Another Option for Aggression and Self-Injury, Alternative Benzodiazepines for Catatonia in Profound Autism.

Introduction: Individuals with profound autism often present for inpatient care due to aggression. Diagnostic and treatment options are limited. Agitated catatonia is a treatable comorbidity in autism, which should be considered in cases of aggression. Preliminary data report high clinical response rates of catatonia in autism when treated with electroconvulsive therapy (ECT), with poor response to lorazepam. However, access to ECT is often limited, especially in pediatric populations. Methods: We conducted a retrospective chart review to identify cases of hyperactive catatonia with partial response to lorazepam in profoundly autistic children presenting to the pediatric medical hospital. Five cases were identified, all of whom were followed by the child and adolescent psychiatry consult-liaison service during admission and treated without the use of ECT. Data from the medical record were obtained after institutional review board (IRB) approval including the following: (1) treatment course, (2) Bush-Francis Catatonia Rating Scale (BFCRS) scores, and (3) Kanner Catatonia Rating Scale (KCRS) severity scores. The Clinical Global Impressions-Improvement (CGI-I) Scale was applied retrospectively to each case. Results: All five patients demonstrated clinically significant improvements. The average CGI-I score was 1.2. The average percentage reduction in the BFCRS and KCRS severity scores was 63% and 59%, respectively. Two of five patients were first stabilized with infusions midazolam and dexmedetomidine due to the symptom severity and then transitioned to long-acting oral benzodiazepines. Overall, four of five patients were stabilized with oral clonazepam and one of five with oral diazepam. Notably, four of five patients experienced an acute worsening of aggression, self-injury, and other catatonic symptoms with escalating dosages of antipsychotic treatment, which occurred before inpatient admission. All patients experienced resolution of physical aggression toward self and/or others, experienced improvement in their communicative abilities, and were able to return home or enter residential level of care upon discharge. Conclusions: Given the limited availability of ECT and the unclear utility of lorazepam for hyperactive catatonia in autism, the use of long-acting benzodiazepines and/or midazolam infusion may offer a safe and readily available treatment alternative.

Morbidity Due to Disparity in Pediatric Electroconvulsive Therapy.

Dr. Miller and colleagues recently submitted a Letter to the Editor discussing current state laws that result in disparity of electroconvulsive therapy (ECT) availability.1 In this current letter, we present a case of treatment-resistant childhood-onset schizophrenia (COS), with morbidity due to limited access to ECT. The patient and his family presented from Kentucky to Tennessee, despite less legislative regulation in the former. The patient's family provided informed consent for this report to be published.

Lung, Laryngeal and Other Respiratory Cancer Incidence among Japanese Atomic Bomb Survivors: An Updated Analysis from 1958 through 2009.

The Life Span Study (LSS) of Japanese atomic bomb survivors is comprised of a large, population-based cohort offering one of the best opportunities to study the relationship between exposure to radiation and incidence of respiratory cancers. Risks of lung, laryngeal and other cancers of the respiratory system were evaluated among 105,444 LSS subjects followed from 1958 to 2009. During this period, we identified 2,446 lung, 180 laryngeal and 115 other respiratory (trachea, mediastinum and other ill-defined sites) first primary incident cancer cases. Ten additional years of follow-up, improved radiation dose estimates, revised smoking data, and updated migration information were used to investigate the joint effects of radiation and smoking using Poisson regression methods. For nonsmokers, the sex-averaged excess relative risk per Gy (ERR/Gy) for lung cancer (at age 70 after radiation exposure at age 30) was estimated as 0.81 (95% CI: 0.51, 1.18) with a female-to-male ratio of 2.83. There was no evidence of curvature in the radiation dose-response relationship overall or by sex. Lung cancer risks increased with pack-years of smoking and decreased with time since quitting smoking at any level of radiation exposure. Similar to the previously reported study, which followed cohort members through 1999, the ERR/Gy for lung cancer was significantly higher for low-to-moderate smokers than for heavy smokers, with little evidence of any radiation-associated excess risk in heavy smokers. Of 2,446 lung cancer cases, 113 (5%) could be attributed to radiation exposure. Of the 1,165 lung cancer cases occurring among smokers, 886 (76%) could be attributed to smoking. While there was little evidence of a radiation effect for laryngeal cancer, a nonsignificantly elevated risk of other respiratory cancers was observed. However, significant smoking effects were observed for both laryngeal (ERR per 50 pack-years = 23.57; 95% CI: 8.44, 71.05) and other respiratory cancers (ERR per 50 pack-years = 1.21; 95% CI: 0.10, 3.25).

