Best practice in undertaking and reporting health technology assessments : Working Group 4 report

[Executive Summary] The aim of Working Group 4 has been to develop and disseminate best practice in undertaking and reporting assessments, and to identify needs for methodologic development. Health technology assessment (HTA) is a multidisciplinary activity that systematically examines the technical performance, safety, clinical efficacy, and effectiveness, cost, costeffectiveness, organizational implications, social consequences, legal, and ethical considerations of the application of a health technology (18). HTA activity has been continuously increasing over the last few years. Numerous HTA agencies and other institutions (termed in this report “HTA doers”) across Europe are producing an important and growing amount of HTA information. The objectives of HTA vary considerably between HTA agencies and other actors, from a strictly political decision making–oriented approach regarding advice on market licensure, coverage in benefits catalogue, or investment planning to information directed to providers or to the public. Although there seems to be broad agreement on the general elements that belong to the HTA process, and although HTA doers in Europe use similar principles (41), this is often difficult to see because of differences in language and terminology. In addition, the reporting of the findings from the assessments differs considerably. This reduces comparability and makes it difficult for those undertaking HTA assessments to integrate previous findings from other HTA doers in a subsequent evaluation of the same technology. Transparent and clear reporting is an important step toward disseminating the findings of a HTA; thus, standards that ensure high quality reporting may contribute to a wider dissemination of results. The EUR-ASSESS methodologic subgroup already proposed a framework for conducting and reporting HTA (18), which served as the basis for the current working group. New developments in the last 5 years necessitate revisiting that framework and providing a solid structure for future updates. Giving due attention to these methodologic developments, this report describes the current “best practice” in both undertaking and reporting HTA and identifies the needs for methodologic development. It concludes with specific recommendations and tools for implementing them, e.g., by providing the structure for English-language scientific summary reports and a checklist to assess the methodologic and reporting quality of HTA reports

Stress corrosion cracking behavior of irradiated model austenitic stainless steel alloys.

Slow-strain-rate tensile tests (SSRTs) and posttest fractographic analyses by scanning electron microscopy were conducted on 16 austenitic stainless steel (SS) alloys that were irradiated at 289 C in He. After irradiation to {approx}0.3 x 10{sup 21} n{center_dot}cm{sup {minus}2} and {approx}0.9 x 10{sup 21} n{center_dot}cm{sup {minus}2} (E >1 MeV), significant heat-to-heat variations in the degree of intergranular and transgranular stress corrosion cracking (IGSCC and TGSCC) were observed. Following irradiation to a fluence of {approx}0.3 x 10{sup 21} n{center_dot}cm{sup {minus}2}, a high-purity laboratory heat of Type 316L SS (Si {approx} 0.024 wt%) exhibited the highest susceptibility to IGSCC. The other 15 alloys exhibited negligible susceptibility to IGSCC at this low fluence. The percentage of TGSCC on the fracture surfaces of SSRT specimens of the 16 alloys at {approx}0.3 x 10{sup 21} n{center_dot}cm{sup {minus}2} (E > 1 MeV) could be correlated well with N and Si concentrations; all alloys that contained <0.01 wt.% N and <1.0 wt. % Si were susceptible, whereas all alloys that contained >0.01 wt.% N or >1.0 wt.% Si were relatively resistant. High concentrations of Cr were beneficial. Alloys that contain <15.5 wt.% Cr exhibited greater percentages of TGSCC and IGSCC than those alloys with {approx}18 wt.% Cr, whereas an alloy that contains >21 wt.% Cr exhibited less susceptibility than the lower-Cr alloys under similar conditions

Defense-Inducing Volatiles: In Search of the Active Motif

Herbivore-induced volatile organic compounds (VOCs) are widely appreciated as an indirect defense mechanism since carnivorous arthropods use VOCs as cues for host localization and then attack herbivores. Another function of VOCs is plant–plant signaling. That VOCs elicit defensive responses in neighboring plants has been reported from various species, and different compounds have been found to be active. In order to search for a structural motif that characterizes active VOCs, we used lima bean (Phaseolus lunatus), which responds to VOCs released from damaged plants with an increased secretion of extrafloral nectar (EFN). We exposed lima bean to (Z)-3-hexenyl acetate, a substance naturally released from damaged lima bean and known to induce EFN secretion, and to several structurally related compounds. (E)-3-hexenyl acetate, (E)-2-hexenyl acetate, 5-hexenyl acetate, (Z)-3-hexenylisovalerate, and (Z)-3-hexenylbutyrate all elicited significant increases in EFN secretion, demonstrating that neither the (Z)-configuration nor the position of the double-bond nor the size of the acid moiety are critical for the EFN-inducing effect. Our result is not consistent with previous concepts that postulate reactive electrophile species (Michael-acceptor-systems) for defense-induction in Arabidopsis. Instead, we postulate that physicochemical processes, including interactions with odorant binding proteins and resulting in changes in transmembrane potentials, can underlie VOCs-mediated signaling processes

