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An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)†, † †
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The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.
In August 2006 a live, oral, pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq™, Merck Frosst Canada, Inc.) was approved for use in Canada for the prevention of rotavirus (RV) gastroenteritis in infants 6 to 32 weeks of age. It was licensed in the United States (US) in February 2006 by the Food and Drug Administration (FDA) and recommended for routine use in infants by the Advisory Committee on Immunization Practices in August 2006 and by the Committee on Infectious Diseases of the American Academy of Pediatrics in 2007. The European Rotavirus Vaccination Advocacy Committee has recently advocated introduction of rotavirus vaccine into childhood immunization programs, although the members agree that further studies on the burden of rotavirus gastroenteritis in Europe need to be done for a better evaluation of the costs and benefits of rotavirus vaccination programs.
In order to facilitate preparation of the National Advisory Committee on Immunization (NACI) recommendations for use of this vaccine, a systematic review of the literature was undertaken focusing on the epidemiology of RV gastroenteritis in Canada and the safety, immunogenicity and efficacy of the vaccine in clinical trials(1). This statement provides recommendations for use of RotaTeq™ in Canadian infants and summarizes what is known regarding the burden of illness associated with RV in Canada, as well as the current knowledge of vaccine efficacy and safety data. As new information regarding RotaTeq™ and/or the burden of illness becomes available, the recommendations in this statement will be reviewed.
Rotavirus is a double-stranded RNA virus composed of an inner core, an internal capsid and an outer capsid. Viral serotype is defined by two structural viral proteins (VP) in the outer capsid: VP7, the glycoprotein (G protein), and VP4, the protease-cleaved protein (P protein)(2,3). These outer capsid proteins elicit neutralizing antibodies believed to be important for protection(2). Ten VP7 (G) serotypes and 11 VP4 (P) serotypes are known to cause disease in humans. Because the two gene segments that encode these proteins can segregate independently, there is the potential for many VP7/VP4 combinations, and a typing system consisting of both G and P types has been developed(2).
In the US and, according to limited data, in Canada, viruses containing six distinct G and P combinations are the most prevalent: P1A[8] G1, P1B[4] G2, P1A[8] G3, P1A[8] G4, P1A[8] G9 and P2A[6] G9; these strains are generally designated by their G serotype specificity (serotypes G1-4 and G9)(4-7) (Table 1). A number of reports suggest that P1A[8] G9 is emerging and spreading(8-15).
Table 1. Prevalent strains of RV among children aged < 5 years, United States 1996-1999, and in two Canadian studies, 1997-1998 and 2005
|RV type
|Frequency of types (%)
|Toronto Study, 1997-98(4)
|MIRAGE Study, Canada 2005(5)
|Total identified
The prevalence of rotavirus G and P serotypes varies geographically and from year to year. While non-G1 serotypes are generally less common, each of the other G types can predominate and cause > 50% of illness in some years(16). These shifting patterns of G-type prevalence from year to year have been clearly demonstrated in the US over a number of years(16,17).
RV is a common infectious agent that causes gastroenteritis in children worldwide. Because RV gastroenteritis is not a nationally notifiable disease and there are few published population-based Canadian studies, estimates of the prevalence of RV infection and its associated disease burden in Canada are based on several studies in children seen in family physician offices, pediatric clinics, emergency departments and those admitted to hospital (Table 2).
Rotavirus infection has an incubation period of 18 hours to 3 days(22). The disease is transmitted by the fecal-oral route through both close person-to-person contact and through fomites, such as toys and hard surfaces(23). Seasonal peaks in RV disease typically occur in late winter/early spring. Almost all children are infected by 5 years of age. In the first 3 months of life, illness is generally mild as a result of passively transferred maternal RV antibodies. Between 3 months and 5 years of age, there is a spectrum of disease, from mild gastroenteritis to dehydration with shock, electrolyte imbalance and, very rarely in Canada, death. Over half of RV hospitalizations occur in the 6 to 24 month age group, and > 70% of all hospital admissions for diarrhea in this young age group during the peak season (~2 months) are due to RV. In the greater Toronto region during an 8-month study period, over 75% of all children hospitalized for diarrhea were between 6 and 35 months of age, 7% < 6 months of age and 18% aged 36 months to 18 years(19).
