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Background: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer's disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy.Objective: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients.Methods: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET.Results: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman's rho (17)  = -0.596, 95% -CI [-0.905, -0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit.Conclusion: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures. [ABSTRACT FROM AUTHOR]

Background: The ability for independent bipedal locomotion is an important prerequisite for autonomous mobility and participation in everyday life. Walking requires not only a functional musculoskeletal unit but relies on coordinated activation of muscles and may even require cognitive resources. The time-resolved monitoring of the position of joints, feet, legs and other body segments relative to each other alone or in combination with simultaneous recording of ground reaction forces and concurrent measurement of electrical muscle activity, using surface electromyography, are well-established tools for the objective assessment of gait.Research Question: The Gait Real-time Analysis Interactive Lab (GRAIL) has been introduced for gait analysis in a highly standardized and well-controlled virtual environment. However, apart from high computing capacity and sophisticated software required to run the system, handling of GRAIL data is challenging due to the utilization of different software packages resulting in a huge amount of data stored using different file formats and different sampling rates. These issues make gait analysis even with such a sophisticated instrument rather tedious, especially within the frame of an experimental or clinical study.Methods: A user-friendly Matlab based toolset for automated processing of motion capturing data recorded using the GRAIL, with the inherent option for batch analysis was developed.Results: The toolset allows the reading, resampling, filtering and synchronization of data stored in different input files recorded with the GRAIL. It includes a coordinate-based algorithm for the detection of initial contact and toe-off events to split and normalize data relative to gait cycles. Batch processing of multiple measurements and automatic detection of outliers is possible.Significance: The authors hope that the toolset will be useful to the research community and invite everyone to use, modify or implement it in their own work. [ABSTRACT FROM AUTHOR]

Objective: To determine whether vaginal progesterone for programmed endometrial preparation is noninferior to intramuscular progesterone in terms of live birth rates from frozen embryo transfer (FET).Design: Three-armed, randomized, controlled noninferiority trial.Setting: Multicenter fertility clinic.Patient(s): A total of 1,346 volunteer subjects planning vitrified-warmed transfer of high-quality nonbiopsied blastocysts were screened, of whom 1,125 subjects were ultimately enrolled and randomly assigned to treatment.Intervention(s): The subjects were randomly assigned to receive, in preparation for FET, 50 mg daily of intramuscular progesterone (control group), 200 mg twice daily of vaginal micronized progesterone plus 50 mg of intramuscular progesterone every third day (combination treatment), or 200 mg twice daily of vaginal micronized progesterone.Main Outcome Measure(s): The primary outcome was live birth rate per vitrified-warmed embryo transfer. The secondary outcomes were a positive serum human chorionic gonadotropin test 2 weeks after FET, biochemical pregnancy loss, clinical pregnancy, clinical pregnancy loss, total pregnancy loss, serum luteal progesterone concentration 2 weeks after FET, and patient's experience and attitudes regarding the route of progesterone administration, on the basis of a survey administered to the subjects between FET and pregnancy test.Result(s): A total of 1,060 FETs were completed. The live birth rate was significantly lower in women receiving only vaginal progesterone (27%) than in women receiving intramuscular progesterone (44%) or combination treatment (46%). Fifty percent of pregnancies in women receiving only vaginal progesterone ended in miscarriage.Conclusion(s): The live birth rate after vaginal-only progesterone replacement was significantly reduced, due primarily to an increased rate of miscarriage. Vaginal progesterone supplemented with intramuscular progesterone every third day was noninferior to daily intramuscular progesterone, offering an effective alternative regimen with fewer injections.Clinical Trial Registration Number: NCT02254577. [ABSTRACT FROM AUTHOR]

Introduction: Empirical evidence on Ronald Inglehart's theory of value change shows that subsequent generations show a decline in values of physical and economic security (materialism) in favor of an increase in values of self-expression and autonomy (postmaterialism).Methods: We investigate in a pre-registered study whether Inglehart's theory also applies to partnership, such that millennials think less that they need a partner to be happy. We used data from the German Socio-Economic Panel (SOEP) study on 4540 17-year-olds from 16 birth cohorts.Results: Results show that adolescents' estimated importance of a romantic partner for personal happiness decreases on average with each subsequent birth cohort. Further significant predictors were socialization and relationship status of the parents, birth year of the father, as well as education and sex of the adolescent. Socioeconomic status and education level of the parents and birth year of the mother were not significant.Conclusions: Findings provide initial evidence that as society becomes more individualized, even personal happiness is increasingly seen as independent of significant others. Ronald Inglehart's theory of value change, however, seems to have only limited applicability as an explanatory model for this development. [ABSTRACT FROM AUTHOR]

Background: To date, it remains unclear how amyloid plaques and neurofibrillary tangles are related to neural activation and, consequently, cognition in Alzheimer's disease (AD). Recent findings indicate that tau accumulation may drive hippocampal hyperactivity in cognitively normal aging, but it remains to be elucidated how tau accumulation is related to neural activation in AD.Objective: To determine whether the association between tau accumulation and hippocampal hyperactivation persists in mild cognitive impairment (MCI) and mild dementia or if the two measures dissociate with disease progression, we investigated the relationship between local tau deposits and memory-related neural activation in MCI and mild dementia due to AD.Methods: Fifteen patients with MCI or mild dementia due to AD underwent a neuropsychological assessment and performed an item memory task during functional magnetic resonance imaging. Cerebral tau accumulation was assessed using positron emission tomography and [18F]-AV-1451.Results: Entorhinal, but not global tau accumulation, was highly correlated with hippocampal activation due to visual item memory encoding and predicted memory loss over time. Neural activation in the posterior cingulate cortex and the fusiform gyrus was not significantly correlated with tau accumulation.Conclusion: These findings extend previous observations in cognitively normal aging, demonstrating that entorhinal tau continues to be closely associated with hippocampal hyperactivity and memory performance in MCI and mild dementia due to AD. Furthermore, data suggest that this association is strongest in medial temporal lobe structures. In summary, our data provide novel insights into the relationship of tau accumulation to neural activation and memory in AD. [ABSTRACT FROM AUTHOR]

Aim: Current guidelines suggest the use of epinephrine in patients with cardiac arrest (CA). However, evidence for increased survival in good neurological condition is lacking. In experimental settings, epinephrine-induced impairment of microvascular flow was shown. The aim of our study was to analyze the association between epinephrine treatment and intestinal injury in patients after CA.Methods: We have included 52 patients with return of spontaneous circulation (ROSC) after CA admitted to our medical intensive care unit (ICU). Blood was taken on admission and levels of circulating intestinal fatty acid binding protein (iFABP) were analyzed.Results: Patients were 64 (49.8-73.8) years old and predominantly male (76.9%). After six months, 50% of patients died and 38.5% of patients had a cerebral performance category (CPC)-score of 1-2. iFABP levels were lower in survivors (234 IQR 90-399 pg/mL) as compared to non-survivors (283, IQR 86-11500 pg/mL; p < 0.05). Plasma levels of iFABP were not associated with time to ROSC but correlated with epinephrine-dose (R = 0.32; p < 0.05). 40% of patients receiving ≥3 mg of epinephrine as compared to 10.5% of patients treated with <3 mg (p < 0.05) developed iFABP plasma levels >1500 pg/mL, which was associated with dramatically increased mortality (HR4.87, 95%CI 1.95-12.1; p < 0.001). iFABP levels predicted mortality independent from time to ROSC and the disease severity score SAPS II. In contrast to mortality, iFABP plasma levels were not associated with neurological outcome.Conclusions: In this small, single centre study, cumulative dose of epinephrine used in cardiac arrest patients was associated with an increase in biomarker indicative of intestinal injury and 6-month mortality. [ABSTRACT FROM AUTHOR]

