[The French medecine pricing committee]. / Le Comité économique des produits de santé et la politique économique du médicament.

The French medicine pricing committee (CEPS) has to reconcile several major constraints, including optimal patient access to medicines and a good control of expenditures on reimbursable medicines. From 2013 to 2015, drug price decreases and discounts obtained by CEPS contributed more than € 5 billion to the balance of the health insurance accounts. As for price setting, there is a significant drop in the prices of medicines in France once they are registered for reimbursement. France is affected by a limited, but costly, flow of innovative medicines, whose prices are higher than those of previous generations, a reflection of an international gradient to which France is obviously subject, despite prices that remain at the low end of the range in Western Europe. The provision of innovative medicines for all patients who need them has been ensured in France over the last fifteen years at a controlled cost. But with the arrival of new expensive products, a resolute policy of control of expenditures must take over from the fall in prices, and original financing channels will have to be explored.

[The French medecine pricing committee and the medicine economic policy: Rules and competences]. / Le comité économique des produits de santé et la politique économique du médicament : règles et compétences.

The French medicine pricing committee (CEPS), a governmental and inter-institutional body exercises essential competences for the regulation of the economy of the reimbursable drugs in France. It provides a good example of administered price regulation. It also supervises the proper use of products (control of promotion, conventional control of sales volumes). Finally, it regulates the annual envelope of drug expenditures by means of discounts paid by pharmaceutical companies. The article presents the legal criteria and the doctrine of price setting used in France. It details the types of market access contracts concluded by the CEPS. It specifies the conditions governing the annual envelope of expenditures on reimbursable medicines.

Face morphology: Can it tell us something about body weight and fat?

This paper proposes a method for an automatic extraction of geometric features, related to weight parameters, from 3D facial data acquired with low-cost depth scanners. The novelty of the method relies both on the processing of the 3D facial data and on the definition of the geometric features which are conceptually simple, robust against noise and pose estimation errors, computationally efficient, invariant with respect to rotation, translation, and scale changes. Experimental results show that these measurements are highly correlated with weight, BMI, and neck circumference, and well correlated with waist and hip circumference, which are markers of central obesity. Therefore the proposed method strongly supports the development of interactive, non obtrusive systems able to provide a support for the detection of weight-related problems.

Effectiveness of vision rehabilitation treatment through MP-1 microperimeter in patients with visual loss due to macular disease.

PURPOSE: To evaluate the effectiveness of biofeedback treatment for low-vision rehabilitation in patients affected by macular disease. MATERIALS AND METHODS: 171 eyes of 99 patients (42 female and 57 male) between 50 to 75 years old (mean age: 64.6) were included in this study. All patients were suffering from age-related macular degeneration (AMD) (122 eyes) or macular myopic degeneration (MMD) (49 eyes). All patients underwent an assessment of examinations including visual acuity, reading speed test, slit lamp examination and tonometry, ophthalmoscopic fundus examination, microperimetry, fixation test, retinal sensitivity, fluorangiography (FAG), optical coherence tomography (OCT). The treatment was divided in 16 sessions, the patients underwent other examination assessment at 6 and 12 months, except for FAG and OCT. Statistical analysis was performed using Student's t-test, and p-value <=0.05 was considered statistically significant. RESULTS: After training 130 eyes of 171 in the study group (76.02%) had a statistically significant improvement of the distant visual acuity (p<0.01): 38 eyes suffering from MMD and 92 eyes suffering from AMD. After 12 months of follow-up a group of 25 eyes of 130 (19.23%) had a loss of benefits that were observed at the end of the treatment sessions: 16 eyes and 9 eyes were suffering from MMD and AMD respectively. Examination assessment during follow-up showed that 4 eyes and 2 eyes of the group that lost benefits had a worsening of MMD and AMD primary disease respectively. CONCLUSIONS: It is not yet understood how biofeedback produces amelioration of visual function. According to the 'Eccentric fixation' theory, with biofeedback rehabilitation patients are trained to use the non-damaged retina areas to develop a new preferred retinal locus. In our study group we found a significant improvement in both visual acuity and fixation.

Assessment of the cardiovascular effects of electroconvulsive therapy in individuals older than 50 years.