In the US, RVs are responsible for 5%-10% of all gastroenteritis episodes among children < 5 years of age; in Toronto they caused 18% and 20% of gastroenteritis in day care centre attendees and in pediatric practices, respectively(20). In the MIRAGE (Measuring the Impact of Rotavirus Acute Gastroenteritis) study, a more recent Canadian study performed over a 6-month period in 2005 and not yet published, 395 children with diarrhea were enrolled in 59 family physician offices and pediatric clinics across the country(21). In that study, 55.4% of episodes (186/336) for which stool samples were available were due to RV. While the proportion of gastroenteritis seen in outpatient settings varies considerably, the majority of severe gastroenteritis requiring rehydration or hospitalization is caused by RV(18,24,25). In Toronto and Quebec, 37% (0 to 18-year-olds) and 72% (0 to 5-year-olds) of childhood gastroenteritis hospitalizations, respectively, were due to RV(18,19). This compares with 39% of childhood gastroenteritis hospitalizations generally reported elsewhere in the literature(26).
The proportion of gastroenteritis attributable to RV in young hospitalized children varies seasonally from a high of 60% to 78% between April and May among children aged 6 months to 3 years of age to 30% to 50% between December and February(18,20). A similar early spring increase in the proportion of gastroenteritis caused by RV was observed in emergency departments, pediatric practices and day care centres, where RV accounted for half to two-thirds of diarrhea in children 6 to 35 months of age in April and May(20).
In general, few clinical or epidemiologic features distinguish the child with RV diarrhea from those with diarrhea due to other causes(27). Vomiting occurs in 89% to 97% of cases and usually precedes the onset of diarrhea(18,21,25). Fever occurs in 53% to 89% of cases(18,21,25). The presence of fever, vomiting and diarrhea is reported more commonly with RV than with other gastrointestinal viruses. Children from whom RV is isolated are more likely to experience all three symptoms than RV-negative children with gastroenteritis (61.8% vs. 38.7%)(21). The duration of RV illness is < 1 week in 80% of patients with a mean of 5.8 to 6.1 days. Of hospitalized children, the mean duration of hospitalization is 2-3 days, and < 1% have persistence of fever, vomiting or diarrhea for > 2 weeks(18,25). At 1-month follow-up, 88% of children have returned to their usual health status, and the remainder have almost regained any weight lost during the episode(25).
Although RV gastroenteritis is typically self-limited and rarely results in long-term sequelae or death, it is associated with considerably more health care utilization than gastroenteritis due to other causes. Among children < 3 years of age with gastroenteritis recruited from physician offices and pediatric clinics across the country between January and June 2005, the expected epidemic RV period in Canada, 55% (186/336) were RV positive; of these RV positive cases, 12% (22) were hospitalized, 27% (50) had an emergency department visit, and 12% (22) required intravenous (IV) rehydration(21). Children with RV were 3.3 times more likely to be hospitalized (13% vs. 4%, p = 0.008), 1.9 times more likely to visit the emergency department (27% vs. 14%, p = 0.0082) and 4.1 times more likely to receive (IV) rehydration (13% vs. 3%, p = 0.0027) than patients with gastroenteritis due to other causes(21). Similarly, children requiring more health care are more likely to have RV infection than diarrhea due to other viral agents. In the Toronto Study, only 10% of children in child care centres with diarrhea who did not see a physician had RV-associated diarrhea(19,20). In contrast 27% of children making a health care visit and 75% of those hospitalized or who received IV hydration in the emergency department had RV-associated diarrhea(19,20). While 20% of children with gastroenteritis in pediatric practices had RV, of those whose condition required hospitalization or IV hydration in the emergency department the proportion with RV rose to 60%(19,20).
