Inadequate Hospital Practices to Prevent Mother-to-Child Transmission of Hepatitis B Virus Infection: A European Survey.

OBJECTIVES: Prevention of vertical transmission of hepatitis B virus (HBV) infection is crucial to eliminate viral hepatitis as a major public health threat by 2030. We aimed to assess the current hospital policies and practices implemented before, at, and after birth, and to evaluate potential barriers to the full application of international guidelines. METHODS: A web-based survey was supported by PENTA Foundation and distributed across Europe from October to December 2021. RESULTS: Overall, 76 centers with delivery departments completed the survey. Hepatitis B surface antigen (HBsAg) maternal screening is performed in the first trimester of pregnancy in 53% of the centers and in the third in 46%. HBsAg positive pregnant women are tested for serologic HBV markers and HBV-DNA in 78% and 63% of the departments; 38% of the HBeAg positive women with high HBV-DNA levels are treated during the last trimester of pregnancy. At birth, 91% of the departments administer HBV vaccine to infants born to HBsAg positive mothers within 12 hours of birth; 74% test women with unknown HBsAg status and 78% of them wait for the maternal testing results before administering HBV vaccine to their newborns. After birth, 47% of the departments provide postvaccination serological testing for infants born to HBsAg positive mothers. The timing of the HBV vaccine schedule varies greatly. CONCLUSIONS: There is significant heterogeneity in the hospital policies and correlated procedures. The implementation of a multidisciplinary clinical pathway is a must if a stronger connection between the prenatal, perinatal, and postnatal phases is to be established.

Prioritizing the First Doses of SARS-CoV-2 Vaccine to Save the Elderly: The Case Study of Italy.

SARS-CoV-2 is currently causing hundreds of deaths every day in European countries, mostly in not yet vaccinated elderly. Vaccine shortage poses relevant challenges to health authorities, called to act promptly with a scarcity of data. We modeled the mortality reduction of the elderly according to a schedule of mRNA SARS-CoV-2 vaccine that prioritized first dose administration. For the case study of Italy, we show an increase in protected individuals up to 53.4% and a decrease in deaths up to 19.8% in the cohort of over 80's compared with the standard vaccine recalls after 3 or 4 weeks. This model supports the adoption of vaccination campaigns that prioritize the administration of the first doses in the elderly.

The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric trial center in Italy.

Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians' participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure.However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children's Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present 10 years' experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.

The conect4children (c4c) Consortium: Potential for Improving European Clinical Research into Medicines for Children.

The need for information about new and existing drugs used in children was recognized in the European Union (EU) with the implementation of the Paediatric Regulation in 2007. In 2017, the 10-year review of the Paediatric Regulation identified barriers to the conduct of clinical trials, including delays in setting up and completing paediatric trials. Across Europe, the difficulties with clinical research are compounded by variation within countries and between countries. Ethics and regulatory review have national specificities. This paper describes the Collaborative Network for European Clinical Trials for Children (conect4children, c4c), which addresses selected difficulties in the design and conduct of paediatric clinical trials. c4c is a time-limited public-private consortium funded by the Innovative Medicines Initiative (IMI2). The elements of c4c are as follows: expert advice providing input on study design and/or paediatric development programmes (including patient involvement activities); a network of sites following harmonised procedures coordinated by National Hubs and a single point of contact for Europe; a facility for education and training for sites and trial teams; and support for managing data used by the network and a common paediatric data dictionary. c4c does not sponsor trials. c4c is taking a phased approach with careful piloting through industry and non-industry studies intended to demonstrate the viability of the network (proof-of-viability studies). c4c uses a co-design approach involving industry and academics within a clearly defined scope. A sustainable, successor organization open to all potential service users will be open for business before the end of IMI2 funding in 2024.

MRI monitoring of macaque monkeys in neuroscience: Case studies, resource and normative data comparisons.

