The association between anti-insulin aspart antibodies and the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in children and adolescents with type 1 diabetes.

BACKGROUND: Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) ensuring ultrafast absorption and effect. AIM: To compare the pharmacokinetics between faster aspart and IAsp, based on free or total IAsp measurement, and investigate the association between anti-IAsp antibodies and faster aspart and IAsp pharmacological properties in children and adolescents with type 1 diabetes (T1D). METHODS: In a randomized, two-period crossover trial, 12 children, 16 adolescents, and 15 adults (6-11, 12-17, and 18-64 years) received 0.2 U/kg double-blindsingle-dose subcutaneous faster aspart or IAsp followed by a standardized liquid meal test. RESULTS: Across age groups, the pharmacokinetic profile was left-shifted including greater early exposure for faster aspart vs IAsp irrespective of free or total IAsp assay. Onset of appearance occurred 2.4 to 5.0 minutes (free) or 1.8 to 3.0 minutes (total) earlier for faster aspart vs IAsp (P < .05). Treatment ratios (faster aspart/IAsp) for 0 to 30 minutes IAsp exposure were 1.60 to 2.11 and 1.62 to 1.96, respectively (children, free: P = .062; otherwise P < .05). The ratio of free/total IAsp for overall exposure (AUCIAsp,0-t ) was negatively associated with anti-IAsp antibody level across age. Pooling with a previous similar trial showed no clear association between anti-IAsp antibodies and meal test 1- or 2-hour postprandial glucose increment independent of age and insulin treatment (R2 ≤ .070; P ≥ .17). CONCLUSIONS: In children and adolescents with T1D, faster aspart provides ultrafast pharmacokinetics irrespective of free or total IAsp assay. Elevated anti-IAsp antibodies are associated with higher total IAsp concentration, but do not impact faster aspart and IAsp glucose-lowering effect.

Early mobilisation of patients with community-acquired pneumonia reduce length of hospitalisation-a pilot study.

[Purpose] To examine if length of stay was reduced following an early mobilisation programme in patients with community-acquired pneumonia, and secondary, if such a program influenced short-term rehospitalisation and mortality rates. [Participants and Methods] Ninety seven consecutive patients (51% men; over all mean ± SD age 71.9 ± 16.5 years) with community-acquired pneumonia were included in the intervention group, and compared with a historical control group of 97 patients, matching at case level. Early mobilisation was defined as more than 20 minutes out of bed within 24 hours of hospitalisation. [Results] Eighty out of 97 patients in the intervention group were mobilised within 24 hours and length of stay for all patients was reduced with an average of 1.5 (95%CI: -0.2; 3.2) days compared to the control group. There was no significant difference between the two groups according to 30-day rehospitalisation and mortality. [Conclusion] An early mobilisation program seem to reduce the length of stay for patients with community-acquired pneumonia, and without an increase in short-term mortality and re-hospitalisation rates.

Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma.

PURPOSE: Secondary CNS involvement (SCNS) is a profoundly adverse complication of diffuse large B-cell lymphoma. Evidence from older series indicated a median overall survival (OS) < 6 months; however, data from the immunochemotherapy era are limited. METHODS: Patients diagnosed with SCNS during or after first-line immunochemotherapy were identified from databases and/or regional/national registries from three continents. Clinical information was retrospectively collected from medical records. RESULTS: In total, 291 patients with SCNS were included. SCNS occurred as part of first relapse in 254 (87%) patients and 113 (39%) had concurrent systemic relapse. With a median post-SCNS follow-up of 48 months, the median post-SCNS OS was 3.9 months and 2-year OS rate was 20% (95% CI: 15-25). In multivariable analysis of 173 patients treated with curative/intensive therapy (such as high-dose methotrexate [HDMTX] or platinum-containing regimens), age ≤60 years, performance status 0-1, absence of combined leptomeningeal and parenchymal involvement, and SCNS occurring after completion of first-line therapy were associated with superior outcomes. Patients ≤60 years with performance status 0-1 and treated with HDMTX-based regimens for isolated parenchymal SCNS had a 2-year OS of 62% (95% CI: 36-80). In patients with isolated SCNS, the addition of rituximab to HDMTX-based regimens was associated with improved OS. Amongst patients with isolated SCNS in CR following intensive treatment, high-dose chemotherapy and autologous stem cell transplantation did not improve OS (P = 0.9). CONCLUSIONS: In this large international cohort of patients treated with first-line immunochemotherapy, outcomes following SCNS remain poor. However, a moderate proportion of patients with isolated SCNS who received intensive therapies achieved durable remissions.