Objective: To evaluate characteristics associated with treatment failure 1 year after midurethral sling in women with mixed urinary incontinence.Methods: Four hundred three women who participated in a randomized trial that compared midurethral sling and behavioral and pelvic floor muscle therapy (combined group) against midurethral sling alone for mixed incontinence with 1 year of follow-up data were eligible for this planned secondary analysis. Overall treatment failure was defined as meeting criteria for subjective failure, objective failure, or both. Subjective failure was defined as not meeting the minimal clinically important difference for improvement on the UDI (Urogenital Distress Inventory)-total score (26.1 points). Objective failure was not achieving 70% improvement on mean incontinence episodes of any type per day or having undergone any additional treatment for urinary symptoms at 12 months postoperative. Logistic regression models for treatment failure were constructed. Independent variables included site and treatment group, and clinical and demographic variables based on bivariate comparisons (P<.2). Treatment group interaction effects were evaluated.Results: Previous overactive bladder medication use (unadjusted odds ratio [OR] 2.19, adjusted odds ratio [aOR] 1.89, 95% CI 1.10-3.25), detrusor overactivity on cystometrogram (OR 2.25, aOR 2.72, 95% CI 1.53-4.84), body mass index (OR 1.29, aOR 1.27, 95% CI 1.03-1.57), and Valsalva leak point pressure less than 60 cm H2O (OR 1.96, aOR 3.13, 95% CI 1.65-5.94) were associated with overall failure. Worse UDI urgency scores were associated with failure in the midurethral sling-alone group. Sling type (retropubic vs transobturator) was not associated with failure.Conclusion: Certain clinical and urodynamic variables are associated with treatment failure after midurethral sling among women with mixed urinary incontinence. Women with more severe urgency symptoms at baseline may benefit from perioperative behavioral and pelvic floor muscle therapy combined with midurethral sling. This information is helpful for counseling women with mixed incontinence who are considering surgery.Clinical Trial Registration: ClinicalTrials.gov, NCT01959347. [ABSTRACT FROM AUTHOR]

Background: Extracorporeal photopheresis (ECP) is an immunosuppressive treatment that involves leukocyte apheresis, psoralen and UV light treatment, and subsequent reinfusion. Patients treated with ECP are usually immunosuppressed. Bacterial contamination therefore poses a much unwanted risk, but incidence data are lacking.Patients and Methods: We screened all 1922 consecutive ECP procedures scheduled within a roughly 3-year period for eligibility. Those with missing data on ECP method (inline or offline) or type of venous access (peripheral or central) were excluded. ECPs with complete aerobic and anaerobic microbial testing of baseline patient blood samples (n = 1637) and of ECP cell concentrates (n = 1814) were included in the analysis.Results: A test for microbial contamination was positive for 1.82% of the cell concentrates, with central venous access was the most significant risk factor for the contamination (odds ratio = 19). Patient blood samples were positive in 3.85% of cases, but no patients became septic. Staphylococcus spp. were most abundant, and products with bacterial contamination did not cause side effects after reinfusion. There were no significant differences in contamination rates between inline and offline ECP.Conclusion: These findings stress the importance of sterile procedures and the benefits of using peripheral over central venous access for reducing the risk of bacterial contamination in ECP. [ABSTRACT FROM AUTHOR]

Objective: To determine the pharmacokinetics (PK) of drospirenone (DRSP), alone versus in combination with ethinyl estradiol (EE), after single and repeated administration.Study Design: We conducted a single-centre, open-label, crossover, 2-treatment, 2-period, 2-sequence study in which non-micronized DRSP 4 mg or a combination of DRSP 3 mg and EE 0.02 mg were administered to healthy female subjects on day 1 to obtain a single-dose kinetic profile, and from day 4 to day 15 to obtain a repeated-dose kinetic profile. The maximum observed concentration (Cmax) and area under the concentration/time curve (AUC) were determined in a model-independent way using non dose corrected data. Statistical analysis was based on a parametric method (ANOVA-log).Results: A total of 24 healthy female subjects were randomized 1:1 into the study. The mean relative, non-dose-corrected PK estimates after single-dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 543.5 ng*h/mL, 296.1 ng*h/mL and 27.3 ng/mL for DRSP alone, and 442.0 ng*h/mL, 264.7 ng*h/mL and 37.5 ng/mL for the DRSP/EE combination; p < 0.001. The mean relative, non-dose-corrected PK estimates after repeated dose administration for the endpoints AUC(0-72h), AUC(0-24h) and Cmax were 1066.8 ng*h/ml, 570.2 ng*h/mL and 41.0 ng/mL for DRSP alone, and 1394.5 ng*h/mL, 732.8 ng*h/mL and 61.4 ng/mL for the DRSP/EE combination; p < 0.001.Conclusions: DRSP alone exhibits a lower accumulation ratio than together with EE. The extent of systemic exposure at steady-state is about 32% less with the new formulation (AUC(0-24h), steady-state geometric mean ratio: 77.8%; 90% confidence interval: 74.6%-81.1%). This PK profile may be caused by EE.Implications: Our results suggest that metabolic pathways of DRSP can be inhibited by EE resulting in higher DRSP plasma concentrations in DRSP/EE formulations than in a DRSP-alone formulation. The enzymes CYP3A4 and SULT1A1 may play a role. Additional drug-drug-interaction studies are needed to better understand these metabolic pathways and their future clinical implications. [ABSTRACT FROM AUTHOR]

Objective: To explore antecedents and outcomes of nurse self-reported job satisfaction and dissatisfaction-based turnover cognitions, theorizing (using Self-Determination Theory) that leaders can foster work conditions that help fulfill innate needs, thereby fostering satisfaction of nurses and patients, and reducing adverse events.Data Sources/study Setting: Primary and secondary data were collected within a 4-month period in 2015, from 2,596 nurses in 110 Army treatment facilities (hospitals and clinics) across 35 health care systems.Data Collection/extraction: We collected individual nurse responses to the Practice Environment Scale-Nursing Work Index, in addition to aggregated archival data from the same timeframe, including both facility-level patient satisfaction records (the Army Provider Level Satisfaction Survey) and health care system-level adverse events records (provided by the Army Programming, Analysis, and Evaluation office).Principal Findings: Five predictors of nurse satisfaction and turnover cognitions emerged-supportive leadership, staffing levels, nurse-physician teamwork, adoption of nursing care practice, and advancement opportunities. Aggregated nurse satisfaction was the most consistent predictor of both patient satisfaction and adverse events.Conclusion: These findings provide evidence of the importance of nurse attitudes in improving perceived and actual performance across facilities and health care systems; in addition to practical steps, managers can take to improve satisfaction and retention. [ABSTRACT FROM AUTHOR]

Background: Early growth faltering accounts for one-third of child deaths, and adversely impacts the health and human capital of surviving children. Social as well as biological factors contribute to growth faltering, but their relative strength and interrelations in different contexts have not been fully described.Objective: The aim of this study was to use structural equation modelling to explore social and biological multidetermination of child height at age 2 y in longitudinal data from 4 birth cohort studies in low- and middle-income countries.Methods: We analyzed data from 13,824 participants in birth cohort studies in Brazil, India, the Philippines, and South Africa. We used exploratory structural equation models, with height-for-age at 24 mo as the outcome to derive factors, and path analysis to estimate relations among a wide set of social and biological variables common to the 4 sites.Results: The prevalence of stunting at 24 mo ranged from 14.0% in Brazil to 67.7% in the Philippines. Maternal height and birthweight were strongly predictive of height-for-age at 24 mo in all 4 sites (all P values <0.001). Three social-environmental factors, which we characterized as "child circumstances," "family socioeconomic status," and "community facilities," were identified in all sites. Each social-environmental factor was also strongly predictive of height-for-age at 24 mo (all P values <0.001), with some relations partly mediated through birthweight. The biological pathways accounted for 59% of the total explained variance and the social-environmental pathways accounted for 41%. The resulting path coefficients were broadly similar across the 4 sites.Conclusions: Early child growth faltering is determined by both biological and social factors. Maternal height, itself a marker of intergenerational deprivation, strongly influences child height at 2 y, including indirect effects through birthweight and social factors. However, concurrent social factors, many of which are modifiable, directly and indirectly contribute to child growth. This study highlights opportunities for interventions that address both biological and social determinants over the long and short term. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114.Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported.Interpretation: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.Funding: ELN Foundation and France National Cancer Institute. [ABSTRACT FROM AUTHOR]

