Reduced mesiodistal tooth dimension in individuals with osteogenesis imperfecta: a cross-sectional study.

OBJECTIVE: Osteogenesis imperfecta (OI) is a rare, hereditary disease affecting collagen type-1 in connective tissue. Collagen type-1 is a substantial component of dentine, and it is speculated, whether affected dentine could cause altered mesiodistal tooth dimension possibly affecting restorative treatment regimen. Therefore, the aim of the present study was to measure mesiodistal tooth dimensions in individuals with OI and compare them with healthy controls. MATERIALS AND METHODS: Fifty-seven individuals aged 20-77 years with OI type 1-4 were included and 70 control patients aged 11-34 years were drawn from an orthodontic database. Mesiodistal tooth dimensions of all tooth types, except third molars, were measured in mm (two decimals) on digital 3 D-models of the tooth-bearing arches. RESULTS: Multilevel mixed-effects linear regression analysis showed that mesiodistal tooth dimension on average was 0.17 mm (95% CI = (-0.33; -0.01)) reduced for the OI group compared to controls. The analysis revealed variation between tooth types; incisors and first premolars were most affected and molars minimally affected. CONCLUSIONS: The mesiodistal tooth dimension in individuals diagnosed with OI is significantly smaller compared to healthy controls, which should be taken into consideration in the restorative treatment planning of individuals with OI, although the magnitude of the deviation is relatively small. The results on mesiodistal tooth dimensions of the present controls may be used as a standard for comparisons in future studies on tooth dimensions.

Preferred Reporting items for OBservational studies in Endodontics (PROBE) guidelines: a development protocol.

Observational studies have a significant role in establishing the prevalence and incidence of diseases in populations, as well as determining the benefits and risks associated with health-related interventions. Observational studies principally encompass cohort, case-control, case series and cross-sectional designs. Inadequate reporting of observational studies is likely to have a negative impact on decision-making in day-to-day clinical practice; however, no reporting guidelines have been published for observational studies in Endodontics. The aim of this project is to develop reporting guidelines for authors when creating manuscripts describing observational studies in the field of Endodontology in an attempt to improve the quality of publications. The new guidelines for observational studies will be named: 'Preferred Reporting items for OBservational studies in Endodontics (PROBE)'. A steering committee was formed by the project leaders (PD, VN) to develop the guidelines through a five-phase consensus process. The steering committee will review and adapt items from the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement and the Clinical and Laboratory Images in Publications (CLIP) principles, as well as identify new items that add value to Endodontics. The steering committee will create a PROBE Delphi Group (PDG), consisting of 30 members across the globe to review and refine the draft checklist items and flowchart. The items will be assessed by the PDG on a nine-point Likert scale for relevance and inclusion. The agreed items will then be discussed by a PROBE Face-to-Face meeting group (PFMG) made up of 20 individuals to further refine the guidelines. After receiving feedback from the PFMG, the steering committee will pilot and finalize the guidelines. The approved PROBE guidelines will be disseminated through publication in relevant journals, and be presented at national and international conferences. The PROBE checklist and flowchart will be available and downloadable from the Preferred Reporting Items for study Designs in Endodontics (PRIDE) website: www.pride-endodonticguidelines.org. The PROBE steering committee encourages clinicians, researchers, editors and peer reviewers to provide feedback on the PROBE guidelines to inform the steering group when the guidelines are updated.

PRIRATE 2020 guidelines for reporting randomized trials in Endodontics: a consensus-based development.

In evidence-based health care, randomized clinical trials provide the most accurate and reliable information on the effectiveness of an intervention. This project aimed to develop reporting guidelines, exclusively for randomized clinical trials in the dental specialty of Endodontology, using a well-documented, validated consensus-based methodology. The guidelines have been named Preferred Reporting Items for RAndomized Trials in Endodontics (PRIRATE) 2020. A total of eight individuals (PD, VN, HD, LB, TK, JJ, EP and SP), including the project leaders (PD and VN) formed a steering committee. The committee developed a checklist based on the items in the Consolidated Standards of Reporting Trials (CONSORT) guidelines and Clinical and Laboratory Images in Publications (CLIP) principles. A PRIRATE Delphi Group (PDG) and PRIRATE Face-to-Face Meeting group (PFMG) were also formed. Thirty PDG members participated in the online Delphi process and achieved consensus on the checklist items and flowchart that make up the PRIRATE guidelines. The guidelines were discussed at a meeting of the PFMG at the 19th European Society of Endodontology (ESE) Biennial congress, held on 13 September 2019 in Vienna, Austria. A total of 21 individuals from across the globe and four steering committee members (PD, VN, HD and LB) attended the meeting. As a consequence of the discussions, the guidelines were modified and then piloted by several authors whilst writing a manuscript. The PRIRATE 2020 guidelines contain a checklist consisting of 11 sections and 58 individual items as well as a flowchart, considered essential for authors to include when writing manuscripts for randomized clinical trials in Endodontics.

