The pattern of incident fractures according to fracture site in people with T1D.

Higher incidences of fractures are seen in people with type 1 diabetes (T1D), but knowledge on different fracture sites is sparse. We found a higher incidence mainly for distal fracture sites in people with T1D compared to controls. It must be further studied which fractures attributed to the higher incidence rates (IRs) at specific sites. INTRODUCTION: People with T1D have a higher incidence of fractures compared to the general population. However, sparse knowledge exists on the incidence rates of individual fracture sites. Therefore, we examined the incidence of various fracture sites in people with newly treated T1D compared to matched controls. METHODS: All people from the UK Clinical Practice Research Datalink GOLD (1987-2017), of all ages with a T1D diagnosis code (n = 6381), were included. People with T1D were matched by year of birth, sex, and practice to controls (n = 6381). Fracture IRs and incidence rate ratios (IRRs) were calculated. Analyses were stratified by fracture site and sex. RESULTS: The IR of all fractures was significantly higher in people with T1D compared to controls (IRR: 1.39 (CI95%: 1.24-1.55)). Compared to controls, the IRR for people with T1D was higher for several fracture sites including carpal (IRR: 1.41 (CI95%: 1.14-1.75)), clavicle (IRR: 2.10 (CI95%: 1.18-3.74)), foot (IRR: 1.70 (CI95%: 1.23-2.36)), humerus (IRR: 1.46 (CI95%: 1.04-2.05)), and tibia/fibula (IRR: 1.67 CI95%: 1.08-2.59)). In women with T1D, higher IRs were seen at the ankle (IRR: 2.25 (CI95%: 1.10-4.56)) and foot (IRR: 2.11 (CI95%: 1.27-3.50)), whereas in men with T1D, higher IRs were seen for carpal (IRR: 1.45 (CI95%: 1.14-1.86)), clavicle (IRR: 2.13 (CI95%: 1.13-4.02)), and humerus (IRR: 1.77 (CI95%: 1.10-2.83)) fractures. CONCLUSION: The incidence of carpal, clavicle, foot, humerus, and tibia/fibula fractures was higher in newly treated T1D, but there was no difference at other fracture sites compared to controls. Therefore, the higher incidence of fractures in newly treated people with T1D has been found mainly for distal fracture sites.

Microvesicles in active lupus nephritis show Toll-like receptor 9-dependent co-expression of galectin-3 binding protein and double-stranded DNA.

Circulating microvesicles (MVs) from patients with systemic lupus erythematosus (SLE) express the type 1 interferon (IFN)-inducible protein galectin-3 binding protein (G3BP), which may enhance their deposition in the glomerular basement membrane. The release of G3BP-expressing MVs from normal peripheral blood mononuclear cells (PBMCs) is induced by Toll-like receptor 9 (TLR-9) ligands, and these vesicles contain autoantibody-accessible double-stranded DNA (dsDNA). This study compares the release of MVs expressing G3BP and dsDNA from PBMCs derived from SLE patients with or without active lupus nephritis (LN) and from healthy donors, and taps further into the potential dependency on IFN-α for their generation and impacts of TLR-7/TLR-9 co-stimulation. PBMCs from 10 healthy donors and 12 SLE patients, six of whom had active LN at study inclusion, were stimulated in-vitro with recombinant human IFN-α and the TLR-9 agonists oligodeoxynucleotide (ODN)2216 or ODN2395 alone or in combination with the TLR-7 agonist gardiquimod. MVs in the supernatants were subsequently isolated by differential centrifugation and their expression of G3BP and dsDNA was quantified by flow cytometry. Stimulation with ODN2395 significantly increased the release of MVs co-expressing G3BP and dsDNA from PBMCs isolated from healthy donors and SLE patients. The expression of G3BP on individual MVs and the proportion of G3BP and dsDNA double-positive MVs released were increased in active LN patients. Neither co-stimulation with gardiquimod nor with the IFN-α inhibitor IN-1 had any effect on the MV release induced by ODN2395. In conclusion, the TLR-9-mediated inducibility of MVs co-expressing G3BP and dsDNA is increased in SLE patients with active LN.

Diabetes and fractures: new evidence of atypical femoral fractures?