Objective: To assess the noninferiority of vaginal P (Endometrin) compared with daily intramuscular P for replacement in programmed vitrified-warmed blastocyst transfer cycles and to assess the noninferiority of vaginal P in combination with intramuscular progesterone every third day compared with daily intramuscular P.Design: Three-arm randomized controlled noninferiority study. To enable early recognition of inferiority if present, an a priori interim analysis was planned and completed once ongoing pregnancy data were available for 50% of the total enrollment goal. The results of this interim analysis are presented here.Setting: Assisted reproduction technology practice.Patient(s): Women undergoing transfer of nonbiopsied high quality vitrified-warmed blastocyst(s) in a programmed cycle.Intervention(s): Vitrified-warmed blastocyst transfer with mode of P replacement determined by randomization to either: (1) 50 mg daily intramuscular P only; (2) 200 mg twice daily vaginal Endometrin; or (3) 200 mg twice daily Endometrin plus 50 mg intramuscular P every 3rd day.Main Outcome Measure(s): Live birth. The primary outcome of this interim analysis was ongoing pregnancy.Result(s): A total of 645 cycles were randomly assigned to one of the three treatment arms, received at least one dose of P replacement therapy according to this assignment and underwent vitrified-warmed blastocyst transfer. These cycles were included in the intention-to-treat analysis. The study team, including the statistician, were blinded to the identity of the treatment arms, which were randomly labeled "A," "B," and "C" in the dataset. Ongoing pregnancy occurred in 50%, 47%, and 31% of cycles in arms A, B, and C respectively. Although arm C had an rate of positive hCG equivalent to the other two arms, the rate of pregnancy loss for arm C was significantly higher than for either of the two arms, resulting in a more than one-third lower rate of ongoing pregnancy. There were no statistically significant differences for any outcome tested between arms A and B. Results of a per-protocol analysis were nearly identical to those of the intention-to-treat analysis. On completion of these analyses, arm C was revealed to be the vaginal P only arm.Conclusion(s): Relative to regimens inclusive of intramuscular P, vaginal-only P replacement for vitrified-warmed blastocyst transfer results in decreased ongoing pregnancy, due to increased miscarriage, and should be avoided. Randomization to the vaginal-only arm was terminated with these findings. This trial is ongoing to assess the noninferiority of the vaginal plus every 3rd day intramuscular P arm compared with daily intramuscular P in terms of live birth.Clinical Trial Registration Number: NLM identifier NCT02254577. [ABSTRACT FROM AUTHOR]

Purpose: To determine the accuracy of particle range prediction for proton and heavier ion radiation therapy based on dual-energy computed tomography (DECT) in a realistic inhomogeneous geometry and to compare it with the state-of-the-art clinical approach.Methods and Materials: A 3-dimensional ground-truth map of stopping-power ratios (SPRs) was created for an anthropomorphic head phantom by assigning measured SPR values to segmented structures in a high-resolution CT scan. This reference map was validated independently comparing proton transmission measurements with Monte Carlo transport simulations. Two DECT-based methods for direct SPR prediction via the Bethe formula (DirectSPR) and 2 established approaches based on Hounsfield look-up tables (HLUTs) were chosen for evaluation. The SPR predictions from the 4 investigated methods were compared with the reference, using material-specific voxel statistics and 2-dimensional gamma analysis. Furthermore, range deviations were analyzed in an exemplary proton treatment plan.Results: The established reference SPR map was successfully validated for the discrimination of SPR and range differences well below 0.3% and 1 mm, respectively, even in complex inhomogeneous settings. For the phantom materials of larger volume (mainly brain, soft tissue), the investigated methods were overall able to predict SPR within 1% median deviation. The DirectSPR methods generally performed better than the HLUT approaches. For smaller phantom parts (such as cortical bone, air cavities), all methods were affected by image smoothing, leading to considerable SPR under- or overestimation. This effect was superimposed on the general SPR prediction accuracy in the exemplary treatment plan.Conclusions: DirectSPR predictions proved to be more robust, with high accuracy in particular for larger volumes. In contrast, HLUT approaches exhibited a fortuitous component. The evaluation of accuracy in a realistic phantom with validated ground-truth SPR represents a crucial step toward possible clinical application of DECT-based SPR prediction methods. [ABSTRACT FROM AUTHOR]

Objective: To assess the relationship between diminished ovarian reserve and pregnancy outcomes in a large cohort of women achieving pregnancy through in vitro fertilization (IVF). We evaluated antral follicle count (AFC) and baseline FSH as a measure of ovarian reserve. Secondarily, we assessed whether diminished ovarian reserve was associated with aneuploidy among spontaneous abortions.Design: Retrospective cohort study.Setting: Multicenter private practice.Patient(s): All patients aged 21-44 years undergoing fresh autologous IVF cycles during 2009-2013 that resulted in positive serum hCG with recorded baseline FSH levels.Intervention(s): None.Main Outcome Measure(s): Live births per early pregnancy, biochemical pregnancies, clinical pregnancy losses, and aneuploidy rates in products of conception among pregnancy losses.Result(s): A total of 9,489 cycles among 8,214 patients were analyzed. There was no association between live birth and ovarian reserve among pregnant IVF patients under the age of 35 years. Among patients 35 years of age and older, elevated baseline FSH was associated with a higher risk of pregnancy loss, which increased with increasing age. AFC was not significantly associated with pregnancy loss at any age. No associations were found between ovarian reserve measures and aneuploidy in products of conception in age-adjusted analyses, although the power to effectively evaluate this was limited.Conclusion(s): Diminished ovarian reserve is not associated with an increase in miscarriage among younger women achieving pregnancy through IVF. Elevated FSH is associated with a higher risk of IVF pregnancy loss among older patients. We found no evidence to confirm that diminished ovarian reserve is associated with increased aneuploidy among spontaneous abortions. [ABSTRACT FROM AUTHOR]

Purpose: This is the first study to evaluate the long-term effectiveness of a school-based prevention program in Germany. The aim is to determine the long-term effects of the primary prevention program PriMa (Primary prevention of anorexia nervosa in preadolescent girls) on disordered eating and body self-esteem from childhood to young adulthood.Methods: PriMa was conducted and successfully evaluated in a quasi-experimental pre-post design with a control group from 2007 to 2008 consisting of 11-13year old girls (N=1508) from Thuringian schools in Germany. Seven to eight years after the intervention, the same cohort (mean age 19.8years) was invited to complete an online survey. Disordered eating (EAT-26), body self-esteem (FBeK) and BMI were assessed via self-report. The response rate at seven-to-eight-year follow-up was very low (7%). Data of N=100 girls were analyzed.Results: Concerning changes in disordered eating, results revealed no significant long-term effect of PriMa seven to eight years after the intervention. During this time, disordered eating remained stable without a significant increase or decrease. Regarding changes in body self-esteem, group courses differed significantly from each other. The results revealed a significant main effect of group, indicating significant differences in changes of body self-esteem between the intervention and the control group. Following the analysis of these changes of body self-esteem over time, it was found that the intervention group revealed an increase of body self-esteem after program participation and remained stable over time. By contrast, the control group revealed a decrease of body self-esteem over time.Conclusions: Long-term intervention effects of PriMa could be found for body self-esteem but not for disordered eating. The findings suggest that PriMa prevented a decrease of body self-esteem from childhood to young adulthood. For a broader dissemination it is necessary to implement prevention programs consistently in school settings. In order to maintain the prevention effects, it would be interesting to investigate the effects of booster sessions which refresh the programs content on a regular basis. Furthermore, the results of this study revealed the implementation difficulties of primary prevention programs especially concerning the retention of the sample size. [ABSTRACT FROM AUTHOR]

The Child Feeding Questionnaire (CFQ) is a self-report questionnaire for assessing parental attitudes to child weight and parental feeding practices. Previous evaluations of its psychometric properties were conducted primarily with small to medium-sized samples (N < 500) and a small range of children's age. The present study aims to analyze the psychometric properties of the CFQ in a large German community sample and, for the first time, to establish normative data. Within the population-based LIFE Child study, the CFQ was administered to N = 982 mothers of 2- to 13-year-old children. Psychometric analyses on item statistics and internal consistency were conducted. Using structural equation modeling, four empirically-based factorial models of the CFQ were evaluated, and measurement invariance across child age groups and sex was examined. Age-specific norms for the CFQ subscales were computed. Item statistics were highly favorable for the majority of items, but floor and ceiling effects were found for 14 of 31 items. Internal consistency of the CFQ subscales ranged from acceptable to excellent (0.71 ≤ α ≤ 0.91), except for the subscale Perceived Responsibility (α = 0.65). Regarding factorial validity, an eight-factor model with the newly created Reward subscale provided the best fit to the data. This model was factorial invariant across child sex and adjacent age groups. Maternal and child weight status showed large effects on CFQ subscale scores. The analyses established good psychometric properties for the German version of the CFQ and confirmed an eight-factor model. The provided norms allow for the comparison of individual parental feeding practices and change over time. The CFQ's sensitivity to change and longitudinal associations of parental feeding practices and child weight status warrant further research. [ABSTRACT FROM AUTHOR]

