A lifestyle intervention during pregnancy to reduce obesity in early childhood: the study protocol of ADEBAR - a randomized controlled trial.

BACKGROUND: The prevalence of obesity in childhood is increasing worldwide and may be affected by genetic factors and the lifestyle (exercise, nutrition behavior) of expectant parents. Lifestyle factors affect adipokines, namely leptin, resistin, and adiponectin as well as cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), which are involved in the regulation of maternal metabolic homeostasis, glucose metabolism, and the development of insulin resistance, metabolic syndrome, gestational diabetes mellitus, and hypertension. However, studies focusing on the effect of exercise or a combination of parental exercise and nutrition on the above-mentioned markers in newborns (venous cord blood) and especially on the long-term development of infants' weight gain are lacking. The study will investigate the effects of a multimodal intervention (regular exercise, diet) on parental and childhood adipocytokines (leptin, resistin, adiponectin, TNF-α, IL-6, BDNF). The effect of a lifestyle-related change in "fetal environmental conditions" on the long-term weight development of the child up to the age of two will also be assessed. METHODS/DESIGN: A randomized multi-center controlled trial will be conducted in Germany, comparing supervised aerobic and resistance training 2x/week (13th to 36th weeks of gestation) and nutritional counseling (6th to 36th weeks of gestation) during pregnancy with usual care. Thirty women (pre-pregnancy Body Mass Index ≥25 kg/m2, 6th-10th week of gestation) will be included in each group. Maternal anthropometric and physical measurements as well as blood sampling will occur at the 6th-10th, 13th-14th, 21st-24th, and 36th week of gestation, at delivery as well as 8 weeks and 24 months postpartum. Neonatal measurements and umbilical blood sampling will be performed at birth. Maternal and infants' weight development will be assessed every 6 months till 24 months postpartum. A difference in childhood BMI of 1 kg/m2 at the age of two years between both groups will be assumed. A power size of 80% using a significance level of 0.05 and an effect size of 1.0 is presumed. DISCUSSION: A better understanding of how lifestyle-related changes in the fetal environment might influence infants' outcome after two years of life could have a profound impact on the prevention and development of infants' obesity. TRIAL REGISTRATION: The trial is registered at the German Clinical Trial Register (DRKS00007702); Registered on 10th of August 2016; retrospectively registered https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00007702.

Comparison of central and local serial CT assessments of metastatic renal cell carcinoma patients in a clinical phase IIB study.

Background Clinical oncological studies attempt to improve precision of data by central radiological assessments. However, it is unclear, to which extent local and central assessments diverge. Purpose To quantify inter-reader variability and the deviation of local from central radiological assessments of computed tomography (CT) scans. Material and Methods This was a sub-study of a randomized clinical phase IIb trial in metastatic renal cell carcinoma (RCC), comparing first-line sorafenib with interferon-alpha-2a (IFN-α-2a). It analyzed agreements of local with central RECIST CT assessments by Cohen's kappa (κ), symmetry tests, deviations in waterfall plots, Bland-Altman plots, and parametric survival analyses. Results The concordance between local and central radiologic review was quantified by κ = 0.53. While local assessment yielded progressive disease (PD) in 18.6%, central assessment classified 22.5% of patient time points as PD exhibiting only a partial overlap with the 18.6% The tumor shrinkage rates in waterfall plots were 68.1% in local and 55.8% in central review (57.8% and 59% by Reader 1 and Reader 2). Bland-Altman plots identified a systematic shift of tumor change rates by -7.5% in local compared to central assessments, that may reflect a systematic tendency of more favorable results in local assessments. The discordance between local and central review was reflected by a time to progression (TTP) hazard ratio (HR) of 1.73 ( P = 0.0003). Conclusion These data suggest that central radiologic review may reduce technical measurement variability in clinical trials, which should be scrutinized in future studies compared to a volumetric reference.

First-line therapy for non-transplant eligible patients with multiple myeloma: direct and adjusted indirect comparison of treatment regimens on the existing market in Germany.

