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There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no consensus in the classification or nomenclature. We set this study to review the literature systematically, to identify the proposed trial designs, and to develop a classification scheme. We searched MEDLINE, EMBASE, Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial designs. In each eligible article, we identified the trial designs presented and extracted the term used for labeling the design, components of patient flow (marker status of eligible participants, intervention, and comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein 315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing patient flow components, we could classify the 134 unique design labels into four basic patient flow categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all, and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow categories. Our review showed that a considerable number of labels has been proposed for trial designs evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified into five basic categories. The classification system proposed here could help clinicians and researchers in designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling and reporting. Clin Cancer Res; 19(17); 4578–88. ©2013 AACR.

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Background: The body of evidence on gene-environment interaction (GEI) related to type 2 diabetes (T2D) has grown in the recent years. However, most studies on GEI have sought to explain variation within individuals of European ancestry and results among ethnic minority groups are inconclusive. Objective: To investigate any interaction between a gene and an environmental factor in relation to T2D among ethnic minority groups living in Europe and North America. Methods: We systematically searched Medline and EMBASE databases for the published literature in English up to 25th March 2019. The screening, data extraction and quality assessment were performed by reviewers independently. Results: 1068 studies identified through our search, of which nine cohorts of six studies evaluating several different GEIs were included. The mean follow-up time in the included studies ranged from 5 to 25.7 years. Most studies were relatively small scale and few provided replication data. All studies included in the review included ethnic minorities from North America (Native-Americans, African- Americans, and Aboriginal Canadian), none of the studies in Europe assessed GEI in relation to T2D incident in ethnic minorities. The only significant GEI among ethnic minorities was HNF1A rs137853240 and smoking on T2D incident among Native-Canadians (Pinteraction = 0.006). Conclusion: There is a need for more studies on GEI among ethnicities, broadening the spectrum of ethnic minority groups being investigated, performing more discovery using genome-wide approaches, larger sample sizes for these studies by collaborating efforts such as the InterConnect approach, and developing a more standardized method of reporting GEI studies are discussed.

Purpose of investigation: To externally validate the rule of Van Meurs et al. for selecting patients with advanced epithelial ovarian cancer for treatment with primary surgery or neoadjuvant chemotherapy (NACT). Materials and Methods: We analysed a historical cohort of 900 consecutive patients with FIGO stage IIIC/IV ovarian cancer treated for advanced stage epithelial ovarian cancer at the Centre of Gynaecologic Oncology Amsterdam between 1998 and 2012. To externally validate the treatment-selection rule of Van Meurs et al. four groups were defined based on metastatic tumour size (smaller or larger than 45 mm) and FIGO stage (IIIC vs. IV). Within these groups, we compared survival outcomes of primary surgery and NACT. Results: Differential treatment benefit in model-defined subgroups based on metastatic tumour size and FIGO stage was confirmed (interaction p = 0.008). Survival after primary surgery was significantly better compared to NACT plus interval debulking surgery for patients in FIGO stage IIIC (p = 0.001) or IV (p = 0.028) with metastases ≤ 45 mm, and those in FIGO stage IIIC with metastases > 45 mm (p = 0.011). Survival was not significantly worse for FIGO stage IV patients with metastases > 45 mm (p = 0.094). In patients with such large metastases, the location (omentum versus elsewhere in the body) was not prognostic (p = 0.44). Conclusion: Our study has externally validated the treatment-selection rule first described by van Meurs et al. Primary surgery was shown to be superior for all patients except for the FIGO stage IV patients with a large metastatic tumour size (> 45 mm), irrespective of localisation of the metastasis.

Biomarkers that predict treatment effects may be used to guide treatment decisions, thus improving patient outcomes. A meta-analysis of individual participant data (IPD) is potentially more powerful than a single-study data analysis in evaluating markers for treatment selection. Our study was motivated by the IPD that were collected from 2 randomized controlled trials of hypertension and preeclampsia among pregnant women to evaluate the effect of labor induction over expectant management of the pregnancy in preventing progression to severe maternal disease. The existing literature on statistical methods for biomarker evaluation in IPD meta-analysis have evaluated a marker's performance in terms of its ability to predict risk of disease outcome, which do not directly apply to the treatment selection problem. In this study, we propose a statistical framework for evaluating a marker for treatment selection given IPD from a small number of individual clinical trials. We derive marker-based treatment rules by minimizing the average expected outcome across studies. The application of the proposed methods to the IPD from 2 studies in women with hypertension in pregnancy is presented.

Objective: Gestational hypertension (GH) and mild preeclampsia (PE) represent the most common medical complications of pregnancy, with the majority of cases developing at or near term. There is little knowledge of the course of blood pressure over time in these women. We explored the pattern of systolic and diastolic blood pressure over time in women with GH or mild PE at term participating in the HYPITAT trial, and we attempted to identify clinical factors influencing these blood pressure patterns and the impact of severe hypertension on clinical management.Study design: We used data from the HYPITAT trial, that included women with a singleton pregnancy with a fetus in cephalic position between 36 and 41 weeks of gestation with the diagnosis of GH or mild PE. Blood pressure measurements were performed from randomization or admission until delivery or discharge from the hospital. We included the highest blood pressure of each day. We evaluated systolic and diastolic blood pressure change over time, as well as the influence of clinical characteristics and laboratory findings on the course of blood pressure. We used univariate and multivariate regression analysis with a backward stepwise algorithm for the selection of variables. The model with the best fit (lowest AIC) was selected as the final model. We also compared mode of delivery for women with and without severe hypertension.Results: We studied 1076 women who had 4188 blood pressure measurements done. The systolic blood pressure showed a significant non-linear increase over time and for the diastolic blood pressure the pattern was also non-linear. In the multivariable model of systolic blood pressure change over time, nulliparity, ethnicity, systolic blood pressure (at baseline), BMI and LDH at randomization influenced the course of blood pressure. In the diastolic blood pressure model ALT and the baseline diastolic blood pressure had a significant influence. When we explored the association between blood pressure and mode of delivery, it appeared that development of severe hypertension was a risk factor for Caesarean section.Conclusion: The blood pressure in patients with GH or PE at term showed a non-linear increase with time, which was aggravated by clinical characteristics. Development of severe hypertension was a risk factor for Caesarean section, which may explain the elevated Caesarean section rates in the expectant monitoring group in the HYPITAT trial. (C) 2017 Elsevier B.V. All rights reserved.