Importance: Women with refractory urgency urinary incontinence are treated with sacral neuromodulation and onabotulinumtoxinA with limited comparative information.Objective: To assess whether onabotulinumtoxinA is superior to sacral neuromodulation in controlling refractory episodes of urgency urinary incontinence.Design, Setting, and Participants: Multicenter open-label randomized trial (February 2012-January 2015) at 9 US medical centers involving 381 women with refractory urgency urinary incontinence.Interventions: Cystoscopic intradetrusor injection of 200 U of onabotulinumtoxinA (n = 192) or sacral neuromodulation (n = 189).Main Outcomes and Measures: Primary outcome, change from baseline mean number of daily urgency urinary incontinence episodes over 6 months, was measured with monthly 3-day diaries. Secondary outcomes included change from baseline in urinary symptom scores in the Overactive Bladder Questionnaire Short Form (SF); range, 0-100, higher scores indicating worse symptoms; Overactive Bladder Satisfaction questionnaire; range, 0-100; includes 5 subscales, higher scores indicating better satisfaction; and adverse events.Results: Of the 364 women (mean [SD] age, 63.0 [11.6] years) in the intention-to-treat population, 190 women in the onabotulinumtoxinA group had a greater reduction in 6-month mean number of episodes of urgency incontinence per day than did the 174 in the sacral neuromodulation group (-3.9 vs -3.3 episodes per day; mean difference, 0.63; 95% CI, 0.13 to 1.14; P = .01). Participants treated with onabotulinumtoxinA showed greater improvement in the Overactive Bladder Questionnaire SF for symptom bother (-46.7 vs -38.6; mean difference, 8.1; 95% CI, 3.0 to 13.3; P = .002); treatment satisfaction (67.7 vs 59.8; mean difference, 7.8; 95% CI, 1.6 to 14.1; P = .01) and treatment endorsement (78.1 vs 67.6; mean difference; 10.4, 95% CI, 4.3 to 16.5; P < .001) than treatment with sacral neuromodulation. There were no differences in convenience (67.6 vs 70.2; mean difference, -2.5; 95% CI, -8.1 to 3.0; P = .36), adverse effects (88.4 vs 85.1; mean difference, 3.3; 95% CI, -1.9 to 8.5; P = .22), and treatment preference (92.% vs 89%; risk difference, -3%; 95% CI, -16% to 10%; P = .49). Urinary tract infections were more frequent in the onabotulinumtoxinA group (35% vs 11%; risk difference, -23%; 95% CI, -33% to -13%; P < .001). The need for self-catheterization was 8% and 2% at 1 and 6 months in the onabotulinumtoxinA group. Neuromodulation device revisions and removals occurred in 3%.Conclusions and Relevance: Among women with refractory urgency urinary incontinence, treatment with onabotulinumtoxinA compared with sacral neuromodulation resulted in a small daily improvement in episodes that although statistically significant is of uncertain clinical importance. In addition, it resulted in a higher risk of urinary tract infections and need for transient self-catheterizations. [ABSTRACT FROM AUTHOR]

Introduction: Few hospitals treat patients' tobacco dependence. To be effective, hospital-initiated cessation interventions must provide at least 1 month of supportive contact post-discharge.Study Design: Individually randomized clinical trial. Recruitment commenced July 2011; analyses were conducted October 2014-June 2015.Setting/participants: The study was conducted in two large Midwestern hospitals. Participants included smokers who were aged ≥18 years, planned to stay quit after discharge, and spoke English or Spanish.Intervention: Hospital-based cessation counselors delivered the intervention. For patients randomized to warm handoff, staff immediately called the quitline from the bedside and handed the phone to participants for enrollment and counseling. Participants randomized to fax were referred on the day of hospital discharge.Main Outcome Measures: Outcomes at 6 months included quitline enrollment/adherence, medication use, biochemically verified cessation, and cost effectiveness.Results: Significantly more warm handoff than fax participants enrolled in quitline (99.6% vs 59.6%; relative risk, 1.67; 95% CI=1.65, 1.68). One in four (25.4% warm handoff, 25.3% fax) were verified to be abstinent at 6-month follow-up; this did not differ significantly between groups (relative risk, 1.02; 95% CI=0.82, 1.24). Cessation medication use in the hospital and receipt of a prescription for medication at discharge did not differ between groups; however, significantly more fax participants reported using cessation medication post-discharge (32% vs 25%, p=0.01). The average incremental cost-effectiveness ratio of enrolling participants into warm handoff was $0.14. Hospital-borne costs were significantly lower in warm handoff than in fax ($5.77 vs $9.41, p<0.001).Conclusions: One in four inpatient smokers referred to quitline by either method were abstinent at 6 months post-discharge. Among motivated smokers, fax referral and warm handoff are efficient and comparatively effective ways to link smokers with evidence-based care. For hospitals, warm handoff is a less expensive and more effective method for enrolling smokers in quitline services. [ABSTRACT FROM AUTHOR]

Background: Leadership is a key feature in implementation efforts, which is highlighted in most implementation frameworks. However, in studying leadership and implementation, only few studies rely on established leadership theory, which makes it difficult to draw conclusions regarding what kinds of leadership managers should perform and under what circumstances. In industrial and organizational psychology, transformational leadership and contingent reward have been identified as effective leadership styles for facilitating change processes, and these styles map well onto the behaviors identified in implementation research. However, it has been questioned whether these general leadership styles are sufficient to foster specific results; it has therefore been suggested that the leadership should be specific to the domain of interest, e.g., implementation. To this end, an intervention specifically involving leadership, which we call implementation leadership, is developed and tested in this project. The aim of the intervention is to increase healthcare managers' generic implementation leadership skills, which they can use for any implementation efforts in the future.Methods/design: The intervention is conducted in healthcare in Stockholm County, Sweden, where first- and second-line managers were invited to participate. Two intervention groups are included, including 52 managers. Intervention group 1 consists of individual managers, and group 2 of managers from one division. A control group of 39 managers is additionally included. The intervention consists of five half-day workshops aiming at increasing the managers' implementation leadership, which is the primary outcome of this intervention. The intervention will be evaluated through a mixed-methods approach. A pre- and post-design applying questionnaires at three time points (pre-, directly after the intervention, and 6 months post-intervention) will be used, in addition to process evaluation questionnaires related to each workshop. In addition, interviews will be conducted over time to evaluate the intervention.Discussion: The proposed intervention represents a novel contribution to the implementation literature, being the first to focus on strengthening healthcare managers' generic skills in implementation leadership. [ABSTRACT FROM AUTHOR]

Objective: To analyze auditory nerve recovery function (REC), comparing the results after local anesthesia and sedation with those after general anesthesia.Methods: This was a prospective, cross-sectional and descriptive study in a tertiary referral center hospital. We included all patients (37 ears) who underwent surgery for cochlear implant under either general anesthesia or local anesthesia and sedation during 3 years. REC was measured according to the function of 3 components, 'T0', 'A' and 'tau', and was taken for 3 cochlear electrodes (apical, medial and basal).Results: There were no significant differences in 'tau' and in the current level used, but there were significant differences in the parameters 'T0' apical and 'A' basal.Conclusions: There were no significant differences in REC between the 2 types of anesthesia, except for the parameters 'T0' apical and 'A' basal. [ABSTRACT FROM AUTHOR]

Isolated chondral and osteochondral defects of the knee are challenging clinical entities, particularly in younger patients. Cartilage treatment strategies have previously been characterized as palliation (ie, chondroplasty and debridement), repair (ie, drilling and microfracture), or restoration (ie, autologous chondrocyte implantation, osteochondral autograft, and osteochondral allograft). The osteochondral autograft transplantation procedure allows defects to be filled immediately with mature, hyaline articular cartilage by utilizing either an arthroscopic or a mini-open procedure. Graft harvest and placement can be technically demanding, but results show trends toward greater longevity, durability, and improved outcomes in high-demand patients when compared with alternative techniques. Improved results are shown in younger patients with isolated lesions between 1 and 4 cm. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to quantify the variability in spinal radiosurgery (SRS) planning practices between five international institutions, all member of the Elekta Spine Radiosurgery Research Consortium.Methods: Four institutions provided one representative patient case each consisting of the medical history, CT and MR imaging. A step-wise planning approach was used where, after each planning step a consensus was generated that formed the basis for the next planning step. This allowed independent analysis of all planning steps of CT-MR image registration, GTV definition, CTV definition, PTV definition and SRS treatment planning. In addition, each institution generated one additional SRS plan for each case based on intra-institutional image registration and contouring, independent of consensus results.Results: Averaged over the four cases, image registration variability ranged between translational 1.1 mm and 2.4 mm and rotational 1.1° and 2.0° in all three directions. GTV delineation variability was 1.5 mm in axial and 1.6 mm in longitudinal direction averaged for the four cases. CTV delineation variability was 0.8 mm in axial and 1.2 mm in longitudinal direction. CTV-to-PTV margins ranged between 0 mm and 2 mm according to institutional protocol. Delineation variability was 1 mm in axial directions for the spinal cord. Average PTV coverage for a single fraction18 Gy prescription was 87 ± 5 %; Dmin to the PTV was 7.5 ± 1.8 Gy averaged over all cases and institutions. Average Dmax to the PRV_SC (spinal cord + 1 mm) was 10.5 ± 1.6 Gy and the average Paddick conformity index was 0.69 ± 0.06.Conclusions: Results of this study reflect the variability in current practice of spine radiosurgery in large and highly experienced academic centers. Despite close methodical agreement in the daily workflow, clinically significant variability in all steps of the treatment planning process was demonstrated. This may translate into differences in patient clinical outcome and highlights the need for consensus and established delineation and planning criteria. [ABSTRACT FROM AUTHOR]