Irradiation-assisted stress corrosion cracking of austenitic stainless steels: Recent progress and new approaches

Irradiation-assisted stress corrosion cracking (IASCC) of several types of BWR field components fabricated from solution-annealed austenitic stainless steels (SSs), including a core internal weld, were investigated by means of slow-strain-rate test (SSRT), scanning electron microscopy (SEM), Auger electron spectroscopy (AES), and field-emission-gun advanced analytical electron microscopy (FEG-AAEM). Based on the results of the tests and analyses, separate effects of neutron fluence, tensile properties, alloying elements and major impurities identified in the American Society for Testing and Materials (ASTM) specifications, minor impurities, water chemistry, and fabrication-related variables were determined. The results indicate strongly that minor impurities not specified by the ASTM-specifications play important roles, probably through a complex synergism with grain-boundary Cr depletion. These impurities, typically associated with steelmaking and component fabrication processes, are very low or negligible in solubility in steels and are the same impurities that have been known to promote intergranular SCC significantly when they are present in water as ions or soluble compounds. It seems obvious that IASCC is a complex integral problem which involves many variables that are influenced strongly by not only irradiation conditions, water chemistry, and stress but also iron and steelmaking processes, fabrication of the component, and joining and welding. Therefore, for high-stress components in particular, it would be difficult to mitigate IASCC problems at high fluence based on the consideration of water chemistry alone, and other considerations based on material composition and fabrication procedure would be necessary as well

Trends of Exposure to Acrylamide as Measured by Urinary Biomarkers Levels within the HBM4EU Biomonitoring Aligned Studies (2000–2021)

Acrylamide, a substance potentially carcinogenic in humans, represents a very prevalent contaminant in food and is also contained in tobacco smoke. Occupational exposure to higher concentrations of acrylamide was shown to induce neurotoxicity in humans. To minimize related risks for public health, it is vital to obtain data on the actual level of exposure in differently affected segments of the population. To achieve this aim, acrylamide has been added to the list of substances of concern to be investigated in the HBM4EU project, a European initiative to obtain biomonitoring data for a number of pollutants highly relevant for public health. This report summarizes the results obtained for acrylamide, with a focus on time-trends and recent exposure levels, obtained by HBM4EU as well as by associated studies in a total of seven European countries. Mean biomarker levels were compared by sampling year and time-trends were analyzed using linear regression models and an adequate statistical test. An increasing trend of acrylamide biomarker concentrations was found in children for the years 2014–2017, while in adults an overall increase in exposure was found to be not significant for the time period of observation (2000–2021). For smokers, represented by two studies and sampling for, over a total three years, no clear tendency was observed. In conclusion, samples from European countries indicate that average acrylamide exposure still exceeds suggested benchmark levels and may be of specific concern in children. More research is required to confirm trends of declining values observed in most recent years

Engineering Bispecificity into a Single Albumin-Binding Domain

Bispecific antibodies as well as non-immunoglobulin based bispecific affinity proteins are considered to have a very high potential in future biotherapeutic applications. In this study, we report on a novel approach for generation of extremely small bispecific proteins comprised of only a single structural domain. Binding to tumor necrosis factor-α (TNF-α) was engineered into an albumin-binding domain while still retaining the original affinity for albumin, resulting in a bispecific protein composed of merely 46 amino acids. By diversification of the non albumin-binding side of the three-helix bundle domain, followed by display of the resulting library on phage particles, bispecific single-domain proteins were isolated using selections with TNF-α as target. Moreover, based on the obtained sequences from the phage selection, a second-generation library was designed in order to further increase the affinity of the bispecific candidates. Staphylococcal surface display was employed for the affinity maturation, enabling efficient isolation of improved binders as well as multiparameter-based sortings with both TNF-α and albumin as targets in the same selection cycle. Isolated variants were sequenced and the binding to albumin and TNF-α was analyzed. This analysis revealed an affinity for TNF-α below 5 nM for the strongest binders. From the multiparameter sorting that simultaneously targeted TNF-α and albumin, several bispecific candidates were isolated with high affinity to both antigens, suggesting that cell display in combination with fluorescence activated cell sorting is a suitable technology for engineering of bispecificity. To our knowledge, the new binders represent the smallest engineered bispecific proteins reported so far. Possibilities and challenges as well as potential future applications of this novel strategy are discussed

Environmentally assisted cracking in light water reactors. Semiannual report, October 1993--March 1994. Volume 18

