Budget impact of rare diseases: proposal for a theoretical framework based on evidence from Bulgaria.

This study aimed to estimate the impact of rare disease (RD) drugs on Bulgaria's National Health Insurance Fund's (NHIF) total drug budget for 2011-2014. While standard budget impact analysis is usually used in a prospective way, assessing the impact of new health technologies on the health system's sustainability, we adopted a retrospective approach instead. Budget impact was quantified from a NHIF perspective. Descriptive statistics was used to analyse cost details, while dynamics was studied, using chain-linked growth rates (every period preceding the accounting period serves as a base). NHIF costs for RD therapies were expected to increase up to 74.5 million BGN in 2014 (7.8% of NHIF's total pharmaceutical expenditure). Greatest increase in cost per patient and number of patients treated was observed in conditions, for which there were newly approved for funding therapies. While simple cost drivers are well known - number of patients treated and mean cost per patient - in real-world settings these two factors are likely to depend on the availability and accessibility of effective innovative therapies. As RD were historically underdiagnosed, undertreated and underfunded in Bulgaria, improved access to RD drugs will inevitably lead to increasing budget burden for payers. Based on the evidence from this study, we propose a theoretical framework of a budget impact study for RD. First, a retrospective analysis could provide essential health policy insights in terms of impact on accessibility and population health, which are significant benchmarks in shaping funding decisions in healthcare. We suggest an interaction between the classical prospective BIA with the retrospective analysis in order to optimise health policy decision-making. Second, we recommend budget impact studies to focus on RD rather than orphan drugs (OD). In policy context, RD are the public health priority. OD are just one of the tools to address the complex issues of RD. Moreover, OD is a dynamic characteristic and compromises the consistency and comparability of the calculated budget indicators.

EPIDEMIOLOGICAL REGISTRY OF NEUROENDOCRINE TUMORS IN BULGARIA--A PILOT SURVEY.

The National registry of patients with neuroendocrine tumors (NET) in Bulgaria was established in 2013 as a joint initiative of the Bulgarian Surgical Society and the Institute for Rare Diseases. The register aims to explore the epidemiology of NET in Bulgaria, as well as the different diagnostic and treatment approaches for the disease throughout the country. This the first of its kind retrospective study of NET in the country is covering the period January 2012 - January 2013. A total of 127 patients with NET were identified. At the time of the survey the average age of patients with NET was 58.61 ± 15.59 years. The data show almost equal distribution between the genders with a slight predominance of women. The largest relative part of NET is those of NET located in the gastrointestinal tract (54.10 ± 4.51%), followed by those located in the pancreas (12.30 ± 2.97%) and in the lungs (10.66 ± 2.79%). In 72.44 ± 3.96% of the patients a immunohistochemical diagnosis was performed. The study confirmed the leading role of the surgery method of the NET management. In 65.83 ± 4.33% of the patients a radical removal of the tumor was conducted, while the relative part of the undertaken partial resection was 7.50 ± 2.40%. A statistically significant association between the type of surgical treatment and during the follow-up of patients was found. An update of the information in the register will allow a more precise determining of the distribution and management of NET in Bulgaria.

EUROPLAN: a project to support the development of national plans on rare diseases in Europe.

BACKGROUND/AIMS: National Plans for Rare Diseases (RDs) are the common denominator of current public health policy concerns on RDs across the EU. With the aim of a better distribution of the available resources, they conjugate the European objective that aims at ensuring that patients with RDs have access to high-quality care - including diagnostics, treatment and rehabilitation - with the national priorities of selecting specific measures for adoption and implementation. METHODS: The European Project for Rare Diseases National Plans Development (EUROPLAN, www.europlanproject.eu) is cofunded by the EU Commission (DG-SANCO) and is coordinated by the Italian National Center for Rare Diseases of the Istituto Superiore di Sanità (ISS). The EUROPLAN goal is to promote the implementation of National Plans or Strategies to tackle RDs and share relevant experiences within countries, linking national efforts, through a common strategy at a European level. In order to fulfill these objectives, EUROPLAN involved health authorities, clinicians, scientists, the European Organisation for Rare Diseases (EURORDIS), and many other patient groups as associated and collaborating partners from several European countries. RESULTS: The project was launched in 2008 and foresaw 2 implementation phases: phase 1 (2008-2011) to build the consensus definition of operational tools (recommendations and indicators), and the ongoing phase 2 (2012-2015), mainly aimed at capacity building with the proactive involvement of multilevel stakeholders. EUROPLAN is facilitating and accelerating the implementation of National Plans in almost all EU and several non-EU Countries. CONCLUSIONS: EUROPLAN is a European and an international process more than a project, and it could be defined as a 'litmus test' demonstrating how the collaboration between institutions and patients' associations can accelerate the process of awareness and development of policies and actions.

Evaluation of diagnostic and prognostic value of clinical characteristics of migraine and tension type headache included in the diagnostic criteria for children and adolescents in International Classification of Headache Disorders--second edition.