Background: At the time of initial diagnosis, only 15-20% of patients with pancreatic cancer present with a resectable disease. Patients with pancreatic cancer face a poor prognosis. Progression-free survival and overall survival rates are very limited, so it is important to develop concepts to improve the quality of life for their remaining lives.Methods/design: The proposed trial is a randomized controlled intervention study. After pancreatic resection, the intervention group (cohort A, n = 30 patients) will take part in an intensified physiotherapy program consisting of endurance and muscle force exercises. The control group (cohort B, n = 30 patients) will take part in standard physiotherapy. Both groups will receive dietary counseling and, if necessary, substitution for endocrine/exocrine pancreatic insufficiency. Quality of life will be evaluated using the Short Form-8 Health Survey and the European Organization for Research and Treatment of Cancer QLQ-C30/QLQ-PAN26 questionnaires.Discussion: The aim of this study is to investigate whether intensive physiotherapy improves the quality of life of patients after pancreatic resection. If the results for the intervention group are positive, a multicenter study should be performed with appropriate statistical power. The progressive postresection program includes a structured follow-up after pancreatic resection. In this study, all patients will undergo abdominal computed tomography for follow-up 6 and 12 months postoperatively.Trial Registration: German Clinical Trials Register DRKS00006786. Date of registration 1 October 2014. [ABSTRACT FROM AUTHOR]

Background: Charcot osteo-neuroarthropathy (CN) of the foot can induce severe instability and deformity. Results of a consecutive clinical multi-centre study with Midfoot Fusion Bolt (MFB, Synthes GmbH, Oberdorf, Switzerland) are reported.Methods: All patients (aged 18 years and older) treated between 2009 and 2013 with surgical reconstruction of the midfoot with MFB for CN were included. Demographics, pre-surgical health status, details of foot pathology, details of surgery, postoperative treatment, treatment failure, and adverse events were registered. The following radiographic angles were measured on pre-op, post-op and last follow-up radiographs: talo-1st metatarsal (TMT) angle dorsoplantar and lateral view, and calcaneo-5th metatarsal angle.Results: Forty-seven patients (48 feet) were included in three centres. In 38 patients (80.1%) diabetes was diagnosed. Wound healing problems occurred in 21% of patients and recurrent ulceration in 13%. Revision surgery for loss of correction was performed in three cases (6%). Union rate at final follow-up was 98%. Major amputation for deep infection was performed in two patients (4%), minor amputation at the foot level in three cases (6%). Failure was more frequent when only one MFB (instead of 2 or 3) was used and no Gastrocnemius lengthening was performed. Radiographic alignment significantly improved pre- versus postoperatively and preoperatively versus follow-up.Conclusions: Realignment and fixation with MFB in severe CN result in adequate correction with minimal loss of correction in the observed clinical course. The non-union rate was lower than previously reported. Stable fixation with MFB is a valuable treatment option for CN with minimal loss of correction and high union rates. The use of a minimum of two bolts is recommended to avoid recurrent deformity. Clinical Trials.gov: NCT01770639. [ABSTRACT FROM AUTHOR]

Objective: To describe the effectiveness of investigating and treating the cause of refractory chest pain in patients with coronary artery disease who are receiving optimal antianginal therapy.Design: Cohort study.Setting: Tertiary referral center.Patients: Between January 1988 and December 1989, 34 patients were identified as having angiographically proven coronary artery disease and atypical chest pain symptoms despite their having received aggressive medical or surgical antianginal therapy, or both.Intervention: Patients with confirmed acid-related symptoms were treated with high-dose histamine-2 (H2) blockers or omeprazole for 8 weeks in an open-label study.Measurements: Esophageal manometry and simultaneous 24-hour pH and Holter studies; global improvement in or disappearance of chest pain.Results: Of the 34 patients, 30 (88%) experienced their identical chest pain symptoms during the study. A total of 164 pain episodes was recorded: 38 (23.2%) correlated with acid reflux; 6 (3.7%) were related to cardiac ischemia; and the remaining 120 (73.2%) had no identifiable cause. Of these 30 patients, 20 (67%) had some of their episodes of chest pain (range, 14% to 100%) secondary to acid reflux. After 8 weeks of vigorous acid suppression, 13 of these 20 patients had marked improvement or resolution of chest pain. Four other patients had ischemia-related episodes of chest pain that responded to more aggressive antianginal therapy. No episodes of acid reflux were clearly followed by ischemic chest pain. One patient had both acid- and ischemic-related episodes of chest pain that were indistinguishable. Overall, 24 of 34 (71%) patients had a definite cause of chest pain identified by combined pH and Holter monitoring.Conclusions: Gastroesophageal reflux disease is a common, treatable cause of chest pain in patients with coronary artery disease who have atypical symptoms and remain symptomatic despite aggressive antianginal therapy. Combined Holter and 24-hour esophageal pH studies are complementary investigations for elucidating the cause of chest pain in these patients. [ABSTRACT FROM AUTHOR]

Purpose: Inhibition of tumor proliferation rate based on bromodeoxyuridine labelling index (BrdUrdLI), S-phase fraction (SPF) and MIB-1 labelling index (MIB-1 LI) as an early rectal cancer response to preoperative radiotherapy (RT).Methods and Materials: A total of 122 patients qualified either for short RT (5 Gy/fraction/5 days) and surgery about 1 week after RT (schedule I) or for short RT and a 4-week interval before surgery (schedule II). Tumor samples were taken twice from each patient: before RT and at the time of surgery. In each sample, the BrdUrdLI, SPF and MIB-1 were calculated. Early tumor response was assessed by a biologist, a pathologist and surgeons.Results: Fifty-six patients were treated according to schedule I and 66 patients according to schedule II. Mean BrdUrdLI, SPF and MIB-1 LI before RT were 8.8%, 21.0% and 53.3%, respectively, and these values did not differ between the two compared groups. After RT, tumors showed statistically significant growth inhibition based on all assessed biological markers. As pretreatment assessed parameter was not predictive for early clinical and pathologic tumor response, prognostic role of the relative value (RV), that is, the ratio of assessed parameter after RT to before RT for each of the assessed markers, was considered. The ratios were calculated separately for fast and slowly proliferating tumors and separately for male and female patients. Fast proliferating tumors were more responsive. Differences with regard to sex were visible only in slowly proliferating tumors. Accelerated cell repopulation (4.8-28%/day) was noticed in female slowly proliferating tumors about 4 weeks after RT. Only for relative MIB-1 LI it was possible to show significant correlation with pathological tumor regression. Lack of such correlation for BrdUrdLI and SPF might reflect accelerated repopulation, particularly in slowly proliferating female tumors.Conclusions: Accelerated repopulation was noticed in slowly proliferating tumors in females about 4 weeks after RT. [ABSTRACT FROM AUTHOR]

