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.

Budget impact analysis of introducing a non-reconstituted, hexavalent vaccine for pediatric immunization in the United Kingdom.

Objectives: Non-reconstituted, hexavalent vaccines (HV-NRs) can facilitate clinical practice by shortening vaccine preparation and administration time and by reducing the risk of vaccination errors compared to combination vaccines requiring reconstitution. The aim of this study was to determine the budget impact of introducing an HV-NR into the United Kingdom's (UK) pediatric immunization program, which currently uses a hexavalent vaccine requiring reconstitution (HV-R). Methods: Abudget impact model covering a 10-year time horizon was developed. The target population constituted closed UK birth cohorts from 2020 to 2029. Total direct costs from the payer's perspective consisted of four main categories: vaccine acquisition and management, healthcare provider's service provision, (non-)contaminated needle-stick and sharps injury (NSI), and non-NSI vaccination error costs. The net budget impact was calculated by comparing the costs in two different market share scenarios. Results: The use of HV-NR instead of HV-R was estimated to save £9,079,927 over a 10-year time horizon (i.e. £907,993 per year). Assuming all other vaccine criteria are equivalent the budget impact was most sensitive to changes in time spent by the healthcare provider and management costs. Conclusion: Results suggest, introducing an HV-NR into the UK's pediatric immunization program is potentially cost saving for the healthcare system.

Perineal stapled prolapse resection (PSPR) in elderly patients for external rectal prolapse: early experience.

BACKGROUND: Full-thickness rectal prolapse in frail elderly patients is often treated by a perineal approach with considerable attendant morbidity. We report our preliminary results of the perineal stapled prolapse resection (PSPR) technique for resection of full-thickness external rectal prolapse using a new reloadable Contour(®) Transtar™ stapler (Ethicon Endo-Surgery) device. METHODS: Fourteen elderly high-risk patients with an external prolapse up to 10 cm in length were treated between April 2010 and October 2011, and operative factors, outcome and recurrence rates were assessed. RESULTS: There were no intraoperative difficulties and no perioperative morbidity. The median operating time was 35 min (range 25-45 min) with a median hospital stay of 3 days (range 3-5 days). Four patients developed early recurrence over a median follow-up of 32 months (range 25-41 months). CONCLUSIONS: PSPR is safer, faster and easier to perform than other conventional perineal prolapse procedures and is suitable for elderly, high-risk patients for whom an abdominal approach under general anesthesia is not advisable.

CF102 an A3 adenosine receptor agonist mediates anti-tumor and anti-inflammatory effects in the liver.

The Gi protein-associated A(3) adenosine receptor (A(3) AR) is a member of the adenosine receptor family. Selective agonists at the A(3) AR, such as CF101 and CF102 were found to induce anti-inflammatory and anti-cancer effects. In this study, we examined the differential effect of CF102 in pathological conditions of the liver. The anti-inflammatory protective effect of CF101 was tested in a model of liver inflammation induced by Concanavalin A (Con. A) and the anti-cancer effect of CF102 was examined in vitro and in a xenograft animal model utilizing Hep-3B hepatocellular carcinoma (HCC) cells. The mechanism of action was explored by following the expression levels of key signaling proteins in the inflamed and tumor liver tissues, utilizing Western blot (WB) analysis. In the liver inflammation model, CF102 (100 µg/kg) markedly reduced the secretion of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase in comparison to the vehicle-treated group. Mechanistically, CF102 treatment decreased the expression level of phosphorylated glycogen synthase kinase-3ß, NF-κB, and TNF-α and prevented apoptosis in the liver. This was demonstrated by decreased expression levels of Fas receptor (FasR) and of the pro-apoptotic proteins Bax and Bad in liver tissues. In addition, CF102-induced apoptosis of Hep-3B cells both in vitro and in vivo via de-regulation of the PI3K-NF-κB signaling pathway, resulting in up-regulation of pro-apoptotic proteins. Taken together, CF102 acts as a protective agent in liver inflammation and inhibits HCC tumor growth. These results suggest that CF102 through its differential effect is a potential drug candidate to treat various pathological liver conditions.

Intracranial volume and dementia: some evidence in support of the cerebral reserve hypothesis.

The brain reserve hypothesis has been posited as being one important mediating factor for developing dementia, especially Alzheimer's disease (AD). Evidence for this hypothesis is mixed though different methodologies have made these findings difficult to interpret. We examined imaging data from a large cohort (N=194) of mixed dementia patients and controls, 65years old and older from the Cache County, Utah Study of Memory and Aging for evidence of the brain reserve hypothesis using total intracranial volume (TICV) as a quantitative measure of pre-morbid brain size and a vicarious indicator of reserve. A broader spectrum of non-demented elderly control subjects from previous studies was also included for comparison (N=423). In addition, non-parametric Classification and Regression Tree (CART) analyses were performed to model group heterogeneity and identify any subgroups of patients where TICV might be an important predictor of dementia. Parametrically, no main effect was found for TICV when predicting a dementia diagnosis; however, the CART analysis did reveal important TICV subgroups, including a sex differential wherein ε4 APOE allele presence in males and low TICV predicted AD classification. TICV, APOE, and other potential mediator/moderator variables are discussed in the context of the brain reserve hypothesis.