This report summarizes work performed by Argonne National Laboratory (ANL) on fatigue and environmentally assisted cracking (EAC) in light water reactors (LWRs) during the six months from October 1993 to March 1994. EAC and fatigue of piping, pressure vessels, and core components in LWRs are important concerns in operating plants and as extended reactor lifetimes are envisaged. Topics that have been investigated include (a) fatigue of low-alloy steel used in piping, steam generators, and reactor pressure vessels, (b) EAC of wrought and cast austenitic stainless steels (SSs), and (c) radiation-induced segregation and irradiation-assisted stress corrosion cracking (IASCC) of Type 304 SS after accumulation of relatively high fluence. Fatigue tests have been conducted on A302-Gr B low-alloy steel to verify whether the current predictions of modest decreases of fatigue life in simulated pressurized water reactor water are valid for high-sulfur heats that show environmentally enhanced fatigue crack growth rates. Additional crack growth data were obtained on fracture-mechanics specimens of austenitic SSs to investigate threshold stress intensity factors for EAC in high-purity oxygenated water at 289{degrees}C. The data were compared with predictions based on crack growth correlations for wrought austenitic SS in oxygenated water developed at ANL and rates in air from Section XI of the ASME Code. Microchemical and microstructural changes in high- and commercial-purity Type 304 SS specimens from control-blade absorber tubes and a control-blade sheath from operating boiling water reactors were studied by Auger electron spectroscopy and scanning electron microscopy to determine whether trace impurity elements, which are not specified in the ASTM specifications, may contribute to IASCC of solution-annealed materials

Indole is an essential herbivore-induced volatile priming signal in maize

Herbivore-induced volatile organic compounds prime non-attacked plant tissues to respond more strongly to subsequent attacks. However, the key volatiles that trigger this primed state remain largely unidentified. In maize, the release of the aromatic compound indole is herbivore-specific and occurs earlier than other induced responses. We therefore hypothesized that indole may be involved in airborne priming. Using indole-deficient mutants and synthetic indole dispensers, we show that herbivore-induced indole enhances the induction of defensive volatiles in neighbouring maize plants in a species-specific manner. Furthermore, the release of indole is essential for priming of mono- and homoterpenes in systemic leaves of attacked plants. Indole exposure markedly increases the herbivore-induced production of the stress hormones jasmonate-isoleucine conjugate and abscisic acid, which represents a likely mechanism for indole-dependent priming. These results demonstrate that indole functions as a rapid and potent aerial priming agent that prepares systemic tissues and neighbouring plants for incoming attacks

Neural adaptations to electrical stimulation strength training

This review provides evidence for the hypothesis that electrostimulation strength training (EST) increases the force of a maximal voluntary contraction (MVC) through neural adaptations in healthy skeletal muscle. Although electrical stimulation and voluntary effort activate muscle differently, there is substantial evidence to suggest that EST modifies the excitability of specific neural paths and such adaptations contribute to the increases in MVC force. Similar to strength training with voluntary contractions, EST increases MVC force after only a few sessions with some changes in muscle biochemistry but without overt muscle hypertrophy. There is some mixed evidence for spinal neural adaptations in the form of an increase in the amplitude of the interpolated twitch and in the amplitude of the volitional wave, with less evidence for changes in spinal excitability. Cross-sectional and exercise studies also suggest that the barrage of sensory and nociceptive inputs acts at the cortical level and can modify the motor cortical output and interhemispheric paths. The data suggest that neural adaptations mediate initial increases in MVC force after short-term EST

Herbivore-induced terpenoid emission in Medicago truncatula: concerted action of jasmonate, ethylene and calcium signaling

Plant volatiles emitted by Medicago truncatula in response to feeding larvae of Spodoptera exigua are composed of a complex blend of terpenoids. The cDNAs of three terpene synthases (TPSs), which contribute to the blend of terpenoids, were cloned from M. truncatula. Their functional characterization proved MtTPS1 to be a β-caryophyllene synthase and MtTPS5 to be a multi-product sesquiterpene synthase. MtTPS3 encodes a bifunctional enzyme producing (E)-nerolidol and geranyllinalool (precursors of C11 and C16 homoterpenes) from different prenyl diphosphates serving as substrates. The addition of jasmonic acid (JA) induced expression of the TPS genes, but terpenoid emission was higher from plants treated with JA and the ethylene precursor 1-amino-cyclopropyl-1-carboxylic acid. Compared to infested wild-type M. truncatula plants, lower amounts of various sesquiterpenes and a C11–homoterpene were released from an ethylene-insensitive mutant skl. This difference coincided with lower transcript levels of MtTPS5 and of 1-deoxy-d-xylulose-5-phosphate synthase (MtDXS2) in the damaged skl leaves. Moreover, ethephon, an ethylene-releasing compound, modified the extent and mode of the herbivore-stimulated Ca2+ variations in the cytoplasm that is necessary for both JA and terpene biosynthesis. Thus, ethylene contributes to the herbivory-induced terpenoid biosynthesis at least twice: by modulating both early signaling events such as cytoplasmic Ca2+-influx and the downstream JA-dependent biosynthesis of terpenoids