the potential to alter glycan processes involved in cell morphology, signaling, and behavior. We hypothesized that our glycan precursor probes would remain biologically inert until light-initiated decaging conditions were met, avoiding biological activities including metabolism and cytotoxicity. The photocaged analogs of GlcNAc, GalNAc, and ManNAc (sialic acid precursor) sugars, which we call "photo-sugars," were released within minutes of light exposure at their optimal wavelengths. During the course of the study, we characterized the cell compatibility of these sugars under their respective decaging conditions, and found highly cell compatible GlcNAc, GalNAc, and ManNAc photocaged precursors. Release of GlcNAc-1-phosphate precursors led to altered ATP levels in cells, demonstrating preliminary metabolic engineering. We envision these probes as useful additions to the chemical glycobiology field that will enable spatiotemporal control over glycosylation pathways in living mammalian cells.

Bridging Theories for Ecosystem Stability Through Structural Sensitivity Analysis of Ecological Models in Equilibrium.

Ecologists are challenged by the need to bridge and synthesize different approaches and theories to obtain a coherent understanding of ecosystems in a changing world. Both food web theory and regime shift theory shine light on mechanisms that confer stability to ecosystems, but from different angles. Empirical food web models are developed to analyze how equilibria in real multi-trophic ecosystems are shaped by species interactions, and often include linear functional response terms for simple estimation of interaction strengths from observations. Models of regime shifts focus on qualitative changes of equilibrium points in a slowly changing environment, and typically include non-linear functional response terms. Currently, it is unclear how the stability of an empirical food web model, expressed as the rate of system recovery after a small perturbation, relates to the vulnerability of the ecosystem to collapse. Here, we conduct structural sensitivity analyses of classical consumer-resource models in equilibrium along an environmental gradient. Specifically, we change non-proportional interaction terms into proportional ones, while maintaining the equilibrium biomass densities and material flux rates, to analyze how alternative model formulations shape the stability properties of the equilibria. The results reveal no consistent relationship between the stability of the original models and the proportionalized versions, even though they describe the same biomass values and material flows. We use these findings to critically discuss whether stability analysis of observed equilibria by empirical food web models can provide insight into regime shift dynamics, and highlight the challenge of bridging alternative modelling approaches in ecology and beyond.

Prescribing and using vitiligo treatments: lessons from a nested process evaluation within the HI-Light vitiligo randomized controlled trial.

BACKGROUND: The HI-Light Trial demonstrated that for active, limited vitiligo, combination treatment with potent topical corticosteroid (TCS) and handheld narrowband ultraviolet B offers a better treatment response than potent TCS alone. However, it is unclear how to implement these findings. AIM: We sought to answer three questions: (i) Can combination treatment be used safely and effectively by people with vitiligo?; (ii) Should combination treatment be made available as routine clinical care?; and (iii) Can combination treatment be integrated within current healthcare provision? METHODS: This was a mixed-methods process evaluation, including semi-structured interviews with a purposive sample of trial participants, structured interviews with commissioners, and an online survey and focus groups with trial staff. Transcripts were coded by framework analysis, with thematic development by multiple researchers. RESULTS: Participants found individual treatments easy to use, but the combination treatment was complicated and required nurse support. Both participants and site investigators felt that combination treatment should be made available, although commissioners were less certain. There was support for the development of services offering combination treatment, although this might not be prioritized above treatment for other conditions. A 'mixed economy' model was suggested, involving patients purchasing their own devices, although concerns regarding the safe use of treatments mean that training, monitoring and ongoing support are essential. The need for medical physics support may mean that a regional service is more practical. CONCLUSION: Combination treatment should be made available for people seeking treatment for vitiligo, but services require partnership with medical physics and ongoing training and support for patients.

Neonatal early-onset sepsis calculator safety in an Australian tertiary perinatal centre.