Objective The ProTWIN Trial (NTR1858) showed that, in women with a multiple pregnancy and a cervical length

Between 20% and 25% of pregnancies require induction of labor (IOL), especially in situations that indicate better outcomes for mother and child if the pregnancy is not further prolonged. However, the effectiveness of IOL is subject to considerable debate because of concerns regarding the associated high rates of cesarean deliveries in women with an unripe cervix. The objective of this study was to evaluate the risk of cesarean delivery (CD) and adverse neonatal outcome rates after IOL or expectant management in women with an unripe cervix at or near term. This study used combined data from the multicenter, open-label, randomized controlled trials (RCTs) HYPITAT and DIGITAT. The inclusion criteria were women with hypertensive disease (HYPITAT trial) or suspected fetal growth restriction (DIGITAT trial) and a Bishop score of 6 or less. The study compared the outcomes after IOL and expectant management. The primary outcomes of this study were CD and a composite adverse neonatal outcome (defined as 5-minute Apgar scoreResults of the study revealed that of 1172 women with an unripe cervix 572 women had IOL and 600 women had expectant management. It was noted that there was no significant difference in the overall CD rate (difference, -1.1%; 95% CI, -5.4 to 3.2). Also, IOL did not increase CD rates in women with Bishop scores from3 to 6 (difference, -2.7%; 95% CI, -7.6 to 2.2) or adverse neonatal outcome rates (difference, -1.5%; 95% CI, -4.3 to 1.3). Results, however, noted that there was a significant difference in the rates of arterial umbilical cord pH less than 7.05 favoring IOL (difference, -3.2%; 95% CI, -5.6 to -0.9). The study concludes that there is no evidence that IOL increases the CD rate or compromises neonatal outcome as compared with expectant management in term or near-term pregnancies complicated by intrauterine growth restriction (IUGR), gestational hypertension, or preeclampsia. In addition, it was noted that there is no basis for concern regarding any increase in risk of failed induction in women with a Bishop score from 3 to 6.

ObjectiveThe revised version of the International Federation of Gynaecology and Obstetrics (FIGO) staging system (2014) for epithelial ovarian cancer includes a number of changes. One of these is the division of stage IV into 2 subgroups. Data on the prognostic and predictive significance of this classification are scarce. The effect of neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) in relation to the subclassification of FIGO stage IV is also unknown.MethodsWe used data of the EORTC 55971 trial, in which 670 patients with previous stage IIIC or IV epithelial ovarian cancer were randomly assigned to PDS or NACT; 160 patients had previous stage IV. Information on previous FIGO staging and presence of pleural effusion with positive cytology were used to classify tumors as either stage IVA or IVB. We tested the association between stage IVA/IVB and survival to evaluate the prognostic value and interactions between stage, treatment, and survival to evaluate the predictive performance.ResultsAmong the 160 participants with previous stage IV disease, 103 (64%) were categorized as stage IVA and 57 (36%) as stage IVB tumors. Median overall survival was 24 months in FIGO stage IVA and 31 months in stage IVB patients (P = 0.044). Stage IVB patients treated with NACT had 9 months longer median overall survival compared with IVB patients undergoing PDS (P = 0.025), whereas in IVA patients, no significant difference was observed (24 vs 26 months, P = 0.48).ConclusionsThe reclassification of FIGO stage IV into stage IVA or IVB was not prognostic as expected. Compared with stage IVA patients, stage IVB patients have a better overall survival and may benefit more from NACT.

Background Despite the growing interest in developing markers for predicting treatment response and optimizing treatment decisions, an appropriate methodology to identify, combine and evaluate such markers has been slow to develop. We propose a step-by-step strategy for analysing data from existing randomised trials with the aim of identifying a multi-marker model for guiding decisions about treatment. Methods We start with formulating the treatment selection problem, continue with defining the treatment threshold, prepare a list of candidate markers, develop the model, apply the model to estimate individual treatment effects, and evaluate model performance in the study group of patients who meet the trial eligibility criteria. In this process, we rely on some well-known techniques for multivariable prediction modelling, but focus on predicting benefit from treatment, rather than outcome itself. We present our approach using data from a randomised trial in which 808 women with multiple pregnancy were assigned to cervical pessary or control, to prevent adverse perinatal outcomes. Overall, cervical pessary did not reduce the risk of adverse perinatal outcomes. Results The treatment threshold was zero. We had a preselected list of 5 potential markers and developed a logistic model including the markers, treatment and all marker-by-treatment interaction terms. The model was well calibrated and identified 35% (95% confidence interval (CI) 32 to 39%) of the trial participants as benefitting from pessary insertion. We estimated that the risk of adverse outcome could be reduced from 13.5 to 8.1% (5.4% risk reduction; 95% CI 2.1 to 8.6%) through model-based selective pessary insertion. The next step is external validation upon existence of independent trial data. Conclusions We suggest revisiting existing trials data to explore whether differences in treatment benefit can be explained by differences in baseline characteristics of patients. This could lead to treatment selection tools which, after validation in comparable existing trials, can be introduced into clinical practice for guiding treatment decisions in future patients.

Like many other research subjects in obstetrics, research on immediate delivery versus expectant monitoring for women with hypertensive disorders of pregnancy faces certain challenges when it comes to interpretation and generalisation of the results; relatively rare outcomes are studied, in a clinically heterogeneous population, while the clinical practice in some countries has dictated that studies in term pregnancy were completed before earlier gestational ages could be studied. This has resulted in multiple smaller studies, some studying surrogate outcome measures, with different in- and exclusion criteria, and without enough power for reliable subgroup analyses. All this complicates the generation of definitive answers and implementation of the results into clinical practice. Performing multiple studies and subsequently pooling their results in a meta-analysis can be a way to overcome the difficulties of studying relatively rare outcomes and subgroups with enough power, as well as a solution to reach a final answer on questions involving an uncertain and possibly harmful intervention. However, in the case of the current studies on delivery versus expectant monitoring in women with hypertensive disorders of pregnancy, differences regarding eligibility criteria, outcome measures and subgroup definitions make it difficult to pool their results in an aggregate meta-analysis. Individual patient data meta-analysis (IPDMA) has the potential to overcome these challenges, because it allows for flexibility regarding the choice of endpoints and standardisation of inclusion and exclusion criteria across studies. In addition, it has more statistical power for informative subgroup analyses. We therefore propose an IPDMA on immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy, and advocate the use of IPDMA for research questions in obstetrics that face similar challenges. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Study question Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)? Summary answer We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility. What is known already A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI. Study design, size, duration We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples). Participants/materials, setting, methods We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1. Main results and the role of chance None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10). Limitations, reasons for caution Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations. Wider implications of the findings We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples. Study funding/competing interest(s) The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest. Trial registration number The trial was registered at the Dutch trial registry (NTR939).

