Sequential Plan Research Articles

The Effect of Entonox, Play Therapy and a Combination on Pain Relief in Children: A Randomized Controlled Trial

Pediatric pain is often undertreated/neglected due to time constraints, difficulties in timing of oral analgesics, fear of side effects of opioids and anxiolytics, and apprehension of additional pain in the use of local anesthetic injections. In this study, the researcher was prompted to choose rapidly acting interventions that were low dose and allowed the child to stay alert, suitable for a quick discharge. The purpose of this study was to evaluate the effects of Entonox, play therapy, and a combination to relieve procedural pain in children aged 4-15 years. The study was designed as a randomized controlled trial; the subjects were divided into four groups using a sequential allocation plan from 123 total subjects. Group A received Entonox, Group B received play therapy, Group C received both Entonox and play therapy, and Group D received existing standard interventions. The study was vetted by the departmental study review committee. The pain level was assessed using FLACC scale for children aged 4-9 years and the Wong Bakers Faces Pain Scale for children aged 10-15 years; scores ranged from 0 to 10. All the data were analyzed using SPSS 16.0 with descriptive statistics and, inferential statistics. The mean pain scores were as follows: Entonox group, 2.87; Play therapy group, 4; combination group, 3; and control group, 5.87. When statistical testing was applied, a significant reduction in the pain score in all the three experimental groups when compared to the control group was found (p = .002), but not in the pain score among the three experimental groups (p = .350). The findings of this study indicated that all three interventions were effective in lowering pain scores when compared to the control group. Play therapy is as potent as Entonox in relieving procedural pain, though there was no additive effect on pain relief when play therapy and Entonox were combined. A protocol for age-related choice between play therapy and Entonox administration was introduced as a standing order in the Pediatric Surgery department for acute procedural pain relief.

The Sequential Estimation of the Seismoacoustic Source Energy in C-OTDR Monitoring Systems

Abstract—The practical efficient approach is suggested for estimation of the seismoacoustic sources energy in C-OTDR monitoring systems. This approach is represents the sequential plan for confidence estimation both the seismoacoustic sources energy, as well the absorption coefficient of the soil. The sequential plan delivers the non-asymptotic guaranteed accuracy of obtained estimates in the form of non-asymptotic confidence regions with prescribed sizes. These confidence regions are valid for a finite sample size when the distributions of the observations are unknown. Thus, suggested estimates are non-asymptotic and nonparametric, and also these estimates guarantee the prescribed estimation accuracy in form of prior prescribed size of confidence regions, and prescribed confidence coefficient value.

실험계획법을 이용한 전자부품 위치정렬장치 최적 운영조건 사례연구

Purpose: The purpose of this study is to design a systematic method to estimate optimal operation conditions of design variables for an electronic device alignment system. Method: The 2-level factorial design and the central composite design are used in order to plan experiments. Based on the experiment results, a regression model is established to find optimal conditions for the design variables. Results: 3 of 5 design variables are selected as major factors that affect the alignment system significantly. The optimized condition for each variable is estimated by using a sequential experiment plan and a quadratic regression model. Conclusion: The method designed in this study provides an efficient and systematic plan to select the optimized operation condition for the design variables. The method is expected to improve inspection accuracy of the system and reduce the development cost and period.

