The Cost-Effectiveness of Universal Varicella Vaccination in Italy: A Model-Based Assessment of Vaccination Strategies.

BACKGROUND: In 2017, varicella vaccination became mandatory for all children in Italy, based on a two-dose schedule administered at 12-15 months of age and 5 to 6 years of age. Varicella vaccines are available in different formulations (as a single vaccine or as a combination vaccine together with measles, mumps, and rubella) and are made by multiple manufacturers with different effectiveness profiles. This study calculates the cost-effectiveness of a range of varicella vaccination strategies to identify the optimal strategy for Italy. METHODS: A dynamic transmission cost-effectiveness model was applied in Italy to simulate the long-term (50 years) costs and outcomes associated with different varicella vaccination strategies. Five vaccination strategies were evaluated using the model: two doses of two different combination Measles-Mumps-Rubella-Varicella vaccines (either Vaccine A (MSD) [denoted QQVa] or Vaccine B (GSK) [denoted QQVb]); a first dose of a single Varicella vaccine followed by a second dose of a combination vaccine (either Vaccine C (MSD) followed by Vaccine A [denoted MQVa] or Vaccine D (GSK) followed by Vaccine B [denoted MQVb]); or no vaccine at all (NV). The model was adapted for Italy using publicly available Italian data and expert opinion. RESULTS: Over the 50-year time-horizon, in the absence of universal varicella vaccination, there would be 34.8 million varicella cases, 142 varicella-infection-related deaths, and €23 billion in societal costs. The cost per capita from a societal perspective ranged from €164.55 to €392.18 with NV being the most expensive and QQVa the least expensive. The most effective strategy was QQVa, which resulted in a 66% decrease in varicella cases and 30% reduction in varicella-related deaths compared to NV strategy. QQVa led to a net saving in societal cost around €13 billion compared to NV as the cost of vaccination was more than offset by the savings that resulted from the reduced burden of illness. CONCLUSION: Varicella vaccination has a major impact on reducing varicella incidence, prevalence, and societal costs. This analysis supports the policy for universal varicella vaccination in Italy as the NV strategy was the most expensive and resulted in the poorest outcomes. QQVa offers the greatest benefits at the lowest cost and should be considered as a potential priority strategy for Italian population.

Interspecies transfer of vancomycin, erythromycin and tetracycline resistance among Enterococcus species recovered from agrarian sources.

BACKGROUND: Enterococci are now well recognised for their ability to transfer antibiotic resistance and for their association with nosocomial infections, but less is known regarding their relevance in the wider environment. Enterococcus faecalis and Enterococcus faecium were isolated from a range of agrarian associated sources (low-flow water, septic tank, poultry litter, high flow water, slurry/soil) and were assessed for latent ability to transfer antimicrobial resistance. RESULTS: The isolates were tested for phenotypic clumping in the presence of cell-free supernatant from other isolates. Some isolates were identified which demonstrated clumping, indicating that they possessed peptide sex pheromone conjugal machinery. All isolates were also tested for antibiotic resistance phenotypes using both disc diffusion and minimum inhibitory concentration (MIC) assays. These tests revealed that the enterococci demonstrated both phenotypic clumping and antibiotic resistance phenotypes. Based on these selection criteria, the isolates were identified as having the potential for horizontal gene transfer and were used to investigate the transfer of multiple antibiotic resistance phenotypes. Conjugal transfer of antibiotic resistance phenotypes was determined using a solid agar mating method followed by a standard antibiotic selection test resulting in different transfer patterns. An interspecies conjugal transfer of vancomycin resistance from E. faecalis to E. faecium was identified while the remaining reactions were within the same species. Transfer efficiencies ranging from 2 × 10-1 to 2.3 × 10-5 were determined based on the reactions of three donor isolates (MF06036, MF0410 and MF06035) and two recipient isolates (MW01105Rif and ST01109Rif), with the transfer of vancomycin, erythromycin and tetracycline resistance genes. CONCLUSIONS: The conjugation reactions and selection conditions used in this study resulted in a variety of co-transferred resistance phenotypes suggesting the presence of different mobile elements in the set of natural isolates. This study highlights the potential for extensive horizontal gene transfer in a previously neglected reservoir for enterococci.

Modulation of the conformational state of the SV2A protein by an allosteric mechanism as evidenced by ligand binding assays.