Background: The fetal origins hypothesis suggests that an adverse prenatal environment, indexed by low birthweight (LBW), may increase the risk of developing later disease. Recently the hypothesis has been extended to psychological outcomes, especially depression. The aim of this analysis was to test, for the first time in a developing country setting, the association between LBW and psychological symptoms, in Soweto, South Africa.Methods: A sample of 1029 children was drawn from Birth to Twenty, a longitudinal cohort followed from pregnancy to young adulthood. This sample completed the Youth Self Report at age 12 years, a validated psychological measure of behavioural and emotional adjustment. Scores were compared between LBW (<2500 g) and normal birthweight children using multivariate analysis with adjustment for potential birth and life events confounding factors.Results: No associations were found between LBW and total [adjusted odds ratio (OR) 1.09, 95% confidence interval (CI) 0.69-1.74], internalizing (adjusted OR 0.81, 95% CI 0.52-1.28) or externalizing profiles (adjusted OR 0.81, 95% CI 0.49-1.36). The only difference detected was for the internalizing sub-profile of Somatic Complaints (adjusted OR 2.02, 95% CI 1.21-3.38), which on subgroup analysis was greatest among females.Conclusions: We found no convincing evidence of an association between LBW and emotional and behavioural outcomes in 12-year olds in this sample in urban South Africa. To our knowledge, this is the first published assessment of this association in a developing world context. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of steady-state dosing of fluvoxamine, an inhibitor of cytochrome P450 (CYP) 1A2 and CYP2C19, on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 (PDE4) inhibitor and its pharmacodynamically active metabolite roflumilast N-oxide.Methods: In an open-label, non-randomised, one-sequence, two-period, two-treatment crossover study, 14 healthy subjects received a single oral dose of roflumilast 500 microg on study day 1. After a 6-day washout period, repeated doses of fluvoxamine 50 mg once daily were given from days 8 to 21. On day 15, roflumilast 500 microg and fluvoxamine 50 mg were taken concomitantly. Percentage ratios of test/reference (reference: roflumilast alone; test: roflumilast plus steady-state fluvoxamine) of geometric means and their 90% confidence intervals for area under the plasma concentration-time curve, maximum plasma concentration (roflumilast and roflumilast N-oxide) and plasma clearance of roflumilast were calculated.Results: Upon co-administration with steady-state fluvoxamine, the exposure to roflumilast as well as roflumilast N-oxide increased by a factor of 2.6 and 1.5, respectively. Roflumilast plasma clearance decreased by a factor of 2.6, from 9.06 L/h (reference) to 3.53 L/h (test). The combined effect of fluvoxamine co-administration on roflumilast and roflumilast N-oxide exposures resulted in a moderate (i.e. 59%) increase in total PDE4 inhibitory activity.Conclusion: Co-administration of roflumilast and fluvoxamine affects the disposition of roflumilast and its active metabolite roflumilast N-oxide most likely via a potent dual pathway inhibition of CYP1A2 and CYP2C19 by fluvoxamine. The exposure increases observed for roflumilast N-oxide are suggested to be attributable to CYP2C19 co-inhibition by fluvoxamine and thus, are not to be expected to occur when roflumilast is co-administered with more selective CYP1A2 inhibitors. [ABSTRACT FROM AUTHOR]

Background: During the past few years, a variety of energy-based techniques for vessel ligation have been introduced. With the use of a porcine model and different devices for bipolar vessel sealing (BiClamp and LigaSure), we studied the impact of different clamp surface structures on the efficacy and quality of vessel sealing.Methods: Eight Swabian Hall pigs underwent splenectomy, nephrectomy, salpingo-oophorectomy, and small bowel resection with the use of bipolar vessel sealing devices designed for open and laparoscopic surgery. Vessel sealing with clamps with a smooth (nonstructured) surface (BiClamp for open surgery and LigaSure for laparoscopic surgery) was compared to that of clamps with a structured (grooved, wafer-like) surface (BiClamp for laparoscopic surgery and LigaSure for open surgery). Measurements of sealed vessels (2- to 7-mm diameter) included the seal failure rate, instrument sticking, and heat-associated morphological vascular wall alterations.Results: Analysis of seal failures did not reveal significant differences between the different devices for both open [BiClamp, 17.9% (17/95); LigaSure, 15.5% (11/71)] and laparoscopic surgery [BiClamp, 2.8% (1/36); LigaSure, 8.6% (3/35)]. Comparing all data of structured versus smooth clamp surfaces, the seal failure rate was lower using clamps with a structured (11.2%) compared to a smooth surface (15.4%). Instrument sticking and thermal spread were found to be significantly increased after sealing with structured surfaces, regardless of whether devices designed for open (p < 0.05 and p < 0.001, respectively) or laparoscopic surgery (p < 0.001 and p < 0.01, respectively) were used.Conclusion: Clamps with a structured surface seem to be superior to those with a smooth surface for successful bipolar vessel sealing, as indicated by an increase of thermal spread. However, the more pronounced instrument sticking represents an undesired side effect and should encourage the search for more inert materials to further improve the sealing procedure. [ABSTRACT FROM AUTHOR]

Background: Portal venous and mesenteric blood flow are reduced by 40-60% in humans and animals during laparoscopic surgery compared to laparotomy. Little is known about whether these intraabdominal micro- and macrocirculatory changes are associated with alterations in the hepatic energy metabolism.Methods: We operated on male Sprague-Dawley rats, performing either laparoscopy (CO2, 6 mmHg; n = 27) or laparotomy (n = 28), and compared the results with two control groups: intraperitoneal (i.p.) endotoxin administration (n = 28, positive control) and anesthesia only (n = 28, negative control). We investigated the impact of the two different surgical techniques on daily food intake, body weight gain, glycogen content in the liver, levels of blood glucose, and liver function tests (LFTs) on postoperative days 1, 2, 4, and 8. Local (hepatic) and systemic inflammatory responses (interleukin-6 and tumor necrosis factor-alpha) during the postoperative time course were also determined. Data were analyzed using the Kruskal-Wallis test or univariate analysis of variance.Results: Body weight gain, food intake, liver and spleen weights, as well as LFTs [except aspartate aminotransferase (AST)] did not differ among the four groups. The significant increase in the AST level following laparoscopy compared to the anesthesia-only group was found on postoperative days 1 and 2; however, a similar difference was not detected after laparotomy or i.p. endotoxin injection. Laparoscopy showed no alterations in the hepatic glycogen stores compared to anesthesia only, whereas laparotomy and endotoxinemia significantly reduced the hepatic glycogen stores on postoperative days 2 and 4. The systemic postoperative inflammatory response did not differ between laparotomy and laparoscopy, but it was higher in both groups than in anesthesia only. In rats treated with endotoxin, the systemic inflammatory response was even higher than in the two surgical groups. The hepatic inflammatory response did not differ between the four groups.Conclusion: This study shows a significant postoperative decrease in the hepatic glycogen content after laparotomy and i.p. endotoxin injection but not after laparoscopy. Food intake and inflammatory response cannot explain this difference between the two surgical groups, which suggests that alterations in the postsurgical hormonal stress response are the most likely explanation for these findings. [ABSTRACT FROM AUTHOR]

Although smoking increases morbidity and mortality among patients in addictions clinics, few clinics provide routine smoking treatment. To understand staff attitudes toward treatment, we surveyed leaders of outpatient methadone treatment clinics nationwide. Our response rate was 59% (408/697). Most clinic leaders thought they should provide smoking treatment (76%) or refer patients for care (91%); however, fewer than half of these had provided treatment in the month prior to the survey. Leaders said smoking treatment would benefit their clinics, patients and communities, but said barriers-primarily insufficient staff training-prevented routine care. Addressing these barriers could increase smoking treatment in addictions clinics and save lives. [ABSTRACT FROM AUTHOR]

Although arterial bifurcations are frequent sites for obstructive atherosclerotic lesions, the optimal approach to these lesions remains unresolved. Benchtop models of arterial bifurcations were analyzed for flow disturbances known to correlate with vascular disease. These models possess an adaptable geometry capable of simulating the course of arterial disease and the effects of arterial interventions. Chronic in vivo studies evaluated the effect of flow disturbances on the pattern of neointimal hyperplasia. Acute in vivo studies helped propose a mechanism that bridges the early mechanical stimulus and the late tissue effect. Side-branch (SB) dilation adversely affected flow patterns in the main branch (MB) and, as a result, the long-term MB patency of stents implanted in pig arteries. Critical to this effect is chronic MB remodeling that seems to compensate for an occluded SB. Acute leukocyte recruitment was directly influenced by the changes in flow patterns, suggesting a link between flow disturbance on the one hand and leukocyte recruitment and intimal hyperplasia on the other. It is often impossible to simultaneously maximize the total cross-sectional area of both branches and to minimize flow disturbance in the MB. The apparent trade-off between these two clinically desirable goals may explain many of the common failure modes of bifurcation stenting. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of circulating cell adhesion molecules (cCAMs) such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) are found in subjects with vascular diseases and in subjects with several risk factors for atherosclerosis. However, data evaluating cCAMs and biological age are limited.Objective: The purpose of this study was to assess in subjects with different cardiovascular risk profiles the levels of cVCAM-1, cICAM-1, and cE-selectin in dependence on age.Methods: The following groups of subjects were included in the study: 282 apparently healthy subjects of the average population aged 18-89 years, 77 vegetarians who are characterized by a favourable global cardiovascular risk profile, 94 patients with coronary heart disease, and 181 patients with peripheral arterial occlusive disease. Blood samples were obtained after an overnight fast for measurement of cCAMs, lipoproteins, and other clinical/biochemical parameters. The cCAM levels were determined by the use of monoclonal antibody based enzyme-linked immunosorbent assays.Results: Amongst the cCAMs, cVCAM-1 is uniquely elevated in elderly persons with different risks for atherosclerosis, including subjects of the average population, vegetarians with a favourable risk profile, and patients with both coronary heart disease and peripheral arterial occlusive disease. With respect to cICAM-1, an age-dependent elevation was found in the control subjects included in the study. The cE-selectin levels were not correlated with age. Moreover, no associations of cCAMs with serum lipid and lipoprotein levels were found.Conclusion: The results of the present study indicate that cVCAM-1 is an age-dependent parameter independent of cardiovascular risk. [ABSTRACT FROM AUTHOR]

