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ObjectivesHeavy alcohol use can cause somatic and mental diseases, affects patients’ social life and is associated with social isolation, unemployment and reduced quality of life. Therefore, societal costs of alcohol dependence are expected to be high. The aim of this study was to estimate excess costs of patients with alcohol dependence diagnosed using theDiagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria compared with individuals without alcohol dependence in Germany.DesignIn a secondary analysis, baseline data of patients with alcohol dependence enrolled in a randomised controlled trial (German Clinical Trials Register DRS00005035) were compared with data collected via a telephone survey from individuals without alcohol dependence and that had been matched by entropy balancing. Health service use was evaluated retrospectively for a 6-month period.SettingsFour German psychiatric university clinics (patients with alcohol dependence) and the German general adult population (individuals without alcohol dependence).Participantsn=236 adult patients with alcohol dependence and n=4687 adult individuals without alcohol dependence.Primary and secondary outcome measuresThe excess costs of health service use, absenteeism and unemployment of patients with alcohol dependence were calculated and compared with individuals without alcohol dependence. In subgroup analyses, the associations between excess cost and gender, comorbidities and the duration of disease were investigated.ResultsTotal 6-month excess costs of €11 839 (95% CI €11 529 to €12 147) were caused by direct excess costs of €4349 (95% CI €4129 to €4566) and indirect costs of €7490 (95% CI €5124 to €9856). In particular, costs of inpatient treatment, formal long-term care, absenteeism and unemployment were high.ConclusionsAlcohol dependence causes substantial direct and indirect excess costs. Cost-effective interventions to prevent and treat alcohol dependence are urgently needed.Trial registration numberDRKS00005035.

Keywords: Alcohol; average consumption; epidemiology; ischaemic heart disease; Mendelian randomization; patterns of drinking; regular versus irregular drinking

Induction of PM2.5-associated lung cancer in response to EGFR-tyrosine kinase inhibitors (EGFR-TKI) remains unclear. Polycyclic aromatic hydrocarbons (PAHs) and their polar derivatives (oxygenated PAHs: OPAHs and azaarenes: AZAs) were characterized in fine particulates (PM2.5) emitted from indoor coal combustion. Samples were collected in Xuanwei (Yunnan Province), a region in China with a high rate of lung cancer. Human lung adenocarcinoma cells A549 (with wild-type EGFR) and HCC827 (with EGFR mutation) were exposed to the PM2.5, followed by treatment with EGFR-TKI. Two samples showed significant and dose-dependent reduction in the cell viability in A549. EGFR-TKI further demonstrated significantly decreased in cell viability in A549 after exposure to the coal emissions. Chrysene and triphenylene, dibenzo[a,h]anthracene, benzo[ghi]perylene, azaarenes and oxygenated polycyclic aromatic hydrocarbons (carbonyl-OPAHs) were all associated with EGFR-TKI-dependent reduced cell viability after 72-h exposure to the PM2.5. The findings suggest the coal emissions could influence the response of EGFR-TKI in lung cancer cells in Xuanwei.

During the last years in Germany a marked increase in the use of amphetamines such as 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has been observed. The use of these recreational drugs is especially common among young people participating in rave parties. Occasionally ring-methoxylated phenethylamine derivatives like paramethoxymethamphetamine (PMMA) or paramethoxyamphetamine (PMA) are found in street drugs offered as ecstasy. These compounds exhibit a higher toxicity than the methylenedioxyamphetamine derivatives. We report on the death of a 22-year-old man after the ingestion of ecstasy pills containing PMMA and PMA. The PMMA concentration in femoral blood was 0.85 mg/l. Besides PMA (0.61 mg/l), amphetamine (0.21 mg/l), benzoylecgonine (<0.01 mg/l) and ethanol (0.46 per thousand ) were found in the blood. The case reflects the well-known fact that street drugs offered as ecstasy pills contain not necessarily MDMA but frequently differ in composition even if they have the same logo. Users of these pills therefore always take the risk of consuming pills with dangerous life-threatening ingredients. In many laboratories paramethoxyamphetamines are not detectable in routine analytical procedures. If the cause of an intoxication cannot be discovered by analytical routine methods, rarely occurring designer drugs such as PMA or PMMA should also be kept in mind.

