Nucleosome repositioning in chronic lymphocytic leukemia.

The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral blood B cells from patients with chronic lymphocytic leukemia (CLL) and healthy individuals at single-base-pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes-the nucleosome repeat length (NRL)-is shortened in CLL. This effect is stronger in the more aggressive IGHV-unmutated CLL subtype than in the IGHV-mutated CLL subtype. Changes in nucleosome occupancy at specific sites are linked to active chromatin remodeling and reduced DNA methylation. Nucleosomes lost or gained in CLL marks differential binding of 3D chromatin organizers such as CTCF as well as immune response-related transcription factors and delineated mechanisms of epigenetic deregulation. The principal component analysis of nucleosome occupancy in cancer-specific regions allowed the classification of samples between cancer subtypes and normal controls. Furthermore, patients could be better assigned to CLL subtypes according to differential nucleosome occupancy than based on DNA methylation or gene expression. Thus, nucleosome positioning constitutes a novel readout to dissect molecular mechanisms of disease progression and to stratify patients. Furthermore, we anticipate that the global nucleosome repositioning detected in our study, such as changes in the NRL, can be exploited for liquid biopsy applications based on cell-free DNA to stratify patients and monitor disease progression.

The role of Bruton's tyrosine kinase in the immune system and disease.

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

Accuracy of Screening Tests for Celiac Disease in Asymptomatic Patients With Type 1 Diabetes.

INTRODUCTION: To evaluate the diagnostic performance of celiac serologic tests in asymptomatic patients with type 1 diabetes (T1D). METHODS: Patients with T1D asymptomatic for celiac disease were prospectively screened with immunoglobulin A anti-tissue transglutaminase. Test characteristics were calculated and optimal cutoffs for a positive screen determined. RESULTS: Two thousand three hundred fifty-three patients were screened and 101 proceeded to biopsy. The positive predictive value of immunoglobulin A anti-tissue transglutaminase at the assay referenced upper limit of normal (30CU) was 85.9%, and the sensitivity and specificity were 100% and 38%, respectively. DISCUSSION: Thresholds extrapolated from the general population for the diagnostic evaluation of celiac disease are not suitable for use in asymptomatic T1D patients. Population-specific screening cutoffs are required.

Quality control of uroflowmetry and urodynamic data from two large multicenter studies of male lower urinary tract symptoms.

AIM: The International Continence Society (ICS) has standardized quality control and interpretation of uroflowmetry and urodynamics. We evaluated traces from two large studies of male lower urinary tract symptoms (UPSTREAM and UNBLOCS) against ICS standards of urodynamic equipment and practice. METHODS: Ten percent of uroflowmetry and urodynamics traces were selected at random from hospital sites. A data capture template was designed from the ICS Fundamentals of Urodynamic Practice checklist. Two pretrained blinded assessors extracted the data, with a third assessor to arbitrate. Departmental records of calibration checks and equipment maintenance were scrutinized. RESULTS: Seven out of twenty-five (28%) departments reported no calibration checks. Four sites (16%) could not provide annual service records. In 32 out of 296 (10.8%) uroflowmetry traces, findings were affected by artifact. One hundred ten urodynamic study traces were reviewed; in 11 records (10%), key pressure traces were incompletely displayed. In 30 (27.2%), reference zero was not set to atmospheric pressure. Resting pressures were outside the expected range for 36 (32.7%). Pressure drift was seen in 18 traces (16.4%). At pressure-flow study commencement, permission to void was omitted in 15 (13.6%). Cough testing after voiding was done in 71.2%, but the resulting cough spikes were significantly different in 16.5%. Erroneous diagnosis of bladder outlet obstruction (BOO) was identified in six cases (5.5%). CONCLUSIONS: Erroneous diagnosis of BOO is a serious error of interpretation, as it could lead to unnecessary surgery. Other errors of standardization, testing, and interpretation were identified with lower risk of adverse implications. Inconsistent documentation of service records mean equipment accuracy is uncertain.

Return to illicit drug use post-incarceration among formerly incarcerated Black Americans.

