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Le linee guida 2019 delle Società europee di cardiologia e dell'aterosclerosi sulla gestione delle dislipidemie hanno aumentato l'aggressività diagnostico-terapeutica e non distinguono prevenzione primaria e secondaria, con parziale eccezione per gli ultra75enni. Raccomandano nuovi target di cLDL: per pazienti a rischio molto alto si raccomanda una riduzione a55 mg/dl e=50% rispetto al basale; per pazienti a rischio alto una riduzione a70 mg/dl e=50% del basale; per pazienti a rischio moderato una riduzione a100 mg/dl; per pazienti a rischio basso una riduzione a116 mg/dl. In base alle carte SCORE e ai dati di mortalità cardiovascolare in Italia, quasi tutti i maschi dai 70 anni e le donne dai 70-75 anni risulterebbero ad alto rischio per solo effetto dell'età. Anche quasi tutti i 60enni sarebbero a rischio moderato, con target di cLDL100, e spesso necessità di aggiungere costosi ipolipemizzanti per chi già assume statine. Le prove supportano ben poco tale aggressività. Infatti, anche negli studi randomizzati controllati (RCT) i benefici su esiti cardiovascolari non fatali subiscono esagerazioni sistematiche, quello meno distorto e di maggior interesse per gli assistiti è la mortalità totale. Questa, con terapie ipocolesterolemizzanti più intensive, non si è ridotta nelle metanalisi di RCT con pazienti con cLDL tra 80 e100 mg/dl al basale; con inibitori di PCSK9, pazienti con questi valori mostrano persino tendenza all'aumento della mortalità totale. Dunque, abbassare il cLDL a80 mg/dl può non giovare neppure ad anziani coronaropatici. A oggi, ciò vale ancora di più per anziani nella popolazione generale, in cui una revisione sistematica di studi di coorte ha mostrato relazioni nulle o più spesso inverse tra cLDL e mortalità. Le nuove linee guida europee forzano le prove disponibili, trascurano il principio di precauzione e non possono esser base per un equo consenso informato.

Oocyte donations (OD) represent 4.5% of all in vitro fertilization (IVF) cycles. While OD pregnancies face increased risks of obstetrical complications, especially pregnancy-induced hypertension and pre-eclampsia (PE), little is known about the physiology and the physiopathology of placentation. We performed a prospective case-control study to analyze uterine artery Doppler pulsatility index (UtA-PI) and serum maternal 17&beta, ‐estradiol (17&beta, E) at 11+0 to13+6 weeks&rsquo, gestation in singleton pregnancies with different modes of conception. Study groups were: 55 OD, 48 IVF with autologous oocytes from fresh cycles (Autologous‐Fresh IVF), 10 IVF with autologous oocytes from frozen cycles (Autologous‐Frozen IVF) and 122 spontaneously conceived pregnancies (SC). The mean UtA-PI and serum maternal 17&beta, E at 11 to 13+6 weeks were significantly lower in OD as compared to SC and autologous IVF, either from fresh or frozen cycles. Oocyte donation presents lower UtA-PI and lower serum 17&beta, E in the first trimester of pregnancy. The etiology of these particularr differences is likely multifactorial and deserves further investigation.

Pregnancy hormonal milieu represents a crucial determinant of fetal outcome. We aim to determine 17β-estradiol (E2) and progesterone (PGT) concentrations in spontaneous pregnancies during the first trimester. In addition, we aim to determine E2 concentrations as a function of gestational age (GA) and PGT. Between November 2015 and March 2017, 104 healthy women of at least 18 years undergoing medical consultation for voluntary interruption of pregnancy were enrolled in an observational study at University Hospital ASST Fatebenefratelli Sacco, Milan, Italy. Only singleton pregnancies between 5+0 and 13+6 weeks of gestation were eligible. First trimester ultrasound scans were performed for dating and one fasting venous blood sample was collected for E2 and PGT determinations. E2 and PGT concentrations steadily increased according to GA. The correlation between E2 on a logarithmic scale and PGT concentrations was expressed by the following equation, explaining 12.6% of E2 variance: logE2 = 2.57 + 0.1 × PGT, (r = 0.34, p

HIV-1-affected couples’ desire to have children and free sexual intercourses with the use of pre-exposure prophylaxis for the negative partner has emerged as an alternative option to assisted reproduction in aviremic patients under highly active antiretroviral therapy (HAART). It is already known that sperm quality may be impaired in HIV-infected men. The underlying physiopathological mechanism is still debated. The aim of this study was to evaluate the effects of HAART on sperm DNA fragmentation, comparing HIV-1-infected patients taking HAART versus naïve HIV-1-infected patients. This is a prospective case-control study. Sperm nuclear DNA fragmentation rate was evaluated by the sperm chromatin dispersion test in 77 HIV-infected men: 53 HIV-1 patients receiving HAART (Group 1) versus 24 naïve HIV-1 patients not receiving HAART (Group 2). Complete semen analysis was performed according to WHO 2010 recommendations. Patients with HBV infection or HCV infection coinfections and genital tract infections wre excluded. All the patients did not present any clinical signs of their disease. Seminal parameters were examined in the two groups, showing no significant differences. Increased sperm DNA fragmentation > 30% was demonstrated in 67.9% of patients in Group 1 and 37.5% of patients in Group 2, respectively ( p = .02). A positive but nonsignificant trend toward increased fragmentation was reported with advancing patients’ age. In conclusion, sperm nuclear fragmentation rate is increased in HIV-1-infected patients taking HAART compared to HIV-1 patients not receiving HAART.

Background & Aims There is uncertainty regarding the optimal duration of treatment with azathioprine (AZA) in ulcerative colitis (UC) and Crohn’s disease (CD). We analyzed the clinical course and predictors of relapse after AZA withdrawal in patients in sustained deep remission. Methods A prospective study was performed on patients who stopped their treatment with AZA while being in steroid-free, extended deep remission (normal clinical, endoscopic, and histologic indexes, C-reactive protein, and fecal calprotectin [FC]). Standard biochemical tests and FC were measured at 3 and 6 months, then every 6 months. Bowel ultrasounds and ileocolonoscopy were performed every 6 and 12 months, respectively. Multivariate analysis for predictors of relapse was performed using a Cox proportional hazards model and hazard ratios were calculated. Spearman nonparametric correlation test was also used. The accuracy of significant predictors was calculated. Results Fifty-seven patients with inflammatory bowel disease stopped AZA after median 7 years (range, 5–19) and were followed up for median 50 months (range, 25–85). Twenty-six patients (18/31 UC, 8/26 CD; P = .003) relapsed, within a median 15 months (range, 2–37). FC was the only variable significantly correlated with later relapse of both diseases (UC: hazard ratio, 3.3; 95% confidence interval, 1.2–10; CD: hazard ratio, 4.5; 95% confidence interval, 1.4–12.5). The sensitivity, specificity, and positive and negative predictive values of FC were 50%, 100%, 100%, and 59% in UC and 50%, 94%, 80%, and 81% in CD. Conclusions More than half patients with UC and one-third of patients with CD relapse after AZA withdrawal despite previous deep remission. FC positivity is associated with high risk of relapse, allowing early correction of the therapeutic strategy.

