Moderate Dose Levels Research Articles

Preliminary efficacy and safety of fruquintinib as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, randomized, open-label clinical trial (the FRONT study).

126 Background: Maintenance therapy and discontinuation of treatment are options to mCRC patients who response to first-line treatment. We conducted this study to evaluate the efficacy and safety of fruquintinib as maintenance therapy after first-line treatment for mCRC. Methods: This is an ongoing, multicenter, open-label, randomized clinical trial. Patients (pts) with unresectable right-sided mCRC or RAS-mutant left-sided mCRC, who hadn’t suffer disease progression after first-line standard treatment (chemotherapy with or without bevacizumab) for four to six months, were eligible. According to the protocol, 110 patients would be randomly assigned (2:1) to fruquintinib (FR) group (4mg once daily for 21 days, followed by 7 days off in 28 day cycles) or observation (OB) group via interactive web response system. The primary endpoint was progression-free survival (PFS). Results: Up to Aug 22, 2023, 28 and 14 patients had been enrolled in FR group and OB group, of whom the median age was 61 (44 to 73) vs. 66.5 (36 to 81), including 20 (71%) vs. 10 (71%) males, respectively. 26 (93%) vs. 11 (79%) patients were RAS-mutant. In the full analysis set (FAS), the median PFS were 5.26 (95% CI: 3.71-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.36; p=0.0158). 25 and 13 pts from two groups received at least one response evaluation after baseline, respectively. The disease control rate (DCR) was 88.00% (22/25) vs. 53.85% (7/13) (OR=6.29, 95% CI: 1.31-36.7; p=0.0267). As to the per-protocol set (PPS), since 6 pts in FR group initiated with a lower dose (3mg), the number of patients was 22 vs. 14. The median PFS were 6.51 (95% CI: 3.88-19.12) months and 2.99 (95% CI: 1.91-4.63) months (HR=0.25; p=0.0061). The DCR was 89.47% (17/19) vs. 53.85% (7/13) (OR=7.29, 95% CI: 1.32-58.9; p=0.0331). The common AEs in FR group were hypertension, hand-foot syndrome, fatigue, rash, oral mucositis, and proteinuria, while AEs of grades≥3 were hand-foot syndrome, hypertension, oral mucositis, and proteinuria. Conclusions: Fruquintinib at a moderate dose level indicated better outcomes of PFS as a maintenance therapy after first-line therapy with acceptable toxicity for patients with mCRC. Clinical trial information: NCT04296019 .

RJX Improves Wound Healing in Diabetic Rats.

BackgroundWe recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). The primary objective of the present study was to examine the effects of GMP-grade RJX on wound and burn injury healing in diabetic rats.MethodsIn the present study, a rat model of T2DM was used that employs HFD in combination with a single injection of STZ intraperitoneally (i.p) at a moderate dose level (45 mg/kg). Anesthetized diabetic rats underwent full-thickness skin excision on the back or were subjected to burn injury via a heated brass probe and then started on treatments with normal saline (NS = vehicle) or RJX administered via intraperitoneal injections for three weeks.FindingsNotably, diabetic rats treated with the 1.25 mL/kg or 2.5 mL/kg RJX (DM+RJX groups) rapidly healed their wounds as fast as non-diabetic control rats. Inflammatory cell infiltration in the dermis along with fibrin and cell debris on the epithelial layer persisted for up to 14 days in the DM+NS group but not in RJX-treated groups. The histopathological score of wound healing on days 7 and 14 was better in diabetic rats treated with RJX than diabetic rats treated with NS and comparable to the scores for non-diabetic healthy rats consistent with an accelerated healing process. The residual wound area of RJX-treated rats was significantly smaller than that of NS-treated diabetic rats at each evaluation time point (P<0.001). The accelerating effect of RJX on diabetic wound healing was dose-dependent. We obtained similar results in the burn injury model. Our results demonstrate that RJX – at a dose level >10-fold lower than its clinical maximum tolerated dose (MTD) – accelerates the healing of excision wounds as well burn injury in diabetic rats.

Feasibility of Ultra-High Resolution Supra-Aortic CT Angiography: An Assessment of Diagnostic Image Quality and Radiation Dose.