Table 2. Overview of Canadian studies of children with diarrhea and RV-associated diarrhea at hospital admission, emergency departments, pediatric practices and day care centres
(n = 7)(18)
(n* = 18)(19)
|Emergency department
(n = 8)(19,20)
|Emergency department
(n = 1)(19,20)
|Pediatric practice
(n = 4)(19,20)
|Day care centres
(n = 19)(19,20)
|Physician office and pediatric clinic (MIRAGE)
(n = 59)(21)
|Study period
|Dec 1999-May 2000 (6 mo)
|Nov 1997-Jun 1998 (8 mo)
|Nov 1997-Jun 1998 (8 mo)
|Nov 1997-Jun 1998 (8 mo)
|Nov 1997-Jun 1998 (8 mo)
|Nov 1997-Jun 1998 (8 mo)
|Jan-Jun 2005 (6 mo)
|Academic and regional centres in Quebec province
|Greater Toronto
|Greater Toronto
|Greater Toronto
|Greater Toronto
|Greater Toronto
|Across Canada
|< 5 yr
|< 18 yr
|< 18 yr
|< 18 yr
|< 18 yr.
|< 6 yr
|< 3 yr
|No. with diarrhea
|No. (%) tested
|No. (%) RV +ve
|*Sample size refers to number of study sites included.
**Requiring intravenous rehydration
†Requiring oral rehydration
In a study of child care centre attendees, the majority (> 60%) sought medical care for any episode of diarrhea(20). While a visit to a pediatrician was adequate for the majority of children with RV diarrhea, > 75% seeking no further care, 17% went on to an emergency department visit, and 6% were either hospitalized or received IV hydration in the emergency department .The Rotavirus Gastroenteritis Cohort Model, an unpublished mathematical model of disease burden which incorporates data from the mirage study as well as published epidemiologic data from Toronto and Quebec, estimates that the majority (57%) of RV-positive cases sought health care resources, 36% visiting a physician, 15% an emergency department and 7% requiring hospitalization(28).
All of these data indicate that RV is a common viral illness in Canada.
The Rotavirus Gastroenteritis Cohort Model, estimated the impact of RV gastroenteritis in Canada by the age of 5 years and determined that one child in seven will have sought health care, one child in 20 will have visited an emergency department or have been hospitalized, and one child in 62 will have been hospitalized (Table 3)(18-20,28-30). This estimate of one in 62 in Canada by the age of 5 years may be high. In the US, estimates have ranged from 1/73 to 1/80. In Canada, several studies have reported RV-associated hospitalization rates. In Toronto, where IV and oral hydration in the emergency department is widely practised, rates of one in 106 were found(20), and in Quebec City a hospitalization rate of 320/100,000, or one in 312, occurred between 1985 and 1998(31). In a subsequent study performed between 1995 and 1999 in Quebec, the hospitalization rate was 450/100,000 or one in 222 children < 5 years of age(18). Thus, the true rate of hospitalization associated with RV in Canadian children is poorly defined. While the rate is likely to vary by geographic region and year, available data suggest that it lies somewhere between 320/100,000 and 1,600/100,000. Given an annual birth cohort of 340,000, as used in the Rotavirus Gastroenteritis Cohort Model, the total annual number of hospitalizations due to RV can be estimated to be between 1,100 and 5,500.
Table 3. Annual RV-associated health care burden among Canadian children < 5 years estimated by the Rotavirus Gastroenteritis Cohort Model(28)
|Average number of episodes/consultations
|95% credibility interval
|RV gastroenteritis
|60,000 to 103,000
|Physician consultations
|27,000 to 56,000
|Emergency department visits
|9,000 to 27,000
|4,200 to 7,000
Mortality due to RV in Canada is now extremely low with only one reported death due to RV in recent years. While the number of deaths due to RV-associated diarrhea may be an underestimate, owing to the lack of routine testing for RV infection, the low mortality rate is comparable to the situation in the US, where deaths are rare: 20 to 60 deaths per year attributable to RV(32). From a global perspective that takes into consideration developing countries, RV mortality is very different, with an estimated 610,000 children dying per year, accounting for 5% of all deaths in children < 5 years of age.
Diarrhea in household contacts
Household transmission of RV gastroenteritis is common. Adults who are in contact with young children are at particularly high risk of RV infection. In one Toronto study, during the 2 weeks before or after RV-associated diarrhea in children < 3 years of age, the rates of diarrhea among contacts < 3 years of age, 3 to 18 years of age and adults were 65% to 74%, 38% to 43% and 29% to 35%, respectively(19,20) A cross-Canada study in 2005 demonstrated that in 47% of RV cases at least one other family member experienced gastroenteritis between 2 weeks before and 2 weeks after the infection. The mean number of additional cases was one. Among these household contacts experiencing diarrhea, 44% were < 2 years old, 37% were 2 to 5 years, 12% were 6 to 18 years, and 22% were adults(21).