Diagnostic accuracy of cone beam computed tomography used for assessment of apical periodontitis: an ex vivo histopathological study on human cadavers.

AIM: To assess the diagnostic accuracy of Cone Beam Computed Tomography (CBCT) to diagnose apical periodontitis (AP) using histopathology of ex vivo human jaws as the reference standard. METHODOLOGY: Based on periapical radiographs of jaw specimens from human bodies donated for science, a sample of 223 teeth with 340 roots including all tooth groups, and different disease and treatment statuses was selected. Cone Beam Computed Tomography was performed using Cranex® 3Dx (Soredex Oy, Tuusula, Finland), small field-of-view (5 × 5 cm), and isotropic resolution 0.085 mm. Three observers assessed the presence of AP using a probability index. Histopathological examination of the periapical area was used as a reference standard to calculate estimates of diagnostic accuracy. RESULTS: For non-root filled teeth all estimates of diagnostic accuracy; sensitivity (SENS), specificity (SPEC), positive predictive value (PPV) and negative predictive value (NPV) were high. All estimates were lower for root filled teeth. When mild AP was classified as 'AP', SENS, SPEC and NPV were significantly lower in root filled roots (P < 0.001 in all cases). The same tendency was seen when mild AP was classified as 'No AP' but here only the difference in SPEC was significant (P < 0.001). CONCLUSION: The diagnostic accuracy of CBCT used for diagnosis of AP is dependent on the treatment status of the tooth. For non-root filled teeth the diagnostic accuracy of CBCT is high and almost all cases of AP can be diagnosed correctly with only a very small risk of over-diagnosis. All diagnostic accuracy parameters were lower for root filled roots, hence the diagnosis of AP on root filled roots using CBCT was less accurate.

Impact of cone beam computed tomography on periapical assessment and treatment planning five to eleven years after surgical endodontic retreatment.

AIM: To evaluate how additional information from Cone Beam CT (CBCT) impacts on periapical assessment and treatment planning based on clinical examination and periapical radiographs (PR) in cases followed up five to eleven years after surgical endodontic retreatment (SER). METHODOLOGY: Patients receiving SER during 2004-2010 were reinvited for follow-up examination including clinical examination, PR, and CBCT. In total, 108 patients (119 teeth) were reinvited, 74 patients (83 teeth) accepted to participate. Three observers initially assessed PR according to the four-scaled, increasing disease severity criteria by Rud et al. (International Journal of Oral Surgery, 1, 1972 and 195) and Molven et al. (International Journal of Oral and Maxillofacial Surgery, 16, and 432): 'Radiographic assessment A'. By including clinical information 'Treatment plan A' was made as follows: 1) no treatment, 2) further observation, 3) SER reoperation (SER-R), or 4) extraction. Hereafter, the CBCT volume was assessed and the information incorporated for 'Radiographic assessment B' followed by 'Treatment plan B'. Agreement between radiographic assessments and between treatment plans was recorded and assessed statistically by Stuart-Maxwell test for marginal homogeneity. RESULTS: Nine teeth had been extracted; thus, the final analysis included 74 teeth (66 patients). The radiographic assessment was changed as a result of the CBCT evaluation in 38 cases (51.4%), of which 35 (47.3%) were to a higher Rud & Molven score, P < 0.001. The treatment plan was changed for 18 teeth (24.3%). For 14 teeth (18.9%), the change was from no treatment or further observation to a more invasive treatment plan (SER-R or extraction), P = 0.005. CONCLUSION: The use of CBCT for long-term follow-up after SER led to more cases diagnosed with persisting or recurrent apical periodontitis and hence often to the recommendation of a more invasive treatment modality.