Patients with diabetes have an increased risk of fractures. In this study, subtrochanteric and femoral shaft fractures were increased in patients with type 1 diabetes compared with the general population. In the light of this, more evidence points towards an association between diabetes and atypical femoral fractures. INTRODUCTION: Patients with diabetes have an increased risk of femoral fractures, but little is known about the risk of atypical femoral fractures (AFFs). The aim of this study was to identify the risk of subtrochanteric and femoral shaft (ST/FS) fractures and estimate the risk of AFFs in patients with type 1 (T1D) and type 2 diabetes (T2D). METHODS: From the nationwide Danish National Patient Register, we identified patients with T1D (n = 19,896), T2D (n = 312,188), and sex- and aged-matched controls without diabetes (n = 996,252) from the general population and all ST/FS fractures (n = 7509). Data were analyzed using a Cox proportional-hazards model and the incidence rate and rate ratio of ST/FS fractures were estimated. RESULTS: The incidence rate of ST/FS fractures in T1D was 52.14 events per 100,000 person years and 73.21 per 100,000 person years in T2D. T1D was associated with an increased risk of ST/FS (HR 2.07 (95% CI 1.68-2.56)), whereas T2D was not (HR 0.99 (95% CI 0.94-1.10)). Previous ST/FS fractures were associated with an increased risk of subsequent ST/FS fractures (HR 6.95 (95% CI 6.00-8.05)) and the use of bisphosphonates with an increased risk of ST/FS fractures (HR 1.72 (95% CI 1.54-1.91)). CONCLUSION: Patients with T1D have a higher risk of ST/FS fractures compared with sex- and age-matched controls. Since a proportion of ST/FS fractures are classified as AFFs, this could point towards the fact that AFFs also are increased in patients with T1D, but not T2D.

Humoral markers of active Epstein-Barr virus infection associate with anti-extractable nuclear antigen autoantibodies and plasma galectin-3 binding protein in systemic lupus erythematosus.

We investigated if signs of active Epstein-Barr virus and cytomegalovirus infections associate with certain autoantibodies and a marker of type I interferon activity in patients with systemic lupus erythematosus. IgM and IgG plasma levels against Epstein-Barr virus early antigen diffuse and cytomegalovirus pp52 were applied as humoral markers of ongoing/recently active Epstein-Barr virus and cytomegalovirus infections, respectively. Plasma galectin-3 binding protein served as a surrogate marker of type I interferon activity. The measurements were conducted in 57 systemic lupus erythematosus patients and 29 healthy controls using ELISAs. Regression analyses and univariate comparisons were performed for associative evaluation between virus serology, plasma galectin-3 binding protein and autoantibodies, along with other clinical and demographic parameters. Plasma galectin-3 binding protein concentrations were significantly higher in systemic lupus erythematosus patients (P = 0.009) and associated positively with Epstein-Barr virus early antigen diffuse-directed antibodies and the presence of autoantibodies against extractable nuclear antigens in adjusted linear regressions (B = 2.02 and 2.02, P = 0.02 and P = 0.002, respectively). Furthermore, systemic lupus erythematosus patients with anti-extractable nuclear antigens had significantly higher antibody levels against Epstein-Barr virus early antigen diffuse (P = 0.02). Our study supports a link between active Epstein-Barr virus infections, positivity for anti-extractable nuclear antigens and increased plasma galectin-3 binding protein concentrations/type I interferon activity in systemic lupus erythematosus patients.

Antibodies to early EBV, CMV, and HHV6 antigens in systemic lupus erythematosus patients.

OBJECTIVES: We investigated the antibody levels against early antigens of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV6) in systemic lupus erythematosus (SLE) patients and healthy controls, and further correlated these antibodies to haematology/biochemistry, serology, and disease activity measures. METHOD: Immunoglobulin (Ig)M, IgG, and IgA levels against the DNA polymerase processivity factors of EBV, CMV, and HHV6, termed early antigen diffuse (EA/D), pp52, and p41, respectively, were determined in plasma samples from 77 SLE patients and 29 healthy controls by using enzyme-linked immunosorbent assays (ELISAs). RESULTS: IgM, IgG, and IgA levels against EBV EA/D, and IgG and IgA levels against CMV pp52, were significantly higher in SLE patients compared with healthy controls. Furthermore, EBV EA/D- and CMV pp52-directed IgG levels were inversely and positively associated, respectively, with lymphocyte counts in SLE patients. None of the findings seemed to be associated with use of immunosuppressive medication. CONCLUSIONS: Our results suggest strong, but opposite, associations of lytic EBV and CMV infections with SLE. The amplified humoral responses to EBV EA/D and CMV pp52 in our SLE patient cohort probably reflect aberrant control of EBV and CMV reactivation. However, reactivation of EBV appeared to correlate with lymphopenic manifestations in SLE patients whereas CMV reactivation seemed to correlate with increments in lymphocyte levels.

Comparability of patients with ANCA-associated vasculitis enrolled in clinical trials or in observational cohorts.

