Planning Benchmark Study for Stereotactic Body Radiation Therapy of Pancreas Carcinomas with Simultaneously Integrated Boost and Protection: Results of the DEGRO/DGMP Working Group on Stereotactic Radiation Therapy and Radiosurgery.

PURPOSE/OBJECTIVE: The proximity or overlap of PTV and OAR poses a major challenge in SBRT of pancreatic cancer (PACA). This international treatment planning benchmark study investigates whether Simultaneously Integrated Boost (SIB) and Protection (SIP) concepts in PACA SBRT can lead to improved and harmonized plan quality. MATERIALS/METHODS: A multiparametric specification of desired target doses (GTVD50%, GTVD99%, PTVD95%, PTV0.5cc) with two prescription doses of GTVD50%=5×9.2Gy (46Gy) and GTVD50%=8×8.25Gy (66Gy) and OAR limits were distributed with planning CT and contours from 3 PACA patients. In phase 1, plans were ranked using a scoring system for comparison of trade-offs between GTV/PTV and OAR. In phase 2, re-planning was performed for the most challenging case and prescription with dedicated SIB and SIP contours provided for optimization after group discussion. RESULTS: For all 3 cases and both phases combined, 292 plans were generated from 42 institutions in 5 countries using commonly available treatment planning systems. The GTVD50% prescription was performed by only 76% and 74% of planners within 2% for 5 and 8 fractions, respectively. The GTVD99% goal was mostly reached, while the balance between OAR and target dose showed initial SIB/SIP-like optimization strategies in about 50% of plans. For plan ranking, 149 and 217 score penalties were given for 5 and 8 fractions, pointing to improvement possibilities. For phase 2, the GTVD50% prescription was performed by 95% of planners within 2% and GTVD99% as well as OAR doses were better harmonized with notable less score penalties. Fourteen of 19 planners improved their plan rank, 9 of them by at least 2 ranks. CONCLUSION: Dedicated SIB/SIP concepts in combination with multiparametric prescriptions and constraints can lead to overall harmonized and high treatment plan quality for PACA SBRT. Standardized SIB/SIP treatment planning in multicenter clinical trials appears feasible after group consensus and training.

Mid-term radiological results of a cementless short humeral component in anatomical and reverse shoulder arthroplasty.

AIMS: Shoulder arthroplasty using short humeral components is becoming increasingly popular. Some such components have been associated with relatively high rates of adverse radiological findings. The aim of this retrospective review was to evaluate the radiological humeral bone changes and mechanical failure rates with implantation of a short cementless humeral component in anatomical (TSA) and reverse shoulder arthroplasty (RSA). PATIENTS AND METHODS: A total of 100 shoulder arthroplasties (35 TSA and 65 RSA) were evaluated at a mean of 3.8 years (3 to 8.3). The mean age at the time of surgery was 68 years (31 to 90). The mean body mass index was 32.7 kg/m2 (17.3 to 66.4). RESULTS: Greater tuberosity stress shielding was noted in 14 shoulders (two TSA and 12 RSA) and was graded as mild in nine, moderate in two, and severe in three. Medial calcar resorption was noted in 23 shoulders (seven TSA and 16 RSA), and was graded as mild in 21 and moderate in two. No humeral components were revised for loosening or considered to be loose radiologically. Nine shoulders underwent reoperation for infection (n = 3), fracture of the humeral tray (n = 2), aseptic glenoid loosening (n = 1), and instability (n = 3). No periprosthetic fractures occurred. CONCLUSION: Implantation of this particular short cementless humeral component at the time of TSA or RSA was associated with a low rate of adverse radiological findings on the humeral side at mid-term follow-up. Our data do not raise any concerns regarding the use of a short stem in TSA or RSA. Cite this article: Bone Joint J 2019;101-B:610-614.

[Placebo and nocebo effects on itch : Methodological and clinical implications]. / Placebo- und Noceboeffekte bei Pruritus : Methodologische und klinische Implikationen.

Patients often experience positive (placebo) or negative (nocebo) treatment effects due to the positive or negative expectations they have about the treatment. Placebo and nocebo effects have only relatively recently received attention for itch. Experimental studies indicate that, in line with research in other areas, such as pain, learning via verbal suggestion and conditioning plays a key role in placebo and nocebo effects on itch. Results on contagious itch emphasize the role of observational learning and suggest that itch sensations might be particularly susceptible to suggestion and therefore placebo and nocebo effects. Substantial itch reductions in the placebo arms of clinical trials suggest that placebo effects are also important for clinical practice. In this article, an overview is given of how placebo and nocebo effects on itch can optimally be used in research and for the treatment of itch.