Prediction of periapical status and tooth extraction.

AIM: To describe and analyse risk factors associated with prediction of periapical status, assessed using the full-scale Periapical Index (PAI) supplemented with extraction as outcome variable. METHODOLOGY: In 1997-1998, 616 randomly selected individuals from Aarhus County, Denmark, underwent a full-mouth radiographic survey. All 616 were re-invited in 2003-2004 and in 2008-2009, when 473 and 363 persons, respectively, consented and attended a new radiographic examination. The study population of the present investigation included 330 persons who had participated in all three examinations, and 143 persons who had participated in the first and second examination only. Using the full-mouth radiographic survey and interview information, the following variables were assessed: on person level - age, gender, smoking habits and number of teeth; on tooth level - presence of tooth, PAI, root filling, caries, marginal bone level, restoration, jaw and tooth group. The outcome variable was the 5 score PAI supplemented with extraction. The observation period was 5 years. Ordered logistic regression analyses were carried out for root filled and non-root filled teeth separately. The Regional Committee of Ethics approved the study. RESULTS: For both root filled teeth and non-root filled teeth, the baseline PAI score was the most important predictive factor of periapical status and extraction (P < 0.0001). Non-root filled teeth had in general a better outcome than root filled teeth. However, in non-root filled teeth, several other factors had a significant influence on the outcome, and the risk estimates were larger and showed a more pronounced variation between the different categories of predictive factors. For root filled teeth few variables, other than baseline PAI score, influenced the outcome significantly. CONCLUSION: The full-scale PAI was the strongest predictive factor of periapical status or extraction even when adjusted for additional factors, such as marginal bone level. A high baseline PAI score increased the risk for an impaired outcome. The large difference in risk estimates for non-root filled compared to root filled teeth documents the importance of separate analyses/studies for identification and quantification of predictive factors associated with periapical status and extraction of a tooth.

Prognostic value of the full-scale Periapical Index.

AIM: To evaluate whether the full-scale Periapical Index (PAI) can predict the periapical status over time in nonroot filled and root filled teeth. METHODOLOGY: Full-mouth radiographic surveys of a random sample from a general population were performed in 1997, 2003 and 2008. The present investigation included 330 persons who participated in all three examinations and 143 persons who participated in the first and second examination. At each examination, the presence or absence of a tooth and of a root filling was recorded, and a PAI score (1-5) was assigned to all teeth. Retreatment of a root filling was recorded for root filled teeth. Statistical analysis was carried out using ordinal logistic regression and logistic regression and computed as Wald's tests. RESULTS: At baseline, nonroot filled teeth had lower PAI scores than root filled teeth (P < 0.0001). A high baseline PAI increased the risk of extraction for both root filled (P < 0.001) and nonroot filled teeth (P < 0.001). At 5-year follow-up, PAI scores were higher when baseline PAI scores had been higher. The overall pattern for root filled and nonroot filled teeth was similar, however, the differences were statistically significant (P < 0.001). In particular, the follow-up PAI score for nonroot filled teeth with baseline PAI score 1 or 2 was significantly lower than that of root filled teeth (P < 0.001). For root filled teeth with baseline PAI score 3, 4 or 5, the trend was reversed as they overall had slightly lower PAI scores at follow-up (P = 0.023). CONCLUSION: Repeated radiographic assessments of teeth using the full-scale PAI reveal that each of the five scores had distinct prognostic value for the course of periapical disease over a 5-year period for both nonroot filled and root filled teeth.

The mitochondrial protein TCAIM regulates activation of T cells and thereby promotes tolerance induction of allogeneic transplants.

Primary T cell activation and effector cell differentiation is required for rejection of allogeneic grafts in naïve recipients. It has become evident, that mitochondria play an important role for T cell activation. Expression of several mitochondrial proteins such as TCAIM (T cell activation inhibitor, mitochondrial) is down-regulated upon T cell receptor triggering. Here we report that TCAIM inhibited spontaneous development of memory and effector T cells. CD4(+) T cells from Tcaim knock-in (KI) mice showed reduced activation, cytokine secretion and proliferation in vitro. Tcaim KI T cells tolerated allogeneic skin grafts upon transfer into Rag-1 KO mice. CD4(+) and CD8(+) T cells from these mice did not infiltrate skin grafts and kept a naïve or central memory phenotype, respectively. They were unable to acquire effector phenotype and functions. TCAIM altered T cell activation-induced mitochondrial distribution and reduced mitochondrial reactive oxygen species (mROS) production. Thus, TCAIM controls T cell activation and promotes tolerance induction probably by regulating TCR-mediated mitochondrial distribution and mROS production.