OBJECTIVES: The purpose of this study was to compare approved first-line therapies for patients with multiple myeloma. METHODS: A systematic literature search for phase III randomized controlled trials (RCTs) comparing first-line chemotherapies approved in Germany and recommended by guidelines at the time of study design was conducted. Random-effects meta-analysis (MA) was used for direct and the Bucher method for adjusted indirect treatment comparison. RESULTS: One RCT comparing melphalan and prednisone plus bortezomib (VMP) vs. melphalan and prednisone (MP) and six RCTs comparing MP plus thalidomide (MPT) vs. MP were analysed. For MPT vs. MP, an individual patient data (IPD) MA was used for sensitivity analyses. VMP and MPT were superior to MP regarding efficacy endpoints (VMP vs. MP, overall survival (OS): hazard ratio (HR) 0.70, 95 % confidence interval (CI) 0.57-0.86; progression-free survival (PFS): HR 0.56, 0.39-0.79; complete response (CR), risk-ratio (RR) for non-response: 0.70, 0.65-0.75; MPT vs. MP, OS: HR 0.83, 0.66-1.03; PFS: HR 0.67, 0.56-0.81; CR, RR for non-response 0.92, 0.88-0.95); but had a higher risk of developing any grade 3-4 adverse events (AEs) (VMP vs. MP: RR 1.13, 1.06-1.20; MPT vs. MP: RR 2.06, 1.43-2.98). The indirect comparison of VMP vs. MPT via MP showed a statistically not significant advantage for VMP regarding survival outcomes (OS: HR 0.85, 0.63-1.14; PFS: HR 0.83, 0.56-1.23) and a significant advantage regarding CR (RR for non-response 0.76, 0.70-0.83) and AEs (RR 0.55, 0.38-0.80). Treatment comparisons using results of IPD MA yielded similar effect sizes. CONCLUSIONS: VMP and MPT seem more effective than MP, VMP was superior to MPT regarding response criteria and AEs. Our results may best be confirmed by a head-to-head trial of VMP vs. MPT.

Indirect comparison of lixisenatide versus neutral protamine Hagedorn insulin as add-on to metformin and sulphonylurea in patients with type 2 diabetes mellitus.

OBJECTIVE: There is currently a lack of evidence from direct comparisons of treatment outcomes with lixisenatide versus neutral protamine Hagedorn (NPH)-insulin in type 2 diabetes mellitus (T2DM) patients with suboptimal glycaemic control with oral antidiabetic drugs (OADs). Hence, the current analysis indirectly compared available evidence on the risk of hypoglycaemia and weight change between lixisenatide and NPH-insulin based on randomized controlled trial (RCT) data with exenatide, insulin glargine and placebo as common references. METHODS: A systematic search of PubMed, Embase, the Cochrane database and clinical registries identified English- and German-language articles published from January 1980 to October 2012 reporting data from RCTs. Only publications of trials that reported outcomes from 24 to 30 weeks comparing glucagon-like peptide-1 receptor agonists or basal insulin versus another antidiabetic agent or placebo were included. Hypoglycaemia, patients at glycated haemoglobin (HbA1c) target and discontinuations due to adverse events (AEs) were treated as binary variables, with risk ratios and odds ratios (ORs) calculated. HbA1c and body weight were treated as continuous variables with difference in mean change from baseline (MD) calculated. Meta-analyses were performed with random effects models and indirect comparisons were performed according to Bucher's method. RESULTS: Seven RCTs (n=3,301 patients) comparing the efficacy and safety of lixisenatide, exenatide, insulin glargine and NPH-insulin with different antidiabetic treatments in adult patients with T2DM were included in the final analysis. In the adjusted indirect comparison, there was a significant difference in symptomatic hypoglycaemia (OR = 0.38; 95% CI = [0.17, 0.85]) and in confirmed hypoglycaemia (OR = 0.46; 95% CI = [0.22, 0.96]) favouring lixisenatide over NPH-insulin and comparable changes in HbA1c from baseline (MD = 0.07%; 95% CI = [-0.26%, 0.41%]). In contrast to NPH-insulin, there was a significant reduction in body weight with lixisenatide (MD = -3.62 kg; 95% CI = [-5.86 kg, -1.38 kg]) at study completion. The number of discontinuations due to AEs numerically favoured NPH-insulin over lixisenatide (OR = 2.64; 95% CI = [0.25, 27.96]), with a broad confidence interval. CONCLUSIONS: Lixisenatide treatment was associated with a lower risk of hypoglycaemia and a greater weight loss compared with NPH-insulin. Glycaemic control with lixisenatide treatment was comparable with NPH-insulin. These data suggest that lixisenatide is a beneficial treatment option for T2DM patients with inadequate glycaemic control on OADs, and is associated with reduced risk of hypoglycaemia and weight gain.