Background : Estimation of left ventricular end-diastolic pressure (LVEDP) among patients with mitral valve disease may help to explain their symptoms. However, conventional Doppler measurements have limitations in predicting LVEDP in this group of patients. The aim of this study was to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves. Methods : Thirty-three patients with moderate to severe mitral stenosis (MS) who had indications for left heart catheterisation enrolled. Two-dimensional, M-mode, colour Doppler and tissue Doppler imaging indices, such as annular early diastolic velocity (Ea), isovolumic relaxation time (IVRT), pulmonary vein systolic and diastolic flow velocities, velocity propagation, left atrium area (LAA), interval between the onset of mitral E and annular Ea (TE-Ea), and Tei index were obtained. LVEDP was measured in all patients during left cardiac catheterisation. Linear correlation and multiple linear regressions were used for analysis. Results : The mean of LVEDP was 9.9 ± 5.3 mmHg. In univariate analysis, the only significant relationship was noted with LAA (p = 0.05, R2 = 0.11). However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP (p = 0.02, R2 = 0.26). For prediction of LVEDP ≥ 15 mmHg, the best model consisted of LAA, IVRT and Ea, and had a sensitivity of 85% and specificity of 85%. Conclusion : Our results provided evidence that, in patients with moderate to severe MS, LVEDP can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results.

Biomarkers that predict treatment effects may be used to guide treatment decisions, thus improving patient outcomes. A meta-analysis of individual participant data (IPD) is potentially more powerful than a single-study data analysis in evaluating markers for treatment selection. Our study was motivated by the IPD that were collected from two randomized controlled trials of hypertension and pre-eclampsia among pregnant women to evaluate the effect of labor induction over expectant management of the pregnancy in preventing progression to severe maternal disease. The existing literature on statistical methods for biomarker evaluation in IPD meta-analysis have evaluated a marker’s performance in terms of its ability to predict risk of disease outcome, which do not directly apply to the treatment selection problem. In this study, we propose a statistical framework for evaluating a marker for treatment selection given IPD from a small number of individual clinical trials. We derive marker-based treatment rules by minimizing the average expected outcome across studies. The application of the proposed methods to the IPD from two studies in women with hypertension in pregnancy is presented.

There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no consensus in the classification or nomenclature. We set this study to review the literature systematically, to identify the proposed trial designs, and to develop a classification scheme. We searched MEDLINE, EMBASE, Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial designs. In each eligible article, we identified the trial designs presented and extracted the term used for labeling the design, components of patient flow (marker status of eligible participants, intervention, and comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein 315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing patient flow components, we could classify the 134 unique design labels into four basic patient flow categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all, and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow categories. Our review showed that a considerable number of labels has been proposed for trial designs evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified into five basic categories. The classification system proposed here could help clinicians and researchers in designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling and reporting. Clin Cancer Res; 19(17); 4578–88. ©2013 AACR.

Objective Available treatment options in couples with unexplained or mild male subfertility are intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) and in vitro fertilisation (IVF). IUI-COH is a less invasive treatment that is often used before proceeding with IVF. Yet as the IVF success rates might be higher and time to pregnancy shorter, expedited access to IVF might be the preferred option. To identify couples that could benefit from immediate IVF over IUI-COH, we assessed whether female age, duration of subfertility or prewash total motile count (TMC) can help to identify couples that would benefit from IVF over IUI-COH. Study design We performed a secondary data-analysis of a multicentre open-label randomised controlled trial in three university and six teaching hospitals in the Netherlands. 116 couples with unexplained or mild male subfertility were randomised to one cycle of IVF with elective single embryo transfer with subsequent frozen-thawed embryo transfers or 3 cycles of IUI-COH. The primary outcome was an ongoing pregnancy within 4 months after randomisation. Our aim was to explore a possible differential effect of specific markers on the effectiveness of treatment. We chose to therefore assess female age, duration of subfertility and TMC as these have previously been identified as predictors. For each prognostic factor we developed a logistic regression model to predict ongoing pregnancy with that prognostic factor, treatment and a factor-by-treatment interaction term. Results Female age and duration of subfertility were not associated with better ongoing pregnancy chances after IVF compared to IUI-COH ( p -value for interaction=0.65 and 0.26, respectively). Only when TMC was lower than 110 (×10 6 spermatozoa/mL), the probability of ongoing pregnancy was higher in women allocated to IVF ( p -value for interaction=0.06). Conclusion In couples with unexplained or mild male subfertility, a low TMC might lead to higher pregnancy rates after IVF than after IUI-COH. This finding needs to be validated in a larger trial before it can be applied in clinical practice.

Please cite this paper as: Tajik P, van der Tuuk K, Koopmans C, Groen H, van Pampus M, van der Berg P, van der Post J, van Loon A, de Groot C, Kwee A, Huisjes A, van Beek E, Papatsonis D, Bloemenkamp K, van Unnik G, Porath M, Rijnders R, Stigter R, de Boer K, Scheepers H, Zwinderman A, Bossuyt P, Mol B. Should cervical favourability play a role in the decision for labour induction in gestational hypertension or mild pre-eclampsia at term? An exploratory analysis of the HYPITAT trial. BJOG 2012;119:11231130. Objective To examine whether cervical favourability (measured by cervical length and the Bishop score) should inform obstetricians decision regarding labour induction for women with gestational hypertension or mild pre-eclampsia at term. Design A post hoc analysis of the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). Setting Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. Population A total of 756 women diagnosed with gestational hypertension or pre-eclampsia between 36 + 0 and 41 + 0 weeks of gestation randomly allocated to induction of labour or expectant management. Methods Data were analysed using logistic regression modelling. Main outcome measures The occurrence of a high-risk maternal situation defined as either maternal complications or progression to severe disease. Secondary outcomes were caesarean delivery and adverse neonatal outcomes. Results The superiority of labour induction in preventing high-risk situations in women with gestational hypertension or mild pre-eclampsia at term varied significantly according to cervical favourability. In women who were managed expectantly, the longer the cervix the higher the risk of developing maternal high-risk situations, whereas in women in whom labour was induced, cervical length was not associated with a higher probability of maternal high-risk situations (test of interaction P = 0.03). Similarly, the beneficial effect of labour induction on reducing the caesarean section rate was stronger in women with an unfavourable cervix. Conclusion Against widely held opinion, our exploratory analysis showed that women with gestational hypertension or mild pre-eclampsia at term who have an unfavourable cervix benefited more from labour induction than other women. Trial registration The trial has been registered in the clinical trial register as ISRCTN08132825.