Ten-year follow-up of root filled teeth: a radiographic study of a Danish population.

AIM: To assess the long-term outcome of root filled teeth in a general adult population examined in 1997, 2003 and 2008. METHODOLOGY: The study provides longitudinal, observational information on endodontic status for 327 randomly selected individuals from a general Danish population receiving three consecutive full-mouth radiographic examinations. The association between root filling quality, periapical disease and the long-term outcome of the root filling and the root filled tooth was assessed using GEE methodology and tests for trend. RESULTS: Overall 13% of the root filled teeth had been extracted, 12% had received a revision of the root filling and 42% of root filled teeth present in 2008 had apical periodontitis (AP) after the 10-year follow-up period. The probability of persistent AP was higher if the root filling was either short or long (P = 0.001), if there were voids (P < 0.001), or if there were radiographic signs of overhang or open margin of the restoration (P = 0.01). Further, the probability of extraction was high if there were radiographic signs of overhang or open margin of the restoration (P = 0.008) and if the overall root filling quality was inadequate (test for trend, P = 0.03). CONCLUSIONS: The root filling quality primarily affected the risk of persistent AP and to a smaller extent the risk of extraction, whereas the quality of the coronal restoration primarily affected the risk of extraction and to a smaller extent the risk of persistent AP. If adjusted for AP present at the initial examination, the associations were less pronounced both in relation to extraction and persistence of AP.

Ten-year follow-up observations of periapical and endodontic status in a Danish population.

AIM: To describe changes in periapical and endodontic status in a general adult Danish population examined in 1997, 2003 and 2008. METHODOLOGY: The study provides longitudinal, observational information on endodontic status for 327 individuals who participated in three consecutive full-mouth radiographic examinations performed with an approximately 5-year interval. The collected data allow changes to be investigated within and between age-cohorts. RESULTS: The median number of teeth declined slightly, but the number of individuals with apical periodontitis (AP) and with root filled teeth increased. The number of teeth with AP and of teeth with root fillings increased, whereas the number of root filled teeth with AP was almost stable. The proportion of individuals who had no AP and the proportion of individuals who had no root fillings decreased during the 10-year observation period. The proportion of teeth with AP/individual increased steadily with age, unaffected by the different time periods. Differences were found between the age groups for the proportion of root filled teeth/individual where the younger age-cohorts had root fillings performed later in life and at a slower rate. In the old age-cohort, the proportion of lost teeth/individual was much larger and showed a stronger increase with age, than in the younger age-cohorts. CONCLUSION: The younger age-cohorts will probably never reach the proportion of root fillings or lost teeth seen in the oldest age-cohort. However, it is disturbing that the proportion of teeth with AP/individual increased steadily with age, completely unaffected by the different time periods.

Incidence of caries lesions in approximal surfaces: a radiographic study of a general adult Danish population.

The aim was to describe the incidence of caries lesions in a randomly selected adult population, and to identify risk factors related to the incidence of caries lesions in approximal surfaces. In 1997, 616 adults participated in a study including a radiographic survey. In 2003 these individuals were contacted again and offered a second radiographic survey; 473 consented and attended this examination. In approximal surfaces, presence/absence of caries lesions and presence and type of coronal fillings were recorded. The incidence of caries lesions in surfaces with no caries lesions in 1997 was studied. Potential risk factors included information at three levels: (1) person, (2) tooth, and (3) surface. The analysis was carried out by multilevel logistic regression. For the analyses 23,701 approximal surfaces were eligible. In 23,243 approximal surfaces no caries lesions were detected in 1997, 17,007 of these were surfaces without fillings, and 6,236 were filled surfaces. In unfilled surfaces several factors affected the risk for development of a caries lesion: young age, high number of fillings, number of teeth and status of the adjacent surface. In filled surfaces few factors affected the incidence of caries lesions: status of the adjacent surface, smoking and distal surfaces. Differences in risk factor patterns for the incidence of caries lesions were found for unfilled and filled surfaces. The study emphasizes the importance of assessing factors related to the incidence of caries lesions in adults. Further it underlines the need to analyse the fate of filled surfaces separately, because once a surface has received a filling it needs continuous attendance.

