Heart failure among people with Type 2 diabetes mellitus: real-world data of 289 954 people from a diabetes database.

AIM: Comparing people with Type 2 diabetes mellitus with and without heart failure in terms of metabolic control, therapeutic regimen and comorbidities. METHODS: The Prospective Diabetes Registry (DPV) is a longitudinal documentation system for demographics, medical care and outcome in people with diabetes mellitus. It consists of follow-up data from people with diabetes mellitus who have agreed to be recorded in the registry. Clinical data are submitted by general practitioners, specialists and clinics throughout Germany and Austria. Some 289 954 people with Type 2 diabetes mellitus (years 2000 to 2015) were analysed using demographic statistics and adjustment for confounders based on linear and logistic regression analysis. RESULTS: People with Type 2 diabetes mellitus (ICD code: E11) and heart failure (ICD code: I50) (N = 14 723) were older, more often women and presented with longer diabetes duration compared with those without heart failure. After adjustment for age, gender and diabetes duration, people with heart failure showed lower HbA1c , higher BMI and more intense insulin therapy. Analysis revealed that people with heart failure were more often treated with insulin, and more frequently received anti-hypertensives and lipid-lowering medication. They presented with lower systolic and diastolic BP. People with heart failure more frequently showed a history of comorbidities. CONCLUSION: Heart failure is common in diabetes mellitus, but the prevalence in the DPV is lower frequent than expected. The reason for improved metabolic control in heart failure may be intensified therapy with insulin, lipid-lowering medication and anti-hypertensives in this cohort.

Distinct trajectories of HbA1c in newly diagnosed Type 2 diabetes from the DPV registry using a longitudinal group-based modelling approach.

AIM: To identify groups of heterogeneous HbA1c trajectories over time in newly diagnosed Type 2 diabetes. METHODS: The study comprised 6355 adults with newly diagnosed Type 2 diabetes (55% men, median age 62 years, baseline BMI 31 kg/m2 ) from the Diabetes Patienten Verlaufsdokumentation (DPV) prospective multicentre diabetes registry (Germany, Austria). Individuals were assessed during the first 5 years after diabetes diagnosis if they had ≥ 3 aggregated HbA1c measurements during follow-up. Latent class growth modelling was used to determine distinct subgroups that followed similar longitudinal HbA1c patterns (SAS: Proc Traj). Multinomial logistic regression models were used to investigate which variables were associated with the respective HbA1c trajectory groups. RESULTS: Four distinct longitudinal HbA1c trajectory (glycaemic control) groups were found. The largest group (56% of participants) maintained stable good glycaemic control (HbA1c 42-45 mmol/mol). Twenty-six percent maintained stable moderate glycaemic control (HbA1c 57-62 mmol/mol). A third group (12%) initially showed severe hyperglycaemia (HbA1c 97 mmol/mol) but reached good glycaemic control within 1 year. The smallest group (6%) showed stable poor glycaemic control (HbA1c 79-88 mmol/mol). Younger age at diabetes diagnosis, male sex, and higher BMI were associated with the stable moderate or poor glycaemic control groups. Insulin therapy was strongly associated with the highly improved glycaemic control group. CONCLUSIONS: Four subgroups with distinct HbA1c trajectories were determined in newly diagnosed Type 2 diabetes using a group-based modelling approach. Approximately one-third of people with newly diagnosed Type 2 diabetes need either better medication adherence or earlier intensification of glucose-lowering therapy.

Lipid profile is associated with treatment regimen in a large cohort of children and adolescents with Type 1 diabetes mellitus: a study from the international SWEET database.