Background and study aims Virtual chromoendoscopy with Fuji Intelligent Color Enhancement (FICE) has never been studied in prospective trials of endoscopic surveillance for ulcerative colitis (UC). We compared FICE and white light endoscopy (WLE) in differentiation of visible lesions in UC. Patients and methods In a prospective parallel study, we compared consecutive outpatients with UC submitted to surveillance colonoscopy with FICE or WLE. At least one visible polypoid or non-polypoid lesion for each patient was required. Random biopsies from normal mucosa, targeted biopsies or removal of suspected neoplastic lesions and targeted biopsies of unsuspected lesions were performed. In the FICE arm, neoplasia was suspected according to a modified Kudo classification (FICE-KUDO/inflammatory bowel disease [IBD]). Sensitivity (SE), specificity (SP), positive and negative likelihood ratios (LR) and negative predictive value (NPV) were analyzed. Results One hundred patients were submitted to FICE (n = 46) or WLE (n = 54). Twenty-two patients (11 in WLE, 11 in FICE) had a least one neoplastic lesion. No neoplasia was found in random biopsies. Among 275 lesions, 17 of 136 by FICE and 27 of 139 by WLE were suspected neoplasia, but 28 (14 in each arm) were true neoplastic lesions. The accuracy of FICE-KUDO/IBD vs WLE (per lesion) was: SE 93 % vs 64 % (P = 0.065), SP 97 % vs 86 % (P = 0.002), positive-LR 28.3 vs 4.5 (P = 0.001), negative-LR 0.07 vs 0.42 (P = 0.092), NPV 99 % vs 96 % (P = 0.083). FICE-KUDO/IBD detected more non-polypoid lesions than WLE (P = 0.016). Conclusions Targeted biopsies of polypoid and non-polypoid lesions, using the modified Kudo classification with FICE are more accurate than WLE in UC surveillance.

The purpose of this study was to compare the performance of gadobenate dimeglumine–enhanced MRI and gadoxetic acid–enhanced MRI in the hepatobiliary phase (HBP) in cirrhotic patients with different degrees of liver dysfunction. In this retrospective cross-sectional study, we analyzed the unenhanced phase and the HBP of 131 gadobenate dimeglumine–enhanced MRI examinations (gadobenate dimeglumine group) and 127 gadoxetic acid–enhanced MRI examinations (gadoxetic acid group) performed in 249 cirrhotic patients (181 men and 68 women; mean age, 64.8 years) from August 2011 to April 2017. For each MRI, the contrast enhancement index of the liver parenchyma was calculated and correlated to the Model For End-Stage Liver Disease (MELD) score (multiple linear regression analysis). A qualitative analysis of the adequacy of the HBP, adjusted for the MELD score (logistic regression analysis), was performed. The contrast enhancement index was inversely related (r = − 0.013) with MELD score in both gadoxetic acid and gadobenate dimeglumine group. At the same MELD score, the contrast enhancement index in the gadoxetic acid group was increased by a factor of 0.23 compared to the gadobenate dimeglumine group (p 10, if the hepatobiliary phase is clinically indicated. • In patients with high MELD score (> 15), the administration of the hepatobiliary agent could be useless; even though, if it is clinically indicated, we recommend to use gadoxetic acid given the higher probability of obtaining clinically relevant information.

Background In ulcerative colitis (UC), the diagnostic accuracy of virtual chromoendoscopy with non-magnified Narrow Band Imaging (NBI) was disappointing in the detection and differential diagnosis of neoplastic lesions in most trials performed according to unclear diagnostic criteria. The Kudo and NICE criteria are validated in the general population, but controversial in UC. Recently, a modified Kudo classification specific for the inflammatory setting of UC has been developed using virtual chromoendoscopy with Fuji Intelligence Color Enhancement (FICE). The performance of NBI according to these three classifications for optical diagnosis of neoplastic and non-neoplastic lesions in UC has never been analysed. Methods All visible, polypoid and non-polypoid, lesions found during consecutive surveillance colonoscopies with non-magnified NBI (Exera II CV180) for long-standing UC (>8 years from disease onset) were included in a prospective, single-centre study, and classified as suspected or not suspected for neoplasia according to the NICE, Kudo and Kudo-modified criteria. The primary endpoint was to compare the sensitivity (SE), specificity (SP), negative (-LR) and positive (+LR) likelihood ratios of the three classifications, using histology as the reference standard. Results 394 lesions (mean size 6 mm, range 2–40 mm; type 0-Is 83%) from 84 patients (males 62%; mean age 57 y, range 30–79 y; mean disease duration 20 y) were found: 21 (5%) were neoplastic, 49 (12%) hyperplastic and 324 (82%) inflammatory lesions. The diagnostic accuracy of the NICE, Kudo and modified-Kudo classifications were, respectively: SE 76% vs. 71% vs. 86% (p = not significant); SP 55% vs. 69% vs. 79% (p < 0.05 Kudo-mod vs. both Kudo and NICE); +LR 1.69 vs. 2.34 vs. 4.15 (p < 0.05 Kudo-mod vs. both Kudo and NICE); -LR 0.43 vs. 0.41 vs. 0.18 (p = not significant). Conclusion The diagnostic accuracy of NBI for the differentiation of neoplastic and non-neoplastic lesions in UC is low if used with the conventional classifications validated in the general population, but it is significantly better with the modified Kudo classification specific for UC. The role of NBI in UC surveillance for neoplasia should be re-evaluated according to more accurate diagnostic criteria.