(1) Background: To evaluate diagnostic image quality and radiation exposure of ultra-high resolution cerebral Computed-Tomography (CT) angiography (CTA) obtained on an ultra-high resolution computed tomography scanner (UHR-CT). (2) Methods: Fifty consecutive patients with UHR-CTA were enrolled. Image reconstruction was processed with a 1024 × 1024 matrix and a slice thickness of 0.25 mm. Quantitative analyses comprising CT values, contrast–noise ratio (CNR) and signal-to-noise ratio (SNR) were performed. Subjective assessment of image quality, vessel contrast, noise, artefacts and delineation of different sized vessels were assessed by two readers on a 4-point scale. Radiation exposure was determined. (3) Results: Hounsfield values (ACI: 461.8 ± 16.8 HU; MCA: 406.1 ± 24.2 HU; BA: 412.2 ± 22.3 HU), SNR (ACI: 35.4 ± 13.1; MCA: 20.8 ± 12.4; BA: 23.7 ± 12.9) and CNR (ACI: 48.7 ± 21; MCA: 63.9 ± 26.9; BA: 48.1 ± 21.4) were remarkably high in all segments. Subjective analysis by two raters (fair agreement, k = 0.26) indicated excellent image qualities (image quality = 4; contrast = 4; noise = 3; artefacts = 4).Our analysis revealed a notably high traceability of the cerebral perforators (3 Points). Radiation exposure was at moderate dose levels (effective dose = 2.5 ± 0.6mSv). (4) Conclusions: UHR-CTA generates highly valuable image qualities that allow the depiction of vessels including cerebral perforators at acceptable dose levels. The UHR-CTA may therefore enhance the detection of small cerebral pathologies and may improve interpretability, especially in settings where high image qualities are crucial for the diagnostic accuracy.

Optimal stereotactic body radiotherapy dosage for hepatocellular carcinoma: a multicenter study

BackgroundThe optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC.MethodsThis multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 < 100 Gy), and ScRT (EQD2 < 74 Gy). Overall survival (OS), progression-free survival (PFS), local control (LC), and intrahepatic control (IC) were evaluated in univariable and multivariable analyses.ResultsThe median tumor size was 5.6 cm (interquartile range [IQR] 1.1–21.0 cm). The median follow-up time was 50.0 months (IQR 6–100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control.ConclusionsIf tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2 < 74 Gy) is recommended as palliative irradiation.

Preclinical Toxicology and Anticholangiocarcinoma Activity of Oral Formulation of Standardized Extract of Zingiber Officinale.

Cholangiocarcinoma (CCA) remains a significant public health problem in Thailand. New effective and safe drugs are urgently needed. Zingiber officinale Roscoe (ZO) is a widely used medicinal plant for the treatment of several ailments, and the animal study suggests a potential anti-CCA activity. The present study aimed to develop the oral formulation of standardized extract of ZO and investigate toxicological profiles (acute, repeated dose, and chronic toxicity), including anti-CCA activity of the ZO formulation. The oral pharmaceutical formulation of the standardized ZO extract was successfully developed with an acceptable level of contamination and physicochemical and pharmaceutical properties. Acute, subacute, and chronic toxicity tests were conducted in healthy Sprague Dawley rats according to the OECD guidelines. The results showed no evidence of toxicity and death in the acute and subacute toxicity testing with the maximum tolerated dose (MTD) of 5000 and 2000 mg/kg body weight, respectively. Chronic toxicity revealed MTD and No-Observed-Adverse-Effect level (NOAEL) of 1000 mg/kg body weight. The anti-CCA activity was evaluated in CCA-xenografted mouse model. The formulated ZO powder was fed to animals daily for 30 days. Significant anti-CCA activity on tumor growth inhibition and prolongation of survival time were demonstrated at the high (2000 mg/kg body weight) and moderate (1000 mg/kg body weight) dose levels. Further investigation to elucidate molecular targets of action of ZO against CCA cells is encouraged.

Cancer Risk from Exposure to Low to Moderate Level of Arsenic Using Meta-Analysis of Flexible Regression Models

These meta-analysis studies on arsenic exposure and disease risk assume linear exposure-response models. The linearity assumption for the logarithm of relative risks and levels of exposure to arsenic is overly simplified and is not adequate to capture the local structure accurately. This article applies fractional polynomial and cubic spline regression models in order to capture the shapes of the exposure-response relationships between both bladder and lung cancer risk and exposure to low to moderate dose arsenic. We consider low to moderate dose levels with concentrations from near 0 to 300µg/l. We also consider more recent studies on low to moderate dose exposure to arsenic and the risk of bladder and lung cancer. These flexible models are used to identify a combined general exposure-response relationship for the logarithm of relative risk and the levels of exposure to arsenic. The primary objective of this study is to predict overall risks of bladder and lung cancers by combining findings from systematically selected studies on these cancers under both linear and non-linear modeling assumptions. We predict overall risks of bladder and lung cancers for a series of exposure levels from the best fitting models.