The growing number of particle therapy facilities worldwide landmarks a novel era of precision oncology. Implementation of robust biophysical readouts is urgently needed to assess the efficacy of different radiation qualities. This is the first report on biophysical evaluation of Monte Carlo simulated predictive models of prescribed dose for four particle qualities i.e., proton, helium-, carbon- or oxygen ions using raster-scanning technology and clinical therapy settings at HIT. A high level of agreement was found between the in silico simulations, the physical dosimetry and the clonogenic tumor cell survival. The cell fluorescence ion track hybrid detector (Cell-Fit-HD) technology was employed to detect particle traverse per cell nucleus. Across a panel of radiobiological surrogates studied such as late ROS accumulation and apoptosis (caspase 3/7 activation), the relative biological effectiveness (RBE) chiefly correlated with the radiation species-specific spatio-temporal pattern of DNA double strand break (DSB) formation and repair kinetic. The size and the number of residual nuclear γ-H2AX foci increased as a function of linear energy transfer (LET) and RBE, reminiscent of enhanced DNA-damage complexity and accumulation of non-repairable DSB. These data confirm the high relevance of complex DSB formation as a central determinant of cell fate and reliable biological surrogates for cell survival/ RBE. The multi-scale simulation, physical and radiobiological characterization of novel clinical quality beams presented here constitutes a first step towards development of high precision biologically individualized radiotherapy.

Opiate antagonists are promising pharmacotherapeutic agents for the treatment of alcohol dependence, reducing craving and relapse rates in weaned alcoholics. However, preclinical findings indicate that they can also increase ethanol consumption and preference in animals with a strong liking for ethanol, depending on the dose and treatment regimen.The present study examined the effects of chronic, intermittent and acute opiate antagonist treatment on the alcohol deprivation effect (ADE) in long-term ethanol- experienced rats, which is an animal model of craving and relapse.Long-term ethanol-experienced rats were either implanted with mini-osmotic pumps delivering 0, 0.5 or 1 mg/kg per hour naloxone (chronic treatment) or received intermittent naltrexone injections (2x5 mg/kg per day SC). Effects of chronic and intermittent treatment on the ADE were studied in a four-bottle home cage drinking paradigm. In a second experiment, long-term ethanol-experienced rats trained in an operant ethanol self-administration paradigm received acute naltrexone treatment (0, 0.1, 1 or 10 mg/kg SC) before a 23-h session either during basal drinking or during the ADE.Chronic naloxone treatment increased ethanol preference during the ADE. Intermittent naltrexone treatment at a dose comparable to the lower dose of chronic treatment moderately attenuated the ADE. Acute naltrexone treatment selectively reduced lever pressing for ethanol both during the ADE and during basal drinking only at the lowest dose, whereas higher doses also suppressed water intake. The ethanol-specific suppressant effect on the ADE was long lasting. Concerning basal drinking, however, naltrexone had a long lasting reductive effect only on lever pressing for water.A low dose of naltrexone and an intermittent treatment regimen seem to be necessary to maintain a specific reduction in ethanol intake in individuals with a high motivation to consume ethanol. These findings are consistent with the notion that, at low doses, opiate antagonists reduce the reward value of reinforcers.