Goals The aim of this study was to analyze the performance of Fuji Intelligent Color Enhancement (FICE) using the classification of Kudo in the differentiation of neoplastic and non-neoplastic raised lesions in ulcerative colitis (UC). Background The Kudo classification of mucosal pit patterns is an aid for the differential diagnosis of colorectal polyps in the general population, but no systematic studies are available for all forms of raised lesions in UC. Study All raised, polypoid and nonpolypoid, lesions found during consecutive surveillance colonoscopies with FICE for long-standing UC were included. In the primary prospective analysis, the Kudo classification was used to predict the histology by FICE. In a post hoc analysis, further endoscopic markers were also explored. Results Two hundred and five lesions (mean size, 8 mm; range, 2 to 30 mm) from 59 patients (mean age, 56 y; range, 21 to 79 y) were analyzed. Twenty-three neoplastic (11%), 18 hyperplastic (9%), and 164 inflammatory (80%) lesions were found. Thirty-one lesions (15%), none of which were neoplastic, were unclassifiable according to Kudo. After logistic regression, a strong negative association resulted between endoscopic activity and neoplasia, whereas the presence of a fibrin cap was significantly associated with endoscopic activity. Using FICE, the sensitivity, specificity, and positive and negative likelihood ratios of the Kudo classification were 91%, 76%, 3.8, and 0.12, respectively. The corresponding values by adding the fibrin cap as a marker of inflammation were 91%, 93%, 13, and 0.10, respectively. Conclusions FICE can help to predict the histology of raised lesions in UC. A new classification of pit patterns, based on inflammatory markers, should be developed in the setting of UC to improve the diagnostic performance.

The optimal emergency department (ED) evaluation of syncope is uncertain. Research reports from multiple countries suggest extensive practice variation, high costs, and questionable benefit associated with current approaches.1–5 Moreover, only a few of the recommendations from international syncope guidelines deal with ED management.6–8 For example, the European Society of Cardiology guidelines, which are the most inclusive syncope guidelines, do not address the ED management. This could be due to limited evidence on how to stratify the risk and decide on disposition of these patients in the ED.1,9 We organized a multi-specialty workshop of North American and European syncope experts on 26–27 September 2013 in Gargnano, Italy, with the aim of obtaining a modified Delphi consensus on the best way to manage ED syncope patients. As already described,10 we followed a four-step conceptual model for the ED decision-making in syncope: (i) Is it syncope? (ii) Is there a serious underlying condition identified in the ED? (iii) If the cause is uncertain, what is the risk of a serious outcome? (iv) For a given risk profile, how can these patients be best managed in the ED and what evaluation and restrictions are required? ( Figure 1 ) . Figure 1 Conceptual model: ED management of syncope. Expert recruitment and consensus development have been described previously.10 Details can be found in Supplementary material online, Appendix S1 . The full list of questions and answers to the first and second survey rounds as well as the degree of agreement on each item is reported in Supplementary material online, Appendix S2 . According to the ESC guidelines, syncope is defined as a …

This study investigates the hypothesis that placenta works differently in oocyte donation (OD) compared to spontaneous pregnancies. To verify this hypothesis we examine the first trimester maternal serum levels of free β-hCG and pregnancy-associated plasma protein-A (PAPP-A). Then we evaluated for potential differences of Down syndrome screening between OD pregnancies, in vitro fertilization/intracytoplasmic sperm injection pregnancies with autologous oocytes (IVF/ICSI) and spontaneous pregnancies.We analyze 13624 spontaneously conceived pregnancies (Controls), 171 oocyte donation pregnancies (OD IVF/ICSI) and 76 IVF pregnancies with autologous oocytes (Autologous IVF/ICSI). Furthermore, we collect a cohort of 802 spontaneously conceived age-matched pregnancies, in order to evaluate how older uteri contribute to explain the changes in markers concentrations (Age-matched controls We compare the multiples of the median (MoM) of free β-hCG and PAPP-A and nuchal translucency.Free β-hCG levels are significantly higher both in OD IVF/ICSI pregnancies (1.44 ± 1.06 MoM) and Autologous IVF/ICSI (1.48 ± 1.02 MoM) compared to Controls (1.15 ± 0.84 MoM; p0.05) and Age-matched Controls (1.18 ± 0.98 MoM; p0.05). PAPP-A levels do not significantly differ among the four groups. Significantly lower nuchal translucency is detected in Controls (1.41 ± 0.36 mm) compared to OD IVF/ICSI (1.46 ± 0.44 mm; p0.05), in Autologous IVF/ICSI (1.51 ± 0.34 mm; p0.05) and Age-matched Controls (1.44 ± 0.42 mm; p0.05).Oocyte donation pregnancies (OD IVF/ICSI) are significantly related to altered maternal serum placenta marker levels. These alterations might be due to the IVF technique.