AIM: To determine if any cases of culture-positive neonatal early-onset sepsis (EOS) would be missed using the neonatal EOS calculator, when compared with current guidelines and practices. METHODS: Retrospective audit of all neonates born at ≥35 weeks and admitted to Royal Brisbane and Women's Hospital with EOS from January 2014 to December 2020. A missed case was defined as antibiotic therapy not being recommended within 24 h of birth. Management recommendations according to the neonatal EOS calculator were compared with current guidelines and current practices. RESULTS: There were significantly more missed cases using the neonatal EOS calculator compared to the current guideline and current management groups. Using the neonatal EOS calculator, 11 neonates (35%, 95% confidence interval 19.2-54.6%) would not have received antibiotics by 24 h of age. In comparison, only one neonate (3%, 95% confidence interval 0.1-16.7%) would not have received antibiotics by 24 h of age using the current guidelines. In terms of the current practice in the cohort of patients, two neonates (6%) did not receive antibiotics by 24 h of age. CONCLUSIONS: The significantly higher rate of missed cases using the neonatal EOS calculator compared with current guidelines and practice supports the concerns many neonatologists have regarding safety of the neonatal EOS calculator.

Multi-decadal increase of forest burned area in Australia is linked to climate change.

Fire activity in Australia is strongly affected by high inter-annual climate variability and extremes. Through changes in the climate, anthropogenic climate change has the potential to alter fire dynamics. Here we compile satellite (19 and 32 years) and ground-based (90 years) burned area datasets, climate and weather observations, and simulated fuel loads for Australian forests. Burned area in Australia's forests shows a linear positive annual trend but an exponential increase during autumn and winter. The mean number of years since the last fire has decreased consecutively in each of the past four decades, while the frequency of forest megafire years (>1 Mha burned) has markedly increased since 2000. The increase in forest burned area is consistent with increasingly more dangerous fire weather conditions, increased risk factors associated with pyroconvection, including fire-generated thunderstorms, and increased ignitions from dry lightning, all associated to varying degrees with anthropogenic climate change.

Bariatric surgery increases the rate of major fracture: self-controlled case series study in UK Clinical Practice Research Datalink.

Conflicting results exist about the relationship between bariatric surgery and fracture risk. Also, prediction of who is at increased risk of fracture after bariatric surgery is not currently available. Hence, we used a combination of a self-controlled case series (SCCS) study to establish the association between bariatric surgery and fracture, and develop a prediction model for postoperative fracture risk estimation using a cohort study. Patients from UK Primary care records from the Clinical Practice Research Datalink GOLD linked to Hospital Episode Statistics undergoing bariatric surgery with body mass index (BMI) ≥30 kg/m2 between 1997 and 2018 were included in the cohort. Those sustaining one or more fractures in the 5 years before or after surgery were included in the SCCS. Fractures were considered in three categories: (i) any except skull and digits (primary outcome); (ii) major (hip, vertebrae, wrist/forearm, and humerus); and (iii) peripheral (forearm and lower leg). Of 5487 participants, 252 (4.6%) experienced 272 fractures (of which 80 were major and 135 peripheral) and were included in the SCCS analyses. Major fracture risk increased after surgery, incidence rate ratios (IRRs) and 95% confidence intervals (CIs): 2.77 (95% CI, 1.34-5.75) and 3.78 (95% CI, 1.42-10.08) at ≤3 years and 3.1 to 5 years postsurgery when compared to 5 years prior to surgery, respectively. Any fracture risk was higher only in the 2.1 to 5 years following surgery (IRR 1.73; 95% CI, 1.08-2.77) when compared to 5 years prior to surgery. No excess risk of peripheral fracture after surgery was identified. A prediction tool for major fracture was developed using 5487 participants included in the cohort study. It was also internally validated (area under the receiver-operating characteristic curve [AUC ROC] 0.70) with use of anxiolytics/sedatives/hypnotics and female as major predictors. Hence, major fractures are nearly threefold more likely after bariatric surgery. A simple prediction tool with five variables identifies high risk patients for major fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Inpatient hypoglycaemia in older people is associated with a doubling in the increased length of stay compared with the younger population.

