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Summary: Background: Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population. Methods: In a multicentre, multinational, parallel randomised controlled trial, participants aged 6–18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA1c levels between 53 and 86 mmol/mol (7·0–10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA1c. The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299. Findings: Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA1c was lower in the closed-loop group than in the control group (between-group difference −3·5 mmol/mol (95% CI −6·5 to −0·5 [–0·32 percentage points, −0·59 to −0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26–53]), but consistently high with CamAPS FX (93% [88–96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis. Interpretation: The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX. Funding: National Institute of Diabetes and Digestive and Kidney Diseases.

ABSTRACT: Objective: Euglycemic diabetic ketoacidosis (DKA) is a known potential complication from sodium-glucose cotransporter 2 (SGLT2) inhibitor use. We present a unique case presentation of a 44-year-old, male patient on an SGLT2 inhibitor who developed euglycemic DKA while following a carbohydrate-restricted diet, the Atkins diet.Methods: The patient was on sitagliptin and metformin after a hemoglobin A1c result of 9.3% (78 mmol/mol). Motivated to obtain better glycemic control and weight loss, he started on the Atkins diet, but stayed in the carbohydrate-restricted first phase of the diet. Canagliflozin was added to his regimen 1 month later. Three to four days after starting on the medication, he developed severe abdominal pain.Results: The patient was found to have anion gap metabolic acidosis with an elevated beta-hydroxybutyrate level of 75.50 mg/dL (the reference range is 0.20 to 2.80 mg/dL) and a blood glucose value of 180 mg/dL.Conclusion: The low-carbohydrate diet likely predisposed our patient to a ketogenic metabolic state and the addition of canagliflozin likely precipitated the worsening of his ketosis and subsequent DKA. For patients taking SGLT2 inhibitors, carbohydrate-restricted diet plans may increase the risk of developing euglycemic DKA.Abbreviations: DKA diabetic ketoacidosis SGLT2 sodium-glucose cotransporter 2

We quantified total phospholipid (PL), total and disaturated phosphatidylcholine (PC and DSPC), phosphatidylglycerol (PG), and total protein in alveolar washings and lung tissue in 22 dog lungs. Quantitative recovery of alveolar material and assessment of its possible contamination by blood lipids were important determinants of methodology. To remove blood, the vessels of half the lungs were perfused with a fluorocarbon emulsion before lavage. The volume of blood removed by perfusion and the quantity and fatty acid patterns of its whole blood and plasma PL and PC were determined. Washings of unperfused lungs contained means of 21% more PL and 24% more PC than those of perfused lungs. Although this excess could be accounted for by the PL and PC in pulmonary blood, the hemoglobin and total protein content of washings and their PC fatty acid patterns indicated that blood lipids were not a major source of the excess lipid in washings of unperfused lungs. Using more recent morphometric estimates rather than the indirect ones previously used by others, the quantity of alveolar DSPC (1 mg/g lung) is calculated to be 1.8 times the amount necessary to form a packed monolayer on the internal surface of the lung at functional residual capacity.

A simple, direct and non-destructive method for quantitative separation of phosphatidylglycerol from other phospholipids in pulmonary washings is described. Total lipid extracts from dog lung washings and phosphatidylglycerol standard were spotted quantitatively on chromatoplates and separated by one-dimensional thin-layer chromatography in chloroform-methanol-water 65:25:4 (v/v/v). Quantification was performed with Rhodamine 6G and fluorometry. Washings from eleven dogs contained (mean +/- S.E.) 236 +/- 25 microgram phosphatidylglycerol per g of parenchymal wet lung tissue which accounted for 8.7% +/- 2.3 of the total phospholipids. The procedure is especially useful for quantification of phosphatidylglycerol in microgram amounts.

Quantities and qualities of lipids in lung lavage and lavaged lung tissue were studied in ethanol-fed male Sprague-Dawley rats. Experimental rats received 36% of daily energy as ethanol for 7 weeks and each control rat, receiving an isocaloric amount of sucrose, was pair-fed with an experimental rat. Body weight gain and lung protein content in these two groups were similar. The mean lung dry weight of ethanol-fed rats as compared to controls was significantly elevated. The quantity of phosphatidylcholine (PC), a key surfactant lipid, recovered from lung lavage of ethanol-fed rats was double that of controls, but the proportion of palmitate in its fatty acids was reduced. The content of cholesterol and cholesteryl ester in lung lavage of ethanol-fed rats was nearly twice that of controls but the content of triglyceride was not different. The quantity and quality of PC in lung tissue were not significantly different between these two groups. Triglyceride content of lung tissue in ethanol-fed rats was nearly three times that of controls. Ethanol increased the proportion of oleic and decreased the relative amount of palmitic, palmitoleic, and linoleic acids in triglycerides of lung tissue.