Specific populations affected and risk factors
One approach to immunization program development is to assess the need for a universal or a targeted approach. Recent studies in the US suggest that while there are factors that may characterize children as priorities for intervention, many of these factors, such as being in child care, being recipients of Medicaid or being without insurance, or the presence of another child in the household < 24 months of age, are shared by large proportions of this population, making a targeted approach to immunization impractical(33). It is important to note that at least two of these factors (i.e. day care attendance and health coverage) are considered to be very different in Canada compared with the US. Further, some factors, such as low birth weight, are clearly risk factors but are relatively uncommon, limiting the impact of a targeted approach. In a Canadian prospective study, socio-economic factors, parental marital status, child care arrangements, including day care centre attendance, and ethnicity did not appear to influence rates of RV hospitalization(20).
Geographic: The risk of RV gastroenteritis and its outcomes does not appear to vary by geographic region within the US. There are limited data regarding the regional distribution of RV within Canada; further data are needed.
Socio-economic: Limited data suggest that US children with lower socio-economic status are at greater risk(34). US children < 24 months of age covered by Medicaid or without insurance (odds ratio [OR] 2.1, 95% confidence interval [CI]1.4 to 3.2) and children having a mother without a high school education (OR 1.5, 95% CI 1.0 to 2.3) are at higher risk of hospitalization due to RV(33). A large Toronto study failed to demonstrate an association between socio-economic-cultural factors and RV hospitalization(19).
Prematurity: A Washington State study found that premature infants are at increased risk of hospitalization from gastroenteritis, including viral gastroenteritis(34). In a Toronto study, a history of prematurity was found in 13% of children admitted with RV in the first year of life, which was higher than the regional rate of prematurity of 7%, suggesting the possibility of more severe disease in this group(19).
Low birth weight: In Washington State, infants with low birth weight (< 2500 g) had an increased risk of hospitalization for up to 24 months of age (OR 2.8, 95% CI 1.6 to 5.0)(34). This has also been identified as a risk factor for mortality from diarrhea in the US(35). Because parental recall of birth weight vs. prematurity may be problematic there may be some overlap between these two risk factors(33).
Breastfeeding: The impact of breastfeeding on the incidence and severity of RV is not entirely clear. In a recent US study, breastfeeding was protective against RV hospitalization in the first 6 months of life (OR 5.1, 95% CI 1.2 to 13.2), and several studies have shown breastfeeding to be protective against symptomatic RV infection(33). However, in a study performed in Bangladesh, although breastfeeding was protective against severe RV diarrhea during the first year of life, with a more pronounced effect among infants exclusively breastfed, there was no overall protection during the first 2 years of life, suggesting that breastfeeding only postponed infection to an older age(36). In one Canadian study, a quarter of all children admitted under 1 year of age were receiving breast milk, suggesting that breastfeeding does not provide complete protection(19). Cohort studies report the highest infection rate between 4 and 6 months of age, coinciding with a number of potential factors, such as weaning, declining maternal antibody or increased opportunity for exposure. The greater protection and likelihood of asymptomatic infection afforded infants whose mothers' breast milk had higher levels of glycoprotein lactadherin supports a role for breast milk itself(37).
Day care centre attendance: US children in child care were more likely to be hospitalized for RV than those cared for at home, particularly those ≥ 24 months of age(33). It is important to note that there are marked differences between US and Canadian child care in levels of provider education, age at entry and child:staff ratios. A Canadian prospective study failed to find an association with child care arrangement, including day care centre attendance(19).
Presence of another child in the house < 24 months old: This is a recently identified risk factor for RV hospitalization (OR 1.6, 95% CI 1.1 to 2.3)(33). It has also been identified as a risk factor for development of RV diarrhea(38). It is important to note that neither study assessed household crowding.
Maternal age < 25 years: This has been identified as a risk for infant RV hospitalization in the United States (OR 1.4, 95% CI 1.0 to 2.0)(33,34).