: ObjectivesTo report on our experience in the management of recurrent urethrocutaneous fistulas in order to understand the etiology and outcome of secondary repair of the failed fistula closure.: MethodsWe reviewed the records of 28 patients between 28 months and 19 years of age, who underwent surgery between January 1990 and December 1998. In all patients, urethrocutaneous fistulas developed postoperatively, and the number of operations for their closure ranged from 2 to 15 attempts. In 17 children, a single large fistula was present, and in 11 children, multiple fistulas were present. The causes of failure were believed to be the awkward fistula site in 12 (coronal fistulas), urethral diverticula in 7, and distal urethral strictures in 4. In 5 children, the cause of fistula formation was unclear.: ResultsThe 12 coronal fistulas were converted into coronal hypospadias. Thereafter, the urethral plate was tubularized using a wider strip (Thiersch tube) with (n = 3) or without (n = 9) a relaxing midline incision (Reddy-Snodgrass). Of the 12 repairs, 11 were successful; 1 child developed wound separation, resulting in a megameatus that was subsequently corrected. In 7 children, the cause of the fistula was a urethral diverticulum, which was excised and closed in multiple layers. All were successful (voiding well and no stricture or fistula). In 4 children (1 with multiple fistulas), the distal urethra was stenotic, and repair of the fistula included repair of the stricture using an island onlay flap in 2 and a buccal mucosal graft in 2. All 4 patients achieved a successful outcome. Dartos flaps were used to cover the repair in 18 patients, and tunica vaginalis flaps were used in 6 children.: ConclusionsRecurrent urethral fistula after hypospadias repair may be a manifestation of another problem, such as urethral stricture and/or urethral diverticulum. Intraoperative calibration of the distal urethra and distension of the repaired hypospadias to search for a diverticulum are recommended. Coronal fistulas are best repaired by converting them into coronal hypospadias, followed by tubularization of the urethral plate with or without a dorsal midline relaxing incision. In resurfacing the operative site, the traditional transposition flaps (Y-V and advancement) may be unreliable, because their vascularity may be compromised by previous surgery. The hairless scrotal island or rotation scrotal flap is more reliable for these cases. [Copyright &y& Elsevier]

Objective: To examine the effects of patient age on the growth and transfer of blastocyst-stage embryos.Design: Retrospective clinical study.Setting: Private assisted reproductive technologies center.Patient(s): Three hundred patients between the ages of 18 and 45 undergoing in vitro fertilization.Intervention(s): Bipronucleate oocytes were grown for up to 144 hours and subsequently transferred when at least one embryo attained the expanded blastocyst stage.Main Outcome Measure(s): Oocytes retrieved and fertilized, blastocyst formation rates, implantation rates, and pregnancy rates per retrieval and transfer.Result(s): The rate of cycle cancellation before oocyte retrieval increased significantly with age, and the average number of oocytes per retrieval declined significantly with age. Fertilization rates were unrelated to patient age. The proportion of cycles with expanded blastocysts declined significantly with age. Pregnancy rates per stimulation declined with age, but pregnancy rates per transfer were approximately 50% across the entire age range studied.Conclusion(s): The decline in female fertility with age appears to be the result of reduced numbers of oocytes and the inability of fertilized oocytes to develop to the blastocyst stage. Implantation and pregnancy rates appear to be unaffected by age when blastocysts do form. [ABSTRACT FROM AUTHOR]

The Wilms tumor gene (WT1) encodes a zinc-finger containing transcription factor present in primitive hematopoietic progenitor cells. WT1 is also highly expressed in most cases of acute myeloid leukemia. Moreover, WT1 can interfere with induced differentiation of leukemic cell lines. These data suggest a function of WT1 in the maintenance of a primitive phenotype and a role in leukemogenesis by interfering with differentiation, prompting us to investigate its function in human hematopoietic progenitor cells. By retroviral transfer, human CD34(+) cord blood progenitor cells were transduced with a vector encoding either of two splicing variants of WT1, with or without the KTS insert in the zinc-finger domain, linked to expression of green fluorescent protein (GFP) via an internal ribosomal entry site. When compared to cells transduced with vector containing GFP only, WT1 expressing cells showed strongly reduced colony formation in methylcellulose and inhibited proliferation in suspension culture, with no apparent reduction in viability. Cell cycle phase distribution was not affected by WT1 expression. No signs of impaired differentiation, as judged by the surface markers CD11b, CD14 and glycophorin were detected. In contrast to the results with human CD34(+) progenitor cells, the proliferation of murine bone marrow cells was not significantly affected by WT1, consistent with previous data. We conclude that forced expression of WT1 in highly enriched human hematopoietic progenitor cells leads to strong anti-proliferative effects but is compatible with induced maturation of these cells. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) disease may occur following renal transplantation and has been shown to have health and cost consequences in this setting.Objective: To compare the cost effectiveness of different CMV management strategies for renal transplant patients: prophylaxis with (i) oral valaciclovir or (ii) intravenous ganciclovir; viral testing for CMV followed by (iii) pre-emptive therapy with intravenous ganciclovir or (iv) adjustment of immunosuppression and intensive monitoring; or (v) waiting to treat when CMV disease develops.Methods: A decision-tree model was constructed that included the different management strategies for the donor seropositive/recipient seronegative (D+R-) population. Clinical outcomes for the D+R- population came from clinical trials. Treatment algorithms and costs for CMV syndrome and tissue invasive disease were developed from published literature and UK physician interviews. One- and 2-way sensitivity analyses were performed.Study Perspective: UK National Health Service.Results: Prophylaxis with either oral valaciclovir or intravenous ganciclovir dominated (lower costs and fewer cases of CMV disease) the pre-emptive treatment and wait-and-treat strategies. The cost per patient was from 157 Pounds to 438 Pounds higher with oral valaciclovir prophylaxis compared with intravenous ganciclovir prophylaxis and the incremental cost per case of CMV disease avoided with valaciclovir prophylaxis ranged from 2243 Pounds to 8111 Pounds (1996 values). These results are sensitive to the efficacy of intravenous ganciclovir prophylaxis and CMV management costs.Conclusions: For D+R- renal transplant patients, prophylaxis is the dominant (more effective and less costly) management strategy compared with pre-emptive and wait-and-treat strategies. The cost per patient with oral valaciclovir prophylaxis compared with intravenous ganciclovir prophylaxis is slightly higher in our base case scenario, but may be lower under reasonable alternative assumptions. [ABSTRACT FROM AUTHOR]

ASD is a neurodevelopmental disorder impacting 1 in 44 children and early identification of children with ASD is critical for the intervention. Several screening measures have been developed for early identification, including the Autism Spectrum Rating Scales, 6–18 years Parent Report (ASRS). The ASRS has been understudied, and the current study assessed the validity of the ASRS in a clinical sample of 490 children at a tertiary ASD-specialty clinic. Results indicated that the ASRS demonstrated favorable sensitivity, but poor specificity. True positive screening results were more likely to occur for children with a multiracial background, while they were less likely to occur for children with a high social capital. Overall, though the ASRS has clinical utility as a screening measure, it did not perform effectively to differentiate ASD from Non-ASD clinical disorders. [ABSTRACT FROM AUTHOR]

Objectives: Toddler milk (i.e. a nutrient-fortified milk-based drink marketed for children 12-36 months old) is increasingly being marketed in the USA despite not being recommended for young children. There is evidence of targeted toddler milk marketing to Latinos in the USA. This study aimed to explore toddler milk perceptions and behaviours among Latino and non-Latino parents.Design: An online survey assessed toddler milk perceptions, behaviours and interpretations of nutrition-related claims. Multivariable logistic and linear regression explored socio-demographic correlates of parent reported past purchases and perceived healthfulness.Setting: Online.Participants: National convenience sample of 1078 US parents of children aged 2-12 years (48 % Latino).Results: About half of parents (51 %) had previously purchased toddler milk and few (11 %) perceived toddler milk as unhealthy. Latino parents were more likely to have purchased toddler milk than non-Latino parents (P < 0·001), but there were no differences in perceived product healthfulness (P = 0·47). Compared to parents born in the USA, parents living in the USA 10 years or less were more likely to have purchased toddler milk (P < 0·001) and perceive toddler milk as healthier (P = 0·002). Open-ended interpretations of claims were primarily positive, suggesting 'health halo' effects.Conclusions: Common misperceptions about toddler milk healthfulness suggest stronger labelling regulations are needed. Greater reported purchases by Latino parents and recent immigrants warrant further investigation. [ABSTRACT FROM AUTHOR]