AIMS: To examine the effect of pump vs injection therapy on the lipid profile of children with Type 1 diabetes mellitus. METHODS: A cross-sectional analysis of the lipid profile of children aged ≤ 18 years with Type 1 diabetes mellitus from SWEET, an international diabetes registry, was conducted with a focus on the effect of treatment regimen. Dyslipidaemia was defined as LDL cholesterol ≥2.6 mmol/l or non-HDL cholesterol ≥3.1 mmol/l. LDL and non-HDL cholesterol values among 14 290 children (52% boys, 51% receiving pump therapy) from 60 SWEET centres were analysed by linear and logistic regression analysis adjusted for sex, age, diabetes duration, HbA1c and BMI-standard deviation score group, region, and common interactions between age, sex, HbA1c and BMI. RESULTS: This study confirmed the established associations of increased lipids with female sex, age, diabetes duration, HbA1c and BMI. LDL and non-HDL cholesterol levels were lower in the pump therapy group compared to the injection therapy group [LDL cholesterol: injection therapy 2.44 mmol/l (95% CI 2.42 to 2.46) vs pump therapy 2.39 mmol/l (95% CI 2.37-2.41), P<0.001; non-HDL cholesterol: injection therapy 2.88 mmol/l (95% CI 2.86 to 2.90) vs pump therapy 2.80 mmol/l (95% CI 2.78-2.82), both P<0.0001]. Similarly, the odds ratios for LDL cholesterol ≥2.6 mmol/l [0.89 (95% CI 0.82-0.97)] and non-HDL cholesterol ≥3.1 mmol/l [0.85 (0.78 to 0.93)] were significantly lower in the pump therapy group, even after all adjustments. CONCLUSIONS: Our results indicate that pump therapy is associated with a better lipid profile.

Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

Both the frequency of HbA1c testing and the frequency of self-monitoring of blood glucose predict metabolic control: A multicentre analysis of 15 199 adult type 1 diabetes patients from Germany and Austria.

BACKGROUND: The objective of this study was to examine the association between metabolic control and frequency of haemoglobin A1c (HbA1c ) measurements and of self-monitoring of blood glucose, as well as the interaction of both. METHODS: Data of 15 199 adult type 1 diabetes patients registered in a standardized electronic health record (DPV) were included. To model the association between metabolic control and frequency of HbA1c testing or of self-monitoring of blood glucose, multiple hierarchic regression models with adjustment for confounders were fitted. Tukey-Kramer test was used to adjust P values for multiple comparisons. Vuong test was used to compare non-nested models. RESULTS: The baseline variables of the study population were median age 19.9 [Q1; Q3: 18.4; 32.2] years and diabetes duration 10.4 [6.8; 15.7] years. Haemoglobin A1c was 60.4 [51.5; 72.5] mmol/mol. Frequency of HbA1c testing was 8.0 [5.0; 9.0] within 2 years, and daily self-monitoring of blood glucose frequency was 5.0 [4.0; 6.0]. After adjustment, a U-shaped association between metabolic control and frequency of HbA1c testing was observed with lowest HbA1c levels in the 3-monthly HbA1c testing group. There was an inverse relationship between self-monitoring of blood glucose and HbA1c with lower HbA1c associated with highest frequency of testing (>6 daily measurements). Quarterly HbA1c testing and frequent self-monitoring of blood glucose were associated with best metabolic control. The adjusted Vuong Z statistic suggests that metabolic control might be better explained by HbA1c testing compared to self-monitoring of blood glucose (P < .0001). CONCLUSION: This research reveals the importance of quarterly clinical HbA1c monitoring together with frequent self-monitoring of blood glucose in diabetes management to reach and maintain target HbA1c .

The role of age on dose-limiting toxicities in phase I dose-escalation trials.

PURPOSE: Elderly oncology patients are not enrolled in early-phase trials in proportion to the numbers of geriatric patients with cancer. There may be concern that elderly patients will not tolerate investigational agents as well as younger patients, resulting in a disproportionate number of dose-limiting toxicities (DLT). Recent single-institution studies provide conflicting data on the relationship between age and DLT. EXPERIMENTAL DESIGN: We retrospectively reviewed data about patients treated on single-agent, dose-escalation, phase I clinical trials sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute. Patients' dose levels were described as a percentage of maximum tolerated dose, the highest dose level at which <33% of patients had a DLT, or recommended phase II dose (RP2D). Mixed-effect logistic regression models were used to analyze relationships between the probability of a DLT and age and other explanatory variables. RESULTS: Increasing dose, increasing age, and worsening performance status (PS) were significantly related to an increased probability of a DLT in this model (P < 0.05). There was no association between dose level administered and age (P = 0.57). CONCLUSIONS: This analysis of phase I dose-escalation trials, involving more than 500 patients older than 70 years of age, is the largest reported. As age and dose level increased and PS worsened, the probability of a DLT increased. Although increasing age was associated with occurrence of DLT, this risk remained within accepted thresholds of risk for phase I trials. There was no evidence of age bias on enrollment of patients on low or high dose levels.