Abstract B102: A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation

Abstract Background: Despite the recent progress made with front-line treatment for advanced pancreatic cancer (PC), most patients (pts) will either relapse or be refractory to treatment. Others may not even be eligible due to the toxicity profile of the available options or due to clinical deterioration. Once the disease progresses following front-line treatment, there is no accepted standard of care. Treatment options are clearly needed for patients with refractory disease. Approximately 5% of unselected PC pts, 10% of PC patients of Ashkenazi Jewish descent, and up to 19% of familial PC cases, harbor a germline BRCA mutation. Though less well characterized to date, somatic BRCA mutations also appear to play a significant role in PC. Clinical data have shown that pts with BRCA-mutant (BRCAmut) tumors, including those with PC, respond to treatment with a PARP inhibitor (PARPi). Early data suggest that other genomic characteristics may be surrogate biomarkers of homologous recombination deficiency (HRD) and define a larger group of responders than just BRCA mutation(s) alone. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with HRD due to a BRCA mutation or other homologous recombination pathway defect. Rucaparib has a desirable PK profile, is well tolerated, and has demonstrated clinical activity (RECIST and/or CA-125 responses) in patients with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Three studies are currently ongoing in ovarian cancer and a trial in BRCAmut pancreatic cancer is now planned. The clinical activity of PARPi, including rucaparib, in BRCAmut PC, combined with the paucity of active 2nd-line therapies, support evaluation of rucaparib in PC pts with a BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous monotherapy rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) who are known to harbor a deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed / progressive disease confirmed by radiologic assessment, or are no longer able to tolerate chemotherapy due to toxicity, and radiologic assessment confirms stable or progressive disease. Other key inclusion criteria include measurable disease, ECOG Performance Status 0 or 1, and adequate organ function. Pts with endocrine tumors or who received prior PARPi treatment are excluded. Pts will take 600 mg BID rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then for survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th patient enrolled has sufficient disease assessment data available. If robust activity is observed in the BRCAmut PC population, the trial may be broadened to include PC pts with HRD due to other than a BRCA mutation. The trial will be open to enrollment at clinical sites in the US and Israel in 2Q 2014. Citation Format: Susan M. Domchek, Robert McWilliams, Andrew Hendifar, Rachna T. Shroff, Lawrence Leichman, Ron Epelbaum, Ravit Geva, George Kim, Steven R. Alberts, Robert A. Wolff, Andrew Allen, Heidi Giordano, Mitch Raponi, Jeff Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide. A phase 2, open-label study of the PARP inhibitor rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B102.

Integrating commercial ambulatory electronic health records with hospital systems: An evolutionary process

ObjectiveThe increase in electronic health record implementation in all treatment venues has led to greater demands for integration within and across practice settings with different work cultures. We study the evolution of coordination processes when integrating ambulatory-specific electronic health records with hospital systems. Materials and methodsLongitudinal qualitative study using semi-structured interviews and archival documentation throughout a 5-year implementation and integration of obstetrical ambulatory and hospital records with a goal of achieving a perinatal continuum of care. ResultsAs users implement and integrate electronic health records, there is an evolution in their focus from technology acceptance to structural adaptation to coordination. The users’ perspective on standardization evolves from initial concern about the unintended consequences of standardization to recognition of its importance and then finally to more active acceptance. The system itself cannot drive all reengineering; the organization must impose specific work process changes and as the user's perspective evolves, more individually adapted and aligned change will occur. Computer integration alone does not result in coordination; users must value integrated information and incorporate this information within their workflows. DiscussionUsers initially view electronic health records as a documentation tool, but over time they come to recognize the benefits of the system for clinical information retrieval, and finally, for care coordination after the integrated information provided through electronic health records becomes more complete, accessible and adapted to meet user needs. As this occurs, coordination mechanisms move beyond pooled standardization through sequential plans coordinated by the organization to reciprocal mutual adjustments for clinical decision making by individuals. Trust in the information source, not software interoperability, is critical for information sharing. ConclusionsOrganizations implementing commercial electronic health records cannot simply assume that reciprocal coordination will immediately occur. It takes time for users to adjust, and enculturate coordination goals, during which time there are adaptive structurations that require organizational response, and changes in mechanisms for achieving coordination.

Optimizing a fixed-precision sequential sampling plan for adult Acrotomopus atropunctellus (Boheman) (Coleoptera: Curculionidae), new pest on sugarcane

Sugarcane weevil borer, Acrotomopus atropunctellus (Boheman) (Coleoptera: Curculionidae) has been detected across all sugarcane planting areas in the Argentinian Northwest with increasing population densities. The monitoring for its occurrence and the population density usually is made by visual inspection and consequently demands much effort and time. The objectives of this study were 1) to describe the sampling distribution pattern of A. atropunctellus adults 2) to develop and validate a fixed-precision sequential sampling plan for density estimation, and 3) to find the optimum inspection time for each sampling unit. On-farm data collection was performed at sugarcane fields located in Ranchillos (Tucumán, Argentina) during 2011–2012 to 2013–2014 sugarcane growing seasons. Thirty sampling units consisting on one meter of sugarcane furrow were randomly selected at 1-wk intervals. Within each sampling unit, weevils were counted and recorded independently for five increasing examination time per sampling unit (ETSU) (2, 4, 6, 8 and 10 min). For each ETSU, the sampling distribution pattern was assessed by Taylor's power law (TPL). The average sample number (ASN) and sampling stop lines were calculated according to Green's sequential sampling model, based on TPL estimated parameters, for fixed precision levels, C = 0.1 and C = 0.25. The resampling for validation of sample plans (RVSP) program was used to evaluate the performance of the different sampling plans. Parameters a and b from TPL regressions did not vary significantly between different ETSUs. All estimates of b coefficients were significantly >1 which can indicate an aggregated sampling distribution pattern. For each precision level, Green's sequential plans predicted very similar ASN between ETSU. This was confirmed through the validation process, with the five sampling protocols providing very similar mean sample sizes and mean precision levels. Variability of these parameters from validation results did not vary significantly among the different ETSUs. The relative net precision was the only performance parameter that varied with the ETSU, with the shortest ETSU resulting in the most efficient sampling plan. We conclude that A. atropunctellus has an aggregated sampling distribution and that the fixed precision sequential sampling plan developed using Green's model and based on a two-minute inspection of the sampling unit is the most convenient choice for estimating its population density in sugarcane. Our analysis of the ETSU effect on the performance of sugarcane weevil sampling protocols could contribute to develop more efficient monitoring plans for other arthropods.