Background People with abdominal aortic aneurysm who receive endovascular aneurysm repair (EVAR) need lifetime surveillance to detect potential endoleaks. Endoleak is defined as persistent blood flow within the aneurysm sac following EVAR. Computed tomography (CT) angiography is considered the reference standard for endoleak surveillance. Colour duplex ultrasound (CDUS) and contrast-enhanced CDUS (CE-CDUS) are less invasive but considered less accurate than CT. Objectives To determine the diagnostic accuracy of colour duplex ultrasound (CDUS) and contrast-enhanced-colour duplex ultrasound (CE-CDUS) in terms of sensitivity and specificity for endoleak detection after endoluminal abdominal aortic aneurysm repair (EVAR). Search methods We searched MEDLINE, Embase, LILACS, ISI Conference Proceedings, Zetoc, and trial registries in June 2016 without language restrictions and without use of filters to maximize sensitivity. Selection criteria Any cross-sectional diagnostic study evaluating participants who received EVAR by both ultrasound (with or without contrast) and CT scan assessed at regular intervals. Data collection and analysis Two pairs of review authors independently extracted data and assessed quality of included studies using the QUADAS 1 tool. A third review author resolved discrepancies. The unit of analysis was number of participants for the primary analysis and number of scans performed for the secondary analysis. We carried out a meta-analysis to estimate sensitivity and specificity of CDUS or CE-CDUS using a bivariate model. We analysed each index test separately. As potential sources of heterogeneity, we explored year of publication, characteristics of included participants (age and gender), direction of the study (retrospective, prospective), country of origin, number of CDUS operators, and ultrasound manufacturer. Main results We identified 42 primary studies with 4220 participants. Twenty studies provided accuracy data based on the number of individual participants (seven of which provided data with and without the use of contrast). Sixteen of these studies evaluated the accuracy of CDUS. These studies were generally of moderate to low quality: only three studies fulfilled all the QUADAS items; in six (40%) of the studies, the delay between the tests was unclear or longer than four weeks; in eight (50%), the blinding of either the index test or the reference standard was not clearly reported or was not performed; and in two studies (12%), the interpretation of the reference standard was not clearly reported. Eleven studies evaluated the accuracy of CE-CDUS. These studies were of better quality than the CDUS studies: five (45%) studies fulfilled all the QUADAS items; four (36%) did not report clearly the blinding interpretation of the reference standard; and two (18%) did not clearly report the delay between the two tests. Based on the bivariate model, the summary estimates for CDUS were 0.82 (95% confidence interval (CI) 0.66 to 0.91) for sensitivity and 0.93 (95% CI 0.87 to 0.96) for specificity whereas for CE-CDUS the estimates were 0.94 (95% CI 0.85 to 0.98) for sensitivity and 0.95 (95% CI 0.90 to 0.98) for specificity. Regression analysis showed that CE-CDUS was superior to CDUS in terms of sensitivity (LR Chi2 = 5.08, 1 degree of freedom (df); P = 0.0242 for model improvement). Seven studies provided estimates before and after administration of contrast. Sensitivity before contrast was 0.67 (95% CI 0.47 to 0.83) and after contrast was 0.97 (95% CI 0.92 to 0.99). The improvement in sensitivity with of contrast use was statistically significant (LR Chi2 = 13.47, 1 df; P = 0.0002 for model improvement). Regression testing showed evidence of statistically significant effect bias related to year of publication and study quality within individual participants based CDUS studies. Sensitivity estimates were higher in the studies published before 2006 than the estimates obtained from studies published in 2006 or later (P < 0.001); and studies judged as low/unclear quality provided higher estimates in sensitivity. When regression testing was applied to the individual based CE-CDUS studies, none of the items, namely direction of the study design, quality, and age, were identified as a source of heterogeneity. Twenty-two studies provided accuracy data based on number of scans performed (of which four provided data with and without the use of contrast). Analysis of the studies that provided scan based data showed similar results. Summary estimates for CDUS (18 studies) showed 0.72 (95% CI 0.55 to 0.85) for sensitivity and 0.95 (95% CI 0.90 to 0.96) for specificity whereas summary estimates for CE-CDUS (eight studies) were 0.91 (95% CI 0.68 to 0.98) for sensitivity and 0.89 (95% CI 0.71 to 0.96) for specificity. Authors' conclusions This review demonstrates that both ultrasound modalities (with or without contrast) showed high specificity. For ruling in endoleaks, CE-CDUS appears superior to CDUS. In an endoleak surveillance programme CE-CDUS can be introduced as a routine diagnostic modality followed by CT scan only when the ultrasound is positive to establish the type of endoleak and the subsequent therapeutic management.

Objective To evaluate accuracy and cost of non-invasive diagnostic strategies including magnetic resonance imaging, intestinal ultrasonography, ileocolonoscopy and video-capsule endoscopy in suspected Crohn's disease. Methods A decision-analytic model was used to assess the costs in low (25%), intermediate (50%) or high (75%) pre-test probability of Crohn's disease. Based on the published accuracy of diagnostic modalities and Bayes' rule, we calculated post-test probability of Crohn's disease using different strategies, starting from ileocolonoscopy, ultrasonography or magnetic resonance. Each strategy was considered successful when post-test probability was > 95% or Results With low pre-test probability, only ileocolonoscopy as the first investigation could exclude or confirm Crohn's disease while a normal ultrasonography may exclude Crohn's disease. With high pre-test probability, ileocolonoscopy or ultrasonography as the first test may confirm Crohn's disease, but at least 3 negative tests are required to exclude Crohn's disease. The cost to diagnose one patient was cheapest utilising an ultrasonography-based strategy both in low (ultrasonography €1076; ileocolonoscopy €2005; magnetic resonance €4515) and high pre-test probability of Crohn's disease (ultrasonography €321; ileocolonoscopy €712; magnetic resonance €1412). Conclusion The accuracy and cost of these strategies depend on pre-test probability of Crohn's disease and vary according to the first test used. Ileocolonoscopy plus ultrasonography is the most accurate and less expensive initial diagnostic strategy.

A new meningococcal serogroup B vaccine (4 CMenB) has recently been licensed. This study assessed the acceptability of 4 CMenB vaccine among parents and healthcare workers (HCWs). From May to July 2013 in Milan, Italy, self-administered questionnaires were distributed to 2050 parents of infants presenting at immunization clinics for the mandatory hexavalent vaccination and submitted to 350 HCWs involved in immunization practices. 1842 parents (89.1%) responded to the survey; 64.4% of parents wanted their child to receive the 4 CMenB vaccine and 5.1% would not vaccinate their children. Multivariate analysis showed that recognition of the severity of meningitis [a life threatening vs a mild or unthreatening disease (Odds ratio (OR): 2.3; confidence interval (CI): 1.4-3.6], awareness of vaccination as a beneficial preventive measure (very beneficial vs not beneficial OR = 6.4; CI 3.0-13.7) and knowledge of the Meningococcal C vaccine (OR = 1.4; CI 1.1-1.8) were strongly associated to willingness to receive 4 CMenB vaccine. On the contrary, level of education was associated with refusal of immunization (university vs education level lower than middle school OR = 0.68; CI 0.47-0.97). Among the parents who were willing to immunize their children, 66.9% would agree with three injections to be administered during the same visit. A total of 291 HCWs (83.1%) agreed to participate in the survey; 73% considered 4 CMenB vaccine a priority in infants' immunization schedule; 26.8% of HCWs suggested the concomitant administration with routine infant immunization. Parental and HCWs acceptability of 4 CMenB vaccine was high. Increasing knowledge about meningitis and vaccine prevention might further increase the acceptability of this vaccine.

The diagnostic research process can be divided into five phases, designed to establish the clinical utility of a new diagnostic test—the index test. The aim of the present review is to illustrate the study designs that are appropriate for each diagnostic phase, using clinical examples regarding liver fibrosis diagnosed with transient elastography, when possible. Phase 0 is the preclinical pilot phase during which the validity, reliability, and reproducibility of the index test are assessed in healthy and diseased people. Phase I is designed to describe the distribution of the index test results in healthy people and its normal values. Phase IIA comprises studies designed to estimate the accuracy (sensitivity and specificity) of the index test in discriminating between diseased and nondiseased people in a clinically relevant population. Phase IIB studies allow the comparison of the accuracy of different index tests; Phase IIC studies aim to evaluate the possible harms of incorporating the index test in a diagnostic-therapeutic strategy. In phase III, diagnostic test-therapeutic randomized clinical trials aim to assess the benefits and harms of the new diagnostic-therapeutic strategy versus the present strategy. Phase IV comprises large surveillance cohort studies that aim to assess the effectiveness of the new diagnostic-therapeutic strategy in clinical practice. Conclusion: As common in clinical research, giving excessive weight to the results of single studies and trials is likely to divert from the totality of evidence obtained through the systematic reviews of these studies, conducted with rigorous methodology and statistical methods. (Hepatology 2014;60:408-418)