Background: Small autopsy studies and clinical practice indicated that carotid atherosclerosis develops in an asymmetrical helical pattern coinciding with regions of low shear stress. We investigated the distribution of carotid atherosclerosis as determined by maximum carotid intima-⊟media thickness (CIMT), to assess if we could confirm this atherosclerotic configuration across various populations with different cardiovascular risk. Methods and results: We used the individual baseline CIMT data from 3364 subjects from four recent international multicentre randomized controlled trials in which the carotid artery was systematically examined using the same ultrasound protocol and method to quantify CIMT. For each subject, circumferential information on the maximum CIMT of the left and right carotid arteries was obtained for the common carotid, bifurcation, and internal carotid artery segments. In each segment (common, bifurcation, internal), mixed modelling was used to study the differences in CIMT between angles, sides, gender, age, race, and studies. Each segment showed a different circumferential CIMT pattern. In all segments there were statistically significant differences between maximum CIMT across circumferential angles ( p

The decade since the publication of the Human Genome Project draft has ended with the discovery of hundreds of genomic markers related to diseases and phenotypes. However, the project has not yet delivered on its promise to tailor treatments for individuals. The number of genomic markers in clinical practice is very small. The number of markers to guide treatment decisions is even smaller. In order to speed up discovery and validation of genomic treatment selection markers, we call for considering the brilliant potential of randomized clinical trials. If biomedical research community can collaborate in organizing large-scale consortium of clinical trials associated with well-designed biobanks, these studies would soon act as huge laboratories for investigating genomic medicine; a big step forward towards personalizing medicine.

We evaluated the protective effects of antioxidant at the onset of fever on renal damage in a rat model of acute pyelonephritis. Twenty rats were allocated to four groups. In groups 1 to 3, the animals were given direct inoculation of Escherichia coli into the right kidney, and group four served as control. All rats in groups 1 to 3 were given once-daily intraperitoneal injections of ceftriaxon for five consecutive days, beginning on the third day after inoculation. The animals' body temperatures were monitored; as soon as body temperature reaches 38 degrees C, the rats in group 2 were given allopurinol co-treatment, whereas, in group 3, vitamin E co-treatment was started at fever onset. Both kidneys were excised 6 weeks later, for the evaluation of histopathologic changes, apoptotic damage, and concentrations of transforming growth factor-beta (TGF-beta). Only minimal changes were found in control samples. Pathologic scores of inflammation and fibrosis in group 1 were higher than in the vitamin E and allopurinol groups (P0.05). Apoptosis index was also decreased in groups 2 and 3, compared to group 1 (P0.05). There was no significant difference in average TGF-beta levels between study groups. These findings suggest that administration of vitamin E or allopurinol following the onset of fever can reduce renal damage in pyelonephritis.

Background: Many studies have investigated the variations in the anatomy of each segment of the cerebral arterial circle while a few have addressed the variations of the cerebral arterial circle as a whole. Methods: Thirty brains of recently deceased Iranian infants and fetuses were dissected. The dissection process was filmed and digitized so as to be readily available for further studies. The variations of the circle as a whole and segmental variations were evaluated. Results: Variants with uni- and bilateral hypoplasia of posterior communicating arteries (PcoAs) were the most common in our study, similar to previous works. No aplasia of the precommunicating part of the anterior cerebral artery (A1), the precommunicating part of the posterior cerebral artery (P1) and anterior communicating artery was seen. Hypoplasia of the right and left PcoA was observed in 8 and 5 cases, respectively. Aplasia of the right PcoA was found in 16.6% and of the left PcoA in 3.3%. Conclusion: In this study, we confirmed the previously described finding that the symmetrical, circular configuration of the circulus arteriosus cerebri is present in only about 42.1%. The main differences between the fetal and adult disposition are the diameter of the PcoA and the circular part of the posterior cerebral artery. According to previous studies, the fetal brain older than 4 months has anatomical characteristics very similar to the adult’s circle; our finding was mostly similar to adult samples as most samples were from infants, not fetuses.

OBJECTIVE: To evaluate the efficacy of aminophylline infusion as a painkiller compared with placebo in patients with acute renal colic. PATIENTS AND METHODS: From March to August 2005, 141 patients with clinical renal colic, who were under 60 years of age, had no history of heart or hepatic failure, asthma, theophylline or beta blocker use, reaction to methylxantines, pregnancy or breast feeding, and were not prescribed spasmolytic or analgesics, entered our study. They were randomly assigned to receive either 375 mg of aminophylline or placebo infusion under double blind conditions. Pain intensity was recorded using a visual analog scale (VAS), before drug administration and 30 and 60 minutes afterwards. The drug effectiveness was defined as > or =40% decrease in pain intensity 60 minutes after the onset of infusion, without exacerbation during the following 4 hours. RESULTS: Seventy patients received aminophylline; it was effective in 45 (64%; 95% confidence interval 52-75%). Alternatively, placebo was effective in 12 of 71 control patients (17%; 95% confidence interval 9-28%); (P < 0.001). Thirty and 60 minutes after administration, aminophylline reduced pain by 24% and 39% respectively, as compared with 6% and 8% pain reduction in the placebo group. CONCLUSION: This prospective study provides remarkable information about the efficacy of aminophylline on pain relief and decreasing narcotic usage in symptomatic urinary calculi. It is safe, inexpensive, with minute side effects and can be considered a good alternative or additive to narcotic analgesics in the management of renal colic.