Trends in diagnostic patterns and mortality in emergency ambulance service patients in 2007-2014: a population-based cohort study from the North Denmark Region.

OBJECTIVE: Demand for ambulances is growing. Nevertheless, knowledge is limited regarding diagnoses and outcomes in patients receiving emergency ambulances. This study aims to examine time trends in diagnoses and mortality among patients transported with emergency ambulance to hospital. DESIGN: Population-based cohort study with linkage of Danish national registries. SETTING: The North Denmark Region in 2007-2014. PARTICIPANTS: Cohort of 148 757 patients transported to hospital by ambulance after calling emergency services. MAIN OUTCOME MEASURES: The number of emergency ambulance service patients, distribution of their age, sex, hospital diagnoses, comorbidity, and 1-day and 30-day mortality were assessed by calendar year. Poisson regression with robust variance estimation was used to estimate both age-and sex-adjusted relative risk of death and prevalence ratios for Charlson Comorbidity Index (CCI) to allow comparison by year, with 2007 as reference year. RESULTS: The annual number of emergency ambulance service patients increased from 24.3 in 2007 to 40.2 in 2014 per 1000 inhabitants. The proportions of women increased from 43.1% to 46.4% and of patients aged 60+ years from 39.9% to 48.6%, respectively. The proportion of injuries gradually declined, non-specific diagnoses increased, especially the last year. Proportion of patients with high comorbidity (CCI≥3) increased from 6.4% in 2007 to 9.4% in 2014, corresponding to an age- and sex-adjusted prevalence ratio of 1.27 (95% CI 1.16 to 1.39). The 1-day and 30 day mortality decreased from 2.40% to 1.21% and from 5.01% to 4.36%, respectively, from 2007 to 2014, corresponding to age-adjusted and sex-adjusted relative risk of 0.43 (95% CI 0.37 to 0.50) and 0.72 (95% CI 0.66 to 0.79), respectively. CONCLUSION: During the 8-year period, the incidence of emergency ambulance service patients, the proportion of women, elderly, and non-specific diagnoses increased. The level of comorbidity increased substantially, whereas the 1-day and 30-day mortality decreased.

The Prevalence of Oropharyngeal Dysphagia in Danish Patients Hospitalised with Community-Acquired Pneumonia.

Community-acquired pneumonia (CAP) and oropharyngeal dysphagia (OD) are prevalent conditions in the elderly. The aim of this study was to explore the relationship between CAP, OD, and frailty in patients admitted to a department of respiratory medicine at a regional hospital. The outcome was mortality during hospitalization and within 30 days of discharge and rehospitalization within 30 days of discharge. A total of 154 consecutive patients (54.5% male, mean age 77.4 years (SD 11.51)) hospitalized because of CAP from September 1, 2013 to March 31, 2014 at North Denmark Regional Hospital were included in this study. The volume-viscosity swallow test was conducted for each patient. A total of 34.42% patients presented with OD. Patients with OD and CAP presented significant differences in age, CURB-65, and dementia compared with those of patients with CAP alone. The majority lived in nursing homes, had a lower body mass index, Barthel 20 score, and handgrip strength, and had poor oral health compared with patients with CAP only. Patients with OD presented an increased length of stay in hospital (P < 0.001), intra-hospital mortality (P < 0.001), and 30-day mortality rate (P < 0.001) compared with those of patients with CAP only. Their rate of rehospitalization 0-30 days after discharge was also increased (P < 0.001) compared with that of patients with CAP only. Thus, OD is related to frailty and poor outcome.

Anthropometrics and prognosis in diffuse large B-cell lymphoma: a multicentre study of 653 patients.

OBJECTIVE: The impact of body mass index (BMI) and body surface area (BSA) on survival in diffuse large B-cell lymphoma (DLBCL) is controversial. Recent studies show superior outcomes for overweight and obese patients. PATIENTS AND METHODS: A total of 653 R-CHOP(-like)-treated DLBCL patients were included in this retrospective cohort study. Patients, baseline clinicopathologic characteristics and treatment information were retrieved from the Danish Lymphoma Registry. Anthropometric measures were obtained from chemotherapy prescription charts. RESULTS: Underweight (BMI <18.5 kg/m2 ) was associated with significantly worse progression-free survival (PFS) for male patients only in sex-stratified analyses (HR 3.92, 95% CI: 1.57-9.75, P = 0.003, for males; HR 1.65, 95% CI: 0.90-3.02, P = 0.107, for females). In multivariate analyses, underweight was associated with worse PFS for both sexes (HR 5.34, 95% CI: 2.07-13.79, P = 0.001, for males; HR 2.14, 95% CI: 1.12-4.08, P = 0.021, for females). Similar results were obtained in analyses of overall survival. In crude analyses, BSA <1.8 m2 was associated with worse PFS for men and women (HR 1.65, 95% CI: 1.03-2.65, P = 0.039, for men; HR 1.62, 95% CI: 1.03-2.56, P = 0.037, for women). In multivariate analyses, however, these associations diminished. CONCLUSIONS: Our study demonstrates that underweight DLBCL patients have worse outcomes following R-CHOP as compared to normal as well as overweight patients.