AIMS: The number of drug dependent individuals incarcerated in the U.S. is exceptionally high, and reportedly 60 percent of incarcerated Black Americans have a substance abuse disorder. The purpose of this study was to identify factors associated with return to illicit drug use post-incarceration. METHODS: A cross-sectional study was conducted with 121 formerly incarcerated Black Americans in New York City to examine predictors of return to illicit drug use. Kaplan-Meier curves were generated on the outcome of time-to-drug use for various predictors and compared using the log-rank test. Cox proportional hazards models were used to identify significant predictors of return to illicit drug use post-incarceration. FINDINGS: Approximately 83 percent (n=100) of the participants reported a history of illicit drug use, not including participants who have only used marijuana. Out of 121 participants, 36 (29.8%) had used drugs within one day after release. By two weeks after release, half had used drugs. Gender and history of heroin use were significant predictors of time-to-drug use according to the log rank test. CONCLUSIONS: The potential for immediate return to drug use among our sample suggests that discharge support programs that focus specifically on healthy decision-making among women and heroin users are especially critical.

Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial.

BACKGROUND: Hyperglycaemia could substantially increase the risk of ischaemic heart disease in patients with type 2 diabetes. We investigated whether intensive lowering of glucose concentrations affects risk. METHODS: We assessed 10,251 adults aged 40-79 years with established type 2 diabetes, mean glycated haemoglobin A1c (HbA1c) concentration of 67 mmol/mol (8·3%), and risk factors for ischaemic heart disease enrolled in the ACCORD trial. Participants were assigned to intensive or standard therapy (target HbA1c less than 42 or 53-63 mmol/mol [less than 6·0% or 7·0-7·9%], respectively). We assessed fatal or non-fatal myocardial infarction, coronary revascularisation, unstable angina, and new angina during active treatment (mean 3·7 years) plus a further mean 1·2 years. This trial is registered with ClinicalTrials.gov, number NCT00000620. FINDINGS: Myocardial infarction was less frequent in the intensive than in the standard therapy group during active treatment (hazard ratio [HR] 0·80, 95% CI 0·67-0·96; p=0·015) and overall (0·84, 0·72-0·97; p=0·02). Findings were similar for combined myocardial infarction, coronary revascularisation, and unstable angina (active treatment HR 0·89, 95% CI 0·79-0·99, overall 0·87 0·79-0·96) and for coronary revascularisation alone (0·84, 0·75-0·94) and unstable angina alone (0·81, 0·67-0·97) during full follow-up. With lowest achieved HbA1C concentrations included as a time-dependent covariate, all hazards became non-significant. INTERPRETATION: Raised glucose concentration is a modifiable risk factor for ischaemic heart disease in middle-aged people with type 2 diabetes and other cardiovascular risk factors. FUNDING: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Eye Intitute, and Centers for Disease Control and Prevention.

Evaluation by microarray of the potential safety of Sarracenia purpurea L. (Sarraceniaceae) a traditional medicine used by the Cree of Eeyou Istchee.

PURPOSE: The purpose of this study was to assess safety of the traditional antidiabetic extracts of either S. purpurea or its lead active principle, morroniside at the transcriptional level. The overarching objective was to profile and validate transcriptional changes in the cytochrome P450 family of genes, in response to treatment with S. purpurea ethanolic extract or its lead active, morroniside. METHODS: Transcriptional activity was profiled using a 19K human cDNA microarray in C2BBe1 cells, clone of Caco-2 intestinal cells, which are a model of first-pass metabolism (1, 2). Cells were treated with S. purpurea extract for 4 and 24 hrs, as well as the pure compound morroniside for 4 hrs, to determine their effects. RESULTS: No evidence of cytochrome P450 transcriptome regulation or of transcriptional activation of other diabetes relevant mRNA was detected after rigorous quantitative-PCR validation of microarray results. CONCLUSION: Our data do not support a transcriptional mechanism of action for either S. purpurea extract or its lead active, morroniside. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

N-of-1 (single-patient) trials for statin-related myalgia.

BACKGROUND: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE: Western University, London, Ontario, Canada.

Assessing primary care veterinarians' use of and confidence in performing point-of-care ultrasound.

BACKGROUND: Point-of-care ultrasound (POCUS) is gaining popularity in the veterinary field, but there is little information on operator confidence. METHODS: A survey was distributed to primary care veterinarians (PCVs) via social media between May and July 2020. Details of participants' training in and use of POCUS were recorded. Participants' confidence in using thoracic and abdominal POCUS was also assessed using a five-point Likert scale. RESULTS: Two hundred and one PCVs used POCUS, of which 32% reported using a non-standardised protocol. Fifty percent of PCVs were self-taught and 17.4% had attended a specific practical course. The median confidence score was 4 out of 5 (interquartile range [IQR] 2-5) for identifying abdominal abnormalities, irrespective of the training method. The median confidence score for thoracic abnormalities was 3 out of 5 (IQR 1-4) for those taught by a colleague or who were self-taught using journal articles or videos. LIMITATIONS: The survey-based nature of the study relies on self-reporting and is therefore liable to recall bias. CONCLUSIONS: PCVs' confidence in using POCUS is lacking, particularly with thoracic POCUS. Standardised practical training for PCVs, particularly in thoracic POCUS, would be beneficial. Future studies should explore how best to deliver this training.