BACKGROUND: Hypoglycaemia during hospital admission is associated with poor outcomes including increased length of stay. In this study, we compared the incidence of inpatient hypoglycaemia and length of stays among people of three age groups: ≤65 years, 65-80 years and >80 years old. METHODS: The study was conducted using a 4-year electronic patient record dataset from Oxford University Hospitals NHS Foundation Trust. The dataset contains hospital admission data for people with diabetes. We analysed the blood glucose (BG) measurements and identified all level 1 (BG <4 mmol/l) and level 2 (BG <3 mmol/l) hypoglycaemic episodes. We compared the length of stays between different age groups and with different levels of hypoglycaemia. RESULTS: We analysed data obtained from 17,658 inpatients with diabetes who underwent 32,758 hospital admissions. The length of stays for admissions with no hypoglycaemia were 3[1,6], 3[1,8] and 4[2,11] (median[interquartile range]) days for age groups ≤65 years, 65-80 years and >80 years, respectively. These were statistically significantly lower (P < 0.01 for all pairwise comparisons) than the length of stays for admissions with level 1 hypoglycaemia, which were 6[3,13], 10[5,20] and 12[6,22] days, and level 2 hypoglycaemia, which were 7[3,14], 11[5,24] and 13[6,24] days. CONCLUSIONS: In all age groups, admissions with either level 1 or level 2 hypoglycaemia were associated with an increased length of stay. However, in both the older groups, the length of stay increments were much higher (double) than the younger counterparts. The clinical consequences of hypoglycaemia were more severe in older people compared with the younger population.

Home-based narrowband UVB, topical corticosteroid or combination for children and adults with vitiligo: HI-Light Vitiligo three-arm RCT.

BACKGROUND: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo. OBJECTIVE: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo. DESIGN: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up. SETTING: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community. PARTICIPANTS: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area. INTERVENTIONS: Topical corticosteroids [mometasone furoate 0.1% (Elocon®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based. MAIN OUTCOME MEASURES: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment). RESULTS: In total, 517 participants were randomised (adults, n = 398; and children, n = 119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%; p = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%; p = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective). LIMITATIONS: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase. CONCLUSION: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed. FUTURE WORK: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN17160087. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.

The Home Interventions and Light therapy for the treatment of vitiligo (HI-Light Vitiligo) trial aimed to find out whether or not treating vitiligo at home with a narrowband ultraviolet B light, either by itself or with a steroid ointment, is better than treatment using a steroid ointment only. We enrolled 517 children (aged ≥ 5 years) and adults who had small, active (i.e. recently changing) patches of vitiligo into the study. Participants received one of three possible treatment options: steroid ointment (plus dummy light), hand-held narrowband ultraviolet B light therapy (plus placebo ointment) or both treatments used together. We asked participants to judge how noticeable their target vitiligo patch was after 9 months of treatment. We considered the treatment to be successful if the participants' responses were either 'a lot less noticeable' or 'no longer noticeable'. The results showed that using both treatments together was better than using a steroid ointment on its own. Around one-quarter of participants (27%) who used both treatments together said that their vitiligo was either 'no longer noticeable' or 'a lot less noticeable' after 9 months of treatment. This was compared with 17% of those using steroid ointment on its own and 22% of those using narrowband ultraviolet B light on its own. All treatments were able to stop the vitiligo from spreading. Patches on the hands and feet were less likely to respond to treatment than patches on other parts of the body. The trial found that the vitiligo tended to return once treatments were stopped, so ongoing intermittent treatment may be needed to maintain the treatment response. The treatments were found to be relatively safe and easy to use, but light treatment required a considerable time commitment (approximately 20 minutes per session, two or three times per week). This trial showed that using steroid ointment and narrowband ultraviolet B light together is likely to be better than steroid ointment alone for people with small patches of vitiligo. Steroid ointment alone can still be effective for some people and remains a useful treatment that is able to stop vitiligo from spreading. The challenge is to make hand-held narrowband ultraviolet B light treatment available as normal care in the NHS for people with vitiligo.