Temsirolimus in VEGF-refractory metastatic renal cell carcinoma.

BACKGROUND: Temsirolimus is an i.v. administered inhibitor of mammalian target of rapamycin with activity in the first-line setting in poor-prognosis patients with metastatic renal cell carcinoma (RCC). The efficacy of this agent after failure of prior inhibitors of vascular endothelial growth factor (VEGF) is unknown. METHODS: a retrospective review of patients with metastatic RCC treated at the Cleveland Clinic Taussig Cancer Institute and three regional cancer centers in Ontario, Canada, through the Torisel (temsirolimus) Compassionate Use Program was conducted. Demographic, toxicity and response data were collected. RESULTS: a total of 87 patients with metastatic RCC were identified who had previously been treated with inhibitors of VEGF subsequently treated with temsirolimus. The majority of patients had either intermediate or poor-prognosis disease at baseline. Expected toxic effects including hyperglycemia and noninfectious pneumonitis were observed. The RECIST-defined objective response rate was 5% and the stable disease rate was 65%. The median time to progression (TTP) was 3.9 months (95% confidence interval 2.8-4.8 months), and median overall survival was 11.2 months. CONCLUSIONS: in a cohort of pre-treated intermediate to poor-prognosis patients with metastatic RCC, weekly i.v. temsirolimus is associated with predictable, but manageable toxicity, and a TTP approaching 4 months.

Prospective analysis of a fever evaluation algorithm after major gynecologic surgery.

OBJECTIVE: We performed a prospective trial to evaluate the feasibility, accuracy, and safety of a postoperative fever algorithm that is based on symptoms and physical examination in an attempt to decrease the random use of urine cultures, blood cultures, and chest radiographs. STUDY DESIGN: Our fever algorithm consisted of assessing all febrile postoperative patients for signs and symptoms of infection. If none were present, no tests were ordered. RESULTS: Twenty-eight of 105 consecutive patients (27%) had postoperative fever after major gynecologic surgery. Three of 28 febrile patients (11%) were evaluated with tests according to the algorithm. Two of 28 febrile patients (7%) were evaluated in violation of the algorithm. Four febrile patients (14%) had documented infections. Two patients had infections within the first 30 days after discharge. Compared with our previous retrospective review, significantly fewer febrile patients were evaluated with testing with a significantly increased yield of positive test results. CONCLUSIONS: Our postoperative fever evaluation algorithm that is based on symptoms and physical examination is feasible, is safe, decreases random testing, and increases the yield of positive test results.

Experiences in HCV-NAT screening prior to releasing cellular components by the German Red Cross Blood Transfusion Service of Baden-Württemberg.

In this report we present the accumulated data on nucleic acid testing (NAT) for hepatitis C virus (HCV) RNA of blood donations by the Blood Transfusion Service of Baden-Württemberg in the period between March 1997 and March 1999. An extra barcoded blood sample was collected from each donor. Samples were tested by NAT in mini-pools of maximally 96 samples. First-time and repeat donors were tested separately. RT/HCV-PCR was performed with the COBAS HCV Amplicortrade mark, versions 1.0 and 2.0 from Roche Diagnostic Systems. Many modifications have been introduced to the original protocol since the implementation of NAT screening aiming at an increase in the sensitivity and specificity of the assay. NAT positive pools containing serologically positive samples were detected. Initially, reactive pools were identified that could not be confirmed by secondary pooling and single testing procedures. So far, no serologically negative but NAT positive sample has been found.

Human Langerhans cells express a novel form of the leukocyte common antigen (CD45).