UNLABELLED: Data about the sensitivity and the specificity of the items included in the diagnostic criteria for migraine and tension type headache (TTH) in children is limited and sometimes controversial. AIM: To evaluate the diagnostic value of characteristics of migraine and TTH included in the diagnostic criteria of ICHD-II and according to results to suggest additional criteria for diagnostic differentiation of primary paediatric headache. PATIENTS AND METHODS: The investigation consisted of an epidemiological school-based study (1029 pupils completed the study and 412 had chronic or recurrent headache) and a clinical study conducted in Paediatric Neurology Ward and outpatient clinic (203 patients with chronic or recurrent headache). Inclusion criterion was at least two episodes of headache during the last year. Exclusion criteria were: headache occurring only during acute infections; withdrawal of informed consent. ICHD - II was used to classify headache. The diagnostic value of characteristics of migraine and TTH was measured using sensitivity, specificity, odds ratio and area under receiver operating characteristic curve (AUC). RESULTS: Regarding the AUC, the best diagnostic items for migraine are: moderate or severe intensity or only severe intensity, pain aggravation by physical activity, pulsating quality, respectively, for TTH - no photophobia, no nausea, no aggravation by physical activity, mild or moderate intensity and non-pulsating quality. The most significant symptom for increasing the migraine risk was pulsating pain and the most significant items for TTH risk were no photophobia, bilateral location and no nausea. Family history of migraine also increased migraine risk and could be either included in the diagnostic criteria for migraine or recommended as additional item in differentiating migraine and TTH with overlapping diagnostic criteria. According to AUC, we could recommend changing the content of the item of intensity for migraine as only severe intensity.

General knowledge and awareness on rare diseases among general practitioners in Bulgaria.

Rare diseases are a serious public health problem and are a threat to the health of EU citizens. Important role in the area of rare diseases have the medical specialists who diagnose and monitor the course of the disease of each patient. General practitioners (GPs) are usually the first to identify "unusual" patients that might have a rare disease. The GPs awareness and knowledge about rare diseases is a strong factor for the timely and accurate diagnosis and adequate treatment of rare diseases conditions. A telephone interview was conducted among the GPs in Bulgaria between January and March 2008. A set of 10 questions with pre-defined answers was constructed and offered to the GPs in order to determine their level of knowledge and awareness of rare diseases. Data were statistically processed using specialized software SPSS version 9.0 (SPSS, Inc., Chicago IL). The responses of surveyed doctor indicate a low level of general knowledge and awareness. This means, that GPs from the primary health care system in Bulgaria could not provide sufficient in quality and timeliness specific information to their patients with rare diseases. A campaign for increasing the awareness of GPs about rare diseases is needed.

Cu/Zn-superoxide dismutase from the fungal strain Humicola lutea 103 improves ram spermatozoa functions in vitro.

In this study we determined the effect of reactive oxygen species (ROS) generation during incubation in media at 39 degrees C on ram spermatozoa and the protection by exogenously added antioxidant enzyme, superoxide dismutase (SOD). A novel Cu/Zn-SOD, isolated from the fungal strain Humicola lutea 103 (HLSOD), was used. Our results point out that the levels of both, superoxide anion radicals (*O2-) and H2O2, increase approximately 8-10- and 2-3-fold, respectively, during incubation of spermatozoa. Enhanced ROS generation coincided with reduction of motility, independently of the type of diluted medium. Addition of HLSOD (30, 60 and 120 U ml(-1) sperm) improved sperm functions, maintaining almost initial percentages of motile spermatozoa and increasing the values of mean cytochemical coefficient. At the same time, a significant diminution of *O2- and H2O2 content in the presence of antioxidant enzyme was established. The results suggest that HLSOD is an effective *O2- scavenger in semen that leads to protection of sperm functions.

Cytomegalovirus infection in infants: an example of a chronopharmacological approach.

A case of a male infant at the age of 3 months with cytomegalovirus (CMV) infection, diagnosed 40 days after the first symptoms, was discussed. While the right dosage and schedule during the initial treatment with ganciclovir (Cymevene) were agreed on, the right time of further application of anti-CMV IgG (Cytotest) and ganciclovir was unclear. Daily mean temperature was taken as an overall measure based on 7 single readings (6:00, 9:00, 12:00, 15:00, 18:00, 21:00 and 24:00 h +/- 10 min). Dynamics of daily mean temperature was studied by descriptive statistics, regression analysis, autocorrelation and periodogram regression analysis (software package "6-D Statistics" PC ver.4.5-98 by B. P. Komitov) with the purpose of identifying the time periods of viral DNA replications and CMV population growth inclinations. A five-step procedure was applied: (1) description of a tendency in the daily mean temperature; (2) studying variations in time series of the daily mean temperature; (3) decomposition of cyclic variations; (4) reconstruction of time series; (5) best model determination and forecasting. Three main cycles in variations of daily mean temperature were revealed (period T approximately 2.25-3.25, 5.5 and 12.25 days, p < 0.05) until the 37th day of therapy, when a strongly decreasing trend of daily mean temperature emerged. The cycle of 2.25-3.25 days disappeared and the daily mean temperature continued to decrease significantly on the background of improvement of the clinical status. It was concluded that (1) cyclic patterns in daily mean temperature (periods T = 2.25-3.25 and 12.25 days) during the etiologic medication stages could be due to the life-cycle of 2-4 days of the cytomegalovirus and a cycle in the viral population growth, respectively. The above findings confirmed previous results on the period of viral DNA replication from in vitro studies. It was possible to forecast the right moment of replication and viral load to adjust the treatment schemes and improve the outcome; (2) the complex time-series approach has shown to be very useful and effective in analyzing and forecasting the temporal dynamics of daily mean temperature in order to optimize the clinical management in this particular case of an infant with CMV infection.