Placebo-like analgesia via response imagery.

BACKGROUND: Placebo effects on pain are reliably observed in the literature. A core mechanism of these effects is response expectancies. Response expectancies can be formed by instructions, prior experiences and observation of others. Whether mental imagery of a response can also induce placebo-like expectancy effects on pain has not yet been studied systematically. METHODS: In Study 1, 80 healthy participants were randomly allocated to (i) response imagery or (ii) control imagery. In Study 2, 135 healthy participants were randomly allocated to (i) response imagery with a verbal suggestion regarding its effectiveness, (ii) response imagery only, or (iii) no intervention. In both studies, expected and experienced pain during cold pressor tests were measured pre- and post-intervention, along with psychological and physiological measures. RESULTS: Participants rated pain as less intense after response imagery than after control imagery in Study 1 (p = 0.044, ηp2 = 0.054) and as less intense after response imagery (with or without verbal suggestion) than after no imagery in Study 2 (p < 0.001, ηp2 = 0.154). Adding a verbal suggestion did not affect pain (p = 0.068, ηp2 = 0.038). The effects of response imagery on experienced pain were mediated by expected pain. CONCLUSIONS: Thus, in line with research on placebo effects, the current findings indicate that response imagery can induce analgesia, via its effects on response expectancies. SIGNIFICANCE: The reported studies extend research on placebo effects by demonstrating that mental imagery of reduced pain can induce placebo-like expectancy effects on pain.

A Simple ab Initio Model for the Solvated Electron in Methanol.

The solvation structure of a solvated electron in methanol is investigated with ab initio calculations of small anion methanol clusters in a polarized dielectric continuum. We find that the lowest-energy structure in best agreement with experiment, calculated with CCSD, MP2, and B3LYP methods with aug-cc-pvdz basis set, is a tetrahedral arrangement of four methanol molecules with OH bonds oriented toward the center. The optimum distance from the tetrahedron center to the hydroxyl protons is ∼1.8 Å, significantly smaller than previous estimates. We are able to reproduce experimental radius of gyration Rg (deduced from optical absorption), vertical detachment energy, and resonance Raman frequencies. The electron paramagnetic resonance g-factor shift is qualitatively reproduced using density functional theory.

Safety of metamizole: a systematic review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Metamizole was withdrawn from the market in the United States and several European countries following reports of fatal agranulocytosis among users, but is still available in many countries in Europe, South America and Asia. Over the past several decades, a number of epidemiologic studies have been conducted to quantify the risk of agranulocytosis and other adverse effects associated with metamizole and other non-narcotic analgesics. The objective of this study was to perform a systematic review of the safety of metamizole. METHODS: Epidemiologic studies published between 1 January 1980 and 15 December 2014 were identified through systematic searches of PubMed and Google Scholar; the reference sections of selected articles were also reviewed to identify potentially relevant studies. Studies included in this review focused on the safety of metamizole, that is on outcomes such as haematologic abnormalities, gastrointestinal bleeding, anaphylaxis and hepatotoxicity. Two study investigators independently reviewed the abstracts and articles to determine relevant studies according to prespecified criteria. RESULTS AND DISCUSSION: A total of 22 articles met the criteria for evaluation. The majority of studies that evaluated agranulocytosis indicated an increased risk associated with metamizole, with relative risk (RR) estimates ranging from 1·5 (95% CI, 0·8-2·7) to 40·2 (95% CI, 14·7-113·3). Findings of three case-control studies do not suggest an association between metamizole and aplastic anaemia. Of the five case-control studies that evaluated the risk of upper gastrointestinal bleeding, four found a statistically significant increased risk associated with metamizole (RR estimates ranging from 1·4 to 2·7). There is insufficient evidence to determine whether metamizole increases the risk of other outcomes (e.g. hepatic effects, anaphylaxis, congenital anomalies). Few studies evaluated the effects of dose, route of administration or duration of therapy. WHAT IS NEW AND CONCLUSION: Published studies reported differences in the magnitude of risk of adverse outcomes associated with metamizole use and often had small sample sizes and a number of other limitations that may have biased the results. Further research is needed to better quantify the potential risks associated with metamizole compared to other non-narcotic analgesics.

Isotope Dependence and Quantum Effects on Atomic Hydrogen Diffusion in Liquid Water.