Long-term reproducibility of ambulatory blood pressure is superior to office blood pressure in the very elderly.

Although it is known that reproducibility of ambulatory blood pressure (BP) is superior to office BP in middle-aged subjects, little is known in older age groups. Hence, we compared the long-term reproducibility of ambulatory and office BP readings in subjects over the age of 75 years. A cohort of 72 subjects 75-90 years of age (mean, 82 years at baseline) had repeat office and ambulatory BPs 2 years apart under similar conditions. On the same day, patients underwent office BP measurements by a semi-automated device and then by ambulatory BP monitoring. Awake and sleep periods were divided according to a diary kept by each patient. The agreement between studies was assessed using the standard deviation of the differences (SDD) and Bland-Altman plots. There were minimal mean changes in office, 24-h, and awake and sleep mean BP values between baseline and 2 years later. The SDDs between visits were lower for 24-h BP compared with the office BP (11.7/5.9 mm Hg versus 17.8/9.0 mm Hg, P<0.01). The SDD for 24-h BP was also lower than the SDDs for the awake and sleep BP (P<0.05). Nocturnal BPs defined by absolute values were more reproducible than categories of dippers and non-dippers. These data demonstrate that long-term reproducibility of 24-h BP is superior to office measurements for very elderly subjects. In a clinical trial involving this age group, far fewer subjects would be required if 24-h BP was the primary efficacy endpoint rather than the office BP.

Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment.

OBJECTIVE: Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. METHODS: OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. RESULTS: CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. CONCLUSION: CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA.

IB-MECA, an A3 adenosine receptor agonist prevents bone resorption in rats with adjuvant induced arthritis.

OBJECTIVES: The anti-inflammatory effect of adenosine is partially mediated via the A3 adenosine receptor (A3AR), a Gi protein associated cell surface receptor. The highly selective A3AR agonist, IB-MECA was earlier shown to prevent the clinical and pathological manifestations of arthritis in experimental animal models of collagen and adjuvant induced arthritis (AIA). In this study we tested the effect of IB-MECA on the prevention of bone resorption in AIA rats and looked at the molecular mechanism of action. METHODS: Rats with AIA were treated orally twice daily with IB-MECA starting upon onset of disease and the clinical score was evaluated every other day. At study termination the foot, knee and hip region of both vehicle and IB-MECA treated animals were subjected to histomorphometric analysis. Western blot analysis was carried out on paw protein extracts. RESULTS: IB-MECA ameliorated the clinical manifestations of the disease and reduced pannus and fibrosis formation, attenuated cartilage and bone destruction and decreased the number of osteoclasts. In cell protein extracts derived from paw of AIA rats, A3AR was highly expressed in comparison to naïve animals. In paw extracts derived from IB-MECA treated AIA rats, down-regulation of the A3AR protein expression level was noted. PI3K, PKB/Akt, IKK, NF-kappaB, TNF-alpha and RANKL were down-regulated whereas caspase 3 was up-regulated. CONCLUSION: IB-MECA, a small highly bioavailable molecule, induces modulation of proteins which control survival and apoptosis resulting in the amelioration of the inflammatory process and the preservation of bone mass in AIA rats.

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101.

Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A(2A), A(2B), and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, P<0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.

Older people with impaired mobility have specific loci of periventricular abnormality on MRI.

BACKGROUND: Recent investigations using MRI suggest that older persons with mobility impairment have a greater volume of abnormal cerebral white matter compared with persons with normal mobility, thus raising the possibility that those with impairment have lesions in areas critical for the control of mobility. OBJECTIVE: To utilize automated image analysis methods to localize the specific regions of abnormal white matter that distinguish subjects with lower mobility from subjects with higher mobility. METHODS: Tissue classification was performed on subjects' dual-echo long repetition time spin-echo MRI using computer algorithms operating on intensity criteria integrated with anatomic information. Statistical analysis of group differences was obtained after spatially normalizing each brain to a standard reference brain. RESULTS: Four discrete periventricular regions, including bilaterally symmetric frontal and bilateral occipitoparietal regions, were identified as being sensitive (frontal) or specific (occipitoparietal) in discriminating the subjects with lower mobility from subjects with higher mobility. The symmetry of these lesions in individual subjects suggested pathology other than arteriolar infarction. CONCLUSIONS: These results suggest that damage to discrete frontal and occipitoparietal periventricular white matter locations may be associated with a mobility disorder of aging.

