Efficient uncertainty quantification for Monte Carlo dose calculations using importance (re-)weighting.

Objective. To present an efficient uncertainty quantification method for range and set-up errors in Monte Carlo (MC) dose calculations. Further, we show that uncertainty induced by interplay and other dynamic influences may be approximated using suitable error correlation models.Approach. We introduce an importance (re-)weighting method in MC history scoring to concurrently construct estimates for error scenarios, the expected dose and its variance from a single set of MC simulated particle histories. The approach relies on a multivariate Gaussian input and uncertainty model, which assigns probabilities to the initial phase space sample, enabling the use of different correlation models. Through modification of the phase space parameterization, accuracy can be traded between that of the uncertainty or the nominal dose estimate.Main results. The method was implemented using the MC code TOPAS and validated for proton intensity-modulated particle therapy (IMPT) with reference scenario estimates. We achieve accurate results for set-up uncertainties (γ2 mm/2%≥ 99.01% (E[d]),γ2 mm/2%≥ 98.04% (σ(d))) and expectedly lower but still sufficient agreement for range uncertainties, which are approximated with uncertainty over the energy distribution. Here pass rates of 99.39% (E[d])/ 93.70% (σ(d)) (range errors) and 99.86% (E[d])/ 96.64% (σ(d)) (range and set-up errors) can be achieved. Initial evaluations on a water phantom, a prostate and a liver case from the public CORT dataset show that the CPU time decreases by more than an order of magnitude.Significance. The high precision and conformity of IMPT comes at the cost of susceptibility to treatment uncertainties in particle range and patient set-up. Yet, dose uncertainty quantification and mitigation, which is usually based on sampled error scenarios, becomes challenging when computing the dose with computationally expensive but accurate MC simulations. As the results indicate, the proposed method could reduce computational effort while also facilitating the use of high-dimensional uncertainty models.

Impact of Gaussian uncertainty assumptions on probabilistic optimization in particle therapy.

Range and setup uncertainties in charged particle therapy may induce a discrepancy between the planned and the delivered dose. Countermeasures based on probabilistic (stochastic) optimization usually assume a Gaussian probability density to model the underlying range and setup error. While this standard assumption is generally taken for granted, this study explicitly investigates the dosimetric consequences if the actual range and setup errors obey a different probability density function (PDF) over the course of treatment to the one used during the probabilistic treatment plan optimization. Discrete random sampling was performed for conventionally and probabilistically optimized proton and carbon ion treatment plans utilizing various PDFs that modeled the setup and range error. This method allowed us to assess the treatment plan robustness against different PDFs of conventional and probabilistic plans, which both explicitly assume Gaussian uncertainties. The induced uncertainty in dose was quantified by estimating the expectation value and standard deviation of the RBE-weighted dose for each PDF on the basis of 2500-5000 random dose samples. Probabilistic dose metrics and standard deviation volume histograms were computed to quantify treatment plan robustness of both optimization approaches. It was shown that the classical planning target volume margin extension concept did not compensate the influence of range and setup errors and consequently resulted in a non-negligible average standard deviation in dose of 7.3% throughout the clinical target volume (CTV). In contrast, probabilistic optimization on normally distributed errors yielded treatment plans that not only entailed a lower standard deviation against normally distributed errors accounted for during optimization, but also lower standard deviations for other symmetric PDFs. It was shown that the impact of an incorrect probability distribution assumption is of lower importance after probabilistic optimization as the average uncertainty in the CTV drops to 3.9%. Probabilistic optimization is an effective tool to create robust particle treatment plans. Normally distributed range and setup error assumptions for probabilistic optimization are a reasonable first approximation and yield treatment plans that are also robust against other PDFs.

Analytical probabilistic modeling of RBE-weighted dose for ion therapy.

Particle therapy is especially prone to uncertainties. This issue is usually addressed with uncertainty quantification and minimization techniques based on scenario sampling. For proton therapy, however, it was recently shown that it is also possible to use closed-form computations based on analytical probabilistic modeling (APM) for this purpose. APM yields unique features compared to sampling-based approaches, motivating further research in this context. This paper demonstrates the application of APM for intensity-modulated carbon ion therapy to quantify the influence of setup and range uncertainties on the RBE-weighted dose. In particular, we derive analytical forms for the nonlinear computations of the expectation value and variance of the RBE-weighted dose by propagating linearly correlated Gaussian input uncertainties through a pencil beam dose calculation algorithm. Both exact and approximation formulas are presented for the expectation value and variance of the RBE-weighted dose and are subsequently studied in-depth for a one-dimensional carbon ion spread-out Bragg peak. With V and B being the number of voxels and pencil beams, respectively, the proposed approximations induce only a marginal loss of accuracy while lowering the computational complexity from order [Formula: see text] to [Formula: see text] for the expectation value and from [Formula: see text] to [Formula: see text] for the variance of the RBE-weighted dose. Moreover, we evaluated the approximated calculation of the expectation value and standard deviation of the RBE-weighted dose in combination with a probabilistic effect-based optimization on three patient cases considering carbon ions as radiation modality against sampled references. The resulting global γ-pass rates (2 mm,2%) are [Formula: see text]99.15% for the expectation value and [Formula: see text]94.95% for the standard deviation of the RBE-weighted dose, respectively. We applied the derived analytical model to carbon ion treatment planning, although the concept is in general applicable to other ion species considering a variable RBE.