Dose–surface maps identifying local dose–effects for acute gastrointestinal toxicity after radiotherapy for prostate cancer

Background and purposeWe evaluated dose distributions in the anorectum and its relation to acute gastrointestinal toxicities using dose surface maps in an image-guided (IG) IMRT and 3D-conformal radiotherapy (3D-CRT) population. Material and methodsFor patients treated to 78Gy with IG-IMRT (n=260) or 3D-CRT (n=215), for whom acute toxicity data were available, three types of surface maps were calculated: (1) total anorectum using regular intervals along a central axis with perpendicular slices, (2) the rectum next to the prostate, and (3) the anal canal (horizontal slicing). For each toxicity, an average dose map was calculated for patients with and without the toxicity and subsequently dose difference maps were constructed, 3D-CRT and IG-IMRT separately. P-values were based on permutation tests. ResultsDose distributions in patients with grade ⩾2 acute proctitis were significantly different from dose distributions in patients without toxicity, for IG-IMRT and 3D-CRT. At the cranial and posterior rectal site, in areas receiving moderate dose levels (≈25–50Gy), dose differences up to 10Gy were identified for IG-IMRT. For pain, cramps, incontinence, diarrhea and mucus loss significant differences were found as well. ConclusionsWe demonstrated significant relationships between acute rectal toxicity and local dose distributions. This may serve as a basis for subsequent dose–effect modeling in IG-IMRT, and improved dose constraints in current clinical practice.

Unintended irradiation of internal mammary chain – Is that enough?

AimTo evaluate the unintentional coverage of the internal mammary chain (IMC) with tangential fields irradiation to the breast, and its relation with the type of surgery employed. BackgroundThe dose distribution in regions adjacent to the treatment targets (mammary gland or chest wall), with incidental irradiation of the IMC, could translate into clinical benefit, due to the proximity of these regions. Materials and methodsOne hundred and twelve consecutive conformal radiotherapy plans were correlating the average dose to the IMC with the type of surgery employed, the extent of disease and the irradiation techniques. ResultsThe mean doses to IMC after modified radical mastectomy (MRM), modified radical mastectomy with immediate reconstruction (MRM+R), and breast conservative surgery (BCS) were 30.34Gy, 30.26Gy, and 18.67Gy, respectively. Significant differences were identified between patients who underwent MRM or MRM+R over BCS (p=0.01 and 0.003, respectively), but not between MRM and MRM+R (p=0.88). Mean doses to IMC were greater in patients with T3–T4 tumors when compared with more initial stages (≤T2) (p=0.0096). The lymph node involvement also correlated with higher average doses to IMC (node positive: 26.1Gy×node negative: 17.8Gy, p=0.0017). ConclusionsThe moderate dose level to the IMC in the unintentional irradiation scenario seems to be insufficient to treat the subclinical disease, although it could have an impact in patients undergoing mastectomy.

Accounting for neutron exposure in the Japanese atomic bomb survivors.

The Japanese atomic bomb survivors that were directly exposed to both γ rays and neutrons have been followed by the Radiation Effects Research Foundation (RERF). The estimation of the γ-ray risks requires some adjustment for the greater biological effect of the neutrons per unit dose. Because the small neutron doses and the predominant γ-ray doses are highly correlated, the neutron relative biological effectiveness (RBE) cannot be reliably estimated from the survivors' data and information from radiobiology must be invoked. As data became available on neutron doses, RERF has used a constant neutron RBE value of 10, even though radiobiological studies indicate that the RBE values appear to have considerably larger values at low doses. The approximation RBE = 10 assumes that if the RBE is variable it takes roughly this value in the range of total dose most relevant for linear risk estimation, namely about 1 Gy. We consider some possible RBE functions to explain the correct use and the impact of a dose-dependent RBE. However, we do not advocate any particular choice or even that a variable RBE be employed. Rather we show that the assumed neutron RBE, within a wide range of choices, is far less important to the outcome of risk assessment of the RERF data than generally believed. Some of these misperceptions have been related to the consideration of variable RBE functions, and without due attention to the fact that in the case of the A-bomb survivors' data, the mixed field of neutrons and γ rays must be considered. Therefore, the RBE value of neutrons is much lower than the RBE in pure neutron fields that are used in radiobiological experiments. Thus, applying the pure neutron field RBE to the mixed-field A-bomb radiation can lead to an overestimation of the actual neutron RBE for moderate total dose levels of 1 Gy by a factor of more than four. While in a pure neutron exposure the RBE depends on the neutron dose, in the mixed field it depends on both components of exposure, and in particular, we show that in the RERF setting the RBE depends mainly on the accompanying γ-ray dose.