Steering Evolution Strategically: Computational Game Theory and Opponent Exploitation for Treatment Planning, Drug Design, and Synthetic Biology

Living organisms adapt to challenges through evolution. This has proven to be a key difficulty in developing therapies, since the organisms evolve resistance.I propose the wild idea of steering evolution strategically — using computational game theory for (typically incomplete-information) multistage games and opponent exploitation techniques. A sequential contingency plan for steering evolution is constructed computationally for the setting at hand. In the biological context, the opponent (e.g., a disease) has a systematic handicap because it evolves myopically. This can be exploited by computing trapping strategies that cause the opponent to evolve into states where it can be handled effectively. Potential application classes include therapeutics at the population, individual, and molecular levels (drug design), as well as cell repurposing and synthetic biology.

가톨릭 성당건축의 장애인 편의시설 설치현황 및 개선방안 - 대전광역시 유성구 소재 본당을 중심으로 -

This study is regarding the accessibility for the disabled in the catholic churches. The purpose is to check the current condition of the accessibility for the disabled and to suggest the improvement plans targeted at 10 churches located in Yuseong-gu, Daejeon metropolitan city. Especially the current condition of the obligations and recommendations specified in the accessibility enhancement law for the disabled was performed through field investigation. Firstly, the accessibility for the disabled of each church was evaluated qualitatively as well as quantitatively. And then sequential improvement plans divided into three stages were suggested. Above all, the parish, management authority of catholic churches should establish medium and long-term plans besides legal standards. Even though the scope of this research was limited to catholic churches of certain areas, the result of this research is expected to help investigation the current condition of the accessibility for the disabled and to suggest the improvement plans in other catholic churches.

Improving quality in a national intestinal failure unit: greater efficiency, improved access and reduced mortality

ProblemIn 2010, there was a significant waiting list for admission to the intestinal failure unit (IFU) at the Salford Royal National Health Service (NHS) Foundation Trust. There had been a...

Sequential sampling for panicle caterpillars (Lepidoptera: Noctuidae) in sorghum.

Panicle caterpillars comprise an economically important insect pest complex of sorghum throughout the Great Plains of the United States, particularly in Kansas, Oklahoma, and Texas. The sorghum panicle caterpillar complex consists of larvae of two polyphagous lepidopteran species: the corn earworm, Helicoverpa zea (Boddie), and fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae). Sampling for panicle caterpillars in sorghum fields is usually accomplished by the beat bucket sampling technique with a fixed sample size of 30 beat bucket samples of one sorghum panicle each per 16.2 ha of field. We used Wald's sequential probability ratio test for a negative binomial distribution to develop a sequential sampling plan for panicle caterpillars. In total, 115 sorghum fields were sampled in Kansas, Oklahoma, and Texas from June to August 2010. Panicle caterpillars had an aggregated distribution of counts confirmed by Pearson's chi-square statistic for lack of fit to the negative binomial distribution for each sampled field. A sequential sampling plan was developed using a high threshold (an economic threshold) of 0.5 caterpillars per sorghum panicle, a low threshold (a safe level) of 0.20 caterpillars per panicle, and fixed error rates (alpha = 0.10 and beta = 0.05). At caterpillar densities > 0.45 and < 0.12 per panicle, the average number of panicles inspected to make a decision was less than the current recommendation of 30. In a 2013 validation test of 25 fields, the expected number of samples taken from average sample number curve was in close agreement with the number of samples required using the sequential plan (r2 = 0.93), and all fields were correctly classified when compared with a fixed sample size result. The plan improved upon current sampling recommendations for panicle caterpillars in sorghum because at known acceptable fixed error rates fewer samples were required when caterpillars are scarce or abundant, whereas more samples were required to make decisions with the same acceptable error rates when densities were near the economic thresholds.