Relative diffusion coefficients were determined in water for the D, H, and Mu isotopes of atomic hydrogen by measuring their diffusion-limited spin-exchange rate constants with Ni(2+) as a function of temperature. H and D atoms were generated by pulse radiolysis of water and measured by time-resolved pulsed EPR. Mu atoms are detected by muonium spin resonance. To isolate the atomic mass effect from solvent isotope effect, we measured all three spin-exchange rates in 90% D2O. The diffusion depends on the atomic mass, demonstrating breakdown of Stokes-Einstein behavior. The diffusion can be understood using a combination of water "cavity diffusion" and "hopping" mechanisms, as has been proposed in the literature. The H/D isotope effect agrees with previous modeling using ring polymer molecular dynamics. The "quantum swelling" effect on muonium due to its larger de Broglie wavelength does not seem to slow its "hopping" diffusion as much as predicted in previous work. Quantum effects of both the atom mass and the water librations have been modeled using RPMD and a qTIP4P/f quantized flexible water model. These results suggest that the muonium diffusion is very sensitive to the Mu versus water potential used.

Transparency and Reproducibility of Observational Cohort Studies Using Large Healthcare Databases.

The scientific community and decision-makers are increasingly concerned about transparency and reproducibility of epidemiologic studies using longitudinal healthcare databases. We explored the extent to which published pharmacoepidemiologic studies using commercially available databases could be reproduced by other investigators. We identified a nonsystematic sample of 38 descriptive or comparative safety/effectiveness cohort studies. Seven studies were excluded from reproduction, five because of violation of fundamental design principles, and two because of grossly inadequate reporting. In the remaining studies, >1,000 patient characteristics and measures of association were reproduced with a high degree of accuracy (median differences between original and reproduction <2% and <0.1). An essential component of transparent and reproducible research with healthcare databases is more complete reporting of study implementation. Once reproducibility is achieved, the conversation can be elevated to assess whether suboptimal design choices led to avoidable bias and whether findings are replicable in other data sources.

[Methodological challenges concerning the selection of diseases for a standardized multimorbidity index]. / Methodische Herausforderungen bei der Auswahl von Erkrankungen für einen standardisierten Multimorbiditätsindex.

Multimorbidity is defined as the coexistence of two or more chronic diseases. However, this complex health status, which primarily affects elderly, is still insufficiently understood. One reason is the underrepresentation of older, multimorbid people in studies. Another reason is that there is no agreement on the number and type of diseases, which have to be considered in the assessment of multimorbidity. Therefore, this article provides an overview on the status quo of research on multimorbidity indices and describes in detail, what kind of methodological challenges have to be faced regarding the development of a standardized index. Finally, recommendations are made for criteria, which can be used for the selection of diseases relevant for multimorbidity.

Incidence of road injuries in Mexico: country report.

We used data from various sources to triangulate to a national snapshot of the incidence of fatal and non-fatal road traffic injuries in Mexico in 2005. Data sources used include national death registration data, national hospital discharge data and a nationally representative health survey. We estimate that in 2005, 19,389 people died due to injuries and nearly one million were injured in road traffic crashes. While deaths in high-income countries are declining, this is not the case in Mexico. Young adult males are the demographic at the highest risk in non-fatal crashes, but the elderly have the highest road death rates primarily due to pedestrian crashes. Pedestrians alone comprise nearly half (48%) of all deaths. Cars pose a substantial threat to occupants (38% of deaths and 39% of hospital admissions) and to other road users.

A role for a cell wall localized glycine-rich protein in dehydration and rehydration of the resurrection plant Boea hygrometrica.

The acquisition of desiccation tolerance in dicotyledonous angiosperms requires the induction of a co-ordinated programme of genetic and biochemical processes during drying and the adaptive mechanisms are primarily protoplasmic in nature. Recent studies have shown that changes in cell wall structure and composition are also important for recovery after drying, however, the molecular mechanisms that underpin these adaptive responses are largely unknown. Here, the desiccation-tolerant plant Boea hygrometrica was used as a model system to investigate the changes in gene expression and cell wall adaptation that take place during extreme dehydration. A cDNA macroarry analysis of dehydration-inducible genes led to the identification of a gene encoding a glycine-rich protein (BhGRP1). The corresponding transcript was up-regulated during drying in B. hygrometrica leaves. In silico analysis revealed that BhGRP1 is targeted to the cell wall and this was confirmed in planta. Morphological changes in the cell wall architecture were also observed during the process of drying and re-watering. Concomitant with this observation, cell wall profiling by Fourier transform infrared spectroscopy indicated that protein levels increased upon desiccation and remained broadly similar upon re-watering. These findings suggest that the deposition of BhGRP1 may play a role in cell wall maintenance and repair during dehydration and rehydration in B. hygrometrica.