Case of Primary Breast and Ipsilateral Axillary T-Cell Lymphoma: a Rare Occurrence.

BACKGROUND: Malignant lymphomas of the breast are rare and can be primary or secondary. Non-Hodgkin Lymphoma involving the breast is even rarer comprising 0.04-0.5% of all breast malignancies (Takemura). The incidence is even lower for T-cell lymphomas compared with B-cell subtype. We report the rare incidence of primary T-cell lymphoma involving both breast and ipsilateral axilla. CASE: This is the case of an 80-year-old female who initially presented with asymmetry of her right breast. Initial mammograms were inconclusive. MRI could not be performed due to the patient's severe claustrophobia. The patient was then lost to follow-up but re-presented with a new palpable density in the same breast. Subsequent mammogram showed a suspicious lesion with suspicious right axillary lymphadenopathy. Core biopsy was consistent with T-cell lymphoproliferative disorder involving both the breast and the axilla. She was then referred to medical oncology for management. CONCLUSION: Although rare, lymphoproliferative disorders of the breast can be encountered during workup for suspicious breast lesions. It is imperative that the surgeon is aware of this rare diagnosis to facilitate appropriate therapeutic intervention.

Adipostatins E-J, New Potent Antimicrobials Identified as Inhibitors of Coenzyme-A Biosynthesis.

Phosphopantetheine is a key structural element in biological acyl transfer reactions found embedded within coenzyme A (CoA). Phosphopantothenoylcysteine synthetase (PPCS) is responsible for installing a cysteamine group within phosphopantetheine. Therefore, it holds considerable potential as a drug target for developing new antimicrobials. In this study, we adapted a biochemical assay specific for bacterial PPCS to screen for inhibitors of CoA biosynthesis against a library of marine microbial derived natural product extracts (NPEs). Analysis of the NPE derived from Streptomyces blancoensis led to the isolation of novel antibiotics (10-12, and 14) from the adipostatin class of molecules. The most potent molecule (10) displayed in vitro activity with IC50= 0.93 µM, against S. pneumoniae PPCS. The whole cell antimicrobial assay against isolated molecules demonstrated their ability to penetrate bacterial cells and inhibit clinically relevant pathogenic strains. This establishes the validity of PPCS as a pertinent drug target, and the value of NPEs to provide new antibiotics.

Bacterial colonisation of the endotracheal tube in ventilated very preterm neonates: A retrospective cohort study.

AIM: To determine the rate, type and timing of bacterial endotracheal tube (ETT) colonisation in neonates born <32 weeks gestational age (GA); and if bacterial colonisation is associated with chronic lung disease (CLD), septicaemia, length-of-stay or mortality. METHODS: All intubated newborns born <32 weeks GA were included. Endotracheal aspirates were routinely obtained three times-per-week. Cohort was divided into three colonisation groups: no growth, normal respiratory flora only, significant bacteria. Logistic regression was performed to identify if ETT bacterial colonisation was associated with CLD, septicaemia or mortality. A general linear model was fitted for length-of-stay. RESULTS: ETT aspirates were sent from 1054 infants: no growth n = 319, only normal respiratory flora n = 357, and significant bacteria n = 378. ETTs became colonised in 70%, most in the first week of life (82%). Most grew normal respiratory flora (642 infants). In those with significant bacteria, 40% grew Gram-negative species; Klebsiella in 34%. Staphylococcus aureus grew in 104 patients. Adjusted odds ratios for CLD (43% of cohort) compared with no growth were, for normal respiratory flora, 0.58 (95% confidence interval (CI) 0.34-0.99) and, for significant bacteria, 0.48 (95% CI 0.24-0.93). With no overall association between colonisation group and CLD in the adjusted model P = 0.07. The odds of septicaemia (10% of cohort) were 4.50 (95% CI 1.98-10.23, P < 0.001) times greater for significant bacteria compared with no growth. No significant associated was found with mortality or length-of-stay. CONCLUSIONS: Bacterial colonisation of ETTs is common. It is associated with more septicaemia. There was no significant association with CLD, longer admission or mortality.