To evaluate short-term ureteral catheterization in patients undergoing ureteroscopic lithotripsy for ureteral calculi.Patients (n = 140) with ureteral calculi who were candidates for ureterolithotripsy were enrolled. Stone size was 5-10mm. The operation was performed with an 8-9.8F semirigid ureteroscope without active dilatation and stones were fragmented with a 1F pneumatic lithotrite. Uncomplicated cases (109 patients) were randomized to catheterized (C) and noncatheterized (NC) groups. In the 54 C group patients, a polyurethane catheter (5F) was passed through the ureter after lithotripsy with the end attached to a Foley placed in urethra, which was removed after 24h. Postoperatively, all patients were evaluated for flank and suprapubic pain, renal colic, irritative urinary symptoms, peritonism, frequency of analgesic usage, urinary tract infection, duration of hospitalization, postdischarge visits (due to renal colic/pain), readmission, and residual stone rates.On the first postoperative day, the percentage of patients experiencing flank pain and renal colic was significantly higher in the NC group (76% and 45%) compared with the C group (20% and 2%); 67% of NC patients required analgesic administration during hospital stay versus 20% of C patients (p0.001). Suprapubic pain and urethral irritation were reported by 13% and 37% of C patients, respectively, and 5% and 4% of NC patients. However, peritonism was developed more often in NC patients (27% vs. 13%). Hospital stay was 1 d for all patients. Three days postoperatively, 40% of NC patients complained of at least one episode of flank pain compared with 7% of C patients (p0.001). Incidence of urinary tract infections was 4% in NC and 7% in C group patients. Postdischarge visits were necessary in 20% of NC patients and 5% of C patients. No patient in either group required readmission. No complaints were reported nor residual stones discovered on 2-wk follow-up radiographs in either group.Short-term ureteral catheterization in uncomplicated ureteroscopy and lithotripsy has a role in reducing early postoperative morbidities. It may also decrease pain and colic after discharge.

Object. Meningomyelocele (MMC) is a common central nervous system birth defect. As one of many problems facing patients with MMC, learning disabilities are often overlooked. The aim of this study was to evaluate IQs in a group of children with MMCs and determine if a correlation exists between intelligence level and the presence of an MMC and/or its complications. Methods. A case‐control study was conducted at the Children’s Hospital Medical Center in Tehran, Iran, from December 2004 through December 2005. The patient group included 50 children with MMC from 5 to 12 years of age who were referred to the authors’ institution for treatment of complications or for follow up after surgery for MMC closure. The patient group was individually matched for age and sex with a control group of 50 children referred to the hospital for other reasons and who did not have MMC or other neurological abnormalities. The IQs in all children in this study were evaluated using the Ravens Progressive Matrices test. The children in both groups were similar in the socioeconomic status of the family (p = 0.347) and educational status of the father (p = 0.117) and mother (p = 0.439). Patient age at the time of surgery for MMC closure varied from 1 day to 96 months (mean 4.1 months). Only 20% of the patients with MMC could walk with a normal gait. Forty-six percent of the patients had undergone placement of a ventriculoperitoneal shunt, and half of these patients experienced shuntrelated complications; 72% of the children in the patient group were completely incontinent for both urine and feces. The IQ results obtained in the patient group ranged from 73 to 134 with a mean (6 standard deviation) of 96.62 6 13.01. In the control group the IQ range was 70 to 128, and the mean was 104.82 6 12.30. Compared with the control group there was a statistically significant correlation between having an MMC and having a lower IQ (p , 0.001, paired t-test). Conclusions. Although the average IQ in the patient group was significantly lower than that in the control group, it is important to note that all children in the patient group had an average or above-average IQ. In contrast with the results reported in other studies, earlier repair of the MMC, the presence of a shunt or shunt-related complications, walking difficulty, and the spinal level of the lesion did not correlate significantly with IQs. Therefore, the lower IQ and reduced cognitive levels noted in these patients result from the disease process itself and not from the associated complications.

Objectives. To evaluate the efficacy of botulinum toxin A in the treatment of children with detrusor hyperreflexia caused by myelomeningocele and the effects of this treatment on neuropathic bladder and bowel dysfunction. Methods. In a prospective study, 26 children with myelomeningocele (20 boys and 6 girls, mean age 6.9 years) were included. All patients had been nonresponders to medical treatment and required clean intermittent catheterization. Under cystoscopic guidance, 10 IU/kg of botulinum toxin A was injected into the detrusor muscle, sparing the trigone and ureteral orifices. In each patient, urinary incontinence grade and improvement in parameters of interest in the evaluation of bowel dysfunction were assessed before and 4 months after injection. Conventional urodynamic studies to determine maximal bladder capacity and maximal detrusor pressure and voiding cystoureterography were also performed. Results. Four months after procedure, 19 patients (73%) had become completely dry between clean intermittent catheterizations, and the total improvement in urine incontinence was 88%. The mean maximal detrusor pressure was decreased to 83.2 4.6 cm H2O from the baseline of 139.3 11.2 (P 0.01). The average maximal bladder capacity increased from 102.8 6.3 mL to 270.2 9.5 mL (P 0.01). Of the 15 patients who had varying degrees of vesicoureteral reflux before the procedure, 11 (73%) had decrease in the vesicoureteral reflux grade. Also, bowel dysfunction improved in 10 (66%) of the 15 patients. Conclusions. Botulinum toxin A appears to be a safe, minimally invasive procedure for the management of neuropathic bladder and bowel dysfunction in children with myelomeningocele. UROLOGY 68: 1091‐1097, 2006. © 2006 Elsevier Inc.

Purpose: We evaluated the effect of Urocol injection for the endoscopic treatment of VUR in children.Materials and Methods: A total of 208 children (62 boys and 146 girls, mean age 4.78 years) with 346 refluxing ureters underwent subureteral injection of Urocol between January 2000 and February 2002. VCUG was performed at 6 months, and ultrasound was performed at 1 week and 3 months postoperatively.Results: Followup VCUG showed no evidence of reflux in 240 ureters (69%), significant decrease in reflux grade in 62 (18%) and no change in 44 (13%). Ultrasound revealed no obstruction or hydronephrosis.Conclusions: The results of this study demonstrate that subureteral injection of Urocol was effective for the treatment of VUR. We conclude that Urocol represents a new, safe, simple, less expensive and repeatable technique in treating VUR.

Objective.—To assess the effectiveness and safety of cinnarizine as a migraine-preventive therapy. Methods.—Sixty patients with more than 2 migraine headache attacks during a 4-week baseline entered the study and received a 25-mg tablet cinnarizine twice daily for the first 3 days and then 3 times daily. They were assessed on weeks 2, 6, 10, and 14. Reduction from baseline in 4-week migraine headache rate was the primary efficacy variable. Reduction in migraine attacks duration and severity was also evaluated. Results.—The mean reduction in 4-week migraine headache rate was 4.6 ± 2.2 from the baseline of 6.2 ± 2.2 after 14 weeks of treatment, which was statistically significant (P < 0.001). Percent reduction in 4-week migraine frequency was 35% after 2 weeks, 74% after 6 weeks, 74% after 10 weeks, and 75% after 14 weeks of treatment. Significant reduction in attack duration (P < 0.001) and severity (P < 0.001) was also noted. No serious adverse events were observed in this series of patient. Conclusion.—Cinnarizine is an efficacious and well-tolerated prophylactic antimigraine medication, which has early onset effectiveness.