Randomised trial of structured antenatal training sessions to improve the birth process.

OBJECTIVE: To compare the birth process in nulliparous women enrolled in a structured antenatal training programme, the 'Ready for Child' programme, with women allocated to routine care. DESIGN: A randomised controlled trial. SETTING: A Danish university hospital. PARTICIPANTS: Thousand hundred and ninety-three nulliparous women, recruited before week 22 + 0. Methods Compliance to the protocol was monitored by questionnaires sent to the women by email, and by data from the local birth cohort database. Data were analysed according to the 'intention-to-treat' principle. INTERVENTION: Women were randomised to receive 9 hours of antenatal training or no formalised training. Of the 1193 women, 603 were randomised to the intervention group and 590 were allocated to the reference group. MAIN OUTCOME MEASURES: Cervix dilatation on arrival at the maternity ward, use of pain relief and medical interventions during the birth process, and the women's birth experience. RESULTS: Women who attended the 'Ready for Child' programme arrived at the maternity ward in active labour more often than the reference group [relative risk (RR) 1.45, 95% confidence interval (95% CI) 1.26-1.65, P < 0.01], and they used less epidural analgesia during labour (RR 0.84, 95% CI 0.73-0.97, P < 0.01) but not less pain relief overall (RR 0.99, 95% CI 0.94-1.04, P < 0.72). Medical interventions and the women's self-reported birth experiences were similar in the two groups. We found no adverse effects of the intervention. CONCLUSION: Attending the 'Ready for Child' programme may help women to cope better with the birth process. Adverse effects are few, if any.

Waiting time to pregnancy according to maternal birthweight and prepregnancy BMI.

BACKGROUND: An association between a woman's own birthweight and her fecundity has been suggested, but no empirical data have been published on the association between maternal birthweight and waiting time to pregnancy (TTP). METHODS: In the Danish National Birth Cohort (1996-2002), which is an ongoing study of 92 274 women and their pregnancies, information about TTP and prepregnancy BMI was collected during pregnancy. At the 7-year follow-up of the children, 21 786 mothers reported their own birthweight and whether they were born at term or preterm. The association between maternal birthweight and TTP is presented as adjusted odds ratios with 95% confidence intervals. RESULTS: Low maternal birthweight (< or =2500 g for term and < or =1500 g for preterm birth) was associated with an increased risk of TTP of >1 year [term: 1.2 (1.0-1.5); preterm: 1.8 (1.1-3.1)]. The latter association was strongest in women with a BMI < 25 kg/m(2) [2.6 (1.4-4.7)]. High maternal birthweight (>4500 g for term and >3500 g for preterm) was also associated with an increased risk of TTP of >1 year [1.5 (1.0-2.0) and 1.3 (0.7-2.4), respectively], especially in women with a BMI > or = 25 kg/m(2) [1.8 (1.1-3.1) and 2.5 (1.0-6.4), respectively]. CONCLUSIONS: High or low maternal birthweight was associated with TTP > 1 year. Longer waiting times in women with very low birthweight may reflect an effect of being born very preterm. Subfecundity may partly be programmed in foetal life by factors that cause or correlate with foetal growth.

Prevalence and incidence of caries lesions in relation to placement and replacement of fillings: a longitudinal observational radiographic study of an adult Danish population.