To evaluate the impact of electroconvulsive therapy on arterial blood pressure, heart rate, heart rate variability, and the occurrence of ischemia or arrhythmias, 38 (18 men) depressive patients free from systemic diseases, 50 to 83 years old (mean: 64.7 +/- 8.6) underwent electroconvulsive therapy. All patients were studied with simultaneous 24-h ambulatory blood pressure and Holter monitoring, starting 18 h before and continuing for 3 h after electroconvulsive therapy. Blood pressure, heart rate, heart rate variability, arrhythmias, and ischemic episodes were recorded. Before each session of electroconvulsive therapy, blood pressure and heart rate were in the normal range; supraventricular ectopic beats occurred in all patients and ventricular ectopic beats in 27/38; 2 patients had non-sustained ventricular tachycardia. After shock, systolic, mean and diastolic blood pressure increased 29, 25, and 24% (P < 0.001), respectively, and returned to baseline values within 1 h. Maximum, mean and minimum heart rate increased 56, 52, and 49% (P < 0.001), respectively, followed by a significant decrease within 5 min; heart rate gradually increased again thereafter and remained elevated for 1 h. Analysis of heart rate variability showed increased sympathetic activity during shock with a decrease in both sympathetic and parasympathetic drive afterwards. No serious adverse effects occurred; electroconvulsive therapy did not trigger any malignant arrhythmias or ischemia. In middle-aged and elderly people free from systemic diseases, electroconvulsive therapy caused transitory increases in blood pressure and heart rate and a decrease in heart rate variability but these changes were not associated with serious adverse clinical events.

Assessment of the cardiovascular effects of electroconvulsive therapy in individuals older than 50 years

To evaluate the impact of electroconvulsive therapy on arterial blood pressure, heart rate, heart rate variability, and the occurrence of ischemia or arrhythmias, 38 (18 men) depressive patients free from systemic diseases, 50 to 83 years old (mean: 64.7 ± 8.6) underwent electroconvulsive therapy. All patients were studied with simultaneous 24-h ambulatory blood pressure and Holter monitoring, starting 18 h before and continuing for 3 h after electroconvulsive therapy. Blood pressure, heart rate, heart rate variability, arrhythmias, and ischemic episodes were recorded. Before each session of electroconvulsive therapy, blood pressure and heart rate were in the normal range; supraventricular ectopic beats occurred in all patients and ventricular ectopic beats in 27/38; 2 patients had non-sustained ventricular tachycardia. After shock, systolic, mean and diastolic blood pressure increased 29, 25, and 24 percent (P < 0.001), respectively, and returned to baseline values within 1 h. Maximum, mean and minimum heart rate increased 56, 52, and 49 percent (P < 0.001), respectively, followed by a significant decrease within 5 min; heart rate gradually increased again thereafter and remained elevated for 1 h. Analysis of heart rate variability showed increased sympathetic activity during shock with a decrease in both sympathetic and parasympathetic drive afterwards. No serious adverse effects occurred; electroconvulsive therapy did not trigger any malignant arrhythmias or ischemia. In middle-aged and elderly people free from systemic diseases, electroconvulsive therapy caused transitory increases in blood pressure and heart rate and a decrease in heart rate variability but these changes were not associated with serious adverse clinical events.

Monitoring surgical treatment of screen-detected breast lesions in Italy.

The object of this study was to assess quality of care and adherence to treatment guidelines of screen-detected lesions in Italy using a new audit system. Data on screen-detected cases surgically treated in 1997 were collected using a system (QT 2.3) developed within the Italian Group for Planning and Evaluating Mammographic Screening Programmes (GISMa) and the European Breast Cancer Screening Network. Results of 18 performance parameters were considered compared with the reference standards. In 1997, 515 lesions (335 invasive, 60 in situ and 120 benign) in 496 patients were collected from 14 departments in the Central and Northern area of Italy. The 18 indicators were analysed and grouped according to six quality objectives. Some results were good and others were excellent, such as intraoperative identification, breast conservation surgery, adequate axillary procedures and completeness of pathology reports, but most of them failed: waiting times, preoperative diagnosis, employment of frozen section on small lesions and avoiding axillary procedures in ductal carcinoma-in-situ. This work is a first attempt in Italy to evaluate and uniform the criteria adopted for quality control of breast cancer treatment, using a standardised system. Some results are good or excellent, the overall level of compliance with quality indicators is not satisfactory and corrective actions should be undertaken for a number of issues. A continuous monitoring should be performed and appropriate action taken in order to verify the effectiveness of the corrective actions and to provide screen-detected patients with the best quality of care.

Colorectal cancer screening programme by faecal occult blood test in Tuscany: first round results.