OBJECTIVES: To analyse the differences between patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) entered into randomised clinical trials (RCTs) and those followed in large observational cohorts. METHODS: The main characteristics and outcomes of patients with generalised and/or severe GPA or MPA with a five-factor score ≥ 1 enrolled in the French Vasculitis Study Group (FVSG) or the US-Canadian-based Vasculitis Clinical Research Consortium cohorts were compared to those enrolled in one of 2 FVSG clinical RCTs (WEG91, WEGENT) or 3 European Vasculitis Society clinical trials (CYCLOPS, CYCAZAREM, IMPROVE). RESULTS: 657 patients (65.3% with GPA) in RCTs were compared to 437 in cohorts (90.6% with GPA). RCT patients were older at diagnosis than the cohort patients (56.6 ± 13.9 vs. 46.8 ± 17.3 years), had higher Birmingham vasculitis activity score (19.5 ± 9.1 vs. 16.9 ± 7.4), and more frequent kidney disease (84.0% vs. 54.9%) but fewer ear, nose, and throat symptoms (56.8% vs. 72.2%). At 56 months post-diagnosis, mortality and relapse rates, adjusted for age and renal function, were higher for patients with GPA in RCTs vs. cohorts (10.7% vs. 2.5% [p=0.001] and 22.5% vs. 15.6% [p=0.03], respectively) but similar for patients with MPA (6.2% vs. 6.6% [p=0.92] and 16.6% vs. 10.1% [p=0.39], respectively). CONCLUSIONS: Patients with GPA or MPA in RCTs and those in observational cohorts show important differences that should be remembered when interpreting results based on these study populations.

Changes in proteinase 3 anti-neutrophil cytoplasm autoantibody levels in early systemic granulomatosis with polyangiitis (Wegener's) may reflect treatment rather than disease activity.

OBJECTIVES: To investigate the nature of the relationship between proteinase 3 anti-neutrophil cytoplasm autoantibody (PR3-ANCA) and relapse in patients with early systemic granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: Clinical data from 16 relapsing and 12 non-relapsing patients with early systemic GPA from a randomised clinical trial were correlated to monthly PR3-ANCA values over 18 months. Each sample was examined using 9 different enzyme-linked immunosorbent assays (ELISAs) to ensure reliability of ANCA results. PR3-ANCA peaks were identified by the highest sum of logarithmic transformation values from all assays in samples after remission. RESULTS: A PR3-ANCA peak was identified in all relapsing and non-relapsing patients and coincided with relapse in all 14 evaluable relapsing patients. The monthly increment before the peak, however, was similar in relapsing and non-relapsing patients in all assays. Increments from remission to peak were higher in relapsing patients in 2/9 assays. PR3-ANCA values at entry and peak PR3-ANCA values were higher in relapsing patients in 3/9 and 2/9 assays, respectively. However, large overlaps of PR3-ANCA values prevented a distinction between relapsing and non-relapsing patients. The median time to reach peak values was 14 months in relapsing and 12 months in non-relapsing patients with scheduled termination of treatment at 12 months. CONCLUSIONS: The predictive value for relapses of PR3-ANCA determinations confirm and extend previous reports. Although all relapses were related to PR3-ANCA increases, reduction or withdrawal of immunosuppression without relapse was also related to increases and may explain the lack of predictive value of sequential PR3-ANCA determinations.

Laryngeal morbidity after tracheal intubation: the Endoflex(®) tube compared to conventional endotracheal intubation with stylet.

BACKGROUND: Tracheal intubation may cause vocal fold damage. The trial was designed to assess laryngeal morbidity comparing the Endoflex(®) tube with a conventional endotracheal tube with stylet. We hypothesised that laryngeal morbidity within the first 24 h after extubation would be lower with the Endoflex tube than with the conventional endotracheal tube with stylet because of less rigidity. METHODS: This randomised trial included 130 elective surgical patients scheduled for general anaesthesia with endotracheal intubation. Pre- and post-operative assessment of hoarseness, vocal fold pathology, and voice analysis using the Multidimensional Voice Program was performed. Induction of anaesthesia was standardised. After complete neuromuscular paralysis, intubation was done with an Endoflex tube or a conventional endotracheal tube with stylet. RESULTS: Post-operative hoarseness was found in 45% with the Endoflex tube and 55% with the endotracheal tube with stylet at 24 h after extubation (P = 0.44). Post-operative vocal fold injury was present in 23% in the Endoflex tube group and in 36% in the endotracheal tube with stylet group (P = 0.13). The increase in shimmer, the voice analysis variable reflecting vocal fold oedema, was 0.5% in the Endoflex tube group and 2.5% in the endotracheal tube with stylet group (P = 0.02). CONCLUSION: No significant difference was found in the incidence of hoarseness or vocal fold injury using the Endoflex tube. However, the statistically significant lower increase in the shimmer values in that group implies that the Endoflex may be associated with less laryngeal morbidity.