Efficiency of analytical and sampling-based uncertainty propagation in intensity-modulated proton therapy.

The sensitivity of intensity-modulated proton therapy (IMPT) treatment plans to uncertainties can be quantified and mitigated with robust/min-max and stochastic/probabilistic treatment analysis and optimization techniques. Those methods usually rely on sparse random, importance, or worst-case sampling. Inevitably, this imposes a trade-off between computational speed and accuracy of the uncertainty propagation. Here, we investigate analytical probabilistic modeling (APM) as an alternative for uncertainty propagation and minimization in IMPT that does not rely on scenario sampling. APM propagates probability distributions over range and setup uncertainties via a Gaussian pencil-beam approximation into moments of the probability distributions over the resulting dose in closed form. It supports arbitrary correlation models and allows for efficient incorporation of fractionation effects regarding random and systematic errors. We evaluate the trade-off between run-time and accuracy of APM uncertainty computations on three patient datasets. Results are compared against reference computations facilitating importance and random sampling. Two approximation techniques to accelerate uncertainty propagation and minimization based on probabilistic treatment plan optimization are presented. Runtimes are measured on CPU and GPU platforms, dosimetric accuracy is quantified in comparison to a sampling-based benchmark (5000 random samples). APM accurately propagates range and setup uncertainties into dose uncertainties at competitive run-times (GPU [Formula: see text] min). The resulting standard deviation (expectation value) of dose show average global [Formula: see text] pass rates between 94.2% and 99.9% (98.4% and 100.0%). All investigated importance sampling strategies provided less accuracy at higher run-times considering only a single fraction. Considering fractionation, APM uncertainty propagation and treatment plan optimization was proven to be possible at constant time complexity, while run-times of sampling-based computations are linear in the number of fractions. Using sum sampling within APM, uncertainty propagation can only be accelerated at the cost of reduced accuracy in variance calculations. For probabilistic plan optimization, we were able to approximate the necessary pre-computations within seconds, yielding treatment plans of similar quality as gained from exact uncertainty propagation. APM is suited to enhance the trade-off between speed and accuracy in uncertainty propagation and probabilistic treatment plan optimization, especially in the context of fractionation. This brings fully-fledged APM computations within reach of clinical application.

Prevalence of Gardnerella vaginalis in prepubertal males.

OBJECTIVES: To determine the rate of occurrence of Gardnerella vaginalis in the genital tract and rectum of the asymptomatic prepubertal boy and to examine the effect of circumcision on the rate of recovery. DESIGN: A prospective survey design was used. Cultures for G vaginalis were obtained from the urethral meatus, surrounding glans, and rectum of prepubertal boys. Boys who had a history of sexual abuse, current urogenital symptoms, or who had taken antibiotics in the preceding 2 weeks were excluded from this study. SETTING: The study was conducted in ambulatory clinical settings at a children's hospital within a major medical center that serves as a statewide referral center. PARTICIPANTS: A group of 99 circumcised and uncircumcised prepubertal boys participated in the study. The participants ranged in age from 1 month to 7 years 4 months. MAIN OUTCOME MEASURE: Results of cultures for G vaginalis. RESULTS: No cultures were positive for G vaginalis from the urethra, glans, or rectum in any of the participants in this study. CONCLUSIONS: The findings of this study provide preliminary evidence that G vaginalis is not an organism that commonly colonizes the urogenital or gastrointestinal tract in asymptomatic prepubertal boys. Based on these findings, it does not seem prudent to apply the concept of asymptomatic colonization to prepubertal boys unless further studies refute these findings.

Pregnant adolescents in the emergency department: diagnosed and not diagnosed.