Information from Magnetic Resonance Imaging (MRI) is useful for diagnosis and treatment management of human neurological patients. MRI monitoring might also prove useful for non-human animals involved in neuroscience research provided that MRI is available and feasible and that there are no MRI contra-indications precluding scanning. However, MRI monitoring is not established in macaques and a resource is urgently needed that could grow with scientific community contributions. Here we show the utility and potential benefits of MRI-based monitoring in a few diverse cases with macaque monkeys. We also establish a PRIMatE MRI Monitoring (PRIME-MRM) resource within the PRIMatE Data Exchange (PRIME-DE) and quantitatively compare the cases to normative information drawn from MRI data from typical macaques in PRIME-DE. In the cases, the monkeys presented with no or mild/moderate clinical signs, were well otherwise and MRI scanning did not present a significant increase in welfare impact. Therefore, they were identified as suitable candidates for clinical investigation, MRI-based monitoring and treatment. For each case, we show MRI quantification of internal controls in relation to treatment steps and comparisons with normative data in typical monkeys drawn from PRIME-DE. We found that MRI assists in precise and early diagnosis of cerebral events and can be useful for visualising, treating and quantifying treatment response. The scientific community could now grow the PRIME-MRM resource with other cases and larger samples to further assess and increase the evidence base on the benefits of MRI monitoring of primates, complementing the animals' clinical monitoring and treatment regime.

Common fronto-temporal effective connectivity in humans and monkeys.

Human brain pathways supporting language and declarative memory are thought to have differentiated substantially during evolution. However, cross-species comparisons are missing on site-specific effective connectivity between regions important for cognition. We harnessed functional imaging to visualize the effects of direct electrical brain stimulation in macaque monkeys and human neurosurgery patients. We discovered comparable effective connectivity between caudal auditory cortex and both ventro-lateral prefrontal cortex (VLPFC, including area 44) and parahippocampal cortex in both species. Human-specific differences were clearest in the form of stronger hemispheric lateralization effects. In humans, electrical tractography revealed remarkably rapid evoked potentials in VLPFC following auditory cortex stimulation and speech sounds drove VLPFC, consistent with prior evidence in monkeys of direct auditory cortex projections to homologous vocalization-responsive regions. The results identify a common effective connectivity signature in human and nonhuman primates, which from auditory cortex appears equally direct to VLPFC and indirect to the hippocampus. VIDEO ABSTRACT.

Foreground stimuli and task engagement enhance neuronal adaptation to background noise in the inferior colliculus of macaques.

Auditory neuronal responses are modified by background noise. Inferior colliculus (IC) neuronal responses adapt to the most frequent sound level within an acoustic scene (adaptation to stimulus statistics), a mechanism that may preserve neuronal and behavioral thresholds for signal detection. However, it is still unclear whether the presence of foreground stimuli and/or task involvement can modify neuronal adaptation. To investigate how task engagement interacts with this mechanism, we compared the response of IC neurons to background noise, which caused adaptation to stimulus statistics, while macaque monkeys performed a masked tone detection task (task-driven condition) with responses recorded when the same background noise was presented alone (passive listening condition). In the task-dependent condition, monkeys performed a Go/No-Go task while 50-ms tones were embedded within an adaptation-inducing continuous background noise whose levels changed every 50 ms and were drawn from a probability distribution. The adaptation to noise stimulus statistics in IC neuronal responses was significantly enhanced in the task-driven condition compared with the passive listening condition, showing that foreground stimuli and/or task-engagement can modify IC neuronal responses. Additionally, the response of IC neurons to noise was significantly affected by the preceding sensory information (history effect) regardless of task involvement. These studies show that dynamic range adaptation in IC preserves behavioral and neurometric thresholds irrespective of noise type and a dependence of neuronal activity on task-related factors at subcortical levels of processing.NEW & NOTEWORTHY Auditory neuronal responses are influenced by maskers and distractors. However, it is still unclear whether the neuronal sensitivity to the masker stimulus is influenced by task-dependent factors. Our study represents one of the first attempts to investigate how task involvement influences the neural representation of background sounds in the subcortical, midbrain auditory neurons of behaving animals.

Survey by TEDDY European Network of Excellence for Paediatric Clinical Research demonstrates potential for Europe-wide trials.