Retrieval practice promotes retention more than restudying (i.e., the testing effect) and is applied to many educational settings. However, little research has investigated means to enhance this effect in educational settings. Theoretical accounts assume retrieval practice to be the most effective whenever retrieval is difficult but successful. Therefore, we developed a novel retrieval practice procedure, which adapts to learners' abilities and can be applied irrespective of learning content. This adaptive procedure aims to make retrieval gradually easier whenever students provide an incorrect answer. In a field experiment, students read book chapters as part of a weekly university course. In three consecutive weeks, they then practiced reading assignments by (a) adaptive testing, (b) non‐adaptive testing and (c) restudy. In Week 4, a surprise criterial test took place. Restudy outperformed both testing conditions, whereas adaptive testing performed equally well as non‐adaptive testing. However, exploratory analyses revealed that with increasing retention intervals, the superiority of restudy disappeared. Furthermore, whenever participants fully read the assignments and retention intervals increased, adaptive testing outperformed non‐adaptive testing. In sum, adaptive retrieval practice did not prove to be generally superior, but retention interval and students' preparation for class might be conditions rendering adaptive retrieval useful in educational settings. Lay Description: What is already known about this topic: Testing is a commonly used technique to assess progress in computer‐assisted learning environmentsStudents often benefit from the testing effect, that is practicing retrieval of information (testing) from memory benefits long‐term retention compared to restudyingCurrently, empirical evidence how to enhance the benefits of this technique in educational contexts is scarce What this paper adds: We propose a new approach to increase the benefit of the testing effect: For each question in retrieval practice the individual ability to retrieve this information from memory is consideredTo do so, cue informativeness of retrieval cues adapts to the individual ability level and thus makes the tests cognitively effortful but solvableThis adaptive approach is put to test in a higher education context and by using multiple‐choice questionsIn sum, adaptive retrieval practice did not prove to be generally superior to non‐adaptive retrieval practice or restudy However, retention interval and students' preparation for class might be conditions rendering adaptive retrieval useful in educational settings Implications for practice and/or policy: Findings can be implemented in educational contexts when multiple‐choice questions are used to enhance learningLearning can be optimized in computer‐assisted learning environments that allow adaptive testingWe advise adaptive retrieval only when students are well prepared for practice and when time between practice and final assessment exceeds two weeks [ABSTRACT FROM AUTHOR]

Objective: To evaluate factors associated with cryopreserved blastocyst transfer birth outcomes, including age, expansion time, cryopreservation protocol, cryodamage, and number of embryos transferred.Design: Retrospective cohort study.Setting: Private infertility practice.Patient(s): Cryopreserved blastocyst transfer patients from January 2003 to April 2012.Intervention(s): None.Main Outcome Measure(s): Birth per transfer and children per embryo.Result(s): Overall live birth per transfer was 32%, with 17% twin births and 0.3% triplets. Live birth per transfer was significantly higher for vitrification compared with slow-freeze (day 5 cryopreservation: 47% vs. 35%; day 6 cryopreservation: 46% vs. 24%), as was live born children per transferred embryo (39% vs. 29% for day 5; 36% vs. 18% for day 6). Birth rates declined only slightly with increasing age at cryopreservation through 37 years, followed by an increasingly rapid decline in success with increasing age thereafter. Live birth rates declined rapidly (49%-18% for vitrification and 37%-10% for slow-freeze) as the percentage of intact cells after cryopreservation decreased from 95%-100% to 70%-79%, with almost no births when the percentage of intact cells was <70%. Increasing numbers of embryos per transfer were associated with significant increase in live birth per transfer but significant decrease in children per transferred embryo. Birth rates were much lower for blastocysts with delayed expansion on day 7 (10% per transfer).Conclusion(s): Birth outcomes from cryopreserved blastocyst transfer are influenced by age, timing of expansion, cryopreservation protocol, visible cryodamage, and the number of embryos transferred. Vitrification substantially improves outcomes versus slow freezing. [ABSTRACT FROM AUTHOR]

Background: Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 y of age in at least three continents. Choroidal neovascularization (CNV) is the process by which abnormal blood vessels develop underneath the retina. CNV develops in 10% of patients with AMD but accounts for up to 90% of the blindness from AMD. Although the precise etiology of CNV in AMD remains unknown, the macrophage component of the inflammatory response, which has been shown to promote tumor growth and support atherosclerotic plaque formation, is thought to stimulate aberrant angiogenesis in blinding eye diseases. The current theory is that macrophage infiltration promotes the development of neovascularization in CNV.Methods and Findings: We examined the role of macrophages in a mouse model of CNV. IL-10(-/-) mice, which have increased inflammation in response to diverse stimuli, have significantly reduced CNV with increased macrophage infiltrates compared to wild type. Prevention of macrophage entry into the eye promoted neovascularization while direct injection of macrophages significantly inhibited CNV. Inhibition by macrophages was mediated by the TNF family death molecule Fas ligand (CD95-ligand).Conclusions: Immune vascular interactions can be highly complex. Normal macrophage function is critical in controlling pathologic neovascularization in the eye. IL-10 regulates macrophage activity in the eye and is an attractive therapeutic target in order to suppress or inhibit CNV in AMD that can otherwise lead to blindness. [ABSTRACT FROM AUTHOR]

Objective: Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress-associated factors in these patients.Methods: The PROSa-study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross-sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ-4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models.Results: Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9-15.0), and those with a disability pension (OR 3.1; 95% CI 1.9-5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2-2.7). Lowest distress was observed in patients 2 to <5 years and ≥5 years after diagnosis (comparison: <6 months) (OR 0.4; 95% CI 0.2-0.6) and (0.3; 95% CI 0.2-0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress (OR 2.0; 95% CI 1.1-3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1-2.8).Conclusion: The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease. [ABSTRACT FROM AUTHOR]

Objective: The prognosis for ovarian cancer patients remains poor. A key to maximizing survival rates is early detection and treatment. This requires an accurate prediction of malignancy. Our study seeks to improve the accuracy of prediction by focusing on early subjective assessment of malignancy. We therefore investigated the assessment of patients themselves in comparison to the assessment of physicians.Methods: One thousand three hundred and thirty patients participated in a prospective and multicenter study in six hospitals in Berlin. Using univariate analysis and multivariate logistic regression models, we measured the accuracy of the early subjective assessment in comparison to the final histological outcome. Moreover, we investigated factors related to the assessment of patients and physicians.Results: The patients' assessment of malignancy is remarkably accurate. With a positive predictive value of 58%, the majority of patients correctly assessed a pelvic mass as malignant. With more information available, physicians achieved only a slightly more accurate prediction of 63%.Conclusions: For the first time, our study considered subjective factors in the diagnostic process of pelvic masses. This paper demonstrates that the patients' personal assessment should be taken seriously as it can provide a significant contribution to earlier diagnosis and thus improved therapy and overall prognosis. [ABSTRACT FROM AUTHOR]

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function. [ABSTRACT FROM AUTHOR]

Objective: To examine cycle outcomes among patients demonstrating an attenuated ovarian response that proceeded to oocyte retrieval to those converted to intrauterine insemination (IUI).Design: Retrospective cohort study.Setting: Large private fertility center.Patient(s): First planned autologous assisted reproductive technology (ART) cycles among women demonstrating a poor ovarian response to hyperstimulation (≤4 follicles≥14 mm, peak E2<1,000 IU/L at hCG administration).Intervention(s): Oocyte retrieval or IUI conversion.Main Outcome Measure(s): Live birth and clinical pregnancy.Result(s): A total of 269 IUI conversions and 167 oocyte retrievals followed a poor ovarian response to gonadotropins among first planned ART cycles. Number of follicles≥14 mm (2.3 vs. 3.5) and peak E2 levels (555 vs. 743 pg/mL) were lower for IUI conversions compared with those proceeding to ART. Peak E2 was similar between groups after adjusting for follicle number (IUI: 611 pg/mL; ART: 652 pg/mL). Stimulation response was similar between treatment groups with equivalent follicle numbers. Undergoing oocyte retrieval was associated with significantly improved pregnancy (odds ratio [OR] 3.6, 95% confidence interval [CI] 1.8-7.4) and live birth outcome (OR 3.5, 95% CI 1.7-8.0) after adjusting for age and follicle number.Conclusion(s): Among women demonstrating a poor ovarian response to gonadotropins, proceeding with planned ART resulted in significantly higher pregnancy rates than converting these cycles to IUI. [ABSTRACT FROM AUTHOR]

Background: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF.Methods: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h (51)Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU ml(-1)).Results: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing+/-s.d., 65.6+/-3.7%, range 57.5-77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC.Conclusion: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities. [ABSTRACT FROM AUTHOR]