Evaluation of radiation dose to cardiac and pulmonary tissue among patients with stage IV Wilms tumor and pulmonary metastases

Most patients with stage IV Wilms tumor (WT) and pulmonary metastases are treated with surgery, local radiotherapy (RT), and whole-lung irradiation (WLI). The Children's Oncology Group is studying whether WLI should only be given if metastatic lung lesions persist following induction chemotherapy. We hypothesized that radiation dose to cardiac and pulmonary organs are increased when WLI and abdominal RT fields are administered sequentially. We retrospectively identified 16 patients with stage IV WT and pulmonary metastases to model dosimetry plans for concurrent and sequential flank or whole abdomen and whole-lung fields. Treatment plans were evaluated for dosimetric endpoints to the heart and the lungs. The mean dose (Gy) was significantly higher to the heart (15.8 vs. 12.1, P < 0.0001) and lungs (14.1 vs. 12.2, P < 0.0002) when patients with stage IV WT and pulmonary metastases were treated with sequential RT. The percent tissue organ volumes (V) receiving high RT doses of 15 and 20 Gy (V(15) and V(20)) were negligible in concurrent treatment plans. Comparatively, mean V(15) and V(20) values for sequential treatment plans were 35% and 27%, respectively, for the heart, and 15% and 12%, for the lungs. The dose to the heart and lung tissue is significantly increased when WLI and abdominal RT fields are administered sequentially. While omission of WLI may be beneficial for patients achieving good response to induction chemotherapy, the less favorable response group may be subjected to increased risk of cardiac and pulmonary toxicities from sequential WLI.

Decreasing Hypothermia During Delivery Room Stabilization of Preterm Neonates

Hypothermia during delivery room stabilization of very low birth weight (VLBW) newborns is independently associated with mortality, yet it occurred frequently both in collaborative networks and at our institution. We aimed to attain admission temperatures in the target range of 36 °C to 38 °C in ≥ 90% of inborn VLBW neonates through implementation of a thermoregulation bundle. This quality improvement project extended over 60 consecutive months, using sequential plan-do-check-act cycles. During the 14 baseline months, we standardized temperature measurements and developed the Operation Toasty Tot thermoregulation bundle (including consistent head and torso wrapping with plastic, warmed blankets, and a closed stabilization room). We introduced this bundle in month 15 and added servo-controlled, battery-powered radiant warmers for stabilization and transfer in month 21. We provided results and feedback to staff throughout, using simple graphics and control charts. There were 164 inborn VLBW babies before and 477 after bundle implementation. Introduction and optimization of the bundle decreased the incidence of hypothermia, with rates remaining in the target range for the last 13 study months. The incidence of temperatures >38 °C was ~ 2% both before and after bundle implementation. This thermoregulation bundle resulted in sustained improvement in normothermia rates during delivery room stabilization of VLBW newborns. Our benchmark goal of ≥ 90% admission temperatures above 36 °C was met without increasing hyperthermia rates. Because these results compare favorably with those of recently published research or improvement collaboratives, we aim to maintain our performance through routine surveillance of admission temperatures.

Finding Critical Values to Control Type I Error for a Biomarker Informed Two-Stage Winner Design

Adaptive clinical trial designs have been getting very popular in recent years. The PhRMA Working Group defines an adaptive design as a clinical study design that uses accumulating data to direct modification of aspects of the study as it continues, without undermining the validity and integrity of the [1]. These designs can assist in potentially accelerating clinical development and improving efficiency. However, the multiple interim looks and adaptive adjustments with the design can lead to inflation of type I error. Over the past decade, several statistical approaches have been proposed to control the inflation, some of which have been widely applied in practice. Some of these approaches include: error spending approach for classical group sequential plans [2-4]; Combination of p-values, such as Fisher’s combination test [5,6], Inverse Normal Method [7], sum of p-values approach [8]; conditional error function [9-11]; fixed weighting method [12]; variance spending method [13,14]; and multiple testing methodology such as closed test procedures [15-17].

A Double Sequential Weighted Probability Ratio Test for One-Sided Composite Hypotheses

For sequential test plans, we propose the weighted expected sample size (WESS) to evaluate the overall performance on the parameter interval of interest. Based on minimizing the WESS to control the expected sample sizes, we develop the method of double sequential weighted probability ratio test (2-SWPRT) for one-sided composite hypotheses. It is proved that the 2-SWPRT has a finite stopping time and is the asymptotically optimal test. Simulation studies show that the 2-SWPRT not only has the smallest WESS compared with the SPRT and 2-SPRT, but also is superior to the 2-SPRT and comparable with the SPRT under the null and alternative hypotheses. Moreover, the relative mean index (RMI) also shows the 2-SWPRT is an efficient method to improve the overall performance.