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.

Instrumenting the balance error scoring system for use with patients reporting persistent balance problems after mild traumatic brain injury.

OBJECTIVE: To determine whether alterations to the Balance Error Scoring System (BESS), such as modified conditions and/or instrumentation, would improve the ability to correctly classify traumatic brain injury (TBI) status in patients with mild TBI with persistent self-reported balance complaints. DESIGN: Cross-sectional study. SETTING: Outpatient clinic. PARTICIPANTS: Subjects (n=13; age, 16.3±2y) with a recent history of concussion (mild TBI group) and demographically matched control subjects (n=13; age, 16.7±2y; control group). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures included the BESS, modified BESS, instrumented BESS, and instrumented modified BESS. All subjects were tested on the noninstrumented BESS and modified BESS and were scored by visual observation of instability in 6 and 3 stance conditions, respectively. Instrumentation of these 2 tests used 1 inertial sensor with an accelerometer and gyroscope to quantify bidirectional body sway. RESULTS: Scores from the BESS and the modified BESS tests were similar between groups. However, results from the instrumented measures using the inertial sensor were significantly different between groups. The instrumented modified BESS had superior diagnostic classification and the largest area under the curve when compared with the other balance measures. CONCLUSIONS: A concussion may disrupt the sensory processing required for optimal postural control, which was measured by sway during quiet stance. These results suggest that the use of portable inertial sensors may be useful in the move toward more objective and sensitive measures of balance control postconcussion, but more work is needed to increase sensitivity.

Assessing the adequacy of postexperimental inquiries in deception research and the factors that promote participant honesty.

The primary aim of this research was to assess the adequacy of postexperimental inquiries (PEI) used in deception research, as well as to examine whether mood state, reward, or administering the PEI as a face-to-face interview or computer survey impacts participants' willingness to divulge suspicion or knowledge about a study. We also sought to determine why participants are not always forthcoming on the PEI. Study 1 examined how frequently PEIs are included in research and found that most researchers employing deception do use a PEI. Studies 2 and 3 showed that participants are often unwilling to divulge suspicion or awareness of deception or to admit to having prior knowledge about a study, though offering a reward and completing the PEI on a computer modestly improved awareness and admission rates. Study 4 indicated several reasons why participants may not reveal suspicion or knowledge about a study on the PEI.

Allowance for random dose estimation errors in atomic bomb survivor studies: a revision.

Allowing for imprecision of radiation dose estimates for A-bomb survivors followed up by the Radiation Effects Research Foundation can be improved through recent statistical methodology. Since the entire RERF dosimetry system has recently been revised, it is timely to reconsider this. We have found that the dosimetry revision itself does not warrant changes in these methods but that the new methodology does. In addition to assumptions regarding the form and magnitude of dose estimation errors, previous and current methods involve the apparent distribution of true doses in the cohort. New formulas give results conveniently and explicitly in terms of these inputs. Further, it is now possible to use assumptions about two components of the dose errors, referred to in the statistical literature as "classical" and "Berkson-type". There are indirect statistical indications, involving non-cancer biological effects, that errors may be somewhat larger than assumed before, in line with recommendations made here. Inevitably, methods must rely on uncertain assumptions about the magnitude of dose errors, and it is comforting to find that, within the range of plausibility, eventual cancer risk estimates are not very sensitive to these.