A study was conducted to compare the presenting complaints and historical information of adolescents diagnosed as pregnant (DP) in the emergency department (ED) with adolescents seen in the ED who were pregnant and not diagnosed (MP). Medical records for the period 1980-94 were retrospectively analyzed to identify patients 16 years of age or younger who were diagnosed as pregnant in the ED or who had a live birth and had an ED visit during pregnancy. This analysis was done in a university-affiliated tertiary referral hospital with approximately 65,000 ED visits and 3,500 deliveries each year. The DP patients had complaints referable to the abdomen or genitourinary system more commonly than the MP patients (91% v 22%). Less than 10% of the DP patients mentioned the possibility of pregnancy at initial triage, 10.5% denied being sexually active, and 5% had a pelvic examination and sexually transmitted disease screening; 68% of MP patients did not have sexual or menstrual history documented, and 5% had a pelvic examination. The diagnosis of pregnancy can be a challenge in patients who present to a busy ED with complaints that are not necessarily suggestive of pregnancy. Historical information regarding menses and sexual activity is either not obtained or is incomplete or inaccurate. We recommend a low threshold for the consideration of pregnancy in adolescents irrespective of the presenting complaint.

PIP: A retrospective study was performed at a tertiary care hospital in Mississippi to compare the emergency room (ER) presenting complaints during 1980-1994 of the 171 pregnant adolescents 16 years old and younger whose pregnancies were diagnosed with the 100 whose pregnancies were not diagnosed. Data were collected from the medical records of those diagnosed as pregnant and from the 2945 records available of the 4125 patients under 16 who delivered babies at the hospital during the same period. It was found that 100/2945 were seen in the ER while pregnant but the pregnancy was not diagnosed. It was found that 91% of the pregnancy diagnosed patients versus 22% of the missed diagnosis patients had complaints relating to the abdomen or genitourinary system. Less than 10% of the diagnosed patients indicated the possibility of pregnancy at the initial examination, and 10.5% denied being sexually active. No sexual or menstrual history was documented for 68% of the missed diagnosis patients, and 5% of each group had pelvic examinations. No significant differences were found for patient age or demographics, gestation at ER visit, or gestation at delivery. In 30 cases of missed diagnoses (all with gestation at 8 weeks or more), 23 presented with abdominal, genitourinary, or mammary complaints, and 7 presented with drug overdoses. In 22 patients, diagnosis was missed even though the pregnancy was at 22 weeks gestation or more. One extraordinary case involved a 14-year-old who was admitted for treatment of a gunshot to the head. Her pregnancy was not diagnosed until her second follow-up visit after a lengthy hospital stay (gestation was 30 weeks at ER presentation). Because many treatments are modified by pregnancy, it is recommended that pregnancy be assumed in all females of child-bearing age presenting to the ER with consideration given to degree of sexual maturity.

Long-term tocolysis with combined intravenous terbutaline and magnesium sulfate: a 10-year study of 1000 patients.

OBJECTIVE: To determine whether long-term intravenous (IV) tocolysis using combined terbutaline and magnesium sulfate is safe and effective. METHODS: One thousand consecutive women in preterm labor were treated with combination IV tocolytic therapy. Terbutaline was initiated with an infusion rate of 1.75 micrograms/minute and increased to a maximum of 80 micrograms/minute. Magnesium sulfate was infused at 2 g/hour without any bolus and increased to maintain a serum level of 6.5-7.5 mg/dL. Tocolysis was continued until fetal lung maturity was achieved or delivery occurred. RESULTS: Combination tocolytic therapy prolonged pregnancy by a mean (+/- standard deviation) of 61 +/- 23.6 days in 751 women with intact membranes and by 20.5 +/- 17.4 days in 249 with ruptured membranes. The longest durations of continuous IV tocolysis were 123 days in a patient with intact membranes and 77 days in one with ruptured membranes. The most common side effects were nausea and vomiting, followed by chest tightness and shortness of breath. CONCLUSION: Long-term IV tocolysis appeared to be safe and to have acceptable side effects, allowing patients to receive combined terbutaline and magnesium sulfate until delivery.

Henoch-Schönlein purpura: four cases and a review.

Henoch-Schönlein Purpura (HSP) is a common, usually self-limited, vasculitis affecting children and young adults. Manifested by a characteristic rash, the course of HSP is typically a benign one, but may be accompanied by varying degrees of abdominal pain, arthritis or arthralgia, gastrointestinal bleeding, and nephritis. The various manifestations of HSP may present at any stage during the illness and mimic other disease processes, some of which may be life threatening. Thus, the emergency physician must consider the diagnosis of HSP in order to detect complications and avoid needless intervention in what usually is an otherwise benign process. We present four cases and a brief review of the literature to highlight HSP in the differential diagnosis of patients who present with any of the typical clinical signs and symptoms.

Only the rich kids had 'em.

Seven former orthodontic patients who were treated during the 1920s, '30s, and early '40s were questioned with respect to their perceptions of treatment. Two of the subjects were orthodontists and one was a general dentist, thus offering technological insights. Emphasis was placed on treatment acceptance, social and financial impact, pain, techniques, and overall result. Replies indicate that, while technological improvements were yet to come, patients coped at least as well as do today's counterparts. Orthodontic treatment in those days, like life in general, was simple and stern. Nevertheless, there was overall patient satisfaction with both the doctor and the result.