Acute alveolar injury closely resembling that seen in humans was induced in dogs by subcutaneous injection of N-nitroso-N-methylurethane. Necrosis of alveolar epithelial cells was observed during early injury. Proliferation of immature epithelial cells which began during early injury and became massive after peak injury was followed by their differentiation to mature type II cells during recovery. Quantities of diphosphatidylglycerol (DPG) and of phosphatidylglycerol (PG) in alveolar lavage and in post-lavage lung tissue were measured. An increase in tissue DPG coincided with a sharp decrease in tissue and lavage PG during early injury. DPG was not detectable in the lavage. During late recovery, tissue DPG increased threefold over controls. This increase was accompanied by persistence of a 50% decrease in tissue PG and 83% decrease in lavage PG. Biosynthesis of DPG and PG in isolated lung mitochondria demonstrated that DPG was formed from PG in the presence of CDP-diglyceride. These findings suggest that the low level of PG in the surfactant complex during acute alveolar injury is due to increased turnover of PG to DPG in the lung.

Lung surfactant was isolated from bronchoalveolar lavage of dogs during the late phase of recovery (15 days) from acute alveolar injury induced by subcutaneous injection of N-nitroso-N-methylurethane. This surfactant was compared with surfactant from control dogs in terms of in vitro surface properties, phospholipid composition and protein content, and those of its subfractions. Phospholipid composition and protein content were similar in the two groups, except that phosphatidylglycerol (PG) was markedly reduced and phosphatidylinositol (PI) was increased in the experimental group. In both, isopycnic densities of their subfractions in continuous sucrose density gradient were identical. The time course of surfactant adsorption was similar in both groups. Minimum surface tension (gamma min) was 4.1 +/- 1.5 dynes/cm in the experimental dogs and 3.8 +/- 1.3 dynes/cm in the controls. Surface compressibility (SC), stability index (SI), and dynamic respreadability (DR) of the surfactants from the two groups were nearly identical. When compared to an artificial surfactant composed of dipalmitoyl phosphatidylcholine (DPPC) and PG in 9:1 molar ratio a mixture of DPPC-PI 9:1 prepared identically showed similar gamma min, SC, SI, and DR, and a much higher surface adsorption rate. These results suggest that PG is not essential for normal in vitro surfactant function and that its role may be assumed by PI.