Age at marriage and intrafamily planning in young families.

INTRODUCTION: The sociological inquiry on current problems of intrafamily planning carried out in 1995 provided opportunities for finding the effect of a number of social and demographic factors on the formation of family. OBJECTIVE: The present study has investigated the influence of the age of woman at marriage on the main indicators characterizing the reproductive behavior. MATERIAL AND METHODS: Direct individual inquiry was performed and 500 young families from the town of Plovdiv were approached. Data were analyzed by percentage distribution methods and non-parametric tests. RESULTS AND DISCUSSION: We should note here the high percentage of spouses who had not planned the number of children in their future family--33.1% of women and 34.3% of men. Paradoxically, the percentage of women that had not planned the number of children in their families increases with age. The intended number of children does not depend on the age of women at marriage. The women aged below 19 have indicated the highest number of children. The "ideal number of children" indicator has the highest value in women aged below 19 (2.25 children), but there is no statistically significant difference in the ideal number of children between the different age groups. The opinion about a "large family" is studied in spouses and relatives of the young family. With the increase of age, the number of children in the "large family" decreases in all three groups (P < 0.001). There is no difference in length of the protogenetic interval between different age groups. Intergenetic interval between the first and second birth is about three years in all three age groups. The largest interval between the second and third birth is registered in women aged above 25. About half of the women have admitted that they do not wish to have a third child. The age at last delivery is highly correlated with age at marriage (P < 0.05); the correlation is strongest in women above 25 years of age.

Assistance with generalized net models to the differential diagnosis of some pathologic somatic muscular and neurologic conditions in stomatology.

Some somatic pathologic muscular and neurologic conditions in stomatology are difficult to differentiate. For example, the myofascial pain dysfunction syndrome, trigger point muscle pains and a number of temporomandibular joint related pathoses often cause diagnostic difficulties. With the purpose to assist general clinicians and students to understand and differentiate more easily these difficult occasions, the authors try to offer a model simulating the decision-making process in some of the aforementioned pathoses. The model is based on the Generalized Nets Models which represent extensions of Petri's nets and their modifications.

The most common cause of cascade stomach.

In a random sample of 396 patients with stomach complaints, 54 were found to have cascade stomach (overall frequency 13.6%). The analysis of the results showed the leading cause of this condition to be adhesion of the front costal diaphragm sinus.

[Echocardiographic research on the left ventricular function of patients with a complete atrioventricular block before and after pacemaker implantation]. / Ekhokardiografski izsledvaniia na levokamernata funktsiia pri bolni s pulen atrio-ventrikularen blok predi i sled implantirane na peismeikur.

Twenty seven patients with total atrioventricular (AV) block at the age of 29-83 were examined (average age--69 years, females--13, males--14); with cardiac decompensation stage 1-8 patients, stage II--13 patients and stage III--1 patient; without cardiac decompensation--5 patients. During the examination period, no cardiotonics and dehydrating drugs were administered. The examination was carried out prior to and 10 days post the implantation of an electro-stimulator VVI with an echocardiograph M-type in the standard method. The examination prior to the implanted pacemaker manifested moderately to strongly expressed pathological deflection of the mean values of all echocardiographic indices for the pumping and contractile function of the left cardiac ventricle: increased diastolic size, diastolic index and diastolic volume of the left ventricle, mean values of the fraction of contraction, ejection fraction, velocity of circumferential fibers shortening in the lower limits of the norm and increased mean values of stroke volume and reduction of minute volume. The results from the examination are given in Table 1a and 1b. The second examination of the same indices after 10 days gives the improvement of the mean as well as of the final values of the basic echocardiographic indices with a very good correlative coefficient R = 0.92-0.96, P = 0.001. Decrease of the diastolic size with 8.4% was determined as well as of the systolic size with 3.8%, of the diastolic volume with 23.2%, of the systolic volume--with 19.4%, increase of the minute volume with 19.8%.(ABSTRACT TRUNCATED AT 250 WORDS)