Sound levels and their effects on children in a German primary school.

Considerable sound levels are produced in primary schools by voices of children and resonance effects. As a consequence, hearing loss and mental impairment may occur. In a Cologne primary school, sound levels were measured in three different classrooms, each with 24 children, 8-10 years old, and one teacher. Sound dosimeters were positioned in the room and near the teacher's ear. Additional measurements were done in one classroom fully equipped with sound-absorbing materials. A questionnaire containing 12 questions about noise at school was distributed to 100 children, 8-10 years old. Measurements were repeated after children had been taught about noise damage and while "noise lights" were used. Mean sound levels of 5-h per day measuring period were 78 dB (A) near the teacher's ear and 70 dB (A) in the room. The average of all measured maximal sound levels for 1 s was 105 dB (A) for teachers, and 100 dB (A) for rooms. In the soundproofed classroom, Leq was 66 dB (A). The questionnaire revealed certain judgment of the children concerning situations with high sound levels and their ability to develop ideas for noise reduction. However, no clear sound level reduction was identified after noise education and using "noise lights" during lessons. Children and their teachers are equally exposed to high sound levels at school. Early sensitization to noise and the possible installation of sound-absorbing materials can be important means to prevent noise-associated hearing loss and mental impairment.

Rheopheresis for idiopathic sudden hearing loss: results from a large prospective, multicenter, randomized, controlled clinical trial.

Idiopathic sudden hearing loss (ISHL) has been suggested to precipitate as final common pathway of microcirculatory impairment of the inner ear associated with a variety of etiologies and characterized by a local hyperviscosity syndrome in cochlear vessels. Therefore, we investigated the effect of Rheopheresis, a method of therapeutic apheresis reducing plasma viscosity and improving microcirculation on hearing recovery. Patients were randomly assigned to receive two Rheopheresis treatments, or treatment according to current German guidelines consisting either of i.v. corticosteroids (methylprednisolon 250 mg for 3 days and subsequent oral dosing with tapering to zero) or i.v. hemodilution (500 mL 6% hydroxyethyl starch plus 600 mg pentoxifylline per day), each applied for 10 days. The primary outcome parameter was absolute recovery of hearing as measured by pure tone audiometry 10 days after the start of treatment. Secondary outcomes were recovery of hearing at day 42, the improvement of speech audiometry, tinnitus and feeling of pressure and the frequency of adverse events. In total, 240 patients with sudden hearing loss were enrolled from otorhinolaryngological departments at hospitals as well as out-patient clinics in Germany. Analysis was performed for the intention-to-treat as well as per protocol population. Mean absolute recovery of hearing on day 10 within the intention-to-treat population (ITT, n = 193) was 23.95 dB (SD 15.05) in the Rheopheresis group and 24.29 dB (SD 15.48) in the control group. Equal efficacy of Rheopheresis and tested standard treatments was demonstrated (P = 0.00056). Single Rheopheresis led to a higher recovery of hearing after 48 h in patients with high plasma viscosity (>1.8 mPas s; P = 0.029) or high total protein (>74 g/dL; P = 0.02). However, an overall good recovery of ISHL was observed with none of the tested therapies being superior regarding the primary outcome parameter. Improvement of health-related quality of life as documented by the SF36 was higher in the Rheopheresis group, exhibiting a significant difference for the physical summary scale at the final follow-up at day 42 (P = 0.006). In conclusion, Rheopheresis proved to be an effective treatment option within the ENT armamentarium for ISHL. Two Rheopheresis treatments within 3 days lasting for about 2 h each could be used to replace a 10-day infusion regimen, especially in patients who desire fast recovery from acute hearing loss. Also, this may be a second line treatment option for patients refractory to i.v. corticosteroids or hemodilution.

Herbal medicine with curcuma and fumitory in the treatment of irritable bowel syndrome: a randomized, placebo-controlled, double-blind clinical trial.