Gastrointestinal Symptoms in Type 1 Diabetes: Relationship With Autoimmune and Microvascular Complications.

PURPOSE: To assess reported rates of gastrointestinal (GI) symptoms and their association with autoimmune diseases and microvascular complications in adults and children with type 1 diabetes. METHODS: The Gastrointestinal Symptom Scale was used to assess GI symptom type and severity in 2370 patients with type 1 diabetes aged 8 to 45 years evaluated as part of a clinical trial screening for celiac disease (CD). The presence and severity of GI symptoms and relationships with demographic, clinical, and other diabetes-related factors were evaluated. RESULTS: Overall, 1368 adults (57.7%) aged 19 to 45 years and 1002 (42.3%) pediatric patients aged 8 to 18 years were studied. At least 1 GI symptom was reported in 34.1% of adults as compared with 21.7% of children (P < 0.0001). Common symptoms in children included upper and lower abdominal pain while adults more frequently reported lower GI symptoms. Participants with GI symptoms had higher hemoglobin A1c (HbA1c) levels (68 ±â€…14mmol/mol; 8.35 ±â€…1.37%) than those without symptoms (66 ±â€…15mmol/mol; 8.22 ±â€…1.40%; P = 0.041). Patients with microvascular complications (nephropathy, retinopathy, and/or neuropathy) were 1.8 times more likely to report GI symptoms (95% CI: 1.26-2.60; P < 0.01) after adjusting for age and sex. No association was observed between GI symptoms and the presence of autoimmune conditions, including thyroid and biopsy-confirmed CD (odds ratio = 1.1; 95% CI: 0.86-1.42; P = 0.45). MAIN CONCLUSIONS: These results highlight that GI symptoms are an important clinical morbidity and are associated with increasing age, duration of type 1 diabetes, HbA1c, and microvascular complications but not with autoimmune comorbidities including CD.

Randomized double-blinded clinical trial on acute transfusion reactions in dogs receiving leukoreduced versus nonleukoreduced packed red blood cells.

BACKGROUND: Leukoreduction of blood products is commonly performed in human medicine, but its effect on outcome or incidence of transfusion reactions (TRs) in dogs is unknown. OBJECTIVES: To prospectively evaluate the incidence of acute TRs in, and the outcome of, dogs receiving either leukoreduced (LR) or nonleukoreduced (N-LR) packed red blood cells (PRBC). ANIMALS: Dogs (n = 194) administered PRBC between August 2017 and June 2020. METHODS: Prospective randomized double-blinded clinical trial. Dogs were randomized to receive either LR or N-LR PRBC and clinicians, nurses and investigators were blinded to the group allocations. The incidence of TRs, change in PCV, hospitalization duration, and survival to discharge were recorded. RESULTS: Out of the 194 dogs, 96 received LR and 98 received N-LR PRBCs. The mean 12-hour change in PCV value was +9.22% (SD 5.27%) for dogs that received N-LR and +10.69% (SD 6.44%) for dogs that received LR PRBC (effect size 0.26, 95% confidence interval [CI] -0.02 to 0.55), which was not significantly different (P = .08). TRs were documented in 16/194 (8.24%) dogs, with 1/194 (0.51%) being a mild allergic reaction, while 15/194 (7.73%) had suspected febrile nonhemolytic TRs (FNHTRs). FNHTR incidence was not significantly different between the LR (6/96, 6.25%, 95% CI 2.8-13.56) and N-LR (9/98, 9.18%, 95% CI 4.92-17.11) groups (P = .81). Of the 156 dogs that survived to discharge, 80/156 received N-LR PRBC and 76/156 received LR PRBC which was not significantly different (P = .66). CONCLUSIONS AND CLINICAL IMPORTANCE: A clinical advantage of using LR over N-LR PRBC in terms of TRs and increase in PCV after transfusion was not detected.