We evaluated the outcome of pubic bone approximation and internal fixation using a miniature metal plate and screws without osteotomy in children with bladder exstrophy.A total of 17 children with bladder exstrophy underwent surgery. Mean patient age was 27 months. Of the patients 15 had a history of 1 or more failed bladder closures with or without osteotomy. All children underwent bladder closure and complete posterior and anterior urethroplasty with bladder neck wrap. Both ureteral orifices were brought together by the Gil-Vernet antireflux procedure. The pubes were brought together with 3 deeply placed 1 mm polyglactin sutures through the bone and fixed by placing a miniature metal plate with 6 to 7 screws. Patients remained in a frog leg bandage for 1 to 3 weeks. The plate was removed during additional surgery. Median followup was 61 months (range 14 to 71).All children had an uneventful postoperative period without any serious complications, except for skin erosion caused by a screw without bone infection in 1 patient, and miniature plate subluxation following cystoscopy for reinsertion of urethral catheter 3 days after initial surgery in 1. Operating time and hospital stay were significantly lower than in children undergoing osteotomy or Bryant's traction. Overall continence rate was 53.8%.Although the number of patients is low, these results are promising. Pubic bone adaptation with miniature plate fixation without any type of osteotomy or leg traction is safe and less invasive than bilateral osteotomy and postoperative leg traction or plaster.

Objective To investigate whether vaginal Group B Streptococcus (GBS) colonisation or other baseline characteristics of women with preterm premature rupture of membranes (PPROM) can help in identifying subgroups of women who would benefit from immediate delivery.Design Secondary analysis of the PPROMEXIL trials.Setting Sixty hospitals in the Netherlands.Population Women with PPROM between 34 and 37 weeks of gestation.Methods Random assignment of 723 women to immediate delivery or expectant management.Main outcome measures Early onset neonatal sepsis.Results Vaginal GBS colonisation status was the only marker which was significantly associated with the benefit of immediate delivery (P for interaction: 0.04). GBS colonisation was observed in 14% of women. The risk of early onset neonatal sepsis in GBS-positive women was high (15.2%) when they were managed expectantly but this risk was reduced to 1.8% with immediate delivery. The early onset neonatal sepsis risk was much lower in neonates of GBS-negative women: 2.6% after expectant management and 2.9% with immediate delivery. We estimated that by inducing labour only in GBS-positive women, there would be a 10.4% increase in term delivery rate, while keeping neonatal sepsis and caesarean delivery rates comparable to a strategy of labour induction for all.Conclusions Our post hoc findings suggest that women with PROM between 34 and 37 weeks might benefit from immediate delivery if they have GBS vaginal colonisation, while in GBS-negative women labour induction could be delayed until 37 weeks.

BACKGROUND: To investigate whether biomarkers consisting of baseline characteristics of advanced stage ovarian cancer patients can help in identifying subgroups of patients who would benefit more from primary surgery or neoadjuvant chemotherapy. METHODS: We used data of the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial in which 670 patients were randomly assigned to primary surgery or neoadjuvant chemotherapy. The primary outcome was overall survival. Ten baseline clinical and pathological characteristics were selected as potential biomarkers. Using Subpopulation Treatment Effect Pattern Plots (STEPP), biomarkers with a statistically significant qualitative additive interaction with treatment were considered as potentially informative for treatment selection. We also combined selected biomarkers to form a multimarker treatment selection rule. FINDINGS: The size of the largest metastatic tumour and clinical stage were significantly associated with the magnitude of the benefit from treatment, in terms of five-year survival (p for interaction: 0.008 and 0.016, respectively). Stage IIIC patients with metastatic tumours ⩽45 mm benefited more from primary surgery while stage IV patients with metastatic tumours >45 mm benefited more from neoadjuvant chemotherapy. In stage IIIC patients with larger metastatic tumours and in stage IV patients with less extensive metastatic tumours both treatments were equally effective. We estimated that by selecting treatments for patients based on largest metastatic tumour and clinical stage, the potential five-year survival rate in the population of treated patients would be 27.3% (95% confidence interval (CI) 21.9-33.0), 7.8% higher than if all were treated with primary surgery, and 5.6% higher if all were treated with neoadjuvant chemotherapy. INTERPRETATION: Although survival was comparable after primary surgery and neoadjuvant chemotherapy in the overall group of patients with ovarian cancer in the EORTC 55971 trial, we found in this exploratory analysis that patients with stage IIIC and less extensive metastatic tumours had higher survival with primary surgery, while patients with stage IV disease and large metastatic tumours had higher survival with neoadjuvant chemotherapy. For patients who did not meet these criteria, both treatment options led to comparable survival rates.

1 Farooq V, van Klaveren D, Steyerberg EW, et al. Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II. Lancet 2013; 381: 639–50. 2 Janes H, Pepe MS, Bossuyt PM, Barlow WE. Measuring the performance of markers for guiding treatment decisions. Ann Intern Med 2011; 154: 253–59. 3 Huang Y, Gilbert PB, Janes H. Assessing treatment-selection markers using a potential outcomes framework. Biometrics 2012; 68: 687–96. 4 Song X, Pepe MS. Evaluating markers for selecting a patient’s treatment. Biometrics 2004; 60: 874–83. SYNTAX score II

Background The most common neurologic manifestation of gluten sensitivity is ataxia, which accounts for up to 40% of idiopathic sporadic ataxia. Timing of diagnosis of gluten ataxia is vital as it is one of the very few treatable causes of sporadic ataxia and causes irreversible loss of Purkinje cells. Antigliadin antibody (AGA) of the IgG type is the best marker for neurological manifestations of gluten sensitivity. This study was conducted to measure the prevalence of gluten ataxia in a group of Iranian patients with idiopathic ataxia. Methods For 30 patients with idiopathic cerebellar ataxia, a questionnaire about clinical and demographic data was completed. Serum AGA (IgA and IgG) and antiendomysial antibody (AEA) were assessed. Gluten ataxic patients underwent duodenal biopsy. Magnetic resonance imaging was done for all patients to see if cerebellar atrophy is present. Results Only 2 patients had a positive IgG AGA (6.7%) who both had a positive AEA while none of them showed changes of celiac disease in their duodenal biopsies. Only presence of gastrointestinal symptoms and pursuit eye movement disorders were higher in patients with gluten ataxia. Conclusion Prevalence of gluten ataxia in Iranian patients with idiopathic ataxia seems to be lower than most of other regions. This could be explained by small sample size, differences in genetics and nutritional habits and also effect of serologic tests in clinical versus research setting. Further researches with larger sample size are recommended.