AIM: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. METHODS: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. RESULTS: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. CONCLUSION: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.

Neuronal adaptation to sound statistics in the inferior colliculus of behaving macaques does not reduce the effectiveness of the masking noise.

The detectability of target sounds embedded within noisy backgrounds is affected by the regularities that summarize acoustic sceneries. Previous studies suggested that the dynamic range of neurons in the inferior colliculus (IC) of anesthetized guinea pigs shifts toward the mean sound pressure level in irregular acoustic environments. Yet, it is unclear how this neuronal adaptation processes may influence the effectiveness of sounds as a masker, both behaviorally and in terms of neuronal encoding. To answer this question, we measured the neural response of IC neurons while macaque monkeys performed a Go/No-Go tone detection task. Macaques detected a 50-ms tone that was either simultaneously gated with a burst of noise or embedded within a continuous noise background, whose levels were randomly sampled (every 50 ms) from a probability distribution. The mean of the distribution matched the level of the gated burst of noise. Psychometric and IC neurometric thresholds to tones did not differ between the two masking conditions. However, the neuronal firing rate versus level function was significantly affected by the temporal characteristics of the noise masker. Simultaneously gated noise caused higher baseline responses and greater dynamic range compression compared with noise distribution. The slopes of psychometric and neurometric functions were significantly shallower for higher variance distributions, suggesting that neuronal sensitivity might change with the variability of the sound. Our results suggest that the adaptive response of IC neurons to sound regularities does not affect the effectiveness of the noise-masking signal, which remains invariant to surrounding noise amplitudes. NEW & NOTEWORTHY Auditory neurons adapt to the statistics of sound levels in the acoustic scene. However, it is still unclear to what extent such adaptation influences the effectiveness of the stimulus as a masker. Our study represents the first attempt to investigate how the adaptation to the statistics of masking stimuli may be related to the effectiveness of masking, and to the single-unit encoding of the midbrain auditory neurons in behaving animals.

Criterion-free measurement of motion transparency perception at different speeds.

Transparency perception often occurs when objects within the visual scene partially occlude each other or move at the same time, at different velocities across the same spatial region. Although transparent motion perception has been extensively studied, we still do not understand how the distribution of velocities within a visual scene contribute to transparent perception. Here we use a novel psychophysical procedure to characterize the distribution of velocities in a scene that give rise to transparent motion perception. To prevent participants from adopting a subjective decision criterion when discriminating transparent motion, we used an "odd-one-out," three-alternative forced-choice procedure. Two intervals contained the standard-a random-dot-kinematogram with dot speeds or directions sampled from a uniform distribution. The other interval contained the comparison-speeds or directions sampled from a distribution with the same range as the standard, but with a notch of different widths removed. Our results suggest that transparent motion perception is driven primarily by relatively slow speeds, and does not emerge when only very fast speeds are present within a visual scene. Transparent perception of moving surfaces is modulated by stimulus-based characteristics, such as the separation between the means of the overlapping distributions or the range of speeds presented within an image. Our work illustrates the utility of using objective, forced-choice methods to reveal the mechanisms underlying motion transparency perception.

Optimizing Research to Speed Up Availability of Pediatric Antiretroviral Drugs and Formulations.

Globally 1.8 million children are living with human immunodeficiency virus (HIV), yet only 51% of those eligible actually start treatment. Research and development (R&D) for pediatric antiretrovirals (ARVs) is a lengthy process and lags considerably behind drug development in adults. Providing safe, effective, and well-tolerated drugs for children remains critical to ensuring scale-up globally. We review current approaches to R&D for pediatric ARVs and suggest innovations to enable simplified, faster, and more comprehensive strategies to develop optimal formulations. Several approaches could be adopted, including focusing on a limited number of prioritized formulations and strengthening existing partnerships to ensure that pediatric investigation plans are developed early in the drug development process. Simplified and more efficient mechanisms to undertake R&D need to be put in place, and financing mechanisms must be made more sustainable. Lessons learned from HIV should be shared to support progress in developing pediatric formulations for other diseases, including tuberculosis and viral hepatitis.