Secondary Prevention of New Vascular Events with Lifestyle Intervention in Patients with Noncardioembolic Mild Ischemic Stroke: A Single-Center Randomized Controlled Trial

Background: Lifestyle modification is associated with a substantially decreased risk of cardiovascular events. However, the role of lifestyle intervention for secondary prevention in patients with noncardioembolic ischemic stroke is inadequately defined. We assessed the hypothesis that lifestyle intervention can reduce the onset of new vascular events in patients with noncardioembolic mild ischemic stroke. Methods: We conducted an observer-blind randomized controlled trial that enrolled 70 patients (48 men, mean age 63.5 years) with acute noncardioembolic mild ischemic stroke. The patients were allocated in equal numbers to a lifestyle intervention group or a control group. We performed lifestyle interventions, which comprised exercise training, salt restriction and nutrition advice for 24 weeks. Then all patients were prospectively followed up for occurrence of the primary endpoints, including hospitalization due to stroke recurrence and the onset of other vascular events. We also evaluated systolic blood pressure (SBP) at the clinic and at home, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hemoglobin A1c (HbA1c) and high-sensitivity C-reactive protein (hs-CRP) to compare the efficacy of the lifestyle interventions. Results: This trial was terminated earlier than expected because of the prespecified early stopping rule for efficacy. After the 24-week intervention period, the intervention group showed a significant increase in daily physical activity and a significant decrease in salt intake (physical activity, p = 0.012; salt intake, p < 0.001), with a significant difference between the randomized groups (physical activity, p < 0.001; salt intake, p = 0.018). Similarly, blood pressure was decreased and the HDL-C levels were increased in the intervention group (SBP, p < 0.001; HDL-C, p = 0.018), with significant differences between the randomized groups (SBP, p < 0.001; HDL-C, p = 0.022). In contrast, LDL-C, HbA1c and hs-CRP tended to decrease in the intervention group, but this decrease did not achieve significance. After a median follow-up period of 2.9 years, 12 patients allocated to the control group and 1 patient in the lifestyle intervention group experienced at least 1 vascular event. A sequential plans analysis indicated the superiority of the lifestyle intervention in interim analysis. Kaplan-Meier survival curves after the log-rank test showed a significant prognostic difference between the randomized groups (p = 0.005). Conclusions: Lifestyle intervention with appropriate medication is beneficial for reducing the incidence of new vascular events and improving vascular risk factors in patients with noncardioembolic mild ischemic stroke.

Dorsal parietal area 5 encodes immediate reach in sequential arm movements.

To generate a coherent action sequence, it is essential to integrate all component movements beforehand, and such sequence-related information has been observed in numerous brain regions. However, this high-level sequential plan encompassing multiple motor elements in parallel ultimately must be decomposed into serial motor commands to be executed by the musculoskeletal system. In the present study, we recorded single-neuron activity from dorsal parietal area 5 (area 5d) while monkeys performed a double-reach task, and found that area 5d conveys the immediate upcoming reach, but not the subsequent movement, as opposed to the entire movement sequence being encoded as in other cortical sensorimotor areas. The elementary movement coded in area 5d suggests that unfolding of the motor sequence begins in the parietal-frontal cortex, instead of being exclusively implemented by downstream subcortical and spinal circuits.

Dispersion and Sequential Sampling Plan forXylosandrus compactus(Coleoptera: Curculionidae) Infesting Hawaii Coffee Plantations

The black twig borer, Xylosandrus compactus (Eichhoff) (Coleoptera: Curculionidae: Scolytinae), is a serious pest of coffee (Coffea arabica L.) in the Kona region of the island of Hawaii, the center of the largest area of coffee production within the state of Hawaii. This study indirectly characterizes the spatial distribution of X. compactus in coffee plantations through assessment of twig borer damage, and presents a sequential sampling plan for monitoring X. compactus population densities. Taylor's Power Law (TPL) and Iwao's mean crowding index showed that X. compactus infestations were highly aggregated within plantations, with b and ß values significantly larger than 1. The TPL linear regression of log variance against log mean (R2 = 0.92) provided a better fit to the data than the linear regression of mean crowding on the mean (R2 = 0.68). Subsequently, Taylor's power law parameters were used to develop the Green's sequential plan to estimate densities of X. compactus at the 90 and 75% precision levels.

