Design and development of the DE-SPECT system: a clinical SPECT system for broadband multi-isotope imaging of peripheral vascular disease.

Objective. Peripheral Vascular Disease (PVD) affects more than 230 million people worldwide and is one of the leading causes of disability among people over age 60. Nowadays, PVD remains largely underdiagnosed and undertreated, and requires the development of tailored diagnostic approaches. We present the full design of the Dynamic Extremity SPECT (DE-SPECT) system, the first organ-dedicated SPECT system for lower extremity imaging, based on 1 cm thick Cadmium Zinc Telluride (CZT) spectrometers and a dynamic dual field-of-view (FOV) synthetic compound-eye (SCE) collimator.Approach. The proposed DE-SPECT detection system consists of 48 1 cm thick 3D-position-sensitive CZT spectrometers arranged in a partial ring of 59 cm in diameter in a checkerboard pattern. The detection system is coupled with a compact dynamic SCE collimator that allows the user to select between two different FOVs at any time during an imaging study: a wide-FOV (28 cm diameter) configuration for dual-leg or scout imaging or a high-resolution and high-sensitivity (HR-HS) FOV (16 cm diameter) for single-leg or focused imaging.Main results.The preliminary experimental data show that the CZT spectrometer achieves a 3D intrinsic spatial resolution of <0.75 mm FWHM and an excellent energy resolution over a broad energy range (2.6 keV FWHM at 218, 3.3 keV at 440 keV). From simulations, the wide-FOV configuration offers a 0.034% averaged sensitivity at 140 keV and <8 mm spatial resolution, whereas the HR-HS configuration presents a peak central sensitivity of 0.07% at 140 keV and a ∼5 mm spatial resolution. The dynamic SCE collimator enables the capability to perform joint reconstructions that would ensure an overall improvement in imaging performance.Significance. The DE-SPECT system is a stationary and high-performance SPECT system that offers an excellent spectroscopic performance with a unique computer-controlled dual-FOV imaging capability, and a relatively high sensitivity for multi-tracer and multi-functional SPECT imaging of the extremities.

The human factor: does the operator performing the embryo transfer significantly impact the cycle outcome?

STUDY QUESTION: Is Ongoing Pregnancy Rate (OPR) operator-dependent, and can experience improve embryo transfer efficiency? SUMMARY ANSWER: OPR is influenced by the operators who perform the embryo transfer (ET), and experience does not assure proficiency for everyone. WHAT IS KNOWN ALREADY: ET remains the critical step in assisted reproduction. Although many other factors such as embryo quality and uterine receptivity impact embryo implantation, the proper ET technique is clearly an operator-dependent variable and as such it should be objectively standardized. STUDY DESIGN, SIZE, DURATION: Retrospective comparative analysis including all fresh ETs performed between January 1996 and December 2016 at the Humanitas Fertility Center after IVF-ICSI cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: IVF/ICSI fresh ETs performed by 32 operators, 19 824 cycles in all, were analyzed. All transfers consisting of freehand insertion of a preloaded soft catheter into the uterine cavity under transabdominal ultrasound guidance were considered. Two different statistical analyses were performed. First, a logistic regression model with a random intercept for the operator was used to estimate the heterogeneity of the rate of success among operators, accounting for woman age, FSH, number of oocytes retrieved, fertilization rate, year of the procedure, number and stage of transferred embryos and operator's experience. Second, the relationship between experience and pregnancy rate was estimated separately for each operator by logistic regression, and operator-specific results were combined and compared in a random-effects meta-analysis. In both analyses, the operator's experience at time t was measured in terms of number of embryo transfers performed before t. MAIN RESULTS AND THE ROLE OF CHANCE: The heterogeneity among operators was highly significant (P value <0.001) and explained 44.5% of the total variability. The odds ratio of success of the worst operator in respect to the mean was equal to 0.84. For the best operator, the odds ratio of success was equal to 1.13 in respect to the mean. Based on the meta-analysis of the relationship between operator's experience and success rate, it resulted that, on average, the operators' performance did not improve with additional transfers. LIMITATIONS, REASONS FOR CAUTION: At our center, operators become independent for ET's after performing between 30 and 50 transfers under supervision. It is also possible that other relevant factors, such as embryologists on duty for the ET, have not been included in the present analysis and this may represent a potential bias. Among these, it should be mentioned that the embryologists on duty for the ET were not taken into consideration. WIDER IMPLICATIONS OF THE FINDINGS: Continued performance analysis and the use of a digital simulator could help operators to test their expertise over time and either correct poor performance or avoid doing transfers. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NCT03561129.