Impact of a Gluten-Free Diet on Quality of Life and Health Perception in Patients With Type 1 Diabetes and Asymptomatic Celiac Disease.

CONTEXT: Celiac disease (CD) is a common comorbidity seen in patients with type 1 diabetes (T1D) and is frequently asymptomatic. As chronic conditions requiring significant lifestyle changes, there are limited reports assessing changes in health-related quality of life (HRQoL) during transition to a gluten-free diet (GFD) in patients with T1D who are asymptomatic for CD. OBJECTIVE: This work aims to prospectively assess HRQoL and health perception in children and adults with T1D and asymptomatic CD after random assignment to GFD vs usual diet. METHODS: Patients with T1D aged 8 to 45 years without CD symptoms were serologically screened for CD, with positive results confirmed with intestinal biopsy. Participants were randomly assigned in an open-label fashion to a GFD or gluten-containing diet (GCD) for 12 months. Generic and diabetes-specific HRQoL and self-perceived wellness (SPW) were assessed longitudinally. RESULTS: A total of 2387 T1D patients were serologically screened. CD was biopsy-confirmed in 82 patients and 51 participants were randomly assigned to a GFD (N = 27) or GCD (N = 24). Excellent adherence to the assigned diets was observed. Overall, no changes in generic (P = .73) or diabetes-specific HRQoL (P = .30), or SPW (P = .41) were observed between groups over 12 months. Hemoglobin A1c (HbA1c) and gastrointestinal symptoms were consistent predictors of HRQoL and SPW. CONCLUSION: HRQoL and SPW were not significantly affected by the adoption of a GFD over 12 months, but worsened with symptom onset and increased HbA1c. Our findings indicate that transition to a GFD can be made successfully in this population without adversely affecting quality of life.

Screening and Treatment Outcomes in Adults and Children With Type 1 Diabetes and Asymptomatic Celiac Disease: The CD-DIET Study.

OBJECTIVE: To describe celiac disease (CD) screening rates and glycemic outcomes of a gluten-free diet (GFD) in patients with type 1 diabetes who are asymptomatic for CD. RESEARCH DESIGN AND METHODS: Asymptomatic patients (8-45 years) were screened for CD. Biopsy-confirmed CD participants were randomized to GFD or gluten-containing diet (GCD) to assess changes in HbA1c and continuous glucose monitoring over 12 months. RESULTS: Adults had higher CD-seropositivity rates than children (6.8% [95% CI 4.9-8.2%, N = 1,298] vs. 4.7% [95% CI 3.4-5.9%, N = 1,089], P = 0.035) with lower rates of prior CD screening (6.9% vs. 44.2%, P < 0.0001). Fifty-one participants were randomized to a GFD (N = 27) or GCD (N = 24). No HbA1c differences were seen between the groups (+0.14%, 1.5 mmol/mol; 95% CI -0.79 to 1.08; P = 0.76), although greater postprandial glucose increases (4-h +1.5 mmol/L; 95% CI 0.4-2.7; P = 0.014) emerged with a GFD. CONCLUSIONS: CD is frequently observed in asymptomatic patients with type 1 diabetes, and clinical vigilance is warranted with initiation of a GFD.

A review of literature about involving people affected by cancer in research, policy and planning and practice.

OBJECTIVE: To systematically review the literature on involving people affected by cancer in healthcare research, policy and planning and practice. METHODS: Database searches, cited author, and grey literature searches were conducted. RESULTS: 131 documents were included. Rationales for the agenda of involvement represent two polar characteristics of modernity: individualism and collectivism. In research, people acted as advocates, strategists, advisors, reviewers and as participatory researchers. In policy and planning, people were involved in one-off involvement exercises and in longer-term partnerships. Men, those with rare cancers, children, and people who are socially deprived have been rarely involved. There is little research evidence about the impact of involvement. Training and information, resources and a change in attitudes and roles are required to implement an agenda of involvement. CONCLUSION: The USA, the UK, followed by Canada and Australia have promoted an agenda of involvement. PRACTICE IMPLICATIONS: A dissemination strategy to share good practice; involvement of all types of people; an individualised and flexible approach; training, resources and a shift in thinking from paternalism towards partnership working are required. More research is needed about the impact of involvement and relationships between rationales for involvement and implementation.

The effectiveness of beta-blockers after myocardial infarction in patients with type 2 diabetes.