Improved estimates of cancer site-specific risks for A-bomb survivors.

Pawel, D. J., Preston, D. L., Pierce, D. A. and Cologne, J. B. Improved Estimates of Cancer Site-Specific Risks for A-Bomb Survivors. Radiat. Res. 169, 87-98 (2008). Simple methods are investigated for improving summary site-specific radiogenic risk estimates. Estimates in this report are derived from cancer incidence data from the Life Span Study (LSS) cohort of A-bomb survivors that are followed up by the Radiation Effects Research Foundation (RERF). Estimates from the LSS of excess relative risk (ERR) for solid cancer sites have typically been derived separately for each site. Even though the data for this are extensive, the statistical imprecision in site-specific (organ-specific) risk estimates is substantial, and it is clear that a large portion of the site-specific variation in estimates is due to this imprecision. Empirical Bayes (EB) estimates offer a reasonable approach for moderating this variation. The simple version of EB estimates that we applied to the LSS data are weighted averages of a pooled overall estimate of ERR and separately derived site-specific estimates, with weights determined by the data. Results indicate that the EB estimates are most useful for sites such as esophageal or bladder cancer, for which the separately derived ERR estimates are less precise than for other sites.

Selection bias in cancer risk estimation from A-bomb survivors.

We consider the possible bias in cancer risk estimation from A-bomb survivors due to selection of the cohort by survival. The paper considers both relevant information from the data and basic theoretical issues involved. The most direct information from the data comes from making various restrictions on the dose-distance range, partly to reduce differential selection and partly just to reduce the magnitude of the selection. These analyses suggest that there are no serious biases, but they are not conclusive. Theoretical considerations include laying out more explicitly than usual just how biases could result from the selection. This involves heterogeneities in the ability to survive acute effects, in baseline and radiogenic cancer rates, and most importantly the correlation between survival-related and cancer-related heterogeneities. Following on this, idealized modeling is used to quantify the extent of possible bias in terms of the assumed values of the magnitude of these heterogeneities and their correlation. It is indicated that these values would need to be very large to introduce substantial bias. Based on all these considerations, it seems unlikely that the bias in cancer risk estimation could be large in relation to other uncertainties in generalizing from what is seen among A-bomb survivors; in particular, indications are that the bias in relative risks is unlikely to be as large as 0.05 to 0.07. For solid cancer this would correspond to bias in the excess relative risk at 1 Sv of at most about 15-20%.

AND/R: Advanced neutron diffractometer/reflectometer for investigation of thin films and multilayers for the life sciences.

An elastic neutron scattering instrument, the advanced neutron diffractometer/reflectometer (AND/R), has recently been commissioned at the National Institute of Standards and Technology Center for Neutron Research. The AND/R is the centerpiece of the Cold Neutrons for Biology and Technology partnership, which is dedicated to the structural characterization of thin films and multilayers of biological interest. The instrument is capable of measuring both specular and nonspecular reflectivity, as well as crystalline or semicrystalline diffraction at wave-vector transfers up to approximately 2.20 Å(-1). A detailed description of this flexible instrument and its performance characteristics in various operating modes are given.

Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates.