Objective: The objective of this study is to determine if older adults regularly participating in Irish set dancing have superior balance, physical fitness and quality of life compared to age-matched controls., Study Design: This study used a community-based, observational cross-sectional design., Methods: Regular set dancers (n = 39) and age-matched controls (n = 33) were recruited. Participants were assessed using the physical activity scale for the elderly (physical activity levels), mini-BESTest (balance) and senior fitness test (battery of functional fitness tests). Quality of life was also assessed using the EuroQol EQ visual analogue scale., Results: When controlling for between-group differences in levels of physical activity (ANCOVA analysis), the dancers had significantly better balance, functional capacity and quality of life (all P < 0.05) compared to controls. No differences between the groups were observed in other measures of functional fitness., Conclusion: The findings of this study suggest regular participation in set dancing is associated with health benefits for older adults. These results may inform future studies prospectively examining the role of set dancing for falls prevention, emotional well-being and cognitive function in community-dwelling older adults., (Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Poor adherence to treatment diminishes its individual and public health benefit. Financial incentives, provided on the condition of treatment attendance, could address this problem. Injecting drug users are a high-risk group for hepatitis B virus (HBV) infection and transmission, but adherence to vaccination programmes is poor. We aimed to assess whether contingency management delivered in routine clinical practice increased the completion of HBV vaccination in individuals receiving opioid substitution therapy., Methods: In our cluster randomised controlled trial, we enrolled participants at 12 National Health Service drug treatment services in the UK that provided opioid substitution therapy and nurse-led HBV vaccination with a super-accelerated schedule (vaccination days 0, 7, and 21). Clusters were randomly allocated 1:1:1 to provide vaccination without incentive (treatment as usual), with fixed value contingency management (three £10 vouchers), or escalating value contingency management (£5, £10, and £15 vouchers). Both contingency management schedules rewarded on-time attendance at appointments. The primary outcome was completion of clinically appropriate HBV vaccination within 28 days. We also did sensitivity analyses that examined vaccination completion with full adherence to appointment times and within a 3 month window. The trial is registered with Current Controlled Trials, number ISRCTN72794493., Findings: Between March 16, 2011, and April 26, 2012, we enrolled 210 eligible participants. Compared with six (9%) of 67 participants treated as usual, 35 (45%) of 78 participants in the fixed value contingency management group met the primary outcome measure (odds ratio 12·1, 95% CI 3·7-39·9; p<0·0001), as did 32 (49%) of 65 participants in the escalating value contingency management group (14·0, 4·2-46·2; p<0·0001). These differences remained significant with sensitivity analyses., Interpretation: Modest financial incentives delivered in routine clinical practice significantly improve adherence to, and completion of, HBV vaccination programmes in patients receiving opioid substitution therapy. Achievement of this improvement in routine clinical practice should now prompt actual implementation. Drug treatment providers should employ contingency management to promote adherence to vaccination programmes. The effectiveness of routine use of contingency management to achieve long-term behaviour change remains unknown., Funding: National Institute for Health Research (RP-PG-0707-10149)., (Copyright © 2014 Weaver et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.)