CD45 is a family of transmembrane glycoproteins that function as protein tyrosine phosphatases. All isoforms exhibit common CD45 epitopes, whereas the restricted CD45 epitopes (RA, RB, and RO) are each limited to one or more isoforms. In prior studies, we showed that human Langerhans cells in normal epidermis express a novel CD45 phenotype. They express common CD45 epitopes but are characteristically RA- RB- RO-. This suggests that Langerhans cells can express a novel form of CD45. In order to clarify this issue further, mRNA extracted from enriched Langerhans cell preparations was reverse transcribed into cDNA. The 5' portion of CD45 cDNA was then amplified using polymerase chain reaction primers complementary to exon 2 and exons 9-10, which flank the CD45 variable exon region (exons 4-6). Cloning and sequencing of the dominant 441 bp polymerase chain reaction product revealed the following exon configuration for the 5' translated region of Langerhans cells CD45: exon 3/7/8/9/10. This is the same exon configuration associated with the 180 kd CD45 isoform expressed by memory T cells and monocytes/macrophages; however, these cell types are RO+ whereas normal Langerhans cells are RO-. The RO epitope is known to be an oligosaccharide with a terminal sialic acid moiety. Therefore, we determined the expression of a related epitope, OPD4, by Langerhans cells. This is another terminal sialic acid moiety expressed by the 180 kd CD45 isoform of memory T cells but not by monocytes/macrophages. Langerhans cells were OPD4-. Our data suggest that memory T cells, monocytes/macrophages, and Langerhans cells all express a common CD45 transcript lacking exons 4-6; however, this transcript appears to undergo lineage-specific, post-translational glycosylation to create three distinct CD45 glycoproteins: RO+ OPD4+, RO+ OPD4-, and RO- OPD4-, which are expressed typically by memory T cells, monocytes/macrophages, and Langerhans cells, respectively. Because these epitopes are located extracellularly, they are postulated to allow differential responses to extracellular stimuli by creating differential ligand specificity.

Biochemical analysis of a mutant Tetrahymena lacking outer dynein arms.

Tetrahymena thermophila mutants homozygous for the oad mutation become nonmotile when grown at the restrictive temperature, and axonemes isolated from nonmotile mutants lack approximately 90% of their outer dynein arms. Electrophoretic analyses of axonemes isolated from nonmotile mutants (oad axonemes) indicate they contain significantly fewer of the 22 S dynein heavy chains that axonemes isolated from wild-type cells (wild-type axonemes) contain. The 22 S dynein heavy chains that remain in axonemes isolated from nonmotile, oad mutants are assembled into 22 S dynein particles that exhibit wild-type levels of ATPase activity. Two-dimensional gel electrophoresis of oad axonemes show that they are deficient in no proteins other than those proteins thought to be components of 22 S dynein. This report is the first formal proof that outer dynein arms in Tetrahymena cilia are composed of 22 S dynein.

A temperature-sensitive mutation affecting synthesis of outer arm dyneins in Tetrahymena thermophila.

We have characterized a novel, temperature-sensitive mutation affecting motility in Tetrahymena thermophila. Mutants grew and divided normally at the restrictive temperature (38 degrees C), but became nonmotile. Scanning electron microscopic analysis indicated that nonmotile mutants contained the normal number of cilia and that the cilia were of normal length. Transmission electron microscopic analysis indicated that axonemes isolated from nonmotile mutants lacked outer dynein arms, so the mutation was named oad 1 (outer arm deficient). Motile mutants shifted to 38 degrees C under conditions that prevent cell growth and division (starvation) remained motile suggesting that once assembled into axonemes at the permissive temperature (28 degrees C) the outer arm dyneins remain functional at 38 degrees C. Starved, deciliated mutants regenerated a full complement of functional cilia at 38 degrees C, indicating that the mechanism that incorporates the outer arm dynein into developing axonemes is not affected by the oad 1 mutation. Starved, nonmotile mutants regained motility when shifted back to 28 degrees C, but not when incubated with cycloheximide. We interpret these results to rule out the hypothesis that the oad 1 mutation affects the site on the microtubules to which the outer arm dyneins bind. Axonemes isolated from mutants grown for one generation at 38 degrees C had a mean of 6.0 outer arm dyneins, and axonemes isolated from mutants grown for two generations at 38 degrees C had a mean of 3.2 outer arm dyneins. Taken together, these results indicate that the oad 1 mutation affects the synthesis of outer arm dyneins in Tetrahymena.