The Radiation Effects Research Foundation has recently implemented a new dosimetry system, DS02, to replace the previous system, DS86. This paper assesses the effect of the change on risk estimates for radiation-related solid cancer and leukemia mortality. The changes in dose estimates were smaller than many had anticipated, with the primary systematic change being an increase of about 10% in gamma-ray estimates for both cities. In particular, an anticipated large increase of the neutron component in Hiroshima for low-dose survivors did not materialize. However, DS02 improves on DS86 in many details, including the specifics of the radiation released by the bombs and the effects of shielding by structures and terrain. The data used here extend the last reported follow-up for solid cancers by 3 years, with a total of 10,085 deaths, and extends the follow-up for leukemia by 10 years, with a total of 296 deaths. For both solid cancer and leukemia, estimated age-time patterns and sex difference are virtually unchanged by the dosimetry revision. The estimates of solid-cancer radiation risk per sievert and the curvilinear dose response for leukemia are both decreased by about 8% by the dosimetry revision, due to the increase in the gamma-ray dose estimates. The apparent shape of the dose response is virtually unchanged by the dosimetry revision, but for solid cancers, the additional 3 years of follow-up has some effect. In particular, there is for the first time a statistically significant upward curvature for solid cancer on the restricted dose range 0-2 Sv. However, the low-dose slope of a linear-quadratic fit to that dose range should probably not be relied on for risk estimation, since that is substantially smaller than the linear slopes on ranges 0-1 Sv, 0-0.5 Sv, and 0- 0.25 Sv. Although it was anticipated that the new dosimetry system might reduce some apparent dose overestimates for Nagasaki factory workers, this did not materialize, and factory workers have significantly lower risk estimates. Whether or not one makes allowance for this, there is no statistically significant city difference in the estimated cancer risk.

A genome scanning approach to assess the genetic effects of radiation in mice and humans.

We used Restriction Landmark Genome Scanning (RLGS) to assess, on a genome-wide basis, the mutation induction rate in mouse germ cells after radiation exposure. Analyses of 1,115 autosomal NotI DNA fragments per mouse for reduced spot intensity, indicative of loss of one copy, in 506 progeny derived from X-irradiated spermatogonia (190, 237 and 79 mice in 0-, 3-, and 5-Gy groups, respectively), permitted us to identify 16 mutations affecting 23 fragments in 20 mice. The 16 mutations were composed of eight small changes (1-9 bp) at microsatellite sequences, five large deletions (more than 25 kb), and three insertions of SINE B2 or LINE1 transposable elements. The maximum induction rate of deletion mutations was estimated as (0.17 +/- 0.09) x 10(-5)/locus Gy(-1). The estimate is considerably lower than 1 x 10(-5)/locus Gy(-1), the mean induction rate of deletion mutations at Russell's 7 loci, which assumed that deletion mutations comprise 50% of all mutations. We interpret the results as indicating that the mean induction rate of mutations in the whole genome may be substantially lower than that at the 7 loci. We also demonstrate the applicability of RLGS for detection of human mutations, which allows direct comparisons between the two species.

Mechanistic models for radiation carcinogenesis and the atomic bomb survivor data.

Recently, Heidenreich et al. (Radiat. Res., 158, 607-617, 2002) suggested that the Radiation Effects Research Foundation (RERF) A-bomb survivor cohort study is not large enough to discriminate between various possible carcinogenic mechanisms. At least with the current follow-up, this is true to some extent, but I think the specific issues are rather different than they suggest. In particular, I do not think it is true-as they further indicate-that various models fit the data about equally well while estimating very different patterns of excess risk, which would imply that these patterns cannot be reasonably well characterized. I will point to specific criticisms of their approach to the data and offer some more general comments on mechanistic modeling approaches. Although there are important distinctions, I suggest on a very optimistic note that the two major approaches may be converging, and soon the main differences may not be in the assumptions made but in the aims of the modeling.

Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997.