Building national estimates of the burden of road traffic injuries in developing countries from all available data sources: Iran.

OBJECTIVE: To use a range of existing information sources to develop a national snapshot of the burden of road traffic injuries in one developing country-Iran. METHODS: The distribution of deaths was estimated by using data from the national death registration system, hospital admissions and outpatient visits from a time-limited hospital registry in 12 of 30 provinces, and injuries that received no institutional care using the 2000 demographic and health survey. Results were extrapolated to national annual incidence of health burden differentiated by age, sex, external cause, nature of injuries and institutional care. RESULTS: In 2005, 30,721 Iranians died annually in road traffic crashes and over one million were injured. The death rate (44 per 100,000) is the highest of any country in the world for which reliable estimates are available. Road traffic injuries are the third leading cause of death in Iran. While young adults are at high risk in non-fatal crashes, the elderly have the highest total death rates, largely due to pedestrian crashes. While car occupants lead the death count, motorized two-wheeler riders dominate hospital admissions, outpatient visits and health burden. CONCLUSIONS: Reliable estimates of the burden of road traffic injuries are an essential input for rational priority setting. Most low income countries are unlikely to have national injury surveillance systems for several decades. Thus national estimates of the burden of injuries should be built by collating information from all existing information sources by appropriately correcting for source specific shortcomings.

Evaluation of portal venous gas detected by ultrasound examination for diagnosis of necrotising enterocolitis.

BACKGROUND: Early diagnosis of necrotising enterocolitis (NEC) is difficult but essential for timely therapy. The diagnostic hallmarks and specific radiological signs for NEC are pneumatosis intestinalis (PI) and portal venous gas (PVG), but PVG in abdominal ultrasound (PVG-US) has been proposed as an effective tool in the diagnosis of NEC as well. OBJECTIVE: To prospectively assess the value of PVG-US for the diagnosis of NEC. METHODS: The study screened 352 neonates for PVG-US (n = 796 routine examinations) and performed 48 additional screenings in 34/352 neonates with suspected (stage I, n = 28) or definite NEC (stage > or =II, n = 20). Sensitivity and specificity of PVG-US for detection of NEC were computed by using NEC stage > or =II as the reference standard. RESULTS: PVG-US was only present in cases of suspected or definite NEC. The study observed PVG-US in 4/28 NEC stage I and in 9/20 NEC stage > or =II episodes corresponding to a 86% specificity and a 45% sensitivity for diagnosis of NEC stage > or =II. However, 7/20 patients with NEC stage > or =II showed intraoperative findings other than NEC and another 3/20 infants presented with radiologically unspecific intestinal dilatation. None of these 10 infants had detectable PVG-US. Thus, with application of specific radiological signs the sensitivity of PVG-US for diagnosis of NEC stage > or =II increased to 90%. CONCLUSION: Screening for PVG-US is a useful, easy and quick bedside test with a high specificity for NEC. Moreover, these results question the value of the Walsh criteria in the diagnosis of NEC.

[Federal admission criteria for levels of perinatal care: definition, interpretation and first conclusions]. / Aufnahmekriterien nach dem G-BA-Beschluss: definition, interpretation und erste schlussfolgerungen.

BACKGROUND: The outcome of high risk pregnancies is better in tertiary hospitals. The German government introduced levels of perinatal care only in 2006. The aim of this study was to investigate how many children are to be expected for each level, taking the possible width of interpretation of the admission criteria into account. MATERIALS AND METHODS: Perinatal quality assurance data from four German states (2005) were available. Based on the admission criteria used for level definitions, children were categorised into four different levels of care. To illustrate the possible width of interpretation of these admission criteria three analytical strategies were used. In addition, the distribution of children on different types of hospitals prior to the introduction of levels of care was analysed. RESULTS: Most deliveries (86-93 %) correspond to the lowest level, and only 1-5 % to the highest. Up to 15 % of children who should have been cared for in the highest level were born in hospitals with less than 500 annual deliveries. Among the neonates with risk profiles corresponding to the admission criteria for the two highest levels, up to 30 % were born in delivery units without NICUs. The majority (83 %) of attached NICUs had low caseloads (< 50 neonates < 1500 g / year). CONCLUSION: Most children fulfil the admission criteria for the lowest level of care whereas the need for specialised centres is rather low. Optimising the place of birth appropriately remains a challenge. Definition of levels of care based on admission criteria are difficult to implement due to a broad variety of interpretations.