Screening with faecal occult blood test (FOBT) has been shown to be effective in reducing mortality from colorectal cancer. Tuscany was the first region in Italy in which a screening programme for colorectal cancer by FOBT was initiated region-wide. The aim of the paper was to describe organizational aspects, a quality control model and the results of this experience. From June 2000 to December 2001, 192583 subjects aged 50-70 were invited to undergo a 1-day immunochemical test without any dietary restriction. A total of 78505 subjects (41%) performed the screening test, of whom 4537 responders had a positive test result (5.8%). Among them, 1122 refused any form of assessment or underwent a colonoscopy outside the screening referral centres, with an overall assessment compliance of 75.3%. Malignancies were found in 193 patients and at least a high-risk adenomatous polyp in 692 patients. In about a quarter of the positive subjects who underwent assessment, cancer or high-risk adenoma was detected. In conclusion, data from this experience supported the feasibility of biennial colorectal screening programme by FOBT, particularly regarding invitation compliance and positivity rate. Further efforts are necessary to implement screening extension and to improve data collection.

Olfactory receptors.

Olfaction is an ancient sensory system allowing an organism to detect chemicals in its environment. The first step in odor transduction is mediated by binding odorants to olfactory receptors (ORs) which belong to the heptahelical G-protein-coupled receptor (GPCR) superfamily. Mammalian ORs are disposed in clusters on virtually all chromosomes. They are encoded by the largest multigene family (approximately 1000 members) in the genome of mammals and Caenorhabditis elegans, whereas Drosophila contains only 60 genes. Each OR specifically recognizes a set of odorous molecules that share common molecular features. In mammals, signal transduces through the G-protein-dependent signal pathway in the olfactory sensory neurons that synapse ultimately in the glomeruli of the olfactory bulb, and is finally processed in higher brain structures. The expression of a given OR conditions neuron and glomerulus choices. To date, the processes which monitor OR expression and axon wiring have emerged but are not completely elucidated.

Isolation and characterization of S genome specific sequences from Aegilops sect. sitopsis species.

Three S genome specific sequences were isolated from Aegilops sect. sitopsis species using different experimental approaches. Two clones, UTV86 and UTV39, were isolated from a partial genomic library obtained from DNA of Aegilops sharonensis, whereas a third clone, UTV5, was isolated from Aegilops speltoides. The three clones were characterized by sequencing, analysis of methylation, and sequence organization and abundance in some Aegilops and Triticum species. The clones UTV39 and UTV5 belong to the same family of tandem repeated sequences and showed high homology with a sequence already present in nucleotide databases. The UTV86 clone from Ae. sharonensis corresponded to an interspersed low frequency repeated sequence and did not show any significant homology with reported sequences. Southern hybridization experiments, using the cloned sequences as probes, detected polymorphism in the restriction patterns of all the five Aegilops species in section sitopsis. Aegilops speltoides showed the most divergent hybridization pattern. A close relationship was detected between the S genome of Ae. speltoides and the G genome of the wild Triticum timopheevii. In situ hybridization revealed a telomeric and (or) subtelomeric location of the sequences UTV39 and UTV5.

Blood pressure independent association of microalbuminuria and left ventricular hypertrophy in hypertensive men.

BACKGROUND: Rather unique amongst the prognostic predictors, microalbuminuria (MA, albuminuria: 15-200 microg min-1) is associated with several cardiovascular risk factors including left ventricular hypertrophy (LVH). The relationship, usually assumed to reflect an increased blood pressure (BP) load on the heart and the kidney, may, however, represent more than a haemodynamic correlate. METHODS: To evaluate this possibility, we related MA to left ventricular mass index (LVMI) and other functional and structural echocardiographic parameters, office and 24-h BP, weight, lipids and smoking status in 330 never treated nondiabetic hypertensive men. RESULTS: The risk of MA increased linearly by ascending quartiles of LVMI and was 2.3-fold higher in the presence of LVH after adjustment for age, left atrial size, mean fractional shortening. Systolic BP, either office or 24 h, and smoking status were the only additional independent predictors in multivariate logistic regression models. The BP-adjusted risk of MA was about twofold higher in patients with LVH, either concentric or eccentric, and neutral in those with concentric remodelling compared with normal geometry. CONCLUSIONS: The association between elevated LVMI and MA independent of several other potential confounders, systolic BP in particular, is consistent with the existence of cardiac albuminuric factors, possibly of hormonal nature, which are to be identified more precisely. The extent to which LVH explains the predictive power of MA for morbid events independent of the BP load remains unknown.

Coronary microcirculation into different models of left ventricular hypertrophy-hypertensive and athlete's heart: a contrast echocardiographic study.