Five years (2004-2009) of a restrictive law-regulating ART in Italy significantly reduced delivery rate: analysis of 10,706 cycles.

STUDY QUESTION: Was the delivery rate of ART cycles negatively affected by the enactment of the Law 40/2004 by the Italian Parliament which imposed a long list of restrictions for ART procedures? SUMMARY ANSWER: This large and extensive comparative analysis of ART outcomes prior to and after the introduction of the Law 40 revealed a significant reduction in pregnancy and delivery rates per cycle, independent of age or other clinical variables, once the law went into effect. WHAT IS KNOWN ALREADY: Several studies have been published on the effect of Law 40/2004 on ART outcomes, some authors demonstrating a negative impact of the Law in relation to specific etiologies of infertility, other authors showing opposite conclusions. STUDY DESIGN, SIZE, DURATION: Retrospective clinical study of 3808 patients treated prior to the enactment of the Law, September 1996-March 2004 (Group I) and 6898 treated during the Law, March 2004-May 2009 (Group II). PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 10 706 ART cycles were analysed, 3808 performed before and 6898 after the application of the Law. An intention-to-treat statistical analysis was performed to detect pregnancy and delivery rates (pregnancies ≥ 24 weeks) per started cycle. A P value of <0.05 was considered statistically significant. We analysed different outcomes: differences in fertilization, pregnancy and delivery rate, multiple pregnancies and miscarriage rates between the two time periods. MAIN RESULTS AND THE ROLE OF CHANCE: The delivery rate for started cycle was 20% before and 16.0% after the introduction of the Law representing a 25% reduction (P < 0.001). The multivariate analysis, corrected by female age of >38 years, duration of infertility, basal FSH level and number of retrieved oocytes, showed a 16% lower delivery rate (odds ratio: 0.84; confidence interval: 0.75-0.94). This statistical approach removed the risk that the observed effects were due to chance and confirmed unequivocally that the Law was an independent factor responsible for the reduced likelihood of a successful outcome. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study. A prospective randomized study, with patients treated in the same time period and randomized to restrictions or not, would have minimized potential limitations due to differences in years of treatments. WIDER IMPLICATIONS OF THE FINDINGS: Our findings based on the analysis of such a large number of cycles proved clearly and unequivocally that imposing restrictions on the practice of ART penalized patients. These data represent a relevant clinical contribution for countries still debating the enactment of restrictive limitations of ART.

Italian Constitutional Court modifications of a restrictive assisted reproduction technology law significantly improve pregnancy rate.

BACKGROUND: In May 2009, the Italian Constitutional Court banned most of the limitations of a restrictive law regulating assisted reproduction technology on the grounds that it limited a couple's right to have access to the best possible medical treatment and reduce any possible higher risk of complications. The aim of the study was to compare our results in fresh cycles before and after this change. MATERIALS AND METHODS: We analysed retrospectively 3274 IVF cycles: 2248 before and 1026 after the law was modified. RESULTS: There was no significant difference between the two groups in terms of age, basal FSH levels, years of infertility, the number of previous cycles or the number of oocytes retrieved but the number of oocytes used (2.7 ± 0.6 versus 4.6 ± 1.8; P = <0.001), the number of embryos obtained (2.0 ± 0.9 versus 3.3 ± 1.8; P = <0.001) and transferred (2.2 ± 0.7 versus 2.3 ± 0.7; P = <0.001) were all higher after the removal of the previous restrictions, as was the pregnancy rate per started cycle (23.49% versus 20.42%; P = 0.047). Before modification of the law, the pregnancies were single in 74.11% of the cases (versus 71.43% afterwards), twins in 23.44% (versus 26.89%; P = 0.318) and triplets in 2.46% (versus 1.68%; P = 0.594). CONCLUSIONS: Our preliminary results after the removal of the previous legal restrictions show a higher pregnancy rate per started cycle (3.7% represents a 15% difference) and a positive (albeit non-significant) trend towards a reduction in the number of multiple pregnancies.