Comparison of SSFP and IR GRE techniques for measurement of total myocardial mass-influence of applied contrast dosage and implication for relative infarct size assessment.

OBJECTIVE: To compare total left ventricular mass assessment using steady state free precession (SSFP) and inversion recovery fast gradient echo (IR GRE) imaging and further to assess the influence of contrast dosage on mass by IR GRE and its implications on relative infarct size assessment with both methods. METHODS: Forty-three patients with first documented myocardial infarction and single vessel disease underwent measurement of total myocardial mass using SSFP technique and an IR GRE sequence. As part of a Phase 2 multi-center dose ranging study for infarct identification patients received 1 of 4 possible dosages (0.05, 0.1, 0.2 or 0.3 mmol/kg body weight) of the contrast agent gadoversetamide (OptiMARK, Tyco Healthcare Mallinckrodt, St. Louis, MO, USA). RESULTS: Left ventricular mass assessment using IR GRE resulted in a slightly greater detection of myocardial mass than from the SSFP images (160.1 and 156.4 g, respectively, p < 0.001). The overall good correlation of both methods (R2 = 0.97 for the total study group, p < 0.001) was further improved by using gadoversetamide at doses of 0.2 or 0.3 mmol/kg (R2= 0.99, p < 0.001), mainly as a result of a considerably higher blood-myocardial contrast-to-noise ratio (CNR) in the IR GRE images. Bland-Altman analysis in these subgroups showed very little scatter of the residuals over the mean (3.5 +/- 5.4 g and 1.3 +/- 6.9 g respectively, 95% confidence interval). The observed differences in total mass calculation, while statistically significant, were not correlated with clinically relevant differences in estimation of relative infarct size. CONCLUSION: Total LV mass calculations using SSFP and IR GRE techniques are interchangeable when using appropriate contrast media, such as gadoversetamide. Late gadolinium enhancement results in good blood myocardial CNR. Hence, for relative infarct size assessment either method for calculation of total myocardial mass can be used.

Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study.

OBJECTIVES: Inflammation plays a role in prematurity, in neonatal disorders of the brain, lung, eye, bowel, and in developmental disability among preterm infants. We initiated a pilot study in preterm children to determine the prevalence of single nucleotide polymorphisms (SNPs) in the infection/inflammation-associated genes for interleukin (IL)-10 (- 1082 G/A), IL-1beta (+ 3953 C/T), tumor necrosis factor (TNF)-alpha (- 308 G/A) and toll-like receptor 4 (TLR-4) (Asp299Gly) and whether these SNPs affect the risk for neonatal disorders. STUDY DESIGN: We genotyped 73 children >/= 2 years of age whose gestational age at birth was < 32 weeks, and explored the associations between genotypes and neonatal disorders and developmental status at age 2 + years. RESULTS: Infants homozygous for the high IL-10 producer - 1082 G-allele (n = 15) were significantly less likely to develop ultrasound-defined periventricular echodensities. A non-significant, but prominent, risk reduction for bronchopulmonary dysplasia, high-grade retinopathy, cerebral palsy, and developmental delay at age 2 + years was present. Polymorphisms in the IL-1beta, TNF-alpha, and TLR-4 genes were too infrequent in our pilot sample to allow for reasonable analysis. CONCLUSION: Infants homozygous for the IL-10 high producer - 1082 G allele might be at reduced risk for prematurity-associated disorders.

Identification of further Craterostigma plantagineum cdt mutants affected in abscisic acid mediated desiccation tolerance.

The resurrection plant (Craterostigma plantagineum) is desiccation tolerant. However, callus derived from this plant, when propagated in vitro, requires exogenously applied abscisic acid (ABA) in order to survive desiccation. Treatment of callus tissue with ABA induces most of the genes that are induced by dehydration in the whole plant. This property has been exploited for the isolation of mutants that show dominant phenotypes resulting from the ectopic expression of endogenous genes induced by the insertion of a foreign promoter. Here we describe new T-DNA tagged Craterostigma desiccation-tolerant (cdt) mutants with different molecular and physiological characteristics, suggesting that different pathways of desiccation tolerance are affected. One of the mutants, cdt-2, constitutively expresses known osmoprotective Lea genes in callus and leaf tissue. Further analysis of this mutant revealed that the tagged locus is similar to a previously characterised gene, CDT-1, which codes for a signalling molecule that confers desiccation tolerance. The nature of the T-DNA insertion provides insight into the mechanism by which the CDT-1/2 gene family functions in ABA signal transduction.