Object Patients with myelomeningoceles (MMCs) are at increased risk of latex allergy and sensitization. Number of surgeries and history of atopy are known risk factors. The object of this study was to evaluate the role of diagnostic procedures and nonsurgical treatments in latex sensitization in young patients with MMC. Methods Seventy-three children with MMC were included in the study. For each child a questionnaire was administered and serum determination of IgE was performed, and 62 children underwent skin prick tests (SPTs), 60 of which had reliable results. Multivariate logistic regression modeling was performed, using latex sensitization as the dependent variable. Results The mean age of the 73 patients was 3.8 years. The SPT results were positive in 30.6%, whereas results of testing for latex-specific IgE were positive in only 8.2%. In univariate analysis, history of untethering, barium enema, and number of clean intermittent catheterizations (CICs) per day were significantly associated with positive results on the SPT. Although the number of surgical procedures was significantly higher in patients who had shunts, no significant relationship between the presence of a shunt and latex sensitization was seen. Conclusions The young age of the patients in this study may account for the low prevalence of latex sensitization that was found. In young patients with MMC, the numbers of CICs per day, a history of untethering, circumcision, and a barium enema performed without latex-free equipment could be risk factors for latex sensitization. The use of latex-free gloves in all procedures performed in these cases, nonlatex polyvinyl chloride catheters in CIC, and ordinary nonballoon tips in barium enemas could decrease the risk of sensitization.

To compare the effectiveness of 5 different modalities, and determine the usefulness of recently proposed extensor grip test (EGT) in predicting the response to treatment.In a randomized controlled clinical trial, 92 of 98 tennis elbow patients in Sina Hospital Tehran, Iran between 2006 and 2007 fulfilled the trial entry criteria. Among these patients 56 (60.9%) had positive EGT result. The stratified EGT result, were randomly allocated to 5 treatment groups: brace, physiotherapy, brace plus physiotherapy, injection, and injection plus physiotherapy.Patients with a positive EGT result had better response to treatments. Among them, injection plus physiotherapy was the most successful, then brace plus physiotherapy, physiotherapy, and brace injection was the worst treatment modality. Response to treatment was comparable in all groups between EGT positive and negative patients except bracing, in which positive EGT was correlated with a dramatic response to treatment.In all patients, injection plus physiotherapy and then brace plus physiotherapy is recommended, but in EGT negatives, bracing seems to be of no use. Injection alone is not recommended in either group.

Shunt infection represents a particularly morbid condition, which can also result in mortality. In order to decrease the high morbidity and mortality rates, prevention is an essential step. The purpose of this study was to compare the prophylactic use of ceftriaxone and trimethoprim-sulfamethoxazole (SXT) for the prevention of ventriculoperitoneal (VP) shunt infection.In this prospective, single-institution, randomized clinical trial, 107 children with hydrocephalus and an indication for shunting were randomly assigned to prophylaxis with ceftriaxone (n = 50) or SXT (55), each administered as a single dose during anesthesia and two divided doses postoperatively. Patients were followed up for at least one year.The mean age of patients was 15 months, and 85% were aged 6 months or younger. During the first postoperative year, meningitis occurred in 13.5% of patients receiving ceftriaxone and 14.5% of the SXT group, with no statistically significant difference between the groups. Younger age, presence of cerebrospinal fluid leakage and aqueductal stenosis as a cause of hydrocephalus showed significant correlation with meningitis occurrence on univariate analysis. However, only the latter 2 factors were associated with meningitis on multivariate analysis. The risk of shunt infection did not correlate with the gender of the patient, time of VP shunt surgery, or duration of hospitalization for shunting.Ceftriaxone and SXT showed similar efficacy in preventing shunt infection. Cerebrospinal fluid leakage before or after VP shunt placement and aqueductal stenosis were independent risk factors for meningitis after VP shunt.

Selenium is a potential chemopreventive agent against prostate cancer. This study sought to evaluate and compare the serum selenium level in men with newly diagnosed prostate cancer and noncancerous patients. Between 2005 and 2006, this prospective case-control study was performed on patients referred to Sina and Imam University hospitals, Tehran, Iran; it included 62 men with clinicopathologically confirmed diagnosis of prostate cancer (case group) and 68 men with no detectable prostate cancer [normal digital rectal examination and prostate-specific antigen (PSA) level] or any other malignant disease (control group). The serum selenium level was assessed using Zeeman graphite furnace atomic absorption spectrometer (Varian Company, Australia). The mean serum selenium level in the case and control group was 66.3 +/- 17.7 microg/l and 77.5 +/- 22.5 microg/l, respectively (P = 0.002). Serum selenium was inversely associated with prostate cancer risk. After adjustment for age, body mass index (BMI), and smoking, the odds ratio was 0.16 and 95% confidence intervals were 0.06 to 0.47 (P trendq = 0.001) comparing the highest with the lowest tertile (or = 89.3 microg/l). No correlation was observed between serum selenium level and age, BMI, or PSA level. In conclusion, serum selenium levels in prostate cancer cases were lower than in controls, which supports the hypothesis that selenium may protect against prostate cancer.

Most clinical laboratories directly measure serum triglyceride, total cholesterol, and high- density lipoprotein cholesterol. They indirectly calculate low-density lipoprotein cholesterol value using the Friedewald equation. Although high serum triglyceride (400 mg/dL or 4.52 mmol/L) devaluates low-density lipoprotein cholesterol calculation by using this formula, effects of low serum triglyceride (100 mg/dL or 1.13 mmol/L) on its accuracy is less defined.Two hundred thirty serum samples were assayed during a one-year period. In 115 samples, the triglyceride level was below 100 mg/dL and in 115 samples from age- and sex-matched patients the triglyceride level was 150 - 350 mg/dL (1.69 - 3.95 mmol/L). In both groups total cholesterol was above 250 mg/dL (6.46 mmol/L). On each sample, total cholesterol, high-density lipoprotein cholesterol, and triglyceride were directly measured in duplicate and low-density lipoprotein cholesterol measured directly and calculated with Friedewald equation as well. Statistical analysis showed that when triglyceride is100 mg/dL, calculated low- density lipoprotein cholesterol is significantly overestimated (average :12.17 mg/dL or 0.31 mmol/L), where as when triglyceride is between 150 and 300 mg/dL no significant difference between calculated and measured low-density lipoprotein cholesterol is observed. In patients with low serum triglyceride and undesirably high total cholesterol levels, Friedewald equation may overestimate low-density lipoprotein cholesterol concentration and it should be either directly assayed or be calculated by a modified Friedewald equation. Using linear regression modeling, we propose a modified equation.