BACKGROUND AND PURPOSE: Synaptic vesicle protein 2A (SV2A) is the specific binding site of the anti-epileptic drug levetiracetam (LEV) and its higher affinity analogue UCB30889. Moreover, the protein has been well validated as a target for anticonvulsant therapy. Here, we report the identification of UCB1244283 acting as a SV2A positive allosteric modulator of UCB30889. EXPERIMENTAL APPROACH: UCB1244283 was characterized in vitro using radioligand binding assays with [(3)H]UCB30889 on recombinant SV2A expressed in HEK cells and on rat cortex. In vivo, the compound was tested in sound-sensitive mice. KEY RESULTS: Saturation binding experiments in the presence of UCB1244283 demonstrated a fivefold increase in the affinity of [(3)H]UCB30889 for human recombinant SV2A, combined with a twofold increase of the total number of binding sites. Similar results were obtained on rat cortex. In competition binding experiments, UCB1244283 potentiated the affinity of UCB30889 while the affinity of LEV remained unchanged. UCB1244283 significantly slowed down both the association and dissociation kinetics of [(3)H]UCB30889. Following i.c.v. administration in sound-sensitive mice, UCB1244283 showed a clear protective effect against both tonic and clonic convulsions. CONCLUSIONS AND IMPLICATIONS: These results indicate that UCB1244283 can modulate the conformation of SV2A, thereby inducing a higher affinity state for UCB30889. Our results also suggest that the conformation of SV2A per se might be an important determinant of its functioning, especially during epileptic seizures. Therefore, agents that act on the conformation of SV2A might hold great potential in the search for new SV2A-based anticonvulsant therapies.

On the road to leucine-rich repeat kinase 2 signalling: evidence from cellular and in vivo studies.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Although PD has long been considered a purely sporadic disorder, genetic research has revealed an underlying genetic cause in at least 10% of all PD cases. To date, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial PD. Moreover, given the strong clinical and neuropathological similarities between LRRK2 PD and the sporadic forms of the disease, the notion is supported that the unravelling of the molecular pathways underlying LRRK2 PD will greatly contribute to our general understanding of PD. Therefore, intense research efforts have been focused on the understanding of the physiological function of LRRK2 and its relation to PD. To date, progress has been made in these fields based on the study of LRRK2 cell culture models, the identification of LRRK2 interaction partners and kinase substrates and the generation of LRRK2 animal models. In this review, the current insights into the cellular role of LRRK2 are discussed. The overview reveals a potential involvement of LRRK2 in major cell signalling pathways including apoptosis, cytoskeleton dynamics, protein translation, mitogen-activated protein kinase signalling and specific dopaminergic functions, consistent with its proposed role as a signal transduction protein.

Antihypertensives.

Management of hypertension requires a thorough knowledge of currently available antihypertensive drugs. This article reviews the mode of action of the major classes of antihypertensives, indications for their use, and adverse effects. The main emphasis is placed on their use, in physiatric practice.

High-performance liquid chromatographic method for the determination of nelfinavir, a novel HIV-1 protease inhibitor, in human plasma.

Nelfinavir mesylate, a potent and orally bioavailable inhibitor of HIV-1 protease (Ki=2 nM), has undergone Phase III clinical evaluation in a large population of HIV-positive patients. A high-performance liquid chromatography analytical method was developed to determine the pharmacokinetic parameters of the free base, nelfinavir, in these human subjects. The method involved the extraction of nelfinavir and an internal standard, 6,7-dimethyl-2,3-di-(2-pyridyl)quinoxaline, from 250 microl of human plasma with a mixture of ethyl acetate-acetonitrile (90:10, v/v). The analysis was via ultraviolet detection at 220 nm using a reversed-phase C18 analytical column and a mobile phase consisting of 25 mM monobasic sodium phosphate buffer (adjusted to pH 3.4 with phosphoric acid)-acetonitrile (58:42, v/v) that resolved the drug and internal standard peaks from non-specific substances in human plasma. The method was validated under Good Laboratory Practice (GLP) conditions for specificity, inter- and intra-assay precision and accuracy, absolute recovery and stability. The mean recovery ranged from 92.4 to 83.0% for nelfinavir and was 95.7% for the internal standard. The method was linear over a concentration range of 0.0300 microg/ml to 10 microg/ml, with a minimum quantifiable level of 0.0500 microg/ml for nelfinavir.

Race: an explanation of patient compliance--fact or fiction?