Importance of questionnaire context for a physical activity question.

Adequate information about physical activity habits is essential for surveillance, implementing, and evaluating public health initiatives in this area. Previous studies have shown that question order and differences in wording result in systematic differences in people's responses to questionnaires; however, this has never been shown for physical activity questions. The aim was to study the influence of different formulations and question order on self-report physical activity in a population-based health interview survey. Four samples of each 1000 adults were drawn at random from the National Person Register. A new question about physical activity was included with minor differences in formulations in samples 1-3. Furthermore, the question in sample 2 was included in sample 4 but was placed in the end of the questionnaire. The mean time spent on moderate physical activity varied between the four samples from 57 to 100 min/day. Question order was associated with the reported number of minutes spent on moderate-intensity physical activity and with prevalence of meeting the recommendation, whereas physical inactivity was associated with the differences in formulation of the question. Questionnaire context influences the way people respond to questions about physical activity significantly and should be tested systematically in validation studies of physical activity questionnaires.

Extensive endoscopic image-guided sinus surgery decreases BPI-ANCA in patients with cystic fibrosis.

Antineutrophil cytoplasm autoantibodies (ANCA) directed against bactericidal/permeability-increasing protein (BPI) are common in patients with cystic fibrosis (CF), and serum levels are correlated with lung colonization by Pseudomonas aeruginosa and the severity of lung damage. The production of BPI-ANCA may be due to the costimulation of BPI when mounting an immune response against P. aeruginosa. The effect of surgery aiming to eradicate bacteria and infected tissue on BPI-ANCA levels is sparsely described. A cohort of patients with CF were included: 53 patients having extensive image-guided sinus surgery (EIGSS) with topical postoperative antibiotic treatment, 131 non-operated controls and 36 who had double lung transplantation (LTX). In all 219 patients, serum samples before and after surgery or at similar intervals were analysed for IgG and IgA BPI-ANCA. The EIGSS group showed a highly significant decrease in both IgA and IgG BPI-ANCA levels compared with their own preoperative values and control group values (P < 0.001-0.02). The LTX patients also showed a highly significant decrease in both IgA and IgG BPI-ANCA levels (P < 0.001). EIGSS and LTX decrease IgA and IgG BPI-ANCA levels in patients with CF, indicating that extensive removal of infected tissue influences the pathogenic process of autoantibody production. The results shown herein are in favour of applying EIGSS in selected patients with CF and for using BPI-ANCA as a surrogate marker for guiding further therapeutic interventions.

Mapping the cell: advent of the thin section and characterization of the ER.

The development of improved techniques for studying tissues by electron microscopy parallelled the discovery and characterization of the endoplasmic reticulum. But researchers had first to be convinced that the endoplasmic reticulum wasn't an artefact produced by electron-microscopic techniques.

Exercise-induced laryngeal obstructions: prevalence and symptoms in the general public.

Respiratory difficulties caused by exercise-induced laryngeal obstructions (EILOs) are reported with increasing frequency. The aim of this study was to assess the prevalence and symptoms of EILOs and their relation to airway hyperresponsiveness (AHR). In total, 556 randomly selected youths in Copenhagen aged 14-24 years were invited over a 2-year period. The study included a mailed questionnaire and two visits: day 1 (an interview-based questionnaire, methacholine bronchial provocation test and physical exertion test); and day 2 [an exercise test with continuous laryngoscopic recordings (CLE test)]. The diagnosis of EILOs was based on the CLE test. In total, 237 answered the mailed questionnaire and 150 participated on day 1 whereof 98 participated on day 2 also. AHR was verified in 23 (4.1% of invitees) and EILOs in 42 (7.5% of invitees). Co-morbidity was verified in 6 cases (26.1% of verified AHR cases). No symptoms were found specific for either AHR or EILOs. The minimum prevalence of EILOs in this cohort was 7.5%. EILOs were verified in 26.1% of participants with AHR. Questionnaires could not differentiate between AHR and EILOs.

Exudative lesions of Reinke's space: a terminology proposal.