Object Previous studies have shown nutritional benefits of breastfeeding for a child's health, especially for protection against infection. Protective factors in human milk locally and systemically prevent infections in the gastrointestinal as well as upper and lower respiratory tracts. It remains unclear whether breastfeeding protects infants against ventriculoperitoneal (VP) shunt infection. Methods A cohort study was conducted from December 2003 to December 2006 at Children's Hospital Medical Center in Tehran, Iran. A total of 127 infants with hydrocephalus who were treated using a VP shunt in the first 6 months of life were enrolled. Each infant's breastfeeding method was classified as either exclusively breastfed (EBF), combination feedings of breast milk and formula (CFBF), or exclusively formula-fed (EFF). Infants were followed up to determine the occurrence of shunt infection within 6 months after operation. Statistical analysis was performed using survival methods. Results Infants ranged in age from 4 to 170 days at the time of shunt insertion (mean 69.6 days), and 57% were males. Regarding the breastfeeding categories, 57.5% were EBF, 25.2% were CFBF, and 17.3% were EFF. During the follow-up, shunt infection occurred in 16 patients, within 15 to 173 days after shunt surgery (median 49 days). The 6-month risk of shunt infection was 8.5% (95% confidence interval [CI] 4–18%) in the EBF group, 16.5% (95% CI 7–35%) in the CFBF group, and 26.0% (95% CI 12–52%) in the EFF group. There was no statistically significant difference between these 3 groups (p = 0.11). The trend test showed a significant trend between the extent of breastfeeding and the risk of shunt infection (p = 0.035), which persisted even after adjustment for potential confounding variables (hazard ratio = 2.01, 95% CI 1.01–4). Conclusions This study supports the protective effect of breastfeeding against shunt infection during the first 6 months of life and the presence of a dose–response relationship, such that the higher the proportion of an infant's feeding that comes from human milk, the lower the incidence of shunt infection. Encouraging mothers of infants with VP shunts to breastfeed exclusively in the first 6 months of life is recommended.

Object The purpose of this study was to evaluate the importance of spina bifida occulta in radiographs of children with lower urinary tract or bowel dysfunction. Methods The authors prospectively investigated the presence of spinal cord abnormalities in 176 patients with functional urinary and bowel problems: 88 children with radiographic evidence of spina bifida occulta (SBO) and 88 age-and sex-matched controls. Each group included 46 boys and 42 girls (age range 5–14 years). Nocturnal enuresis, isolated diurnal enuresis, enuresis during both day and night, urinary tract infection, urinary frequency, encopresis, intractable constipation, and vesicoureteral reflux were assessed in all patients. Magnetic resonance (MR) images were obtained in all patients and evaluated for spinal cord abnormalities. Sacral ratios (SRs) were calculated on the basis of plain radiographs. Results There was no statistically significant difference between the 2 groups on any of the clinical measures. The most common sites of SBO on radiographs were the S-1 (47%) and L-5 and S-1 (25%). The mean SRs (± standard deviations) in the SBO and control groups, respectively, were 0.64 ± 0.45 and 0.68 ± 0.51 (no statistically significant difference). Sacral agenesis was found in 17 children (7 in the SBO group and 10 in the control group, p = 0.44). Abnormal MR imaging findings were observed in 9 children (10.22%) in the SBO group and 3 (3.4%) in the control group. Abnormalities included tethered spinal cord in 5 children, syringomyelia in 4, and club-shaped conus in 2. No significant association was found between the presence of SBO and spinal cord abnormalities identified on MR images (p = 0.13, paired t-test). Conclusions Among children with functional bowel and urinary problems, there was no statistically significant difference in the prevalence of abnormal spinal MR imaging findings in those with radiographic SBO and an age- and sex-matched control group. Spina bifida occulta was not shown to be a reliable indicator of spinal cord structural abnormalities. Its probable role as a finding associated with spinal cord dysfunction remains unclear.

Introduction Premature ejaculation (PE) is regarded as the most common male sexual disorder. To date, there is no accurate and objective diagnostic test for PE. Aim To determine the diagnostic value of serum leptin level for PE. Methods In a case‐control design, the serum leptin level of 46 PE patients referred to our outpatient clinic were determined and compared with 44 control patients referred to the same clinic with the complaint of nephrolithiasis. PE was defined based on the Diagnostic and Statistical Manual of Mental Disorders IV criteria and an intravaginal ejaculatory latency time of less than a minute. Main Outcome Measures Serum leptin level and presence of PE. Results The PE patients had significantly higher serum leptin levels (8.3 ± 3 ng/mL) than the controls (3.3 ± 1 ng/mL) ( P Conclusion According to our results, leptin level in patients with PE was significantly higher than in the control subjects. More studies are necessary to determine the value of serum leptin as a diagnostic tool for PE. Nikoobakht MR, Tajik P, Karami AA, Moradi K, Mortazavi A, and Kosari F. Premature ejaculation and serum leptin level: A diagnostic case‐control study. J Sex Med **;**:**–**.

We evaluated the impact of fasting on the effectiveness of shockwave lithotripsy (SWL) in patients with renal calculi.The study was a randomized controlled trial for patients with renal stones. Between May 2005 and November 2006, patients (n = 97) with a single radio-opaque renal stone (7-21 mm) who were candidates for SWL were enrolled. Patients were randomized to fasting (F, n = 49) and nonfasting (NF, n = 48) groups. F group patients were asked to fast for 12 hours before SWL. Urine specific gravity (SG) was measured after fasting. All patients were monitored every 2 weeks until complete stone clearance. Treatment effectiveness was defined as complete clearance up to 3 months.There were 32 men in the F group and 28 men in the NF group. The mean age was 37.9 +/- 8.5 years in the F group and 39.1 +/- 7.7 years in the NF group. The mean body mass index was 22.8 +/- 2.5 and 23.1 +/- 2.6 in F and NF patients, respectively. The urine SG in the F group (1.036 +/- 0.004) was significantly higher than in the NF group (1.013 +/- 0.004; P0.001). At 3-month follow-up, the overall stone-free rate using SWL was 86.1% in the F group, which was higher than the rate of 72.9% in the NF group; however, the difference was not statistically significant (P = 0.16).Fasting significantly changes the urine SG but does not have a significant impact on the effectiveness of SWL for isolated renal stones.