Spatial and temporal disparity in signals and maskers affects signal detection in non-human primates.

Detection thresholds for auditory stimuli (signals) increase in the presence of maskers. Natural environments contain maskers/distractors that can have a wide range of spatiotemporal properties relative to the signal. While these parameters have been well explored psychophysically in humans, they have not been well explored in animal models, and their neuronal underpinnings are not well understood. As a precursor to the neuronal measurements, we report the effects of systematically varying the spatial and temporal relationship between signals and noise in macaque monkeys (Macaca mulatta and Macaca radiata). Macaques detected tones masked by noise in a Go/No-Go task in which the spatiotemporal relationships between the tone and noise were systematically varied. Masked thresholds were higher when the masker was continuous or gated on and off simultaneously with the signal, and lower when the continuous masker was turned off during the signal. A burst of noise caused higher masked thresholds if it completely temporally overlapped with the signal, whereas partial overlap resulted in lower thresholds. Noise durations needed to be at least 100 ms before significant masking could be observed. Thresholds for short duration tones were significantly higher when the onsets of signal and masker coincided compared to when the signal was presented during the steady state portion of the noise (overshoot). When signal and masker were separated in space, masked signal detection thresholds decreased relative to when the masker and signal were co-located (spatial release from masking). Masking release was larger for azimuthal separations than for elevation separations. These results in macaques are similar to those observed in humans, suggesting that the specific spatiotemporal relationship between signal and masker determine threshold in natural environments for macaques in a manner similar to humans. These results form the basis for future investigations of neuronal correlates and mechanisms of masking.

Visual motion integration is mediated by directional ambiguities in local motion signals.

The output of primary visual cortex (V1) is a piecemeal representation of the visual scene and the response of any one cell cannot unambiguously guide sensorimotor behavior. It remains unsolved how subsequent stages of cortical processing combine ("pool") these early visual signals into a coherent representation. We (Webb et al., 2007, 2011) have shown that responses of human observers on a pooling task employing broadband, random dot motion can be accurately predicted by decoding the maximum likelihood direction from a population of motion-sensitive neurons. Whereas Amano et al. (2009) found that the vector average velocity of arrays of narrowband, two-dimensional (2-d) plaids predicts perceived global motion. To reconcile these different results, we designed two experiments in which we used 2-d noise textures moving behind spatially distributed apertures and measured the point of subjective equality between pairs of global noise textures. Textures in the standard stimulus moved rigidly in the same direction, whereas their directions in the comparison stimulus were sampled from a set of probability distributions. Human observers judged which noise texture had a more clockwise (CW) global direction. In agreement with Amano and colleagues, observers' perceived global motion coincided with the vector average stimulus direction. To test if directional ambiguities in local motion signals governed perceived global direction, we manipulated the fidelity of the texture motion within each aperture. A proportion of the apertures contained texture that underwent rigid translation and the remainder contained dynamic (temporally uncorrelated) noise to create locally ambiguous motion. Perceived global motion matched the vector average when the majority of apertures contained rigid motion, but with increasing levels of dynamic noise shifted toward the maximum likelihood direction. A class of population decoders utilizing power-law non-linearities can accommodate this flexible pooling.

Spatio-temporal templates of transient attention revealed by classification images.

Visual attention is captured by transient signals in the periphery of the visual field, allowing enhanced perceptual representations in spatial tasks. However, it has been reported that the same cues impair performance in temporal tasks (e.g., Yeshurun, 2004; Yeshurun & Levy, 2003). This findings suggest that transient attention enhances the activity of slow, high-resolution channels, like parvocellular neurons, and/or shuts off faster channels better sensitive to low spatial frequencies, such as the ones of the magnocellular system. To test this idea, we have measured the spatio-temporal perceptive fields for transiently cued signals at various eccentricities using the classification images (CI) technique. At near eccentricities transient attention caused the perceptual templates to be sharper in space and characterized by much stronger high spatial frequency components. At the same time, they show a consistently larger temporal integration window. These effects of attention on perceptual filters are strongly reduced at far eccentricities and disappear when using longer target-cue lags. These data provide evidence in support of the parvocellular model of transient, exogenous attention, showing that in the presence of a well timed spatial cue observers rely on noisy evidence lasting longer and with finer spatial configurations.