Changes in Weight and Body Composition Among Women With Breast Cancer During and After Adjuvant Treatment: A Prospective Follow-up Study.

BACKGROUND: Antineoplastic adjuvant treatment for breast cancer can cause changes in women's weight and body composition and influence their general health and survival. OBJECTIVE: The aim of this study is to investigate the extent and patterns of change in weight and body composition after current standard adjuvant antineoplastic treatment for breast cancer. METHODS: Data on weight and body composition from 95 women with breast cancer Stage I to III were obtained during 18 months on a bioelectric impedance analyzer. Changes and odds ratio (OR) were calculated by a linear mixed model and logistic regression. RESULTS: At 18 months, there was an increase in weight of 0.9 kg (95% confidence interval [CI], 0.3-1.5; P = .003) and an average positive association of 0.35 kg/cm increased waist circumference (95% CI, 0.29-0.42 kg; P < .0001). Relative weight changes ranged from -12.7% to 20.5%. Weight gains related to increased body fat were observed mainly in premenopausal women receiving chemotherapy (1.4 kg; 95% CI, 0.4-2.4; P = .007). For menopausal status, OR was 2.9 (95% CI, 1.14-7.1; P = .025), and for chemotherapy, OR was 2.6 (95% CI, 1.03-6.41; P = .043). The OR for weight loss in Stage III breast cancer was 12.5 (95% CI, 1.21-128.84; P = .034) and 4.3 (CI, 1.07-17.24; P = .40) for comorbidity. CONCLUSIONS: Results demonstrate that weight changes in a pooled sample are overestimated. However, premenopausal women receiving anthracycline-based chemotherapy show a tendency toward a body composition with increasing fat mass. IMPLICATIONS FOR PRACTICE: A scheduled assessment of changes in weight and body composition is relevant at 18 months after treatment. To compare future studies, common measuring and cutoff points are needed.

A multifaceted implementation strategy versus passive implementation of low back pain guidelines in general practice: a cluster randomised controlled trial.

BACKGROUND: Guidelines are often slowly adapted into clinical practice. However, actively supporting healthcare professionals in evidence-based treatment may speed up guideline implementation. Danish low back pain (LBP) guidelines focus on primary care treatment of LBP, to reduce referrals from primary care to secondary care. The primary aim of this project was to reduce secondary care referral within 12 weeks by a multifaceted implementation strategy (MuIS). METHODS: In a cluster randomised design, 189 general practices from the North Denmark Region were invited to participate. Practices were randomised (1:1) and stratified by practice size to MuIS (28 practices) or a passive implementation strategy (PaIS; 32 practices). Included were patients with LBP aged 18 to 65 years who were able to complete questionnaires, had no serious underlying pathology, and were not pregnant. We developed a MuIS including outreach visits, quality reports, and the STarT Back Tool for subgrouping patients with LBP. Both groups were offered the usual dissemination of guidelines, guideline-concordant structuring of the medical record, and a new referral opportunity for patients with psycho-social problems. In an intention-to-treat analysis, the primary and secondary outcomes pertained to the patient, and a cost-effectiveness analysis was performed from a healthcare sector perspective. Patients and the assessment of outcomes were blinded. Practices and caregivers delivering the interventions were not blinded. RESULTS: Between January 2013 and July 2014, 60 practices were included, of which 54 practices (28 MuIS, 26 PaIS) included 1101 patients (539 MuIS, 562 PaIS). Follow-up data for the primary outcome were available on 100 % of these patients. Twenty-seven patients (5.0 %) in the MuIS group were referred to secondary care vs. 59 patients (10.5 %) in the PaIS group. The adjusted odds ratio (AOR) was 0.52 [95 % CI 0.30 to 0.90; p = 0.020]. The MuIS was cost-saving £-93.20 (£406.51 vs. £499.71 per patient) after 12 weeks. Conversely, the MuIS resulted in less satisfied patients after 52 weeks (AOR 0.50 [95 % CI 0.31 to 0.81; p = 0.004]). CONCLUSIONS: Using a MuIS changed general practice referral behaviour and was cost effective, but patients in the MuIS group were less satisfied. This study supports the application of a MuIS when implementing guidelines. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01699256.