This continues the series of general reports on mortality in the cohort of atomic bomb survivors followed up by the Radiation Effects Research Foundation. This cohort includes 86,572 people with individual dose estimates, 60% of whom have doses of at least 5 mSv. We consider mortality for solid cancer and for noncancer diseases with 7 additional years of follow-up. There have been 9,335 deaths from solid cancer and 31,881 deaths from noncancer diseases during the 47-year follow-up. Of these, 19% of the solid cancer and 15% of the noncancer deaths occurred during the latest 7 years. We estimate that about 440 (5%) of the solid cancer deaths and 250 (0.8%) of the noncancer deaths were associated with the radiation exposure. The excess solid cancer risks appear to be linear in dose even for doses in the 0 to 150-mSv range. While excess rates for radiation-related cancers increase throughout the study period, a new finding is that relative risks decline with increasing attained age, as well as being highest for those exposed as children as noted previously. A useful representative value is that for those exposed at age 30 the solid cancer risk is elevated by 47% per sievert at age 70. There is no significant city difference in either the relative or absolute excess solid cancer risk. Site-specific analyses highlight the difficulties, and need for caution, in distinguishing between site-specific relative risks. These analyses also provide insight into the difficulties in interpretation and generalization of LSS estimates of age-at-exposure effects. The evidence for radiation effects on noncancer mortality remains strong, with risks elevated by about 14% per sievert during the last 30 years of follow-up. Statistically significant increases are seen for heart disease, stroke, digestive diseases, and respiratory diseases. The noncancer data are consistent with some non-linearity in the dose response owing to the substantial uncertainties in the data. There is no direct evidence of radiation effects for doses less than about 0.5 Sv. While there are no statistically significant variations in noncancer relative risks with age, age at exposure, or sex, the estimated effects are comparable to those seen for cancer. Lifetime risk summaries are used to examine uncertainties of the LSS noncancer disease findings.

Age-time patterns of cancer to be anticipated from exposure to general mutagens.

We explore some stochastic considerations regarding accumulation of mutations in relation to carcinogenesis. In particular, we consider the effect of exposure to specific agents, especially ionizing radiation, that may increase mutation rates. The formulation and consequences are a further development of the Armitage-Doll model; both in terms of background cancer where assumptions are substantially weakened, and in terms of the effect of specific mutagenic exposures through generally increasing mutation rates. Under our model the effect of exposure is equivalent to a change in age scale, adding to age a parametric multiple of cumulative dose to the mutagen, which leads to useful formulae for the relative risk. In particular, the excess relative risk at age a behaves approximately as a parametric multiple of the mean dose over ages prior to a. These results do not require assuming that some fixed number of mutations are required for malignancy. The implications are particularly useful in providing guidance for descriptive analyses since they have characteristics largely independent of parameter values. It is indicated that the model consequences conform remarkably well to observations from cohort studies of the A-bomb survivors, miners with prolonged exposure to radon, and cigarette smokers who stopped smoking at various ages.

Joint effects of radiation and smoking on lung cancer risk among atomic bomb survivors.

Results are given on the joint effect of radiation exposure and cigarette smoking on lung cancer risks among A-bomb survivors, based on 592 cases through 1994. Information on smoking was derived from mail surveys and clinical interviews of 45113 persons in the Radiation Effects Research Foundation cohort. Radiation and smoking effects on lung cancer are found to be significantly sub-multiplicative and quite consistent with additivity. The smoking relative risk, previously very low in studies of this cohort, is now similar to that found in Western populations. This increase is likely to be related to the scarcity of cigarettes during and after the war. The smoking relative risk depends little on sex. After adjusting for smoking, the radiation-related risks relative to background rates for nonsmokers are similar to those for other solid cancers: a sex-averaged ERR/Sv of about 0.9 with a female:male sex ratio of about 1.6. Adjusting for smoking removes a spuriously large female:male ratio in radiation relative risk due to confounding between sex and smoking level. The adjustment also removes an artifactual age-at-exposure effect in the radiation relative risk, opposite in direction to other cancers, which is due to birth cohort variation in lung cancer rates.

Age-time patterns of radiogenic cancer risk: their nature and likely explanations.

It is important for both radiation protection and scientific reasons to understand the age-time patterns of radiation cancer risk. This is surprisingly difficult even for acute exposures and much more so for prolonged exposures. I shall provide current information on this for solid cancers among atomic-bomb survivors, pointing out some of the difficulties in description and interpretation. I shall then take up some stochastic considerations regarding accumulation of mutations, which may help in dealing with these difficulties. These considerations are highly idealised, and their consequences should mainly be used only for guidance rather than as a primary basis for descriptive analyses. They are particularly suitable for this because they provide insights fairly independent of parameter values in the stochastic models involved.