There has been an ongoing confusion among pathologists in their attempt to accurately identify lesions of Reinke's space. Nodules, polyps and Reinke's edema fall in the same basket and differentiation between them relies largely on the clinical description of the pathologic specimen by the operating surgeon than on their distinct pathologic features. By revising the pertinent literature, the need for an establishment of the aforementioned term still remains and is further stressed out, as confusion among the various pathologic descriptions of these lesions still exists. This is further verified by a study conducted in the Department of Otorhinolaryngology-Head and Neck Surgery of the University Hospital of Louvain at Mont-Godinne, Belgium, involving 323 operative specimens obtained from 200 patients with macroscopic picture. Statistical analysis showed lack of agreement between surgical and histopathologic diagnosis in almost a third of the cases (Cohen's kappa coefficient of 0.683 +/- 0.037, P < 0.001). We, therefore, propose the term "exudative lesions of Reinke's space" to include Reinke's edema, polyps and nodules. These lesions share common histologic features, which are located in the Reinke's space and whose macroscopic appearance is largely dependent upon the presence and duration of certain causative factors.

Development of comprehensive disease assessment in systemic vasculitis.

The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.

Socioeconomic differences in the prevalence of common chronic diseases: an overview of eight European countries.

BACKGROUND: Few studies have compared socioeconomic inequalities in the prevalence of both fatal and non-fatal diseases. This paper aims to give the first international overview for several common chronic diseases. METHODS: Micro-level data were pooled from non-standardized national health surveys conducted in eight European countries in the 1990s. Surveys ranged in size from 3700 to 41 200 participants. The prevalence of 17 chronic disease groups were analysed in relation to education. Standardized prevalence rates and age-adjusted odds ratios (ORs) were calculated. RESULTS: Most diseases showed higher prevalence among the lower education group. Stroke, diseases of the nervous system, diabetes, and arthritis displayed relatively large inequalities (OR > 1.50). No socioeconomic differences were evident for cancer, kidney diseases, and skin diseases. Allergy was more common in the higher education group. Relative socioeconomic differences were often smaller among the 60-79 age group as compared with the 25-59 age group. Cancer was more prevalent among the lower educated in the 25-59 age group, but among the higher educated in the 60-79 age group. For diabetes, hypertension, and heart disease, socioeconomic differences were larger among women as compared with men. Inequalities in heart disease were larger in northern European countries as compared with southern European countries. CONCLUSION: There are large variations between chronic diseases in the size and pattern of socioeconomic differences in their prevalence. The large inequalities that are found for some specific fatal diseases (e.g. stroke) and non-fatal diseases (e.g. arthritis) require special attention in equity-oriented research and policies.

Trends in smoking behaviour between 1985 and 2000 in nine European countries by education.

OBJECTIVE: To examine whether trends in smoking behaviour in Western Europe between 1985 and 2000 differed by education group. DESIGN: Data of smoking behaviour and education level were obtained from national cross sectional surveys conducted between 1985 and 2000 (a period characterised by intense tobacco control policies) and analysed for countries combined and each country separately. Annual trends in smoking prevalence and the quantity of cigarettes consumed by smokers were summarised for each education level. Education inequalities in smoking were examined at four time points. SETTING: Data were obtained from nine European countries: Norway, Sweden, Denmark, Finland, the United Kingdom, the Netherlands, Germany, Italy, and Spain. PARTICIPANTS: 451 386 non-institutionalised men and women 25-79 years old. MAIN OUTCOME MEASURES: Smoking status, daily quantity of cigarettes consumed by smokers. RESULTS: Combined country analyses showed greater declines in smoking and tobacco consumption among tertiary educated men and women compared with their less educated counterparts. In country specific analyses, elementary educated British men and women, and elementary educated Italian men showed greater declines in smoking than their more educated counterparts. Among Swedish, Finnish, Danish, German, Italian, and Spanish women, greater declines were seen among more educated groups. CONCLUSIONS: Widening education inequalities in smoking related diseases may be seen in several European countries in the future. More insight into effective strategies specifically targeting the smoking behaviour of low educated groups may be gained from examining the tobacco control policies of the UK and Italy over this period.

Pneumococcal meningitis. Late neurologic sequelae and features of prognostic impact.

We interviewed and neurologically reexamined 94 patients who had previous pneumococcal meningitis. The findings were allocated into groups with and without a causal relationship to the meningitis. The main sequelae after meningitis were dizziness (23%), tiredness (22%), mild memory deficits (21%), and gait ataxia (18%), whereas other focal neurologic signs were rare. By a rating (0 to 5) of the presence and severity of sequelae after meningitis, 54% of the patients were found to have sequelae. The clinical condition at the time of acute illness was studied in subgroups of patients who had different neurologic sequelae or high sequelae ratings. Gait ataxia was associated with a state of agitation and confusion when the patient was admitted for meningitis. High sequelae ratings on reexamination were associated with an affected consciousness at the acute stage of the disease and with high numbers of WBCs in the CSF at the time of hospitalization.