Neural computations governing spatiotemporal pooling of visual motion signals in humans.

The brain estimates visual motion by decoding the responses of populations of neurons. Extracting unbiased motion estimates from early visual cortical neurons is challenging because each neuron contributes an ambiguous (local) representation of the visual environment and inherently variable neural response. To mitigate these sources of noise, the brain can pool across large populations of neurons, pool the response of each neuron over time, or a combination of the two. Recent psychophysical and physiological work points to a flexible motion pooling system that arrives at different computational solutions over time and for different stimuli. Here we ask whether a single, likelihood-based computation can accommodate the flexible nature of spatiotemporal motion pooling in humans. We examined the contribution of different computations to human observers' performance on two global visual motion discriminations tasks, one requiring the combination of motion directions over time and another requiring their combination in different relative proportions over space and time. Observers' perceived direction of global motion was accurately predicted by a vector average readout of direction signals accumulated over time and a maximum likelihood readout of direction signals combined over space, consistent with the notion of a flexible motion pooling system that uses different computations over space and time. Additional simulations of observers' performance with a population decoding model revealed a more parsimonious solution: flexible spatiotemporal pooling could be accommodated by a single computation that optimally pools motion signals across a population of neurons that accumulate local motion signals on their receptive fields at a fixed rate over time.

The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni.

The lack of availability of appropriate medicines for children is an extensive and well known problem. As a consequence off label or unlicensed administration of medicinal products in every day paediatric practice is frequent. A variety of obstacles hinder the development of paediatric indications for drugs primarily intended for the adult market. The barriers to proper research on children's drug development include several complex factors, such as the limited commercial interest, lack of suitable infrastructure and competence for conducting paediatric clinical trials, difficulties in trial design, ethical worries and many others. Medicinal products used to treat children should be subjected to ethical research of high quality and be explicitly authorised for use in children as it happens in adults. Conducting adequate clinical trials in children is challenging and demanding. Identification of paediatric medical needs, extrapolation from adult data, modelling and simulation, specific clinical trial methodology are important features in the development of drugs intended for children. Market forces alone have proven insufficient to stimulate adequate research aimed at specific authorisation of medicinal products for the paediatric population, and for that reason, following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorisation of medicines for use in adults. The impact of the Paediatric Regulation reflects in an increase in the number of paediatric studies to be performed, even if a significant number of these studies have not started yet. The objective of this review is to describe the main regulatory and scientific features which play a role in the complex issue of paediatric drug development.

The European paediatric legislation: benefits and perspectives.

BACKGROUND: The lack of availability of appropriate medicines for children is an extensive and well known problem. Paediatricians and Physicians who take care of the paediatric population are primarily exposed to cope with this negative situation very often as more than half of the children are prescribed off-label or unlicensed medicines. DISCUSSION: Medicinal products used to treat this population should be subjected to ethical research of high quality and be explicitly authorized for use in children as it happens in adults. For that reason, and following the US experience, the European Paediatric Regulation has been amended in January 2007 by the European Commission. The objective of the Paediatric Regulation is to improve the development of high quality and ethically researched medicines for children aged 0 to 17 years, to facilitate the availability of information on the use of medicines for children, without subjecting children to unnecessary trials, or delaying the authorization of medicines for use in adults. SUMMARY: The Paediatric Regulation is dramatically changing the regulatory environment for paediatric medicines in Europe and is fuelling an increased number of clinical trials in the paediatric population. Nevertheless, there are some risks and pitfalls that need to be anticipated and controlled in order to ensure that children will ultimately benefit from this European initiative.

[Drug evaluation: new requirements and perspectives]. / La valutazione del farmaco: nuove esigenze e prospettive.