This article describes a retrospective study that examines the relationship between patient compliance and race among diagnosed hypertensives in the National Health and Nutrition Examination Survey (NHANES II). The study reviewed and analyzed the compliance of 403 blacks diagnosed with hypertension. Patient compliance was measured using the frequency that patients took their hypertensive medicine. Bivariate analysis revealed a statistically significant relationship with patient compliance (dependent) and the independent variables (age, education, gender, and smoking). Multiple regression for the black population revealed that the age of the person accounted for the most explained variance. As age increased among blacks, so did compliance. The results may suggest the need to target school-aged blacks early in order to increase the awareness and importance of monitoring one's blood pressure. The results also may indicate that race is not a marker for other characteristics (income, education, etc) that might be used to explain the difference in the prevalence of hypertension among blacks compared with whites.

Occlusion and the distortion of alignment in three-dimensional space.

When observers are asked to align two rectangular stimuli oriented at 45 degrees to the visual axis there is a slight tendency to set the more distant stimulus closer to the eye than its true coplanar position. However, when a large rectangular surface is interpolated between the two oblique stimuli and the observer, errors of alignment become relatively much larger. The displacement caused by the interpolated stimulus occurs both when the display is viewed monocularly and when it is viewed binocularly. Reducing the obliquity of the rectangles results in smaller judgment errors and increasing obliquity increases errors; this is true with and without occlusion. The addition of texture elements to the surfaces of the rectangles reduces judgment errors significantly, but only under conditions of occlusion. It is possible that misalignments recorded for three-dimensional displays have something in common with the two-dimensional Poggendorff illusion.

Drinking amongst medical patients: levels of risk and models of change.

Results are reported of a study in which 547 general hospital medical in-patients were screened, using a computer-administered questionnaire, for alcohol consumption, problems and concerns. Of males, 22.5% were classified as 'risk drinkers', of women 6.5%. Rates of risk were particularly high amongst younger male patients. It was concluded that certain screening questionnaire items were more useful than others in the general hospital context, and that standard questionnaires developed for other populations should not automatically be used in general hospitals. Comparisons with items relating to other health behaviours suggested that the medical profession, the general public and the patients themselves might be relatively insensitive to the risks associated with heavy drinking in comparison to those associated with smoking, weight and lack of exercise. Data from initial screening and from 75% of patients who were asked to repeat the questionnaire six months later, were used to test certain assumptions of a model of change based in part upon that of Prochaska & DiClemente (1986). Results suggested that processes of change were more complex than the model supposed.

Oxidative damage and the preservation of organic artefacts.

Organic artefacts degrade by a number of mechanisms. Autoxidation is one of the most important and involves free radicals. The importance of free radical reactions in the degradation of paper and other cellulosic materials, rubber and other organics is described. In the case of paper, treatment with calcium and magnesium compounds can inhibit oxidation, while transition metals increase the rate. Antioxidants have not been used a great deal due to unwanted side effects. The Russell effect, a technique for detecting oxidation using photographic materials, is described.

Steady-state response of quadriplegic subjects to inspiratory resistive load.

Normal subjects preserve tidal volume (VT) in the face of added inspiratory resistance by increasing maximal amplitude and duration of the rising phase of respiratory driving pressure (DP) and by changing the shape of this phase to one that is more concave to the time axis. To explore the possible role of chest wall afferents in mediating these responses, we determined averaged DP in eight quadriplegic subjects during steady-state unloaded breathing and while breathing through an inspiratory resistance (8.5 cmH2O X 1(-1) X s). As with normal subjects, quadriplegics preserved VT (loaded VT = 106% control) by utilizing all three mechanisms. However, prolongation of the inspiratory duration derived from the DP waveform (+22% vs. +42%) and shape response were significantly less in the quadriplegic subjects. Shape response was completely absent in subjects with C4 lesions. The results provide strong evidence that respiratory muscle spindles are responsible for shape response and that changes in afferent feedback from the chest wall play an important role in mediating inspiratory prolongation.

General practitioner surveillance of azatadine maleate/pseudoephedrine sulphate ('Congesteze') for the treatment of upper respiratory tract congestion.