OBJECTIVE: Irritable bowel syndrome (IBS) is a common functional disorder for which there is no reliable medical treatment. The aim of this study was to determine the efficacy of two herbal remedies used in the treatment of IBS. MATERIAL AND METHODS: In a randomized, double-blind, placebo-controlled trial, IBS patients were randomly assigned to one of three treatment groups: 1) Curcuma xanthorriza 60 mg daily (curcuma group) (n=24), 2) Fumaria officinalis 1500 mg daily (fumitory group) (n=24) and 3) placebo (n=58). The study treatment was applied three times a day for 18 weeks. The main outcome parameters were changes in global patient ratings of IBS-related pain and distension on a visual analogue scale (0-50 mm) between baseline and at the end of treatment. Additional outcome parameters included global assessments of changes in IBS symptoms and psychosocial stress caused by IBS. RESULTS: A total of 106 patients (mean age 48+/-12 years, 63% F) were included in the intention-to-treat group. IBS-related pain decreased by -0.9+/-11.5 (mm+/-SD) in the fumitory group, -0.3+/-9.9 in the placebo group and increased by 2.0+/-9.5 in the curcuma group (p=0.81). IBS-related distension decreased by -1.4+/-12.5 in the curcuma group, -2.1+/-9.2 in the placebo group and increased by 0.3+/-9.3 in the fumitory group (p=0.48). Additionally, the global assessment of changes in IBS symptoms and psychological stress due to IBS did not differ significantly among the three treatment groups. CONCLUSIONS: Neither fumitory nor curcuma showed any therapeutic benefit over placebo in patients with IBS. Therefore, the use of these herbs for the treatment of IBS cannot be recommended.

Development and validation of a risk score for somatic erectile dysfunction: combined results from three cross-sectional surveys.

OBJECTIVES: Some men with erectile dysfunction (ED) have difficulties discussing their condition with their physicians. Existing screening and diagnostic tools for ED often require the administration of personal questions regarding the condition. We present a simple risk score to estimate the individual likelihood of somatic ED, based on age and existing health conditions. METHODS: Data from the Cologne Male Survey (n = 4396) were used to develop a multivariable logistic regression model for the individual ED likelihood. The regression equation was both internally and externally validated using data from a national study (Berlin study) and a multinational cross-sectional study (MALES study). RESULTS: A final regression equation including age, pelvic surgery, diabetes mellitus, arterial circulatory disorder, heart disease, smoking, and hypertension reached an area under the receiver operating characteristic curve of 0.84 (0.5 means random and 1.0 perfect discrimination). Internal validation did not indicate any relevant overfit and the external validation results (national data: AUC = 0.75; multinational data: AUC = 0.67) are similar to those of other popular risk scores. CONCLUSIONS: The validated ED risk score developed from the regression equation can be used as a screening tool to identify patients who are at a high risk of somatic ED. This tool can facilitate entering into discussions between physicians and patients regarding erectile function.

Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial.

BACKGROUND: Organ-confined renal-cell carcinoma is associated with tumour progression in up to 50% of patients after radical nephrectomy. At present, no effective adjuvant treatment is established. We aimed to investigate the effect of an autologous renal tumour cell vaccine on risk of tumour progression in patients with stage pT2-3b pN0-3 M0 renal-cell carcinoma. METHODS: Between January, 1997, and September, 1998, 558 patients with a renal tumour scheduled for radical nephrectomy were enrolled at 55 institutions in Germany. Before surgery, all patients were centrally randomised to receive autologous renal tumour cell vaccine (six intradermal applications at 4-week intervals postoperatively; vaccine group) or no adjuvant treatment (control group). The primary endpoint of the trial was to reduce the risk of tumour progression, defined as progression or death. All patients were assessed after standardised diagnostic investigations at 6-month intervals for a minimum of 4.5 years. FINDINGS: By preoperative and postoperative inclusion criteria, 379 patients were assessable for the intention-to-treat analysis. At 5-year and 70-month follow-up, the hazard ratios for tumour progression were 1.58 (95% CI 1.05-2.37) and 1.59 (1.07-2.36), respectively, in favour of the vaccine group (p=0.0204, log-rank test). 5-year and 70-month progression-free survival rates were 77.4% and 72%, respectively, in the vaccine group and 67.8% and 59.3%, respectively, in the control group. The vaccine was well tolerated, with only 12 adverse events associated with the treatment. INTERPRETATION: Adjuvant treatment with autologous renal tumour cell vaccine in patients with renal-cell carcinoma after radical nephrectomy seems to be beneficial and can be considered in patients undergoing radical nephrectomy due to organ-confined renal-cell carcinoma of more than 2.5 cm in diameter.