OBJECTIVE: Beta-blocker therapy has been proven to reduce mortality and reinfarction after myocardial infarction (MI), but the impact of beta-blockers on cardiac outcomes in patients with type 2 diabetes in routine practice is not clear. The purpose of this study was to determine the effectiveness of beta-blockers after MI in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Using the Saskatchewan Health Databases, 12,272 patients with newly treated diabetes were identified between 1991 and 1996; 625 patients were subsequently admitted for MI. Beta-blocker exposure within 30 days of discharge was identified in 298 patients, and all were followed until death, coverage termination, or 31 December 1999. Multivariate proportional hazards models were used to assess differences in all-cause mortality, recurrent MI, and 30-day all-cause rehospitalization (the latter a proxy measure for drug safety). RESULTS: Patients were aged 69 +/- 11 years old, 66% were male, and mean follow-up was 2.7 +/- 2.1 years. Overall, beta-blockers were prescribed for 48% of patients. There were fewer deaths in the beta-blocker group versus control subjects (55 of 298 [18.5%] vs. 126 of 327 [38.5%], respectively, P < 0.001). However, beta-blockers were not associated with improved survival in multivariate analyses (hazard ratio [HR] 0.89 [95% CI 0.63-1.25]). There were no differences in rates of recurrent MI (adjusted HR 1.35 [0.93-1.95]) or rehospitalizations (adjusted odds ratio 1.40 [0.83-2.37]) between the groups. CONCLUSIONS: Beta-blocker therapy post-MI was not associated with reduced mortality or fewer recurrent events in people with type 2 diabetes in routine practice, although these medications were safe in this population.

Coronary artery disease is common in nonuremic, asymptomatic type 1 diabetic islet transplant candidates.

OBJECTIVE: Coronary artery disease (CAD) is the most common cause of death in patients with type 1 diabetes. Asymptomatic CAD is common in uremic diabetic patients, but its prevalence in nonuremic type 1 diabetic patients is unknown. The prevalence of CAD was determined by coronary angiography and the performance of noninvasive cardiac investigation evaluated in type 1 diabetic islet transplant (ITX) candidates with preserved renal function. RESEARCH DESIGN AND METHODS: A total of 60 consecutive type 1 diabetic ITX candidates (average age 46 years [mean 24-64], 23 men, and 47% ever smokers) underwent coronary angiography, electrocardiographic stress testing (EST), and myocardial perfusion imaging (MPI) in a prospective cohort study. CAD was indicated on angiography by the presence of stenoses >50%. Models to predict CAD were examined by logistic regression. RESULTS: Most subjects (53 of 60) had no history or symptoms of CAD; 23 (43%) of these asymptomatic subjects had stenoses >50%. CAD was associated with age, duration of diabetes, hypertension, and smoking. Although specific, EST and MPI were not sensitive as predictors of CAD on angiography (specificity 0.97 and 0.93, sensitivity 0.17 and 0.04, respectively) but helped identify two of three subjects requiring revascularization. EST and MPI did not enhance logistic regression models. A clinical algorithm to identify low-risk subjects who may not require angiography was highly sensitive but was applicable only to a minority (n = 8, sensitivity 1.0, specificity 0.27, negative predictive value 1.0). CONCLUSIONS: Nonuremic type 1 diabetic patients with hypoglycemic unawareness and/or metabolic lability referred for ITX are at high risk for asymptomatic CAD despite negative noninvasive investigations. Aggressive management of cardiovascular risk factors and further investigation into optimal cardiac risk stratification in type 1 diabetes are warranted.

Celiac Disease and Type 1 Diabetes in Adults: Is This a High-Risk Group for Screening?

The association between celiac disease (CD), an autoimmune condition involving intestinal inflammation related to gluten ingestion, and type 1 diabetes has long been recognized. CD prevalence rates 4 to 6 times greater in adults with type 1 diabetes than in the general population. Much of the existing literature focuses on important implications related to the impact of a gluten-free diet on short-term outcomes in metabolic control and quality of life. Canadian Diabetes Association guidelines recommend targeted CD screening in patients with type 1 diabetes who have classic symptoms, such as abdominal pain, bloating, diarrhea, unexplained weight loss or labile metabolic control; however, a significant proportion (40% to 60%) of patients may have mild or absent symptoms. Recent evidence suggests that adult patients with both conditions are at higher risk for diabetes microvascular comorbidities, increased mortality and impaired bone health if the CD is untreated. The purpose of this review is to describe the association between CD and type 1 diabetes and to summarize recent literature that evaluates risks in patients with both conditions.