Interpersonal psychotherapy for late-life depression: past, present, and future.

Interpersonal psychotherapy (IPT) has demonstrated efficacy in protecting against a recurrence of major depression in elderly subjects when used alone on a monthly basis and when combined with antidepressant medication. The authors summarize their experience using IPT over the past 10 years and discuss a variety of treatment correlates. In addition, preliminary results using IPT combined with paroxetine in depressed elders reveals no difference in remission rates between cognitively intact and cognitively impaired depressed elders.

Gait and balance dysfunction: a model of the interaction of age and disease.

This article reviews age-associated changes in gait, balance, and sensorimotor function and contrasts them to the changes that occur as a result of disease. Strength peaks in the mid-20s but declines only modestly until the fifth decade, after which there is rapid decline. All aspects of sensory function diminish with age, resulting in modest sensory changes in older patients. Gait speed is stable until the seventh decade and thereafter slows modestly. Age-related changes in the balance of older persons result in an effective response that meets routine needs but may be ineffective under demanding circumstances capable of producing response. Thus, these modest age-related decrements may be an element in the increased incidence of falls in older people. The loss of function caused by disease is of greater magnitude as well as being superimposed on that caused by age and thus may lead to a failure of mobility. Neurologic diseases that impair sensorimotor function compromise mobility in a manner consistent with the deficits that they produce. In mobility dysfunction caused by white matter lesions, the gait/balance abnormalities may not have unique clinical features, making diagnosis difficult. We used quantitative MRI to study the brains of older subjects with mobility impairment. The volume of white matter lesions in mobility-impaired subjects was double that of controls and was unrelated to increasing age, suggesting that white matter lesions are a disease-related rather than an age-related occurrence. We also used stance perturbation evoked potentials to demonstrate delayed conduction in some mobility-impaired older subjects. Prolonged sensory conduction may contribute to maladaptive balance and thus may be useful for diagnosis. Contemporary imaging and neurophysiology thus provides insight into the pathophysiology of mobility impairment and allows for more accurate diagnosis.

Lower standing systolic blood pressure as a predictor of falls in the elderly: a community-based prospective study.

OBJECTIVES: We investigated prospectively the relationships among falls, physical balance, and standing and supine blood pressure (BP) in elderly persons. BACKGROUND: Falls occur often and adversely affect the activities of daily living in the elderly; however, their relationship to BP has not been clarified thoroughly. METHODS: A total of 266 community-dwelling elderly persons age 65 years or over (123 men and 143 women, mean age of 76 years) were selected from among residents of Coop City, Bronx, New York. Balance was evaluated at baseline using computerized dynamic posturography (DPG). During a one-year follow-up, we collected information on subsequent falls on a monthly basis by postcard and telephone follow-up. RESULTS: One or more falls occurred in 60 subjects (22%) during the one-year follow-up. Women fell more frequently than men (28% vs. 16%, p < 0.03), and fallers were younger than nonfallers. Fallers (n = 60) had lower systolic BP (SBP) levels when compared with nonfallers (n = 206) (128 +/- 17 vs. 137 +/- 22 mm Hg for standing, p < 0.006; 137 +/- 16 vs. 144 +/- 22 mm Hg for lying, p < 0.02), whereas diastolic BP was not related to falls. Falls occurred 2.8 times more often in the lower BP subgroup (<140 mm Hg for standing SBP) than in the higher BP subgroup (> or =140 mm Hg, p < 0.0003), and gender-related differences were observed (p = 0.006): 3.4 times for women (p < 0.0001) versus 1.9 times for men (p = 0.30). Loss of balance, as detected by DPG, did not predict future falls and was also not associated with baseline BP levels. Multiple logistic regression analysis demonstrated that female gender (relative risk [RR] = 2.1, p = 0.02), history of falls (RR = 2.5, p = 0.008) and lower standing SBP level (RR = 0.78 for 10 mm Hg increase, p = 0.005) were independent predictors of falls during one year of follow-up. CONCLUSIONS: Lower standing SBP, even within normotensive ranges, was an independent predictor of falls in the community-dwelling elderly. Elderly women with a history of falls and with lower SBP levels should have more attention paid to the prevention of falls and related accidents.

An immunocytochemical approach to the demonstration of intracellular processing of mast cell carboxypeptidase.