Learning to control the program evolution process with cultural algorithms

Traditional software engineering dictates the use of modular and structured programming and top-down stepwise refinement techniques that reduce the amount of variability arising in the development process by establishing standard procedures to be followed while writing software. This focusing leads to reduced variability in the resulting products, due to the use of standardized constructs. Genetic programming (GP) performs heuristic search in the space of programs. Programs produced through the GP paradigm emerge as the result of simulated evolution and are built through a bottom-up process, incrementally augmenting their functionality until a satisfactory level of performance is reached. Can we automatically extract knowledge from the GP programming process that can be useful to focus the search and reduce product variability, thus leading to a more effective use of the available resources? An answer to this question is investigated with the aid of cultural algorithms. A new system, cultural algorithms with genetic programming (CAGP), is presented. The system has two levels. The first is the pool of genetic programs (population level), and the second is a knowledge repository (belief set) that is built during the GP run and is used to guide the search process. The microevolution within the population brings about potentially meaningful characteristics of the programs for the achievement of the given task, such as properties exhibited by the best performers in the population. CAGP extracts these features and represents them as the set of the current beliefs. Beliefs correspond to constraints that all the genetic operators and programs must follow. Interaction between the two levels occurs in one direction through the extraction process and, in the other, through the modulation of an individual's program parameters according to which, and how many, of the constraints it follows. CAGP is applied to solve an instance of the symbolic regression problem, in which a function of one variable needs to be discovered. The results of the experiments show an overall improvement on the average performance of CAGP over GP alone and a significant reduction of the complexity of the produced solution. Moreover, the execution time required by CAGP is comparable with the time required by GP alone.

Cytogenetic abnormalities and microsatellite instability in endometrial adenocarcinoma.

Recently various authors described a new mechanism involved in the genesis of some tumors, which is characterized by a tendency for replication mistakes and by genomic instability of microsatellite repeats. This instability can be revealed through the shift in the electrophoretic mobility of the analyzed fragments, which is due to a different number of repeat units. This phenomenon is widely documented in colorectal tumors of patients affected by hereditary nonpolyposis colorectal carcinoma (HNPCC). We performed a cytogenetic and molecular study of 23 endometrial adenocarcinomas to investigate the presence of genomic instability and to evaluate the possibility of a positive correlation with specific chromosomal changes. The study of genomic instability was performed using 23 microsatellites localized over 8 chromosomes. Genomic instability of microsatellites was observed in 3 cases over all 8 analyzed chromosomes. The tumoral stage of cases with microsatellite instability does not differ significantly from the remaining tumors. As a matter of fact several cases showing no evidence of instability were more advanced (II B, III A) than tumors with instability. In ten cases we observed trisomy of chromosome 10, in some as a sole anomaly. The 3 cases with genomic instability revealed a near-diploid karyotype and all showed the presence of a supernumerary marker derived from chromosome 1 rearrangements. A derivative chromosome 1 was revealed in 4 cases without evidence of microsatellite instability. It should be noted that the presence of many unidentified markers and the small number of tumors with instability do not allow us to give a definitive significance to this observation. Our results indicate that there is not an apparent correlation between microsatellite instability and specific chromosomal abnormalities. Moreover, we did not find any correlation between pathological characteristics of the tumor and genomic instability. Microsatellite instability appears to be a relatively rare event in endometrial carcinoma.

Sonographic endometrial thickness: a useful test to predict atrophy in patients with postmenopausal bleeding. An Italian multicenter study.