The aim was to describe the prevalence and incidence of caries lesions in relation to the placement and replacement of amalgam and non-metal fillings in a randomly selected adult Danish population. In 1997 and in 2003, 470 individuals underwent a full-mouth radiographic survey. All recordings were based on radiographs. A total of 12,361 teeth were examined. Registrations were performed on surfaces: mesial, distal and occlusal or incisal. In 1997 the total number of teeth and the number of unfilled teeth per individual decreased with the age of the individual, whereas the number of caries lesions per individual did not vary systematically with age. In each age group approximately 50% of the individuals had no caries lesions. In 1997 approximately 70% of the filled surfaces were filled with amalgam and 30% with non-metal filling materials. In 2003 60% of the surfaces were amalgam-filled and 40% were non-metal-filled. Overall non-metal filling material was more frequently used than amalgam in both treatments and re-treatments. During the observation period approximately 20% of both amalgam and non-metal-filled surfaces were re-treated. For amalgam fillings this was constant across the tooth groups, but for non-metal fillings the percentage of re-treated surfaces was larger for molars. The percentage of teeth with caries increased from front teeth to posterior teeth. The lowest percentage of surfaces with caries was detected in unfilled surfaces, and the highest in non-metal-filled surfaces. The results from the present study suggest the need for reflection and diligence when using non-metal materials for dental fillings especially in relation to molars.

A field trial of resin-based and glass-ionomer fissure sealants: clinical and radiographic assessment of caries.

OBJECTIVE: The purpose of the present study was to provide further data for comparison of retention and caries-preventive effect of a resin-based sealant (Delton, and a glass-ionomer sealant (Fuji III). METHODS: The study was conducted in the municipality of Vaerløse located 15 km north of Copenhagen, Denmark in the period 1996-2001. The study comprised 153 children aged 8-13 years with a total of 364 site-pairs. Caries was diagnosed both clinically and radiographically, and sealant retention was diagnosed clinically. Sealants were placed either by one of four dentists, who had the responsibility for the children's dental care, by a dental hygienist or a dental assistant. Mean follow-up time was 38-39 months for sites on first permanent molars and 28-29 months for sites on second permanent molars. RESULTS: The retention rates were consistently, and considerably lower for Fuji III than for Delton. Relative risks of caries in Delton-sealed teeth over Fuji III-sealed teeth was 0.435 (95% CI 0.150-0.846) based on the clinical diagnosis, and 0.559 (95% CI 0.342-0.905) based on the radiographic diagnosis. The ratio of the relative risks (clinical over radiographic diagnosis) was close to 1 (0.778; 95% CI 0.272-1.481). CONCLUSION: In the present study, Delton-sealed teeth had a lower risk than Fuji III-sealed teeth of developing caries, independent of the caries diagnostic method used.

Economic and health implications of routine CBCT examination before surgical removal of the mandibular third molar in the Danish population.

OBJECTIVES: This epidemiological study aimed to analyse economical and societal consequences in Denmark if CBCT is used routinely as a diagnostic method before removal of the mandibular third molar. Furthermore, the aim was to calculate the excess cancer incidence from this practice. METHODS: 17 representative dental clinics in the regions of Denmark were visited by two observers, who registered the total number of patients in each clinic, the number of removed mandibular third molars from patients' files together with the age and gender of these patients. The data were collected from 2008 to 2014. The total number of removed mandibular third molars in Denmark each year was derived from the collected data and information on patients' contacts with dentists from Statistics Denmark as a sum of contributions from each region. The contribution of a region was obtained as the number of removed mandibular third molars in the selected clinics in the region times the ratio of the number of patients in the selected clinics in the region to the total number of patients with contact to a general practitioner in the region in 2011. Existing knowledge on the costs for panoramic and CBCT imaging was used to calculate total costs. The cancer incidence was calculated from lifetime attributable risk curves based on linear risk assumptions. RESULTS: The selected clinics included 109,686 patients, and 1369 mandibular third molars had been surgically removed. Using data from Statistics Denmark gave an estimated annual number of removed mandibular third molars of 36,882 at a total cost of €6,633,400. The additional cancer incidence was estimated to be approximately 0.46 per year. CONCLUSIONS: The data should be used in a cost-effectiveness analysis of the clinical efficacy of CBCT imaging before removal of mandibular third molars.

Effect of cancer chemotherapeutic drugs on radiation-induced lung damage in mice.