OBJECTIVEThis study investigated whether preceding ethanol intake impairs glucose response to low-dose glucagon in individuals with type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a randomized, crossover, placebo-controlled study in 12 insulin pump–treated individuals (median [interquartile range] age, 37 [31–51] years; HbA1c, 57 [51–59] mmol/mol or 7.3% [6.8–7.5]; and BMI, 23.9 [22–25] kg/m2). During two overnight study visits, a 6 p.m. dinner (1 g carbohydrates/kg) was served with diet drink (placebo) or diet drink and ethanol (0.8 g/kg). After 8–9 h, ethanol was estimated to be metabolized, and a subcutaneous (s.c.) insulin bolus was given to induce mild hypoglycemia. When plasma glucose (PG) was ≤3.9 mmol/L, 100 µg glucagon was given s.c., followed by another s.c. 100 µg glucagon 2 h later. Primary end point was incremental peak PG induced by the first glucagon bolus.RESULTSEthanol was undetectable before insulin administration at both visits. The insulin doses (mean ± SEM: 2.5 ± 0.4 vs. 2.7 ± 0.4 IU) to induce hypoglycemia (3.7 ± 0.1 vs. 3.9 ± 0.1 mmol/L) did not differ and caused similar insulin levels (28.3 ± 4.6 vs. 26.1 ± 4.0 mU/L) before glucagon administration on ethanol and placebo visits (all, P &gt; 0.05). The first glucagon bolus tended to cause lower incremental peak PG (2.0 ± 0.5 vs. 2.9 ± 0.3 mmol/L, P = 0.06), lower incremental area under the curve (87 ± 40 vs. 191 ± 37 mmol/L × min, P = 0.08), and lower 2-h PG level (3.6 ± 1.0 vs. 4.8 ± 0.4 mmol/L, P = 0.05) after ethanol compared with placebo. The second glucagon bolus had similar responses between visits, but PG remained 1.8 ± 0.7 mmol/L lower after ethanol compared with placebo.CONCLUSIONSThe ability of low-dose glucagon to treat mild hypoglycemia persisted with preceding ethanol intake, although it tended to be attenuated.

PurposeIncreased radiation response after proton irradiation, such as late radiation‐induced toxicity, is determined by high dose and elevated linear energy transfer (LET). Steep dose‐averaged LET (LETd) gradients and elevated LETd occur at the end of proton range and might be particularly sensitive to uncertainties in range prediction. Therefore, this study quantified LETd distributions and the impact of range uncertainty in robust dose‐optimized proton treatment plans and assessed the biological effect in normal tissues and tumors of patients.MethodsFor each of six cancer patients (two brain, head‐and‐neck, and prostate), two nominal treatment plans were robustly dose optimized using single‐ and multi‐field optimization, respectively. For each plan, two additional scenarios with ±3.5% range deviation relative to the nominal plan were derived by global rescaling of stopping‐power ratios. Dose and LETd distributions were calculated for each scenario using the beam parameters of the corresponding nominal plan. The variability in relative biological effectiveness (RBE) and probability of late radiation‐induced brain toxicity (PIC) was assessed.ResultsThe optimization technique (single‐ vs multi‐field) had a negligible impact on the LETd distributions in the clinical target volume (CTV) and in most organs at risk (OARs). LETd distributions in the CTV were rather homogeneous with arithmetic mean of LETd below 3.2 keV/µm and robust against range deviations. The RBE variability within the CTV induced by range uncertainty was small (≤0.05, 95% confidence interval). In OARs, LETd hotspots (>7 keV/µm) occurred and LETd distributions were inhomogeneous and sensitive to range deviations. LETd hotspots and the impact of range deviations were most prominent in OARs of brain tumor patients which translated in RBE values exceeding 1.1 in all brain OARs. The near‐maximum predicted PIC in healthy brain tissue of brain tumor patients was smaller than 5% and occurred adjacent to the CTV. Range deviations induced absolute differences in PIC up to 1.2%.ConclusionsRobust dose optimization generates LETd distributions in the target volume robust against range deviations. The current findings support using a constant RBE within the CTV. The impact of range deviations on the considered probability of late radiation‐induced toxicity in brain tissue was limited for robust dose‐optimized treatment plans. Incorporation of LETd in robust optimization frameworks may further reduce uncertainty related to the RBE‐weighted dose estimation in normal tissues.