Following the "back to sleep" recommendations, a striking rise in deformational plagiocephaly (DP) occurred. However, additional maternal, pregnancy and infant conditions may play a role.We aimed to evaluate the prevalence of and risk factors for DP at birth. Additionally, given the association between assisted reproductive technologies (ART) use and unfavorable pregnancy events, we explored the association between ART and DP.A total of 413 neonates33 weeks born at L. Sacco Hospital (Milan, Italy) from May 2011 through to January 2012 were enrolled. Data regarding parental, conceivement, pregnancy and delivery characteristics were recorded. Infants' skull measurements, including the oblique cranial length ratio (OCLR) were taken within 72 h after birth. Plagiocephaly was defined for OCLR 105.9.The prevalence of DP was 20.3%. It was associated with twinning (OR 5.0; 95%CI 2.22-11.1), pregnancy complications (OR 2.86; 95%CI 1.49-5.26), prematurity (OR 2.13; 95%CI 0.98-4.54), ART use (OR 2.00; 95%CI 0.90-4.35) and male gender (OR 1.79; 95%CI 0.94-2.50). Adjusting for multiple pregnancies however, the association between ART and DP disappeared.Results show that offspring of pregnancies conceived through ART do not have increased risk of DP. However, our numbers are small thus larger studies are needed for definitive conclusions.

OBJECTIVES: Whether the duration of maintenance treatment with azathioprine (AZA) affects the outcome of ulcerative colitis (UC) is unclear. We investigated clinical outcomes and any predictive factors after withdrawal of AZA in UC. METHODS: In this multicenter observational retrospective study, 127 Italian UC patients, who were in steroid-free remission at the time of withdrawal of AZA, were followed-up for a median of 55 months or until relapse. The frequency of clinical relapse or colectomy after AZA withdrawal was analyzed according to demographic, clinical, and endoscopic variables. RESULTS: After drug withdrawal, a third of the patients relapsed within 12 months, half within 2 years and two-thirds within 5 years. After multivariable analysis, predictors of relapse after drug withdrawal were lack of sustained remission during AZA maintenance (hazard ratio, HR 2.350, confidence interval, CI 95% 1.434-3.852; P=0.001), extensive colitis (HR 1.793, CI 95% 1.064-3.023, P=0.028 vs. left-sided colitis; HR 2.024, CI 95% 1.103-3.717, P=0.023 vs. distal colitis), and treatment duration, with short treatments (3-6 months) more disadvantaged than >48-month treatments (HR 2.783, CI 95% 1.267-6.114, P=0.008). Concomitant aminosalicylates were the only predictors of sustained remission during AZA therapy (P=0.009). The overall colectomy rate was 10%. Predictors of colectomy were drug-related toxicity as the cause of AZA withdrawal (P=0.041), no post-AZA drug therapy (P=0.031), and treatment duration (P

One group of six male control rats [12 months old] and one group of six male rats of the same age, singularly maintained in a cage, and treated with acetyl-L-carnitine-HCl [(gamma-trimethyl-beta-acetyl-butyrobetaine-HCl: Sigma-Tau code ST200 or ALCAR: 60 mg/kg/day[7]/po)] for six months were tested in the spatial learning/memory Morris mazewater task and for atrophy and cell loss in seven myelo- and cytostructurally defined basal forebrain (BF) cholinergic regions [Freddi et al., 2009]. Coronal sections 25 ?m thick were cut through the BF regions and processed every 200 ?m for choline acetyltransferase (ChAT) immunohistochemistry. The ALCAR-treated rats had significantly shorter exit times on the Morris maze-water task test than the control rats (average ± SD 28.3 ± 12.4 s vs. 61.16 ± 4.67 s; t = 6.07, DOF = 10, P = 0.0001). Degenerative morphological changes in the BF ChAT-positive cells were observed in the substantia innominata pars anterior of the control rats but not in the treated animals (P < 0.05). In the BF, the counted and estimated average number of ChAT + cells in the 12-month-old ALCAR-treated rats (ChAT-ALCAR-12+ [Nos. 2,3,4]) was higher but not significantly (15.288 ± 3281) than that counted and estimated in the 12-month-old control rats [(ChAT-CT-12 [Nos. 1,2,3]) (11.508 ± 3868), t = 1.82, DOF = 10, P = 0.319]. In the substantia innominata pars posterior, the ChAT+ cells were significantly more numerous (P < 0.05) in the 12-month-old ALCAR-treated rats (ChAT-ALCAR-12 + [Nos. 2,3,4]) than in the control rats (ChAT-CT-12 [Nos. 1,2,3]). Above all, these results dem-onstrate that treatment with ALCAR from the age of 6 up to 12 months significantly attenuated spatial learning/memory impairment on the Morris maze-water behavioral task (P < 0.001) and also importantly reduced degeneration in size and number of cholinergic cells in the nucleus basalis magnocellularis of the BF. Accordingly, the surviving cholinergic neurons found in the BF of the ALCAR-treated rats might play an important role in modulating cortical activity and facilitating processes of attention, learning and memory.

Objective Aim of this study is to examine the epidemiology of paediatric headache and periodic syndromes in a school population and to evaluate the co-existence of environmental predisposing conditions. Design and methods A 60-item questionnaire was completed by a school-based sample ( n = 1536, ages 6–18 years). Diagnostic assessment of primary headache and periodic syndromes was established in first section; predisposing conditions in the second section; while the third section quantified the frequency of self medication and identified drugs most frequently used. Results Headache was reported by 62.1% of subjects. Socioeconomic status, composition of family unit and nutrition habits in the first year of life did not appear significantly different in subjects with headache compared to healthy controls. A good sleep quality was found in 95.2% of healthy controls, in 89.4% of children with occasional headache. Recurrent abdominal pain, motor weakness and car sickness was significantly higher in primary headache group compared to occasional headache. Depressive/anxious traits were significantly higher in primary headache and occasional headache groups than in healthy controls. The frequency of aggressive traits was also higher in children with primary headache compared to occasional headache and healthy control subjects. 72.5% of subjects with primary headache and 58.4% of children with occasional headache assumed medicines to relieve pain. Paracetamol was the most frequently assumed drug. Conclusions Our data show a more frequent occurrence of anxious/depressive profile in children suffering from primary headache. In agreement with literature data, this research points out that self-treatment is a relevant problem in paediatric headache.