The study was carried out in two different models of left ventricular hypertrophy: athlete's heart and essential arterial hypertension. Three groups of strictly age-matched males were studied: one group of 10 young adult untreated essential hypertensive patients (H), a second group of 10 athletes (A), and a group of 10 healthy individuals as controls (C). A Sonos 5500 echograph with S4 harmonic transducer was used with Levovist (ultrasonic tracer) before and after dipyridamole injection; digitised images of quantitative myocardial contrast echocardiography were collected with Power Harmonic Doppler. Angio images were analysed using dedicated PC software by placing a region-of-interest on the septum. Peak intensity, half-time (HT), the area under the curve of appearance and disappearance of microbubbles at 2/3 of PI, both in absolute and indexed values (/LVMi), were sampled. The per cent increase of PI after dipyridamole was significantly higher in C (+73%, P < 0.01) than in H (+31%) and in A (+33%) (P < 0.05). The area of appearance was significantly lower in H in comparison with C and A, both at rest and after vasodilatation. The disappearance area after dipyridamole was significantly higher in C and in A (+124%) than in H (+104%) (P < 0.05). Some hypothesis could be made: an impairment in the coronary microcirculatory function in hypertensive patients could be because of an in-crease in the arteriolar resistance. Angiogenesis and several different functional adaptations are the mechanisms that allow an optimal distribution of oxygen and of substrates to the hypertrophied myocardium of the athletes.

Coronary microcirculation in essential hypertension: a quantitative myocardial contrast echocardiographic approach.

AIMS: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls. METHODS AND RESULTS: Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole. CONCLUSION: The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected.

Quantification of the effect of mammographic screening on fatal breast cancers: The Florence Programme 1990-96.

Breast cancer cases diagnosed in women aged 50-69 since 1990 to 1996 in the City of Florence were partitioned into those who had been invited to screening prior to diagnosis and those who had not. All cases were followed up for vital status until 31 December 1999. The cumulative number of breast cancer deaths among the cases were divided by screening and invitation status, to give the rates of cancers proving fatal within a period of 8 years of observation (incidence-based mortality). We used the incidence-based mortality rates for two periods (1985-86, 1990-96), pre and during screening. The incidence-based mortality ratio comparing 1990-96 and 1985-86 was 0.50 (95% CI : 0.38-0.66), a significant 50% reduction. For noninvited women, compared to 1985-86, there was a 41% significant mortality reduction (RR=0.59, 95% CI : 0.42-0.82). The comparable reduction in those invited was a significant 55% (RR=0.45, 95% CI : 0.32-0.61). The incidence ratio of rates of cancers stage II or worse was close to one when the noninvited in 1990-96 were compared with 1985-86 (RR=0.97, 95% CI : 0.78-1.21). Excluding prevalent cases, the rate of stage II+ breast cancer cases was 42% lower in Screened women compared with the noninvited (RR=0.58, 95% CI : 0.45-0.74). This study confirmed that new treatments and the first rounds of the screening programme contributed to reducing mortality from breast cancer.

Assessment of the early impact of the population-based breast cancer screening programme in Florence (Italy) using mortality and surrogate measures.

The aim of this study was to evaluate the effects by the end of 1999 of the Florence breast screening programme that started in 1990. Approximately 60000 women (aged 50-69 years) were enrolled from 1990 to 1993. Breast cancer cases diagnosed from 1990 to 1996 were partitioned by the method of detection, classified by their tumour size and nodal status and followed-up for mortality at on the 31 December 1999. Incidence-based mortality in the 50-74-year-old women and advanced carcinomas rates were assessed. Due to low compliance (approximately 60%) and the long enrollment phase, only approximately 35% of the total age-specific population person-years were screened. The number of invasive cases diagnosed was 1122, 17% higher than the 958 expected. After the prevalence screening, a reduction of approximately a quarter in advanced carcinomas was observed in the invited women (Odds Ratio (OR): 0.74; 95% Confidence Interval (CI): 0.55-0.98). In the period 1990-1999, 547 breast cancer deaths were observed: 78 (14%) occurred in women invited and half of these in never responders, 385 (70%) occurred in cases diagnosed before screening started. Disproportionate numbers of deaths occurred in women with advanced tumours. The 19% mortality reduction for the invited women was of borderline statistical significance (observed/expected (O/E) deaths: 0.81; 95% CI: 0.64-1.01); by a one-sided test the result would be unequivocally significant. The mortality reduction attributable to screening in the whole population over the 10-year period was 3.2%. The incidence-based mortality analysis confirmed the current follow-up time is too short for screening to have had a major effect on the breast cancer mortality trends. Screening performance might be improved by a higher level of compliance and shorter interval times, but the estimate of the mortality reduction for the invited and the lower rate of advanced carcinomas confirmed that the effect of the programme is in the expected direction.