Disruption of sensory gating by moderate alcohol doses

Evidence from a growing body of literature suggests that alcohol, even at moderate-dose levels, disrupts the ability to ignore distractors. However, little work has been done to elucidate the neural processes underlying this deficit. The present study was conducted to determine if low-to-moderate alcohol doses affect sensory gating, an electrophysiological phenomenon believed to reflect the pre-attentive filtering of irrelevant sensory information. Sixty social drinkers were administered one of three doses intended to produce breath alcohol concentrations of 0.0% (placebo), 0.04% (i.e., low dose), and 0.065% (i.e., moderate dose). A paired-click paradigm consisting of 100 pairs of identical tones (S1 and S2) was used to assess sensory gating. Amplitudes of P50, N100, and P200 auditory evoked potentials (AEPs) were used to calculate gating difference (S1-S2) and ratio (S2/S1) scores. The moderate alcohol dose significantly decreased P50 and N100 gating relative to placebo. Comparisons between the difference and ratio scores helped characterize the gating mechanisms affected at these stages of information processing. Alcohol did not alter P200 sensory gating. These data suggest that alcohol disrupts pre-attentional sensory-filtering processes at breath alcohol concentrations (BrACs) below the current 0.08% legal limit. Future studies should perform a combined assessment of sensory gating and selective attention to better understand the relationship between these two alcohol-induced deficits.

Epicardial Erythropoietin patch most efficiently improves myocardial regeneration and performance after infarction

Objectives: High-dose intramyocardial Erythropoietin (EPO) therapy protects the myocardium from ischemic injury and promotes beneficial remodelling. We investigated the therapeutic efficacy of EPO at a moderate dose level and compared local and systemic delivery routes in a rat myocardial infarction (MI) model.

The effect of gamma irradiation on mechanical, thermal and morphological properties of glass fiber reinforced polyethylene waste/reclaim rubber composites

Composites of waste polyethylene (WPE), collected from municipal solid waste/recycled waste rubber powder (RWRP) reactive compatibilizing agent, maleic anhydride (MA) and glass fiber (GF) up to 20wt%, prepared by melting and irradiated with gamma-rays up to 150kGy have been studied. Tensile strength (TS), elongation at break (Eb), elastic modulus, hardness, thermal and morphological parameters of the irradiated composites were investigated. The examined mechanical properties have been found to improve largely with filler content. Interesting Eb behavior has been detected for the irradiated composites loaded up to ∼10wt% GF and has been basically discussed in view of matrix crystallinity and morphology. TGA thermograms of unirradiated composites revealed enhanced thermal stability than that reported for the blend whereas comparatively slight improvement has been demonstrated by irradiation. Whereby insignificant alteration in Tm values was observed by loading or irradiation, yet ΔHm maximum of 3.41J/g, indicated for the 5wt% GF irradiated composite with an integral dose of 75kGy, emphasizes the influence of the relatively moderate load and dose levels on matrix stability. The phenomenon has been confirmed by the respective SEM micrographs.

Modulation of gene expression by the oxidative stress generated in human skin cells by UVA radiation and the restoration of redox homeostasis

UVA radiation generates a significant oxidative stress in skin cells which is further enhanced by the release of the pro-oxidant catalysts iron and heme, and exacerbated by UVA-mediated destruction of cellular reducing equivalents and the antioxidant enzyme catalase. An important consequence of this altered redox state is the generation of oxidized membrane components in the form of 4-hydroxynonenal, ceramides and oxidized phospholipids, all of which are potent signalling molecules which lead to modulation of the expression of many genes. Transcription factors (such as nuclear factor kappa-light-chain-enhancer of activated B cells) and several genes (e.g. interleukins, intercellular adhesion molecule and 1, hemeoxygenase 1) involved in the inflammatory response are dramatically modified by UVA. Levels of both antioxidant and pro-oxidant proteins, including manganese-dependent superoxide dismutase, glutathione peroxidase, hemeoxygenase 1, NADPH oxidase, ferritin, and methionine-S-sulfoxidereductase, are increased by UVA treatment and following moderate dose levels these will contribute to either the restoration or a further perturbation of redox homeostasis. Finally, UVA induces a whole set of matrix metalloproteinases and proteases, primarily in cells of dermal origin, which can contribute to the long-term consequences of UVA exposure of skin.

Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro

Tea drinking is widely practiced in the world and has recently increased among cancer patients. However, the effects of concurrent consumption of tea on the bioavailability and the net therapeutic potential of co-administered chemical drugs are not clear. In this study, the effects of green tea on the pharmacokinetics of 5-fluorouracil (5-FU) in rats and the pharmacodynamics in human cell lines in vitro were studied. The pharmacokinetic experiment indicated that there was an approximately 151% increase in the maximum plasma concentration (Cmax) and an approximately 425% increase in the area under the plasma concentration curve (AUC) of 5-FU in the green tea-treated group compared with the control group. Green tea consumption increased the plasma concentration of 5-FU. In addition, the pharmacodynamics experiment showed that at the moderate dose level (equivalent to <6 cups daily in human), neither fresh green tea extract nor (−)-epigallocatechin-3-gallate (EGCG) showed significant additive effects on the cytotoxicity of 5-FU in human cell lines. The results showed that it is crucial to perform therapeutic drug monitoring (TDM) when the cancer patients have a habit of drinking green tea.

Objective characterization of GE Discovery CT750 HD scanner: Gemstone spectral imaging mode

To objectively characterize the performance of the gemstone spectral imaging (GSI) mode of GE CT750 HD scanner from a user's perspective. A regular scan protocol that approximates the adult abdomen scan protocol frequently used in the authors' institute was selected as the baseline, and a GSI protocol (preset 11) that is similar to the regular protocol and has a moderate dose level (CTDI(vol) = 26.27 mGy) was compared to the baseline protocol. The resolving power of both protocols was characterized in terms of modulation transfer functions and high contrast resolution bar readings. Their noise characteristics were studied through noise power spectra, and their low contrast detectability was compared via contrast-to-noise ratio. Material decomposition capability of GSI was evaluated by scanning iodine solutions of 9-24 mg/ml iodine concentration in a Gammex CT phantom and by examining the estimated iodine concentration. In addition, a formula describing the dependency of HU in iodine enhanced area on GSI monochromatic energies and iodine concentrations was provided and the theoretical values were compared with the measured results. The resolutions levels of 50%, 10%, and 5% MTF of GSI monochromatic images at 65 keV agree with those of the regular protocol within 0.1 1p/cm. GSI monochromatic images at 65 keV demonstrated the lowest noise level among GSI images of different monochromatic energies and showed very similar noise magnitude and noise power distribution as compared to the regular protocol images. The CNR of 60 and 65 keV GSI monoimages are approximately 100% of those of the regular protocol images. Estimated iodine concentration levels agreed with the actual values within 2% when the iodine solutions were placed at 3, 9, 12 o'clock positions of the phantom; when iodine solutions were placed at the phantom center and at 6 o'clock position, higher discrepancies of 2%-10% were observed. The observed dependency of HU on keV and iodine concentration levels agreed with the expectation from x-ray attenuations. Equivalent performances were observed in the comparison between GSI 65 keV monochromatic images and images from a regular abdomen scan protocol. This suggests the possibility of GSI to be employed in routine abdominal scans, which would potentially offer more information through its capabilities of material decomposition.

Comparison of dose contribution to normal pelvic tissues among conventional, conformal and intensity-modulated radiotherapy techniques in prostate cancer

High-energy external radiotherapy has become one of the most common treatment in localized prostate cancer. We compared the difference of dose distribution, mainly at the 5–30 Gy dose level, in the irradiated pelvic volume among three modalities of radiotherapy for patients with prostate cancer: conventional, conformal and intensity-modulated radiotherapy (IMRT). We selected six patients with prostate cancer treated by conformal radiotherapy at the doses of 46 Gy to PTVN (prostate and seminal vesicles), and 70 Gy to PTV-T (prostate). The conventional technique": an 8-field arrangement was used; the conformal technique 4 fields with a boost through 6 fields. For IMRT, a five-beam arrangement was used. Dose-volume histograms (DVH) were analyzed and compared among the three techniques. The IMRT technique significantly increased the pelvic volume covered by the isodose surfaces below 15 Gy as compared with the conventional and conformal techniques. The mean absolute increase for the pelvic volume included between 5–30 Gy for the IMRT technique, was about 2 900 ml as compared with the conventional technique. However, IMRT significantly reduced the irradiated volume of the rectum in the dose range of 5 to 40 Gy, also significantly reduced the irradiated volume of bladder and femoral heads, and obtained a similar or improved isodose distribution in the PTVs. In addition, the use of IMRT slightly increased the relative dose delivered to the body volume outside the pelvis, as estimated by the use of specific software. A long-term follow-up will be needed to evaluate potential late treatment complications related to the use of IMRT and the low or moderate irradiation dose level obtained in the pelvis and in the whole body.