Objective The aim of this study was to evaluate the diagnostic accuracy of bedside lung ultrasound and chest radiography (CXR) in patients with suspected pneumonia compared with CT scan and final diagnosis at discharge. Design A prospective clinical study. Methods Lung ultrasound and CXR were performed in sequence in adult patients admitted to the emergency department (ED) for suspected pneumonia. A chest CT scan was performed during hospital stay when clinically indicated. Results 120 patients entered the study. A discharge diagnosis of pneumonia was confirmed in 81 (67.5%). The first CXR was positive in 54/81 patients (sensitivity 67%; 95% CI 56.4% to 76.9%) and negative in 33/39 (specificity 85%; 95% CI 73.3% to 95.9%), whereas lung ultrasound was positive in 80/81 (sensitivity 98%; 95% CI 93.3% to 99.9%) and negative in 37/39 (specificity 95%; 95% CI 82.7% to 99.4%). A CT scan was performed in 30 patients (26 of which were positive for pneumonia); in this subgroup the first CXR was diagnostic for pneumonia in 18/26 cases (sensitivity 69%), whereas ultrasound was positive in 25/26 (sensitivity 96%). The feasibility of ultrasound was 100% and the examination was always performed in less than 5 min. Conclusions Bedside chest ultrasound is a reliable tool for the diagnosis of pneumonia in the ED, probably being superior to CXR in this setting. It is likely that its wider use will allow a faster diagnosis, conducive to a more appropriate and timely therapy.

The study aimed to compare the efficacy of the Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) risk score, San Francisco Syncope Rule, and clinical judgment in assessing the short-term prognosis of syncope.We studied 488 patients consecutively seen for syncope at the emergency department of 2 general hospitals between January and July 2004. Sensitivity, specificity, predictive values, and likelihood ratios for short-term (within 10 days) severe outcomes were computed for each decision rule and clinical judgment. Severe outcomes comprised death, major therapeutic procedures, and early readmission to hospital.Clinical judgment had a sensitivity of 77%, a specificity of 69%, and would have admitted less patients (34%, P.05 vs decision rules). The OESIL risk score was characterized by a sensitivity of 88% and a specificity of 60% (admission 43%). San Francisco Syncope Rule sensitivity was 81% and specificity was 63% (admission 40%). According to both clinical rules, no discharged patient would have died. With combined OESIL risk score and clinical judgment, the probability of adverse events was 0.7% for patients with both low risk scores, whereas that for both high risk scores was roughly 16%.Because of a relatively low sensitivity, both risk scores were partially lacking in recognizing patients with short-term high-risk syncope. However, the application of the decision rules would have identified all patients who subsequently died, and OESIL risk score and clinical judgment combined seem to improve the decision-making process concerning the identification of high-risk patients who deserve admission.

Liver disease may alter the pharmacokinetics of antiretrovirals and produce changes in plasma protein binding. The aim was to evaluate the pharmacokinetics of total and unbound lopinavir (LPV) in HIV-infected patients with and without hepatitis C virus (HCV) coinfection. Fifty-six HIV+ patients receiving lopinavir/ritonavir (LPV/r) (group I = 24 controls; II = 23 HIV/HCV-coinfected; III = 9 cirrhotic HIV/HCV-coinfected) were included. Total (n = 56) and unbound (n = 36) LPV pharmacokinetic parameters were determined at steady-state using validated high-performance liquid chromatography with ultraviolet detection and high-performance liquid chromatography-tandem mass spectrometry methods, respectively. Pharmacokinetic parameters (plasma concentration just before drug administration, peak concentrations in plasma, times to maximum plasma concentration, areas under the plasma concentration-time curve from 0 to 12 hours, and CL/F/kg) of both total and unbound LPV were calculated by standard noncompartmental methods and differences among groups evaluated (Kruskal-Wallis test).LPV apparent oral clearance normalized to body weight (median, interquartile range) was 55 (40-68), 59 (44-69), and 71 (53-78) mL/h/kg for groups I, II, and III, respectively (II vs. I, P = 0.52; III vs. I, P = 0.16). The areas under the plasma concentration-time curve from 0 to 12 hours were 110.4 (80.9-135.2), 103.4 (85.5-131.3), and 92.8 (87.4-116.3) microg h/mL for groups I, II, and III, respectively (II vs. I, P = 0.68; III vs. I, P = 0.71). Chronic liver impairment produced a slight, although not significant, decrease in plasma protein binding. The free-fraction of LPV increased ( approximately 21%) from 0.97% (0.80-1.06) in HIV+/HCV- patients to 1.18% (0.89-1.65) in HIV/HCV+ cirrhotic patients. The apparent oral clearance of unbound LPV (CLu/F/kg) in cirrhotic patients did not change significantly, supporting the concept that the clearance of unbound LPV in liver disease is not affected after being inhibited by low-dose ritonavir co-administration.LPV total and unbound pharmacokinetics were not affected by hepatic impairment, suggesting that no adjustment of LPV/r dose is required for HIV/HCV-coinfected patients with and without cirrhosis and moderate impairment of liver function.

A total of 676 subjects were included in the study. Forty-one subjects (6.1%) experienced severe outcomes (5 deaths, 0.7%; 36 major therapeutic procedures, 5.4%) in the 10 days after presentation. An abnormal electrocardiogram, concomitant trauma, absence of symptoms of impending syncope, and male gender were associated with short-term unfavorable outcomes. Long-term severe outcomes were 9.3% (40 deaths, 6.0%; 22 major therapeutic procedures, 3.3%), and their occurrence was correlated with an age 65 years, history of neoplasms, cerebrovascular diseases, structural heart diseases, and ventricular arrhythmias. Short-term major therapeutic procedures were more common (p 0.05) in subjects who had been admitted to hospital (13.3%) than in discharged (1.6%), whereas mortality was similar. One-year mortality was greater (p 0.05) in admitted (14.7%) than in discharged (1.8%) patients.

