Optimizing the response, precision, and cost of a DNA double-strand break dosimeter.

We developed a dosimeter that measures biological damage following delivery of therapeutic beams in the form of double-strand breaks (DSBs) to DNA. The dosimeter contains DNA strands that are labeled on one end with biotin and on the other with fluorescein and attached to magnetic microbeads. Following irradiation, a magnet is used to separate broken from unbroken DNA strands. Then, fluorescence is utilized to measure the relative amount of broken DNA and determine the probability for DSB. The long-term goal for this research is to evaluate whether this type of biologically based dosimeter holds any advantages over the conventional techniques. The purpose of this work was to optimize the dosimeter fabrication and usage to enable higher precision for the long-term research goal. More specifically, the goal was to optimize the DNA dosimeter using three metrics: the response, precision, and cost per dosimeter. Six aspects of the dosimeter fabrication and usage were varied and evaluated for their effect on the metrics: (1) the type of magnetic microbeads, (2) the microbead to DNA mass ratio at attachment, (3) the type of suspension buffer used during irradiation, (4) the concentration of the DNA dosimeter during irradiation, (5) the time waited between fabrication and irradiation of the dosimeter, and (6) the time waited between irradiation and read out of the response. In brief, the best results were achieved with the dosimeter when attaching 4.2 µg of DNA with 1 mg of MyOne T1 microbeads and by suspending the microbead-connected DNA strands with 200 µl of phosphate-buffered saline for irradiation. Also, better results were achieved when waiting a day after fabrication before irradiating the dosimeter and also waiting an hour after irradiation to measure the response. This manuscript is meant to serve as guide for others who would like to replicate this DNA dose measurement technique.

Does endometrial scratching increase the rate of spontaneous conception in couples with unexplained infertility and a good prognosis (Hunault > 30%)? Study protocol of the SCRaTCH-OFO trial: a randomized controlled trial.

BACKGROUND: In the Netherlands, couples with unexplained infertility and a good prognosis to conceive spontaneously (i.e. Hunault > 30%) are advised to perform timed intercourse for at least another 6 months. If couples fail to conceive within this period, they will usually start assisted reproductive technology (ART). However, treatment of unexplained infertility by ART is empirical and can involve significant burdens. Intentional endometrial injury, also called 'endometrial scratching', has been proposed to positively affect the chance of embryo implantation in patients undergoing in vitro fertilization (IVF). It might also be beneficial for couples with unexplained infertility as defective endometrial receptivity may play a role in these women. The primary aim of this study is to determine whether endometrial scratching increases live birth rates in women with unexplained infertility. METHOD: A multicentre randomized controlled trial will be conducted in Dutch academic and non-academic hospitals starting from November 2017. A total of 792 women with unexplained infertility and a good prognosis for spontaneous conception < 12 months (Hunault > 30%) will be included, of whom half will undergo endometrial scratching in the luteal phase of the natural cycle. The women in the control group will not undergo endometrial scratching. According to Dutch guidelines, both groups will subsequently perform timed intercourse for at least 6 months. The primary endpoint is cumulative live birth rate. Secondary endpoints are clinical and ongoing pregnancy rate; miscarriage rate; biochemical pregnancy loss; multiple pregnancy rate; time to pregnancy; progression to intrauterine insemination (IUI) or IVF; pregnancy complications; complications of endometrial scratching; costs and endometrial tissue parameters associated with reproductive success or failure. The follow-up duration is 12 months. DISCUSSION: Several small studies show a possible beneficial effect of endometrial scratching in women with unexplained infertility trying to conceive naturally or through IUI. However, the quality of this evidence is very low, making it unclear whether these women will truly benefit from this procedure. The SCRaTCH-OFO trial aims to investigate the effect of endometrial scratching on live birth rate in women with unexplained infertility and a good prognosis for spontaneous conception < 12 months. TRIAL REGISTRATION: NTR6687 , registered August 31st, 2017. PROTOCOL VERSION: Version 2.6, November 14th, 2018.

Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Arterial embolotherapy for upper gastrointestinal hemorrhage: outcome assessment.

PURPOSE: To identify predictors of clinical outcome after arterial embolotherapy for upper gastrointestinal (UGI) hemorrhage. MATERIALS AND METHODS: Seventy-five consecutive patients (mean age, 62.5 y) underwent arterial embolization for acute UGI hemorrhage. Bleeding was detected at endoscopy and angiography in 22 patients, at endoscopy alone in 29 patients, and at angiography alone in 24 patients. As such, embolization was directed by angiography in 46 patients (61.3%) and by endoscopy (referred to as "blind" embolization) in 29 patients (38.7%). The embolic agents used were metallic coils, polyvinyl alcohol particles (size range, 355-710 microm), gelatin sponge, and tissue adhesive. Predictors of bleeding recurrence and mortality were analyzed with logistic regression and Cox models, respectively. RESULTS: The technical success rate of embolization was 98.7%. Primary clinical success was achieved in 57 patients (76%). Secondary clinical success occurred in five additional patients (82.5%) after repeat embolization. There were four (5.3%) complications: two cases of self-resolving duodenal ischemia, one hepatic infarct, and one inguinal hematoma. The periprocedural mortality rate was 34.6% (26 of 75), mostly related to underlying illness. Early recurrence of bleeding (within 30 days of embolization) was associated with coagulation disorders (international normalized ratio >1.5, partial thromboplastin time >45 seconds, or platelet count <80,000/microL; odds ratio, 19.46; P = .001) and with the use of coils as the only embolic agent (odds ratio, 7.73; P = .01). Cirrhosis and cancer shortened the overall survival of patients after embolic therapy. The mean patient follow-up time was 34.5 months. CONCLUSION: Arterial embolotherapy for UGI hemorrhage is safe, effective, and durable. Coagulopathy and the use of coils as the only embolic agent were associated with a higher risk of early bleeding recurrence.

Parent-child agreement in prepubertal depression: findings with a modified assessment method.

OBJECTIVE: Lack of or low parent-child (P-C) agreement is a well-documented problem in child psychopathology assessment. This study proposed to improve this agreement by using a modified assessment approach. METHOD: Ninety-three depressed prepubertal children, aged 6 to 12 years, and their mothers underwent an assessment procedure that combined multiple assessment measures given separately to child and mother (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode [K-SADS-P], Children's Depression Inventory, and traditional psychiatric interviews), confrontation of either and/or both informants with intra- and interinformant discrepancies, and senior clinician's "best estimate" clinical judgment to solve discrepant ratings. Correlational statistics (r, kappa, and z) were used to compare child's with mother's ratings on 20 K-SADS-P depressive symptoms. RESULTS: The major hypothesis, that using our assessment procedure, P-C agreement would be significant and moderately high (r and kappa = .40 or higher), was confirmed. The second hypothesis on dissociation of P-C agreement on behavioral versus ideational symptoms was partially confirmed; the third hypothesis on adverse effects of maternal "depression" on P-C agreement was not confirmed. CONCLUSION: Our assessment method has potential clinical application in enhancing diagnostic reliability of childhood depression assessment.