A post-marketing, general practitioner surveillance programme involving 12,679 patients with upper respiratory congestion was carried out to assess how well tolerated was symptomatic treatment with a combination oral preparation containing azatadine maleate (1 mg) and pseudoephedrine sulphate (120 mg) given twice daily for up to 15 days. The improvement which patients experienced in the symptoms of sneezing, running nose, stuffy nose, watery eyes and itchy eyes was also evaluated. Analysis of the results showed that 97% of the patients experienced some relief. The incidence of drug-related side-effects was 4% but only 253 (2%) patients discontinued treatment for this reason. The side-effect most frequently reported was drowsiness and this was considered to be probably or possibly due to treatment in 332 (3%) of the patients.

[Crohn's disease and pregnancy]. / Morbus Crohn und Schwangerschaft.

The interrelationship of pregnancy with Crohn's disease is as nebulous as aetiology and pathogenesis of this inflammatory bowel disease. In the years 1964-1981 we have operated upon 342 patients with Crohn's disease. 47 women suffering from this disease became pregnant. Whereas pregnancy appears to have little influence on the course of Crohn's disease, the incidence of miscarriages appears to rise with increasing activity and extent of bowel involvement. Only in case of exacerbation or complications is medical or even surgical therapy indicated in the course of pregnancy. Abortion does not appear to influence the course of Crohn's disease favourably.

[Staging laparotomy for malignant lymphoma: interdisciplinary aspects and results (author's transl)]. / Die Staging-Laparotomie bei malignen Lymphomen. Interdisziplinäre Aspekte und Ergebnisse.

Between 1963 and 1979 a total of 357 patients with malignant systemic lymphatic disease underwent splenectomy in the course of exploratory laparotomy. There were three groups: 1. Hodgkin's disease (215 patients), 2. non-Hodgkin's lymphoma (93), and 3. chronic lymphoid leukaemia (49). Comparing pre- and postoperative findings, primary exploratory laparotomy remained the most exact foundation for the differentiated treatment of Hodgkin's disease in stages I-III. Systematic staging laparotomy was of less importance for non-Hodgkin's lymphoma and chronic lymphoid leukaemia because of the much more frequent invasion of bone marrow, spleen and liver. However, it should be considered more often in the management of such cases.

[Motility of the small intestine in dogs before and after total colectomy, proctomucosectomy and endorectal ileal pull-through]. / Die Dünndarmmotilität des Hundes vor und nach totaler Kolektomie, Proktomukosektomie und endorektalem Ileumdurchzug.

In healthy dogs the parameters (amplitude and frequency) of small intestinal motility of segmental and propulsive contractions demonstrate a pressure-gradient directed from oral to aboral. The frequency of segmental contractions in the colo-rectal region shows a vector in the opposite direction. One rarely finds propulsive activity in this area. Following on colectomy, proctomucosectomy and ileum pull-through a distinct increase in segmental small intestinal activity is noticed, while the frequency of propulsive movements simultaneously decrease. Thus it comes to a slowing of the passage of intestinal contents, and to increased water resorption. From these findings we conclude that the small intestine plays an essential part in the regaining of fecal continence in these animals.

[Emergency endoscopy after operation of the upper gastro-intestinal tract: problems and risks (author's transl)]. / Notendoskopie nach Operationen im Bereich des oberen Gastrointestinaltraktes. Problematik und Risiko.

Upper gastro-intestinal bleeding or other complications after operations on this tract can lead to grave additional risk for the patient, especially in the early postoperative phase. Because of its high degree of diagnostic accuracy, emergency endoscopy is in most cases of decisive importance in planning the type (conservative or surgical) and timing of any necessary treatment. Special investigative techniques as well as the early use of endoscopy in 97 patients achieved a high rate of success at a low risk to the patients. Indications, results and risks of emergency endoscopy of the upper gastro-intestinal tract in the late postoperative phase are similar to those for the non-operated patient.

[Gardner's syndrome. Diagnosis and surgical treatment (author's transl)]. / Das Gardner-Syndrom. Diagnose und chirurgische Therapie.

The early appearance of "hard" and "soft" tumors should give cause to search regularly for intestinal polyposis. Once the diagnosis is made prophylactic total colectomy with ileorectal anastomosis is justified. With regard to a polyposis of the upper gastrointestinal tract, there is room for observation. The possibility of a peripapillary carcinoma with or without simultaneous involvement of stomach and duodenum must be reckoned with even years after a colectomy. Postoperative mesenteric fibroses and widespread adhesions are responsible for subileus and ileus. Because of their tendency to recur, desmoid tumors should only be treated operatively when this appears unavoidable by reason of local symptoms.