Sequential Sampling Plan for Rice Planthoppers with Incorporation of Predator Effect

Spatial distribution of rice planthoppers, Nilaparvata lugens (Stal) and Sogatella furcifera (Horvath) together, and their predators, spiders and mirid bugs was studied on Pusa 1121 rice during rainy season 2010 through Taylor's power law and Iwao's mean crowding regression. Planthoppers as well as their predators followed aggregated distribution in the field. Sequential sampling plans based on Taylor's distribution parameters (a = 0.398, b = 1.614) and economic injury level (10 hoppers/hill) were formulated for rice planthoppers with and without consideration to predation by spiders and mirid bugs. During pre-flowering, sequential plans suggested need for control when two rice hills harboured cumulative planthopper population of 36 hoppers with predators and 27 hoppers without predators. Likewise, during post-flowering phase, control was required if two rice hills had cumulative population of 51 hoppers with predators compared to 27 hoppers without predators. Sequential sampling plans with predator effect thus suggested need for management measures at higher planthopper population. This would be helpful in avoiding unwarranted pesticide application thereby ensuring natural enemy conservation and favourable benefit- cost to farmers.

Analysis of fractionation correction methodologies for multiple phase treatment plans in radiation therapy

Radiation therapy is often delivered by multiple sequential treatment plans. For an accurate radiobiological evaluation of the overall treatment, fractionation corrections to each dose distribution must be applied before summing the three-dimensional dose matrix of each plan since the simpler approach of performing the fractionation correction to the total dose-volume histograms, obtained by the arithmetical sum of the different plans, becomes inaccurate for more heterogeneous dose patterns. In this study, the differences between these two fractionation correction methods, named here as exact (corrected before) and approximate (after summation), respectively, are assessed for different cancer types. Prostate, breast, and head and neck (HN) tumor patients were selected to quantify the differences between two fractionation correction methods (the exact vs the approximate). For each cancer type, two different treatment plans were developed using uniform (CRT) and intensity modulated beams (IMRT), respectively. The responses of the target and normal tissue were calculated using the Poisson linear-quadratic-time model and the relative seriality model, respectively. All treatments were radiobiologically evaluated and compared using the complication-free tumor control probability (P+), the biologically effective uniform dose (D) together with common dosimetric criteria. For the prostate cancer patient, an underestimation of around 14%-15% in P+ was obtained when the fractionation correction was applied after summation compared to the exact approach due to significant biological and dosimetric variations obtained between the two fractionation correction methods in the involved lymph nodes. For the breast cancer patient, an underestimation of around 3%-4% in the maximum dose in the heart was obtained. Despite the dosimetric differences in this organ, no significant variations were obtained in treatment outcome. For the HN tumor patient, an underestimation of about 5% in treatment outcome was obtained for the CRT plan as a result of an underestimation of the planning target volume control probability by about 10%. An underestimation of about 6% in the complication probability of the right parotid was also obtained. For all the other organs at risk, dosimetric differences of up to 4% were obtained but with no significant impact in the expected clinical outcome. However, for the IMRT plan, an overestimation in P+ of 4.3% was obtained mainly due to an underestimation of the complication probability of the left and right parotids (2.9% and 5.8%, respectively). The use of the exact fractionation correction method, which is applying fractionation correction on the separate dose distributions of a multiple phase treatment before their summation was found to have a significant expected clinical impact. For regions of interest that are irradiated with very heterogeneous dose distributions and significantly different doses per fraction in the different treatment phases, the exact fractionation correction method needs to be applied since a significant underestimation of the true patient outcome can be introduced otherwise.

CD21 positive B cell: A novel target for treatment of multiple sclerosis

Etiologic-based therapy is an ideal pharmacological option to treat or prevent diseases. There is no known etiology for multiple sclerosis (MS); however, environmental risk factors have been suggested to predispose genetically susceptible people to be affected by the disease. One of these risk factors is infection with Epstein-Barr virus (EBV). Eradication of this virus has not been effective in modulation of MS, probably due to being inhabitant in the CD21 (EBV receptor) positive B cells. To eradicate this virus, targeting CD21 on these EBV-infected B cells is hypothesized here. A sequential study plan to test this hypothesis has been suggested too. This study might eventually suggest an effective immunopharmacological strategy to treat MS. Moreover, testing this strategy will help in better clarification of the role of EBV in MS disease triggering and predisposition.