To identify predictive factors for moderate/severe liver fibrosis and to analyse fibrosis progression in paired liver biopsies from HIV-positive patients with chronic hepatitis C virus (HCV) infection.HIV/HCV coinfected patients followed at the 2nd Department of Infectious Diseases of L. Sacco Hospital in Milan, Italy, with at least one liver biopsy specimen were retrospectively evaluated.A total of 110 patients were enrolled in the study. In a univariate analysis, predictive factors of Ishak-Knodell stageor =3 were a history of alcohol abuse [odds ratio (OR) 3.6, P=0.004], alanine aminotransferase level100 IU/L at biopsy (OR 2.4, P=0.05), necro-inflammatory gradeor =9 (OR 37.14, P0.0001) and CD4 count350 cells/microL at nadir (OR 5.3, P=0.05). In a multivariate analysis, age35 years (OR 3.19, P=0.04) and alcohol abuse (OR 4.36, P=0.002) remained independently associated with Ishak-Knodell stage. Paired liver biopsies were available in 36 patients; 18 showed an increase of at least one stage in the subsequent liver biopsy. Either in a univariate or in a multivariate analysis, a decrease of CD4 cell count of more than 10% between two biopsies (OR 6.85, P=0.002) was significantly associated with liver fibrosis progression.Our findings highlight the relevance of encouraging a withdrawal of alcohol consumption in people with chronic HCV infection and of carrying out close follow-up of patients, especially if they are more than 35 years old. It is therefore mandatory to evaluate HIV/HCV coinfected patients for anti-HCV treatment and to increase CD4 cell count through antiretroviral therapy in order to reduce the risk of fibrosis progression and to slow the evolution of liver disease.

In patients with chronic liver disease, the accuracy of ultrasound scan (US), spiral computed tomography (CT), magnetic resonance imaging (MRI), and alpha-fetoprotein (AFP) in diagnosing hepatocellular carcinoma (HCC) has never been systematically assessed, and present systematic review was aimed at this issue.Pertinent cross-sectional studies having as a reference standard pathological examinations of the explanted liver or resected segment(s), biopsies of focal lesion(s), and/or a period of follow-up, were identified using MEDLINE, EMBASE, Cochrane Library, and CancerLit. Pooled sensitivity, specificity, and likelihood ratios (LR) were calculated using the random effect model. Summary receiver operating characteristic (SROC) curve and predefined subgroup analyses were made when indicated.The pooled estimates of the 14 US studies were 60% (95% CI 44-76) for sensitivity, 97% (95% CI 95-98) for specificity, 18 (95% CI 8-37) for LR+, and 0.5 (95% CI 0.4-0.6) for LR-; for the 10 CT studies sensitivity was 68% (95% CI 55-80), specificity 93% (95% CI 89-96), LR+ 6 (95% CI 3-12),and LR- 0.4 (95% CI 0.3-0.6); for the nine MRI studies sensitivity was 81% (95% CI 70-91), specificity 85% (95%CI 77-93), LR+ 3.9 (95%CI 2-7), and LR- 0.3 (95% CI 0.2-0.5). The sensitivity and specificity of AFP varied widely, and this could not be entirely attributed to the threshold effect of the different cutoff levels used.US is highly specific but insufficiently sensitive to detect HCC in many cirrhotics or to support an effective surveillance program. The operative characteristics of CT are comparable, whereas MRI is more sensitive. High-quality prospective studies are needed to define the actual diagnostic role of AFP.

Objectives: To evaluate the risk factors for lopinavir/ritonavir (LPV/r)-related liver enzyme elevation (LEE) in HIV antiretroviral-experienced patients. Methods: An open prospective observational study was carried out to analyse the incidence and time of LEE development during LPV/r treatment, and to determine whether LEE development was correlated with epidemiological, clinical and biochemical data, immune and virological profiles, concomitant hepatic diseases, antiretroviral therapy, or histological and ultrasonography liver examination results. A diagnosis of LEE was considered when LEE symptoms occurred after LPV/r introduction and was confirmed by a second control within 2 weeks. Results: A total of 782 HIV-positive outpatients have been enrolled in six different Infectious Diseases Departments in Northern Italy since August 2000. Of these patients, 71 (9.1%) developed LEE within 115 +/- 85 days (mean +/- standard deviation); 13 of these subjects discontinued LPV/r and four were hospitalized. Of the patients with LEE, 74.6% and 25.4% had grade 2 and greater than or equal to3 toxicity, respectively. No correlation between LEE and sex, baseline CD4 cell count, viral load, HIV stage, triglyceride values, histological and ultrasonography liver examination results, nevirapine use, or increase in CD4 cell count was observed. Higher baseline alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) values (P < 0.0001 and P = 0.004, respectively), younger age (P = 0.008), previous hepatitis B virus (HBV) infection (P = 0.012), efavirenz use (P = 0.04), and hepatitis C virus (HCV) and/or HBV coinfection (P < 0.0001, relative risk 4.78) were significantly related to LEE. No correlations between LEE and the same risk factors as investigated in the whole study population were found in subgroups of patients with HCV and/or HBV infection. Conclusions: HCV and HBV testing and measurement of baseline ALT values are essential for screening subjects at risk of LEE before starting LPV/r. Strict monitoring of clinical and biochemical parameters should be performed in these patients.

Objective: To evaluate the prevalence of HIV-related central nervous system (CNS) lesions (HIV-encephalitis and/or HIV-leukoencephalopathy: HIV-E/L) with and without concomitant opportunistic diseases in a large autopsy series, and to correlate it with the changes in antiretroviral treatment that have occurred since the beginning of the epidemic. Methods: We reviewed 1597 consecutive autopsies of HIV-positive patients performed between 1984 and 2000, and divided into four time periods on the basis of the therapeutic regimens available: 1984-1987, no therapy; 1988-1994, monotherapy (zidovudine); 1995-1996, dual combination therapy with nucleoside reverse transcriptase inhibitors (NRTI); and 1997-2000, triple combination therapy including two NRTI and at least one protease inhibitor or non-NRTI. The data concerning the treatment actually received were collected only for the patients who died during the last period. The X 2 -test was used to assess the significance of the differences in prevalence. Results: The CNS of 1210 patients (76%) was affected by opportunistic diseases, HIV-related lesions or both. The prevalence of HIV-related lesions in the four periods was respectively 54%, 32%, 18% and 15%; this reduction was statistically significant (P < 0.000001). During the last period, however, differences in HIV-E/L between treated and untreated patients were not statistically significant, although there were fewer than expected cases among the treated patients (six instead of eight) and more than expected among the untreated patients (10 instead of eight). Conclusions: These neuropathological data from a large autopsy series confirm clinical observations concerning the efficacy of antiretroviral treatment in reducing the frequency of HIV-related CNS lesions in AIDS patients.

Health research based on administrative data and the availability of regional or national administrative databases has been increasing in recent years. We will discuss the general characteristics of administrative data and specific aspects of their use for health research purposes, indicating their advantages and disadvantages. Some fields of application will be discussed and described through examples.