Background: Narrative therapy (White & Epston, 1990) was developed as an approach to counselling, as a response to the power relations that influence people's lives. Its use with people who stutter has been documented. A basic tenet of narrative therapy is that the dominant problem-saturated narrative is challenged by externalizing the problem, in due course facilitating development of an alternative narrative. Within this process, the definitional ceremony involving outsider witnesses is a key procedure used to influence change., Aims: This paper describes definitional ceremonies, and their application within a narrative approach to therapy for stuttering. The analysis of a specific definitional ceremony is presented, leading to an exploration of identity as a public and social achievement., Methods: A definitional ceremony involving a woman who stutters and family members was recorded and analysed using two methods: interpretative phenomenological analysis and Heideggerian hermeneutic phenomenological analysis. Details of the clinical application of definitional ceremonies with this client are described., Results and Conclusions: Results from both methods of analysis were found to be similar. Notable results include the fact that the stuttering per se was not presented as the problem; rather, the impact of stuttering, especially the experience of bullying, was a dominant theme. This paper shows how definitional ceremonies can open opportunities for clients to present themselves in a preferred way, forming the basis for a new story and revised identity. Emerging themes can be identified for reflection and discussion with the client for therapeutic benefit., Educational Objectives: (1) to describe and explain to readers the process of narrative therapy, with special attention to the use of definitional ceremonies; (2) to provide detail regarding the clinical processes involved with a specific definitional ceremony with one client; (3) to have the reader appreciate the specific importance of involving outsider witnesses in the therapy process; (4) to discuss the outcomes of the use of this particular definitional ceremony., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Unlabelled: The IGHV3-21 gene has been shown to be overrepresented in Scandinavian patients with chronic lymphocytic leukemia (CLL). By investigating a population-based cohort of 337 Swedish patients with CLL, a lower (6.5%)IGHV3-21 frequency was determined relative to our previous hospital-based studies (10.1%-12.7%), yet this frequency remained higher compared to other Western CLL cohorts (2.6%-4.1%). Furthermore, we confirmed the poor outcome for patients with IGHV3-21 to be independent of mutational and stereotypy status., Background: Scandinavian patients with CLL have shown an overrepresentation of the poor-prognostic IGHV3-21 gene. Furthermore, approximately 50% of patients with IGHV3-21 carry stereotyped B-cell receptors, which implicate antigen selection in leukemogenesis. These patients have also been reported to have shorter time to progression than patients with nonstereotyped IGHV3-21., Materials and Methods: To investigate the IGHV3-21 frequency and the clinical impact of IGHV3-21 stereotypy, 337 newly diagnosed Swedish CLL patients from a population-based cohort were analyzed., Results: Interestingly, the IGHV3-21 frequency was indeed lower (6.5%) in this indolent patient cohort than in our previous hospital-based cohort studies (10.1%-12.7%). Hence, a selection bias of more-aggressive cases rendered a higher proportion of IGHV3-21 cases in our original studies. Nevertheless, the Swedish IGHV3-21 frequency still remained higher when compared with other larger European or American studies (2.6%-4.1%). Finally, we confirmed the poor outcome for IGHV3-21 patients to be independent of mutational status and found stereotypy to have no impact on survival or time to treatment., Conclusion: The Swedish geographic bias in IGHV3-21 gene frequency was validated albeit at a lower frequency than previously reported. Moreover, no prognostic value could be attributed to IGHV3-21 stereotype status., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs)., Methods: We compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 h (daily oral gavage). In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D(2), ex vivo thromboxane B(2) (TXB(2)) levels and plasma pharmacokinetics., Results: ST0702 is metabolised in vivo to aspirin, niacin and salicylic acid with T(max) values of 30, 45 and 95 min respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 h period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex vivo serum TXB(2) generation was suppressed at 15 min and complete suppression of TXB(2) was sustained at 24h (p<0.01 vs niacin). ST0702 suppressed PGD(2) exposure eightfold (p = 0.012) compared to niacin over the first 24h., Conclusions: This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB(2) and PGD(2) increases and prevents post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Global hypomethylation and regional hypermethylation are well-known epigenetic features of cancer; however, in chronic lymphocytic leukemia (CLL), studies on genome-wide epigenetic modifications are limited. Here, we analyzed the global methylation profiles in CLL, by applying high-resolution methylation microarrays (27,578 CpG sites) to 23 CLL samples, belonging to the immunoglobulin heavy-chain variable (IGHV) mutated (favorable) and IGHV unmutated/IGHV3-21 (poor-prognostic) subsets. Overall, results demonstrated significant differences in methylation patterns between these subgroups. Specifically, in IGHV unmutated CLL, we identified methylation of 7 known or candidate tumor suppressor genes (eg, VHL, ABI3, and IGSF4) as well as 8 unmethylated genes involved in cell proliferation and tumor progression (eg, ADORA3 and PRF1 enhancing the nuclear factor-kappaB and mitogen-activated protein kinase pathways, respectively). In contrast, these latter genes were silenced by methylation in IGHV mutated patients. The array data were validated for selected genes using methylation-specific polymerase chain reaction, quantitative reverse transcriptase-polymerase chain reaction, and bisulfite sequencing. Finally, the significance of DNA methylation in regulating gene promoters was shown by reinducing 4 methylated tumor suppressor genes (eg, VHL and ABI3) in IGHV unmutated samples using the methyl-inhibitor 5-aza-2'-deoxycytidine. Taken together, our data for the first time reveal differences in global methylation profiles between prognostic subsets of CLL, which may unfold epigenetic silencing mechanisms involved in CLL pathogenesis.

Background: Increased frequency of prothrombin time testing, facilitated by patient self-testing (PST) of the International Normalized Ratio (INR) can improve the clinical outcomes of oral anticoagulation therapy (OAT). However, oversight of this type of management is often difficult and time-consuming for healthcare professionals. This study reports the first randomized controlled trial of an automated direct-to-patient expert system, enabling remote and effective management of patients on OAT., Methods: A prospective, randomized controlled cross-over study was performed to test the hypothesis that supervised PST using an internet-based, direct-to-patient expert system could provide improved anticoagulation control as compared with that provided by an anticoagulation management service (AMS). During the 6 months of supervised PST, patients measured their INR at home using a portable meter and entered this result, along with other information, onto the internet web page. Patients received instant feedback from the system as to what dose to take and when the next test was due. During the routine care arm, patients attended the AMS at least every 4-6 weeks and were dosed by the anticoagulation pharmacist or physician. The primary outcome variable was the difference in the time in therapeutic range (TTR) between both arms., Results: One hundred and sixty-two patients were enrolled (male 61.6%, mean age 58.7 years), and 132 patients (81.5%) completed both arms. TTR was significantly higher during PST management than during AMS management (median TTR 74% vs 58.6%; z=5.67, P < 0.001)., Conclusions: The use of an internet-based, direct-to-patient expert system for the management of PST improves the control of OAT as compared with AMS management.