The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) protocol: a randomised controlled study to evaluate treatment of asymptomatic coeliac disease in type 1 diabetes.

INTRODUCTION: Coeliac disease (CD) is an autoimmune condition characterised by gluten-induced intestinal inflammation, and observed at a 5-10 fold greater prevalence in type 1 diabetes. While universal screening for CD in patients with diabetes is frequently advocated, objective data is limited as to benefits on diabetes control, bone health or quality of life related to the adoption of a gluten-free diet (GFD) in the large proportion of patients with diabetes with asymptomatic CD. The Celiac Disease and Diabetes-Dietary Intervention and Evaluation Trial (CD-DIET) study is a multicenter, randomised controlled trial to evaluate the efficacy and safety of a GFD in patients with type 1 diabetes with asymptomatic CD. METHODS AND ANALYSIS: Children and adults (8-45 years) with type 1 diabetes will be screened for asymptomatic CD. Eligible patients with biopsy-proven CD will be randomly assigned in a 1:1 ratio to treatment with a GFD for 1 year, or continue with a gluten-containing diet. The primary outcome will evaluate the impact of the GFD on change in glycated haemoglobin. Secondary outcomes will evaluate changes in bone mineral density, blood glucose variability and health-related quality of life between GFD-treated and the regular diet group over a 1-year period. The study was initiated in 2012 and has subsequently expanded to multiple paediatric and adult centres in Ontario, Canada. ETHICS AND DISSEMINATION: The findings from this study will provide high-quality evidence as to the impact of GFD treatment on glycaemic control and complications in asymptomatic children and adults with CD and type 1 diabetes. TRIAL REGISTRATION NUMBER: NCT01566110.

Cross-sectional and prospective association between proinsulin secretion and graft function after clinical islet transplantation.

Proinsulin levels as a marker of beta-cell dysfunction have not been described after clinical islet transplantation. Proinsulin secretion was studied in 23 type 1 diabetic patients after islet allotransplantation and in 20 age-matched nondiabetic controls. Fasting serum insulin, total proinsulin (TP), intact proinsulin, proinsulin fragments (PFs) and their ratios to insulin were determined 1 and 12 months after patients became insulin independent. TP, PF, and proinsulin/insulin ratios were lower in transplant recipients compared with controls, in patients who retained long-term insulin independence. Insulin, C-peptide, and intact proinsulin values were similar in transplant recipients and controls. Hormone levels remained stable over time in the group of patients who retained long-term insulin independence, but the TP and PF levels were higher at 12 months compared with 1 month in the group of patients who resumed insulin therapy. TP and PF levels were reduced in transplant recipients compared with controls but increased over time if insulin independence was lost.

Changes in liver enzymes after clinical islet transplantation.

BACKGROUND: Clinical islet transplantation (ITx) shows insulin independence with adequate metabolic control in patients with type 1 diabetes. The aim of this study was to characterize the pattern of elevation in liver enzymes observed after ITx and to investigate any correlation between these elevations and graft characteristics or graft functional outcome. METHODS: Eighty-four consecutive ITx procedures were performed in 42 recipients. Liver function tests (LFT) were assessed during the first 40 days posttransplant. LFT elevated greater than or equal to 2.5 times above the upper limit of normal (ULN) were considered relevant. RESULTS: In 54% of the transplants, the aspartate aminotransferase (AST) increased by more than 2.5 times above ULN. A 5-fold increase in AST was observed in 27% of the procedures. The highest AST levels were observed after the first ITx. AST for all transplants peaked at 7+/-0.5 days at a value of 162+/-23 U/L (P<0.001, compared with the pretransplant values). Changes in alanine aminotransferase were similar to AST. Alkaline phosphatase increased more than 2-fold above ULN in 12% of the procedures. LFT normalized in 90% of the recipients within 4 weeks posttransplant. The remaining 10% normalized within 2 months after ITx. Graft characteristics and graft function were not significantly different when comparing LFT with greater than 5-fold versus less than 2.5-fold increase above ULN. The mean bilirubin remained within the normal range. CONCLUSIONS: After intraportal ITx, a significant increase in LFT levels was noticed in more than 50% of the procedures. These levels normalized spontaneously in 90% of the recipients within 4 weeks. No correlation between the increase in LFT and graft characteristics or graft function was found.