Studies on the interaction between Salmonella enterica ser. Typhimurium and intestinal helminths in pigs

Concomitant infections with helminths and bacteria may affect the course and the resulting disease outcome of the individual infections. Salmonella, Oesophagostomum, Trichuris and Ascaris coexist naturally in pig herds in Denmark, and possible interactions were studied. Pigs in one experiment were trickle infected with low or moderate dose levels of Oesophagostomum spp. and challenge infected with S. Typhimurium. In another experiment, pigs were inoculated with S. Typhimurium followed by a challenge exposure to either Oesophagostomum, Trichuris or Ascaris. Enhancement of the Salmonella infection was not demonstrated in either experiment. The helminth effect on the pigs was modest and may explain the lack of influence on the Salmonella infection. A previous experiment with a larger Oesophagostomum infection level resulted in enhancement of the S. Typhimurium infection. A dose dependency of the interaction is therefore suggested. However, the relatively high worm burdens in the present study suggest that infection with these common pig helminths does generally not influence the course of concurrent S. Typhimurium infections under natural conditions.

Radiation effects in micro-electromechanical systems (MEMS): RF relays

GaAs micro-electromechanical RF relays fabricated by surface micromachining techniques were characterized for their response to total ionizing dose. Microrelays with two different geometries were studied. For one geometry, changes in switch actuation voltage at moderate dose levels were observed. For an alternative geometry, no change in actuation voltage was observed. A mechanism for dielectric charge trapping and its effect on the electrostatic force is proposed.

Nondifferentiable errors in beta-compliance integrated logistic models: numerical results

In dose-response models, there are cases where only a portion of the administered dose may have an effect. This results in a stochastic compliance of the administered dose. In a previous paper (Chen-Mok and Sen, 1999), we developed suitable adjustments for compliance in the logistic model under the assumption of nondifferential measurement error. These compliance-adjusted models were categorized into three types: (i) Low (or near zero) dose levels, (ii) moderate dose levels, and (iii) high dose levels. In this paper, we analyze a set of data on the atomic bomb survivors of Japan to illustrate the use of the proposed methods. In addition, we examine the performance of these methods under different conditions based on a simulation study. Among all three cases, the adjustments proposed for the moderate dose case do not seem to work adequately. Both bias and variance are larger when using the adjusted model in comparison with the unadjusted model. The adjustments for the low dose case seem to work in reducing the bias in the estimation of the parameters under all types of compliance distributions. The MSEs, however, are larger under some of the compliance distribution considered. Finally, the results of this simulation study show that the adjustments for the high dose case are successful in achieving both a reduction in bias as well as a reduction in MSE, hence the overall efficiency of the estimation is improved.

A Comparison of Regulatory Implications of Traditional and Exact Two‐Stage Dose‐Response Models

We compare the regulatory implications of applying the traditional (linearized) and exact two‐stage dose‐response models to animal carcinogenic data. We analyze dose‐response data from six studies, representing five different substances, and we determine the “goodness‐ of‐fit” of each model as well as the 95% confidence lower limit ofthe dose corresponding to a target excess risk of 10‐5 (the target risk doseTRD). For the two concave datasets, we find that the exact model gives a substantially better fit to the data than the traditional model, and that the exact model gives aTRD that is an order of magnitude lower than that given by the traditional model. In the other cases, the exact model gives a fit equivalent to or better than the traditional model. We also show that although the exact two‐stage model may exhibit dose‐response concavity at moderate dose levels, it is always linear or sublinear, and never supralinear, in the low‐dose limit. Because regulatory concern is almost always confined to the low‐dose region extrapolation, supralinear behavior seems not to be of regulatory concern in the exact two‐stage model. Finally, we find that when performing this low‐dose extrapolation in cases of dose‐response concavity, extrapolating the model fit leads to a more conservative TRD than taking a linear extrapolation from 10% excess risk. We conclude with a set of recommendations.