The Fondazione Umberto Veronesi ethics committee recently published a statement concerning the inherent ethical issues of randomized clinical trials (RCTs), mainly focusing on randomization, raising many questions, and suggesting possible solutions. The main concern is that the patients enrolled in a RCT are used to improve medical knowledge, but they cannot be the beneficiaries of the results of the trials in which they are participating. Possible solutions come from a wider use of clinical and administrative databases, and an early termination of trials. We discuss this statement, emphasizing that the scientific and ethical reason for embarking on a clinical trial is uncertainty. The uncertainty regarding the comparative benefits and harms of each compared treatment (clinical equipoise) warrants equity in allocation. Randomization allows one to obtain unbiased evidence that we cannot know in advance. The expected probability of a new treatment to be successful describes the limits within which a study can be acceptable both from an ethical as well as a scientific point of view. Most people accept enrollment in a RCT if the probability of success of the experimental treatment is between 50 and 70%. The assumption and concern that there is a conflict between "scientific" and "ethical" aspects of a clinical trial due to randomization should at least be mitigated, considering that only scientifically sounded studies can be considered ethical. Randomization remains the appropriate approach to ensure the study's internal validity. Different aspects seem to be more important, from the ethical point of view, considering RCT and their publication.

Perinatal stroke is a common cause of neurologic disability. Being clinically under-recognized, its true incidence is not known. Maternal thrombophilia is likely to be a predisposing factor. To date, a general consensus for evaluation of babies born to mothers with genetic thrombotic predisposition is missing. This study was undertaken to assess the frequency of cerebral abnormalities in the offspring of women with homozygous C677T mutation in the MTHFR gene, and to seek for association with additional maternal or pregnancy risk factors.Mother-infant pairs were consecutively recruited from October 2006 through February 2013. Neonates underwent a thorough physical examination at birth, and a cerebral ultrasound examination (cUS) was performed within 24 hours of their life. In neonates with major cerebral lesions, a thrombophilia panel test was obtained. Follow-up cUS was performed in babies with major or minor cerebral abnormalities.Ninety-one neonates (47 males) were enrolled. By cUS, abnormalities were detected in 18 (19.8%) neonates. Twelve neonates were diagnosed with a minor lesion; a major ischemic/hemorrhagic lesion was found in 6 neonates. There were a neat male preponderance and significant associations with a history of suspected miscarriage, maternal coagulation factors gene mutations, and reduced protein S or protein C activity.Our data confirmed a high incidence of cerebral abnormalities in neonates born to women with C677T homozygous mutation in the MTHFR gene. cUS at birth proved to be an effective screening tool or a diagnostic test, that should be routinely performed in babies born to mothers with known thrombotic predisposition.

Study objectives: There is limited evidence to guide the emergency department (ED) evaluation and management of syncope. The First International Workshop on Syncope Risk Stratification in the Emergency Department identified key research questions and methodological standards essential to advancing the science of ED-based syncope research. Methods: We recruited a multinational panel of syncope experts. A preconference survey identified research priorities, which were refined during and after the conference through an iterative review process. Results: There were 31 participants from 7 countries who represented 10 clinical and methodological specialties. High-priority research recommendations were organized around a conceptual model of ED decisionmaking for syncope, and they address definition, cohort selection, risk stratification, and management. Conclusion: We convened a multispecialty group of syncope experts to identify the most pressing knowledge gaps and defined a high-priority research agenda to improve the care of patients with syncope in the ED. © 2014 American College of Emergency Physicians.

The authors enrolled 1,029 patients with CD4 counts/= 200/microL and no CNS AIDS-defining events (CNS-AIDS) between January 1993 and December 1998. The primary end point was the first appearance of CNS-AIDS. Three different periods and different antiretroviral regimens were considered. During the median follow-up of 329 days, 144 patients (9.5%) developed CNS-AIDS. The independent predictors were CD4 counts and therapy. All regimens decreased the risk of CNS-AIDS. Highly active antiretroviral therapy led to a 95% risk reduction in comparison with untreated patients.

OBJECTIVE: To report the results of the second phase of a pilot study of an Italian national external quality evaluation program (EQA) aimed at assessing whether participation in the first phase had increased the reliability and accuracy of diagnoses and to what extent. STUDY DESIGN: In the second phase, two sets of cervical smears (similar to the ones examined in the first phase) were circulated among the 14 participating cytologic laboratories throughout Italy. Responses were recorded on a standardized form. Participants were asked to judge the adequacy of each smear and to formulate diagnosis. They were also asked to recommend management of the patient on the basis of the smear report and to evaluate the degree of diagnostic difficulty of each slide. The results were discussed in workshops, and it was possible to reach a consensus diagnosis on 37 of 40 smears. In the statistical analysis, new indices of diagnostic variability were developed and calculated; a gross index of agreement, unweighted and weighted kappas, analysis of exchangeability, sensitivity and specificity were also estimated. RESULTS: The results of the second phase are similar to those of the first phase and no substantial improvement in accuracy and little reduction in variability were observed. The interventions carried out in this study (discussion between representatives of laboratories of diagnostic differences and reassessment of the most controversial slides) were aimed at increasing consensus among the participating pathologists but were insufficient to change the diagnostic routines in their laboratories. CONCLUSION: It may be advisable to promote two kinds of interlaboratory quality programs with two separate but integrated components: (1) a core component with slides having clear-cut diagnoses, and (2) a continuing education component.

The diagnostic research process can be divided into five phases, designed to establish the clinical utility of a new diagnostic test--the index test. The aim of the present review is to illustrate the study designs that are appropriate for each diagnostic phase, using clinical examples regarding liver fibrosis diagnosed with transient elastography, when possible. Phase 0 is the preclinical pilot phase during which the validity, reliability, and reproducibility of the index test are assessed in healthy and diseased people. Phase I is designed to describe the distribution of the index test results in healthy people and its normal values. Phase IIA comprises studies designed to estimate the accuracy (sensitivity and specificity) of the index test in discriminating between diseased and nondiseased people in a clinically relevant population. Phase IIB studies allow the comparison of the accuracy of different index tests; Phase IIC studies aim to evaluate the possible harms of incorporating the index test in a diagnostic-therapeutic strategy. In phase III, diagnostic test-therapeutic randomized clinical trials aim to assess the benefits and harms of the new diagnostic-therapeutic strategy versus the present strategy. Phase IV comprises large surveillance cohort studies that aim to assess the effectiveness of the new diagnostic-therapeutic strategy in clinical practice.As common in clinical research, giving excessive weight to the results of single studies and trials is likely to divert from the totality of evidence obtained through the systematic reviews of these studies, conducted with rigorous methodology and statistical methods. (Hepatology 2014;60:408-418).