Newly synthesized secretory proteins are transported from the rough endoplasmic reticulum to the Golgi complex where they can undergo posttranslational modification and are then packaged for secretion by concentration within membrane-bound very small progranules that fuse to form large immature granules. The contents of these vesicles are thought to be then processed, forming mature secretory granules. After acquiring their mature appearance, the secretory granules reside in the cytoplasm until they are secreted. In this study, we raised antibodies against the first 15 N-terminal amino acids of mast cell pro-carboxypeptidase and the last 14 C-terminal amino acids of mast cell carboxypeptidase. Immunohistochemical localization of the two peptides was carried out in human breast tissue and rat tissue (ear, skin, peritoneum, and tongue). In all cases, both epitopes were demonstrated only in mast cell secretory granules. However, mast cells from 3-week-old rats were more positive for the pro-enzyme compared to 3-month-old rats. Human mast cells in breast tissues were mostly negative for the pro-enzyme and positive for the carboxypeptidase. On the basis of these observations, it seems that posttransitional modification of the pro-enzyme to form the active enzyme occurs in the mast cell secretory granules.

Unexplained systemic symptoms and Gallium-67--guided decisions.

Over 3 months, a healthy man developed prominent systemic symptoms that defied investigation. Physical examination was noncontributory, and extensive studies revealed only a marked acute-phase response associated with increased serum IL-6 levels. A whole body Gallium-67 scan was crucial in diagnosis, directing attention to high uptake in the left paraspinal and psoas muscles. Open surgical excision biopsy was performed, guided by intraoperative use of a gamma-probe. Removed tissue was diagnosed as diffuse, large B-cell non-Hodgkin lymphoma of muscle (stage IE), a rare extranodal lymphoma. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy was given, and the patient became asymptomatic with normal blood tests and was thought to be in remission. However, a repeat Gallium-67 scan revealed recurrent multifocal disease and salvage chemotherapy was instituted. A 47,XXY karyotype (Klinefelter syndrome) was later identified, possibly associated with the lymphoma.

Marriage in eating disorders comparisons between patients and spouses and changes over the course of treatment.

OBJECTIVES: This study examines one aspect of the marital satisfaction, intimacy, of couples where one member has an eating disorder (ED), before and after intensive day hospital treatment for ED. METHODS: Subjects were consecutive patients (n=22) attending a day hospital program for EDs and their spouses. The Waring Intimacy Questionnaire (WIQ) was administered to the couples at admission to and discharge from the treatment program. RESULTS: Patients showed less favorable ratings of the marriage at admission and discharge, compared to spouses, but patient's ratings improved significantly over the course of treatment. Patients generally improved in terms of their ED symptoms during the treatment. Spousal ratings showed satisfactory ratings of intimacy at the start of treatment and did not change over the course of treatment. CONCLUSION: The self-reported marital dissatisfaction of patients with an ED is at least partially alleviated after symptomatic treatment of the ED. Treatment of the ED in one member does not diminish marital satisfaction in the other member of the couple. The long-term prognosis for these couples remains unknown.

Attrition in an exercise intervention: a comparison of early and later dropouts.

OBJECTIVE: To identify reasons for dropout and factors that may predict dropout from an exercise intervention aimed at improving physical function in frail older persons. DESIGN/SETTING: An 18-month randomized controlled intervention in a community setting. The intervention comprised 2 groups: class-based and self-paced exercise. PARTICIPANTS: 155 community-dwelling older persons, mean age 77.4, with mildly to moderately compromised mobility. MEASUREMENTS: The primary outcome measure was dropout. Dropouts were grouped as: D0, dropout between baseline and 3-month assessment, and D3, dropout after 3-month assessment. MEASUREMENTS: Measurements of demographics, health, and physical performance included self-rated health, SF-36, disease burden, adverse events, PPT-8, MacArthur battery, 6-minute walk, and gait velocity. RESULTS: There were 56 dropouts (36%), 31 in first 3 months. Compared with retained subjects (R), the D0 group had greater disease burden (P = .011), worse self-perceived physical health (P = .014), slower usual gait speed (P = .001), and walked a shorter distance over 6 minutes (P<.001). No differences were found between R and D3. Multinomial logistic regression showed 6-minute walk (P<.001) and usual gait velocity (P<.001) were the strongest independent predictors of dropout. Controlling for all other variables, adverse events after randomization and 6-minute walk distance were the strongest independent predictors of dropout, and self-paced exercise assignment increased the risk of dropout. CONCLUSIONS: We observed baseline differences between early dropouts and retained subjects in disease burden, physical function, and endurance, suggesting that these factors at baseline may predict dropout. Improved understanding of factors that lead to and predict dropout could allow researchers to identify subjects at risk of dropout before randomization. Assigning targeted retention techniques in accordance with these factors could result in decreased attrition in future studies. Therefore, the results of selective attrition of frailer subjects, such as decreased heterogeneity, restricted generalizability of study findings, and limited understanding of exercise effects in this population, would be avoided.