Child's gender: In a US study, male children were identified as having a greater risk of RV diarrhea than female children(34). A Canadian study showed that significantly more male (57%) than female children presented with diarrhea, although the proportion who were RV positive was similar(20). This is also consistent with findings of both the Immunization Monitoring Program, Active (IMPACT), in which 60% of rotavirus cases presenting to the emergency department or hospital were male (Lisa Landry, IMPACT/ PHAC database: personal communication, 2007), and MIRAGE, in which 59% of the rotavirus positive cases were male(21).
Immunocompromised persons: Children and adults who are immunocompromised because of congenital immunodeficiency, haematopoetic transplantation or solid organ transplantation sometimes experience severe, prolonged and even fatal RV gastroenteritis(39-42). The median duration of viral shedding is 17 days (4 to 73 days)(43).
Nosocomial RV: Children hospitalized with community-acquired RV infection have the potential to be sources of nosocomial cases of infection. IMPACT identified that 32% to 35% of the cases identified in hospitalized children across Canada were nosocomial (Dr. P. Sockett, IMPACT/ PHAC database: personal communication, 2007). A Canadian study in 1990 noted a nosocomial diarrhea (not exclusively rotavirus) rate of 4.5 infected children per 100 admissions(44).
First Nations and Inuit: Historically in Canada, First Nations and Inuit populations had high rates of RV disease in the 1970s. A prospective study done in the early 1980s found that Inuit infants in remote, isolated northern communities had significantly higher rates of RV-associated diarrhea in the first 6 months of life (0.73 to 1.07 infections per child per year) than First Nations infants (0.36 infections per child per year)(45).
Adults: Among adults in the US, RV infection causes gastroenteritis primarily in travellers returning from developing countries, parents and persons caring for children with RV gastroenteritis, immunocompromised persons, and older adults(46). Outbreaks of RV gastroenteritis have been reported in long-term care facilities and are associated with considerable morbidity in this setting(46-49).
Summary of rotavirus epidemiology
In 1998, Rotashield® (Wyeth-Lederle Vaccines), a rhesus-human reassortant RV vaccine, was recommended for routine vaccination of US infants in a schedule of three doses at ages 2, 4 and 6 months(50,51). However, it was withdrawn from the US market within 1 year of its introduction because of an association with intussusception. In the first 9 months after licensure and immunization of > 600,000 children with one to three doses, intussusception developed in 15 children during the 2-week period immediately following vaccine administration(22). The risk of intussusception was approximately 20-fold within 3 to 14 days following the first dose and approximately five-fold within 3 to 14 days following the second dose(15,52). Overall, the risk associated with the first dose of Rotashield® was estimated to be approximately 1 case per 5,000 to 10,000 children immunized(52). The risk of intussusception appears to have been age-dependent, in that the risk increased with greater age at vaccination, particularly with receipt of the first dose after 3 months of age. Eighty percent of intussusception cases reported occurred in the 38% of infants who were ≥ 90 days old at the time of administration of the first vaccine dose(53). Infants immunized with their first dose of Rotashield® < 3 months of age had a substantially lower risk of intussusception than those who were older (approximately 1/30,000 vs. < 1/8000)(53). No vaccine-associated cases of intussusception were observed among infants who received the first dose of Rotashield® at < 60 days of age(53).
The relationship between vaccine-associated intussusception risk and increased age at first vaccination was confirmed by Rothman et al. using alternative mathematical modeling techniques(54). On the basis of these analyses, the authors have suggested that much of the adverse effect that Rotashield® vaccination had on the occurrence of intussusception could have been averted by confining the administration of the vaccine to very young infants(53,54). The World Health Organization (WHO) Global Advisory Committee on Vaccine Safety (GACVS), after reviewing all available data, concluded that the risk of Rotashield®-associated intussusception was greater in infants vaccinated after 60 days of age but that insufficient evidence was available to conclude that the use of the vaccine among infants < 60 days of age was associated with a lower risk(55). GACVS noted that the possibility of an age-dependent risk of intussusception should be taken into account when assessing future RV vaccines.
In addition to intussusception, post-marketing surveillance has suggested an association between Rotashield® and a spectrum of other gastrointestinal symptoms, including gastroenteritis and hematochezia (bloody stools)(56).