Objective: Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). In our study, microarray technology was used to identify genes, which may impair placentation resulting in IUGR., Study Design: The RNA was isolated from both IUGR term placentas and normal term placentas. Microarray experiments were used to identify differentially expressed genes between the 2 cohorts. Real-time quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry were used in follow-up experiments., Results: Microarray experiments identified increased expression of certain genes including leptin, soluble vascular endothelial growth factor receptor, human chorionic gonadotropin, follistatin-like 3, and hypoxia-inducible factor 2alpha in the IUGR. Real-time quantitative polymerase chain reaction confirmed these results., Conclusion: The upregulation of soluble vascular endothelial growth factor receptor and hypoxia-inducible factor 2alpha at this period in pregnancy indicate that placental angiogenesis is altered in IUGR and that hypoxia is a major contributor to maldevelopment of the placental vasculature.

Purpose: To describe the ophthalmic findings in patients with Danon disease, an X-linked condition causing cardiomyopathy in males and females., Design: Retrospective case series., Participants: Patients with genetically proven Danon disease., Methods: Retrospective chart review of complete eye examinations including electroretinogram, visual fields, and fluorescein angiography., Results: Five females (4 affected) and 2 affected males were examined. The 4 affected females demonstrated a peripheral pigmentary retinopathy. Lens changes, myopia, abnormal electroretinogram and visual fields were also found. The males demonstrated a near-complete loss of pigment in the retinal pigment epithelium., Conclusion: We report the first description of a characteristic retinopathy in patients with Danon disease and the first extracardiac manifestations in affected females. Retinopathy potentially could be used to identify asymptomatic carriers.

Introduction: This retrospective study compared cephalometric variables between responders and nonresponders to a titratable oral appliance (OA) in a group of subjects matched for sex, pretreatment age, and body mass index (BMI)., Methods: Nine nonresponders as defined by an improvement in the apnea hypopnea index (AHI; <20%) and their individually matched responders were selected for this study. The difference in age for each matched pair was +/-5 years, and, for BMI, the difference was +/-15%. The pretreatment AHI was matched to the same category (moderate, >15 to < or =30; severe I, >30 to < or =45; and severe II, >45 AHI)., Results: Middle and inferior airway space and oropharyngeal airway cross-sectional area were significantly larger in the nonresponders. Position of the mandible relative to the cervical spine was the only significant skeletal variable and was larger in nonresponders. Changes in BMI between the groups were statistically significant; the averages were a 2.9% increase in the nonresponders and a 0.5% decrease in responders. The wider airway in nonresponders might reflect an enhanced neuromuscular compensation while awake. The weight gain in nonresponders was relatively small, but it might have reduced the effectiveness of the OA., Conclusion: When treating OSA patients with OA therapy, clinicians should pay particular attention to airway size and weight changes.

The morbidity related to caustic soda (sodium hydroxide) ingestion is well described in the literature. The majority of publications have concentrated on the effects to the trachea and gastrointestinal tract, with little reference to the oral and peri-oral areas. Accidental ingestion of sodium hydroxide-containing substances is fortunately rare; however the consequences can be devastating. Three cases of children who drank caustic substances are described. Treatment included fitting splints, injecting steroids, local surgical procedures, and the use of dynamic appliances to maintain mouth opening. Despite these interventions, all patients developed severe scarring, resulting in stenosis of the oral musculature and extra-articular ankylosis. There is perhaps a role for further investigation of early use of antiproliferative agents to prevent scarring, more aggressive surgery, and long-term physiotherapy appliance use. These patients require lifelong follow-up.

Latinos who present for health services often suffer from a complex interaction of medical and mental health needs, requiring a multifaceted intervention. An essential element of this multilevel approach is cultural and linguistic sensitivity on the part of health providers. New, innovative models of health service organization are needed to address the unique needs of the Latino population. Some of the key characteristics these models need to focus on include interagency collaboration rather than competition for resources, interdisciplinary teams of primary-care providers that also involve other nonmedical professional members, centralized case coordination and decentralized service delivery, flexibility and adaptability to changing priorities, continuity of care for all patients, and mutual support among providers to minimize the effects of stress and burnout.