Diagnosis and mortality in prehospital emergency patients transported to hospital: a population-based and registry-based cohort study.

OBJECTIVE: Knowledge about patients after calling for an ambulance is limited to subgroups, such as patients with cardiac arrest, myocardial infarction, trauma and stroke, while population-based studies including all diagnoses are few. We examined the diagnostic pattern and mortality among all patients brought to hospital by ambulance after emergency calls. DESIGN: Registry-based cohort study. SETTING AND PARTICIPANTS: We included patients brought to hospital in an ambulance dispatched after emergency calls during 2007-2014 in the North Denmark Region (580 000 inhabitants). We reported hospital diagnosis according to the chapters of the International Classification of Diseases, 10th Edition (ICD-10), and studied death on days 1 and 30 after the call. Cohort characteristics and diagnoses were described, and the Kaplan-Meier method was used to estimate mortality and 95% CIs. RESULTS: In total, 148 757 patients were included, mean age 52.9 (SD 24.3) years. The most frequent ICD-10 diagnosis chapters were: 'injury and poisoning' (30.0%), and the 2 non-specific diagnosis chapters: 'symptoms and abnormal findings, not elsewhere classified' (17.5%) and 'factors influencing health status and contact with health services' (14.1%), followed by 'diseases of the circulatory system' (10.6%) and 'diseases of the respiratory system' (6.7%). The overall 1-day mortality was 1.8% (CI 1.7% to 1.8%) and 30-day mortality 4.7% (CI 4.6% to 4.8%). 'Diseases of the circulatory system' had the highest 1-day mortality of 7.7% (CI 7.3% to 8.1%) accounting for 1209 deaths. After 30 days, the highest number of deaths were among circulatory diseases (2313), respiratory diseases (1148), 'symptoms and abnormal findings, not elsewhere classified' (1119) and 'injury and poisoning' (741), and 30 days mortality in percentage was 14.7%, 11.6%, 4.3% and 1.7%, respectively. CONCLUSIONS: Patients' diagnoses from hospital stay after calling 1-1-2 in this population-based study were distributed across all ICD-10 chapters. Mortality varied widely between diagnostic groups. Non-specific diagnoses accounted for one-third of the patients and contributed to mortality in terms of total number of deaths.

Incidence of venous thromboembolism in patients with diffuse large B-cell lymphoma.

Venous thromboembolism (VTE) in patients with diffuse large B-cell lymphoma (DLBCL) is an important complication. We aimed to asses the risk of VTE and the quality of VTE discharge diagnosis in a cohort of DLBCL patients. Objective confirmed VTE events during two years of follow-up were identified by the review of medical records of consecutive patients with DLBCL at Aalborg University Hospital from 2007 until 2013. Information on baseline disease stage, lifestyle factors, and anticoagulant therapy were registered. Cox regression was used to assess VTE risk factors. The data quality on VTE discharge diagnosis was evaluated by comparing data on VTE discharge diagnosis from the Danish National Registry of Patients with information from the medical records. Eleven percent of patients were diagnosed with VTE. Prior VTE, performance status, and Ann Arbor stage were associated with VTE. The positive predictive value of a VTE discharge diagnosis was 85% and the sensitivity 53%.

Four ways to ventilate during cardiopulmonary resuscitation in a porcine model: a randomized study.

BACKGROUND: The optimal method for out-of-hospital ventilation during cardiopulmonary rescue (CPR) is controversial. The aim of this study was to test different modes of ventilation during CPR for a prolonged period of 60 min. METHODS: Pigs were randomized to four groups after the induction of ventricular fibrillation, which was followed by one hour of mechanical cardiac compressions. The study comprised five pigs treated with free airways, five pigs treated with ventilators, six pigs treated with a constant oxygen flow into the tube, and six pigs treated with apnoeic oxygenation. RESULTS: The free airway group was tested for 1 h, but in the first 15 min, the median PaO2 had already dropped to 5.1 kPa. The ventilator group was tested for 1 h and still had an acceptable median PaO2 of 10.3 kPa in the last 15 min. The group was slightly hyperventilated, with PaCO2 at 3.8 kPa, even though the ventilator volumes were unchanged from those before induction of cardiac arrest. In the group with constant oxygen flowing into the tube, one pig was excluded after 47 min due to blood pressure below 25 mmHg. For the remaining 5 pigs, the median PaO2 in the last 15 min was still 14.3 kPa, and the median PaCO2 was 6.2 kPa. The group with apnoeic oxygenation for 1 h had a resulting median PaO2 of 10.2 kPa and a median PaCO2 of 12.3 kPa in the last 15 min. DISCUSSION: Except for the free airway group, the other methods resulted in PaO2 above 10 kPa and PaCO2 between 3.8 and 12.3 kPa after one hour. CONCLUSION: Constant oxgen flow and apnoeic oxygenation seemed to be useable alternatives to ventilator treatment.