Monitoring interval cancers in mammographic screening: the Florence District programme experience.

The aim of the present study was to monitor the occurrence of interval (breast) cancers (IC) as an interim outcome measure of quality assurance in the mammographic screening programme of the District of Florence. IC were identified by linking breast screening data with registrations of breast cancers from the Tuscany Tumour Registry. The main outcome measures were the numbers, rates, and the proportionate incidence of IC. Overall, 90 invasive IC were observed among women who attended the breast screening programme in the District of Florence from 1 January 1985 to 31 December 1993, respectively, 23, 50, on 17 cases, at 1, 2, and 3 years after the last negative screening test. Expressed as a proportion of underlying incidence, the figures are 16, 44, and 46%. As to risk factors for IC, mammographic density was the most important one in the present survey, whereas no effect of age emerges from the present study.

The myosin light chain kinase gene is not duplicated in mouse: partial structure and chromosomal localization of Mylk.

The gene encoding myosin light chain kinase (MYLK) is duplicated on human chromosome 3 (HSA3; 3p13;3q21) and on a chromosome with conserved synteny to HSA3 in most non-human primate species. In human, the functional copy resides on 3q21, whereas the 3p13 site contains a pseudogene. To trace the origin of the duplication, we characterized the mouse gene Mylk. A single sequence corresponding to the functional Mylk was detected. We sequenced a 180-kb bacterial artificial chromosome clone containing the 24 first exons of Mylk; the complete mouse gene is expected to span >200 kb. Comparisons with the draft of the human genome revealed that the sequence and structure of MYLK are conserved in mammals. Fluorescence in situ hybridization (FISH) analysis indicated that the mouse gene localizes to a single site on chromosome 16B4-B5, a region with conserved synteny with HSA3q. Our study provides information on both the structure and the evolution of MYLK in mammals and suggests that it was duplicated after the divergence of rodents and primates.

Cyclic variation of the myocardial integrated backscatter signal in hypertensive cardiopathy: a preliminary study.

BACKGROUND: Ultrasound tissue characterization studies realized through integrated backscatter analysis with end-diastolic sampling in hypertensive cardiopathy have demonstrated that abnormalities in the left ventricular myocardial ultrasonic texture are present in extreme forms of left ventricular hypertrophy (LVH). Such abnormalities are not evident in the athlete's heart. The aim of the present study was to analyze the ultrasonic backscatter myocardial indexes both as peak end-diastolic signal intensity and as cardiac-cyclic variation in two models of LVH: hypertensive cardiopathy and athlete's heart. METHODS: Three groups of 10 subjects each, all men of mean age (31.6+/-3.5 years), and of comparable weight and height, were analyzed. Group A comprised 10 cyclists of good professional level, while hypertensive patients were grouped in Group H. Both groups presented a comparable left ventricular mass (LVM). Group C included 10 healthy subjects acting as controls. The men with hypertension were selected on the basis of the results of ambulatory monitoring of the blood pressure according to ISH-World Health Organization guidelines (International Society of Hypertension). A 2D-color Doppler echocardiography with a digital echograph Sonos 5500 (Agilent Technologies, Andover, Massachusetts, USA), was carried out on all the subjects in the study for conventional analysis of the LVM and function. The ultrasonic myocardial integrated backscatter signal (IBS) was analyzed with an 'acoustic densitometry' module implemented on a AT echograph. The signal was also sampled with a region of interest (ROI) placed at interventricular septum and at posterior left ventricular wall level. The systo-diastolic variation of the backscatter was also considered, as cyclic variation index (CVIibs). RESULTS: According to the inclusion criteria, the LVM was comparable in groups A and H, but it was significantly higher than group C (left ventricular mass (body surface) (LVMbs)=154.5+/-18.7 (A), 146.8+/-25.5 (H), 101.4+/-12.4 (C), p < 0.001). The end-diastolic IBS did not show significant statistical differences among the three groups. The CVI(IBS) both at septum (30.5+/-5.3 (A), 13.2+/-13.1 (H), 27.2+/-7.3(C), p < 0.002) and posterior wall level (43.7+/-9.1 (A), 16.5+/-12.1 (H), 40.7+/-9.1 (C), p < 0.001) though, was significantly lower in the hypertensive patients than in both the athletes and the control group, where the results were comparable. CONCLUSION: A significant alteration of the myocardial CVIibs (both for septum and posterior wall) was found in the hypertensive model. This was probably the expression of an alteration in the intramural myocardial function.