The effect of adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP) on the radiation-induced lung damage in mice was assessed by the ventilation rate (VR) and the lethality. Single drug doses were administered 15 min before graded single doses of irradiation and at different intervals from 28 days before to 28 days after fixed radiation doses. ADM, BLM and CTX administered 15 min before irradiation enhanced the radiation response with dose effect factors (DEF) of 1.46, 1.56 and 2.35, respectively. The effect of MM-C presented a complex picture. The drug had no effect at administration 15 min before 14-20 Gy, but enhanced the radiation response if given 15 min before 6-12 Gy (DEF = 1.57). The radiation-modifying effect of ADM, BLM, CTX and MM-C was most pronounced when the drugs were given 15 min before irradiation. The effect of ADM was present when administered from 7 days before to 7 days after irradiation. BLM and CTX enhanced the radiation response at administration from 24 h before to 3 days after irradiation, and the effect of MM-C was observed when the drug was given from 24 h before to 24 h after irradiation. 5-FU, MTX and cis-DDP had no effect on the radiation response at any of the investigated intervals.

Calculating excess lifetime risk in relative risk models.

When assessing the impact of radiation exposure it is common practice to present the final conclusions in terms of excess lifetime cancer risk in a population exposed to a given dose. The present investigation is mainly a methodological study focusing on some of the major issues and uncertainties involved in calculating such excess lifetime risks and related risk projection methods. The age-constant relative risk model used in the recent analyses of the cancer mortality that was observed in the follow-up of the cohort of A-bomb survivors in Hiroshima and Nagasaki is used to describe the effect of the exposure on the cancer mortality. In this type of model the excess relative risk is constant in age-at-risk, but depends on the age-at-exposure. Calculation of excess lifetime risks usually requires rather complicated life-table computations. In this paper we propose a simple approximation to the excess lifetime risk; the validity of the approximation for low levels of exposure is justified empirically as well as theoretically. This approximation provides important guidance in understanding the influence of the various factors involved in risk projections. Among the further topics considered are the influence of a latent period, the additional problems involved in calculations of site-specific excess lifetime cancer risks, the consequences of a leveling off or a plateau in the excess relative risk, and the uncertainties involved in transferring results from one population to another. The main part of this study relates to the situation with a single, instantaneous exposure, but a brief discussion is also given of the problem with a continuous exposure at a low-dose rate.

The shape of the cancer mortality dose-response curve for the A-bomb survivors.

The shape of the dose-response curve for cancer mortality in the A-bomb survivor data is analyzed in the context of linear-quadratic models. Results are given for all cancers except leukemia as a group, for leukemia, and for combined inferences assuming common curvature. Since there is substantial information aside from these data suggesting a dose-response curve with upward curvature, the emphasis here is not on estimating the best-fitting dose-response curve, but rather on assessing the maximum curvature under linear-quadratic models which is consistent with the data. The apparent shape of the dose-response curve is substantially affected by imprecision in the dose estimates, and methods are applied to correct for this. The extent of curvature can be expressed as the factor by which linear risk estimates from these data should be divided to arrive at appropriate estimates of risk at low doses. Influential committees have in the past recommended ranges of 1.5-4 and of 2-10 for such a factor. Results here suggest that values greater than about 2.0-2.5 are at least moderately inconsistent with these data, within the context of linear-quadratic models. It is emphasized, however, that there is little direct information in these data regarding risks following low doses; the inferences here depend strongly on the assumption of a linear-quadratic model.

Allowing for random errors in radiation dose estimates for the atomic bomb survivor data.

The presence of random errors in the individual radiation dose estimates for the A-bomb survivors causes underestimation of radiation effects in dose-response analyses, and also distorts the shape of dose-response curves. Statistical methods are presented which will adjust for these biases, provided that a valid statistical model for the dose estimation errors is used. Emphasis is on clarifying some rather subtle statistical issues. For most of this development the distinction between radiation dose and exposure is not critical. The proposed methods involve downward adjustment of dose estimates, but this does not imply that the dosimetry system is faulty. Rather, this is a part of the dose-response analysis required to remove biases in the risk estimates. The primary focus of this report is on linear dose-response models, but methods for linear-quadratic models are also considered briefly. Some plausible models for the dose estimation errors are considered, which have typical errors in a range of 30-40% of the true values, and sensitivity analysis of the resulting bias corrections is provided. It is found that for these error models the resulting estimates of excess cancer risk based on linear models are about 6-17% greater than estimates that make no allowance for dose estimation errors. This increase in risk estimates is reduced to about 4-11% if, as has often been done recently, survivors with dose estimates above 4 Gy are eliminated from the analysis.