Lately the European and international regulatory Agencies, responsible for the evaluation of drugs, have not been capable to implement regulatory processes guiding clinical practice efficiently. The sudden withdrawal of innovative drugs, the incapacity of assuring independence, the not controlled trend of pharmaceutical expenditure are signals of the failure of a system which should respond to the mandate of public health and market regulation. Some intrinsic limits of present regulatory systems arise because regulatory Agencies approve medicinal products on the basis of minimum standards of efficacy or owing to fast registration procedures which do not allow to assure the real efficacy and safety of the product approved. Non-inferiority and equivalence trials, short duration studies conducted on small populations (not representing the real setting of utilization in clinical practice) are often considered sufficient for drug registration. Moreover, Agencies often lack data on the safety of approved products and based on post-marketing surveillance and monitoring plans which can assure the real profile of drug safety. Owing to the institution of the Italian Medicines Agency (AIFA), Italy has lately approached European standards of regulation and proposed a new original regulatory approach attempting to go beyond some of the main limitations described above. The main points the model is based on are: promotion of use appropriateness through the analysis of experiences occurring in the area; promotion of independent drug research in order to collect data reliable and useful for drug regulation; publication and distribution of independent information on drug utilization for health professionals. The Italian approach tries to bring regulatory provisions close to clinical practice by promoting a correct and rational use of drugs and developing new areas of intervention for research, vigilance and information.

Current national initiatives about drug policies and cost control in Europe: the Italy example.

Pharmaceutical expenditure is a challenge to the financial compatibility of health systems because it is growing faster (+11% per year in the last 5 years in Italy) than any other health sector. In order to curb public pharmaceutical expenditure 2 interventions are commonly used: delisting (de-reimbursement) and reference price, with the difference being paid by patients. The Italian Ministry of Health implemented a set of interventions with the general aim of pharmaceutical governance based on the following criteria: (a) to assure a complete coverage of all clinically and epidemiologically relevant diseases; (b) to provide health professionals with a range of different active drugs with the same therapeutic indications within the same therapeutic class; and (c) to identify a reimbursement threshold in order to save public money by narrowing the (wide) price differentials among drugs with comparable efficacy and safety. In this context, interventions have been undertaken at several levels including drug price reduction, generic drug promotion, delisting of drugs reimbursed, and direct distribution of medicines (by hospital services). Furthermore, a new National Pharmaceutical Formulary has been implemented. Medicines have been classified into homogeneous categories (ie, medicines with the same main indication(s) and with similar clinical efficacy and safety profile). Within each homogeneous category, a reimbursement level (cutoff) was then identified and, accordingly, pharmaceutical companies were asked to adjust their price. This adjustment was based on price per daily drug dose (DDD), cumulative expenditure (at least 50%), and cumulative utilization (at least 60%). This readjustment, at no cost for patients, is expected to save more than Euro 280 million of public money. Seventy-seven percent of this saving will be due to price readjustment of antiulcers, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, and some antibiotics (mainly cephalosporins). The Italian system was able to cover all relevant diseases and ensured citizens and health professionals a choice among a wide range of valid pharmacological therapies. At the same time it was able to save public money by narrowing wide price differentials among drugs with comparable clinical properties. The set of interventions yielded a new national formulary that was able to have a significant influence on the trend of drug expenditure in Italy. This experience can be a useful reference for other European and non-European states.

Pregnancy outcome after cabergoline treatment in early weeks of gestation.

We collected information on 61 pregnancies in 50 women treated with cabergoline. These pregnancies resulted in 12 (19.7%) early terminations (five induced abortions, six spontaneous abortions, one hydatidiform mole) and 49 (80.3%) live births. In one case, malformations were suspected by a gynecologist based on ultrasound at 12 gestational weeks and the pregnancy was terminated; additional information was not available. There was one case of trisomy 18. The frequency of spontaneous and induced abortions and major congenital malformations was comparable with rates in the general population. The data did not indicate any potential adverse effect of the drug on pregnancy. The data from this study in combination with previous reports can exclude a congenital malformation risk greater than 10% associated with pregnancy exposure to cabergoline.