RotaTeq™ is a live, oral, pentavalent vaccine that contains five live reassortant RVs. The RV parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant RVs express one of the outer capsid proteins (G1, G2, G3 or G4) from the human RV parent strain and the attachment protein (P7) from the bovine RV parent strain. The fifth reassortant virus expresses the attachment protein P1[8] (genotype P[8]) from the human RV parent strain and the outer capsid protein G6 from the bovine RV parent strain. The parent bovine strain RV WC3 - G6, P7[5] used in all reassortants has been passaged in African green monkey cells, and the reassortants are propagated in Vero monkey kidney cell lines using standard tissue culture techniques in the absence of antifungal agents.
Each 2 mL vaccine dose contains a minimum level of the five reassortants as follows:
G1: 2.2 x 106 infectious units
G2: 2.8 x 106 infectious units
G3: 2.2 x 106 infectious units
G4: 2.0 x 106 infectious units
P1[8]: 2.3 x 106 infectious units.
Reassortants are suspended in a buffered stabilizer solution. Each vaccine dose is supplied as a single, pre-filled 2 mL unit dose in a plastic dosing tube with a twist-off cap and contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80 and also cell culture media and trace amounts of fetal bovine serum. There are no preservatives or thimerosal present, and all packaging is latex free. No reconstitution or dilution is required.
The immune correlates of protection from RV infection and disease are not fully understood. In clinical trials, seroconversion, defined as a 3-fold or greater rise in antibody titre from baseline, for neutralizing antibodies to G1, G2, G3, G4 and P1[8] were significantly higher in vaccine recipients than placebo groups (21% to 76% versus 0% to 7.4%)(57). Seroconversion rates for IgA antibody to RV were 95% (95% CI 91.2% to 97.8%) among 189 vaccine recipients versus 14.3% (95% CI 9.3% to 20.7%) among 161 placebo recipients(58).
RotaTeq™ has been evaluated in three phase III trials, the largest of which was the Rotavirus Efficacy and Safety Trial. A total of 71,942 infants have been studied in these phase III trials (36,165 who received RotaTeq™ and 35,560 who received placebo)(15,58). In these trials, three doses of RotaTeq™ were administered orally beginning at 6 to 12 weeks of age with a 4 to 10 week interval between doses. Doses were administered up to 32 weeks of age without restriction due to breastfeeding or administration of other licensed childhood vaccines, except oral poliovirus vaccine.
Overall, the efficacy of three doses of RotaTeq™ against severe RV gastroenteritis caused by G serotypes contained in the vaccine (G1, G2, G3, G4) was 98.2% (95% CI 89.6% to 100%) and against RV gastroenteritis of any severity was 73.8% (95% CI 67.2% to 79.3%) during the first full rotavirus season after completion of vaccination. The vaccine was designed to prevent RV gastroenteritis caused by the individual G serotypes contained in the vaccine (G1, G2, G3, G4); P1[8] was included in the vaccine to potentially provide cross-protection against non-vaccine G serotypes that may contain P1[8]. On the basis of limited data, the efficacy of the vaccine against RV gastroenteritis of any severity caused by the non-vaccine serotype G9 was 74% (95% CI < 0% to 99.5%) (Table 4). However, it should be noted that the frequency of infection with non-G1 strains was very low. The confidence intervals around the efficacy estimate for G2, G3, G4 and G9 strains are broad and, in fact, cross 1 for G3, G4 and G9. Therefore, further data are needed to establish the efficacy of RotaTeq™ against non-G1 strains.
In a smaller sample of 4,512 infants (2,207 RotaTeq™, 2,305 placebo), the second season efficacy of the vaccine against G1-G4 RV gastroenteritis of any severity was 62.6% (95% CI 44.3% to 75.4%) and that against severe disease was 88.0% (95% CI 49.4% to 98.7%) (36/813 vaccine recipients vs. 88/756 placebo recipients for whom data were available)(58).