Inherited Inflammatory Response Genes Are Associated with B-Cell Non-Hodgkin's Lymphoma Risk and Survival.

BACKGROUND: Malignant B-cell clones are affected by both acquired genetic alterations and by inherited genetic variations changing the inflammatory tumour microenvironment. METHODS: We investigated 50 inflammatory response gene polymorphisms in 355 B-cell non-Hodgkin's lymphoma (B-NHL) samples encompassing 216 diffuse large B cell lymphoma (DLBCL) and 139 follicular lymphoma (FL) and 307 controls. The effect of single genes and haplotypes were investigated and gene-expression analysis was applied for selected genes. Since interaction between risk genes can have a large impact on phenotype, two-way gene-gene interaction analysis was included. RESULTS: We found inherited SNPs in genes critical for inflammatory pathways; TLR9, IL4, TAP2, IL2RA, FCGR2A, TNFA, IL10RB, GALNT12, IL12A and IL1B were significantly associated with disease risk and SELE, IL1RN, TNFA, TAP2, MBL2, IL5, CX3CR1, CHI3L1 and IL12A were, associated with overall survival (OS) in specific diagnostic entities of B-NHL. We discovered noteworthy interactions between DLBCL risk alleles on IL10 and IL4RA and FL risk alleles on IL4RA and IL4. In relation to OS, a highly significant interaction was observed in DLBCL for IL4RA (rs1805010) * IL10 (rs1800890) (HR = 0.11 (0.02-0.50)). Finally, we explored the expression of risk genes from the gene-gene interaction analysis in normal B-cell subtypes showing a different expression of IL4RA, IL10, IL10RB genes supporting a pathogenetic effect of these interactions in the germinal center. CONCLUSIONS: The present findings support the importance of inflammatory genes in B-cell lymphomas. We found association between polymorphic sites in inflammatory response genes and risk as well as outcome in B-NHL and suggest an effect of gene-gene interactions during the stepwise oncogenesis.

Normal Value Ranges for Central Retinal Thickness Asymmetry in Healthy Caucasian Adults Measured by SPECTRALIS SD-OCT Posterior Pole Asymmetry Analysis.

PURPOSE: To determine the normal variation in central retinal thickness asymmetry in healthy Caucasian adults using the posterior pole asymmetry analysis (PPAA) of a SPECTRALIS spectral-domain optical coherence tomography (SD-OCT) device. METHODS: Healthy Caucasian individuals aged between 18 and 45 years with a visual acuity of minimum 20/20 and a spherical equivalent between -1.5 and +1.5 diopters were recruited. Retinal thickness and retinal nerve fiber layer thickness (RNFL) were using measured SPECTRALIS SD-OCT. Inter- and intraocular differences in central retinal thickness were calculated using the PPAA. The association between age, sex, and interocular asymmetry was evaluated by a linear model with Gaussian correlation structure. RESULTS: A total of 105 individuals, 30 men and 75 women, were studied. The mean age ± SD was 28.8 ± 7.87 years. The grand mean interocular retinal thickness asymmetry was 5.6 µm (95% confidence interval [CI]: 4.6-6.5) and the grand mean intraocular retinal thickness asymmetry was 8.3 µm (95% CI: 6.8-9.9) in the right eye and 8.4 µm (95% CI: 6.7-10.0) in the left eye. The highest local asymmetries were found in the nasal corners of macula were the posterior pole thickness map overlaps the temporal vascular arches. A slight general age and sex effect on the mean interocular retinal thickness asymmetry was found to be respectively 0.04 µm/year (95% CI: 0.02-0.06 µm) and 0.54 µm (95% CI: 0.19-0.88 µm) for men compared with women. CONCLUSIONS: Statistically significant physiological asymmetries in inter- and intraocular central retinal thickness exist. This must be considered when early signs of glaucoma or other pathologies are evaluated based on the retinal thickness asymmetry. (http://www.controlled-trials.com/isrctn/ number, ISRCTN09017572.).