Eighteen centers took part in this prospective study into which 930 eligible patients were recruited. The selection criteria for admission were atypical bleeding after at least 6 months of postmenopausal amenorrhea, and absence of hormonal therapies for at least 6 months. The sonographic measurement of the maximum bi-endometrial thickness was made in a longitudinal plane. Sonographic measurements were always performed within 3 days prior to histological evaluation. In these patients the mean number of years from menopause (25-75th centile) was 6 (range 2-16). The prevalence of endometrial carcinoma was 11.5% and the prevalence of atrophy was 49.2%. The area under the receiver operator characteristic curves generated by sonographic thickness measurements reached the level of 85%, both for cancer and atrophy. The likelihood ratio for cancer, yielded by an endometrial thickness of < or = 4.0 mm, was 0.05, and for atrophy it was 7.1. This cut-off of > 4.0 mm yielded a sensitivity for the detection of cancer of 98% and a negative predictive value of 99%. The overall sensitivity and positive predictive value for atrophy achieved by this cut-off were 57.2% and 87.3%, respectively. A multivariate logistic model showed that age and body mass index were independent variables associated with a significantly higher risk of endometrial cancer. The post-test probabilities for cancer and atrophy were recalculated on the basis of the integration of age, body mass index and endometrial thickness. The estimated reduction of invasive procedures on the basis of this integration was 31%. Transvaginal sonographic measurement of endometrial thickness, integrated with individual risk factors, can help in the management of postmenopausal patients with atypical bleeding, with regard to either the need for histological evaluation in high risk cases, or the choice of possible expectant management. We have shown that an endometrial thickness of < or = 4.0 mm safely predicts endometrial atrophy and justifies expectant management when the patient understands the need for proper follow up. This could be achieved with a reduction in the use of invasive procedures without unwanted delay in cancer diagnosis.

Endocervical detection of CIN. Cytobrush versus cotton.

Correct methods of sampling are essential for obtaining adequate smears for cytological diagnosis of cervicovaginal abnormalities. In this paper we report on 3 methods of sampling, Ayre spatula, cotton swab and cytobrush on 89 patients who underwent repeat smear and colposcopic examinations because of abnormal screening smears. The cytobrush device was better than Ayre spatula or cotton in collecting both endocervical and neoplastic cells. However, the combination of spatula and cotton was almost the same as spatula and cytobrush in recovering neoplastic cells. Therefore the rate of cervical intraepithelial neoplasia (CIN) diagnosis is more influenced by an adequate sampling of the endocervix than by the type of endocervical device.

[The diathermy loop and diathermic coagulation in the ambulatory treatment of intraepithelial cervical neoplasia]. / Ansa diatermica e DTC nella terapia ambulatoriale della CIN.

Ninety-four patients suffering from CIN, of which 28 CIN1, 37 CIN2 and 29 CIN3 were treated with Cartier diathermal loop (57 cases 60.6%) or DTC (37 cases 29.4%). GSC proved visible in all cases except for a group of 16 patients in whom the combined use of ethinylestradiol and microendocervicoscopy showed GSC localisation within 5 mm of the OUE. The latter cases were all treated with Cartier diathermal loop. Results two months after the intervention showed correction of the colposcopic and cytological examination in 85 cases (94.4%) and bioptic cure in 91 cases (96.8%). In two cases, histological examination showed CIN1 and in one case CIN2.

Comparison of repeat smear, colposcopy, and colposcopically directed biopsy in the evaluation of the mildly abnormal smear.

Repeat smear, colposcopy, and colposcopically directed biopsy were performed in 161 patients referred to our department because of a Pap smear showing mild dysplasia (CIN 1). Colposcopically directed biopsies revealed the presence of CIN of different grades in 61 cases (37.5%). In 33 (20.4%) the CIN grade found at biopsy was higher than 1. Repeat smear confirmed the presence of CIN 1 in 67 women (47.2%). In this group of patients colposcopically directed biopsies showed a CIN grade greater than 1 in 12 cases (17.9%). The repeat smear was negative in 59 patients (41.5%). In this group, biopsy showed varying grades of neoplasia in 12 cases. Colposcopic examination indicated no dysplasia but the presence of minor cervical abnormalities in 76 women (47.2%): at biopsy a CIN grade higher than 1 was found in 9 cases (11.5%). These data suggest that the mildly atypical smear identifies a group of patients at increased risk of CIN but gives little or no information on the disease severity. Repeat smear and colposcopic examination alone appear inadequate to demonstrate the severity of the cervical lesion. Due to the high proportion of CIN 2 and 3 in patients with a mildly abnormal smear, the systematic biopsy of any colposcopically abnormal area seems essential to proper management of the patient.