Table 4. Efficacy of RotaTeq™ rotavirus vaccine against RV gastroenteritis caused by G serotypes contained in the vaccine through the first full RV season after completion of vaccination in phase III trials (adapted from the Product Monograph)
|Number of cases/number of evaluable subjects
|% efficacy
|RV gastroenteritis of any severity
|73.8 (67.2-79.3)*
|75.0 (68.2-80.5)*
|63.4 (2.7-88.2)*
|55.6 (<0-92.6)
|48.1 (<0-91.6)
|74.1 (<0-99.5)
|Severe G1-G4 RV gastroenteritis
|98.2 (89.6-100)*
|*Statistically significant
In the large Rotavirus Efficacy and Safety Trial (REST), among infants included in the per-protocol analysis (28,646 in the vaccine group and 28,488 in the placebo group), RotaTeq™ reduced G1-G4 RV-associated hospitalization or emergency department visits by 94.5% (95% CI 91.2% to 96.6%) and non-urgent office or clinic visits by 86% (95% CI 73.9% to 92.5%)(58). Further, there was a reduction of 58.9% (95% CI 51.7% to 65.0%) in all gastroenteritis-related hospitalizations after the first dose (Table 5). Among the parents/guardians of the 68,038 infants studied, there was an 86.6% (95% CI 78.0% to 91.9%) reduction in work days lost (65 lost days for parents/guardians of vaccine recipients versus 487 lost days for parents/guardians of placebo recipients)(58). Similarly, in the MIRAGE Study, parents of children with RV were more likely to take time off work than parents of children with gastroenteritis of other causes (54% vs. 37%, p = 0.003)(21). Parents of children with RV who took time off work missed an average of 2.6 days compared with 1.8 days for parents of children with gastroenteritis due to other causes (non-significant difference)(21).
Data on the efficacy of fewer than three doses of RotaTeq™ are limited. In a very small study of < 100 children, estimated efficacy in reducing RV hospitalization after one, two and three doses was 29% (95% CI < 0% to 73.3%), 80% (95% CI 8.5% to 95.8%) and 95% (95% CI 91.5% to 96.5%), respectively(59). In the REST trial, the comparatively higher one-dose efficacy, of 58.9%, in reducing all-cause diarrhea hospitalizations(58) may be explained by differences in study time and place. The overall efficacy of RotaTeq™ for the prevention of emergency department visits or hospitalization due to all serotypes of RV was 83%, 81% and 95% 2 weeks following the first, second and third dose, respectively(60).
Table 5. Number of health care contacts and reduction in rates of RV gastroenteritis caused by G serotypes contained in the RotaTeq™ vaccine*
|Type of health care contact
n = 34,035
n = 34,003
|Rate reduction, %
|Combined hospitalization or emergency department (ED) visit†
|94.5 (91.2-98.2)
95.1 (91.6-97.1)
87.6 (< 0-98.5)
93.4 (49.4-99.1)
89.1 (52.0-97.5)
100.0 (67.4-100.0)
95.8 (90.5-98.2)
59.0 (56-65)
|ED visits†
|93.7 (88.8-96.5)
|Non-urgent visits‡
|86.0 (73.9-92.5)
|*Per protocol population (includes only cases that occurred at least 14 days after dose 2)
†n = 68,038 infants vaccinated (34,035 RotaTeq™, 34,003 placebo)
‡n = 5,673 infants vaccinated (2,834 RotaTeq™, 2,839 placebo)
RotaTeq™ or placebo was administered to 2,070 pre-term infants (25 to 36 weeks' gestational age) according to their chronological age in the Phase III trials. Vaccine efficacy was evaluated in a subset of 204 pre-term infants (153 evaluable), who were followed for gastroenteritis. Efficacy (70.3%) (95% CI 15% to 95%) was generally similar to that seen in the overall population. However, the confidence bounds crossed zero because the sample size was small(15). Breastfeeding did not appear to diminish the efficacy of a three-dose series of RotaTeq™. Among 1,566 exclusively breastfed infants, the efficacy of the vaccine against RV gastroenteritis of any severity was 68% (95% CI 54% to 78%), the same as the efficacy observed in 1,632 infants who were never breastfed, of 68% (95% CI 46%-82%)(58).
Vaccine safety and adverse events
Given the relatively low morbidity and mortality associated with natural RV infection in Canada and the US experience with a previous RV vaccine that has now been withdrawn, it is essential that the safety of RV vaccine be carefully reviewed and that it should be deemed considerably safer than natural infection. Experience with the previous rotavirus vaccine and intussusception has demonstrated the importance of conducting post-marketing surveillance to identify rare or very rare adverse events (i.e.1/1000 to 1/10,000 and < 1/10,000, respectively). Detection of an increased risk of intussusception associated with RotaTeq™ will require data on baseline rates of intussusception in the target population in Canada, which are currently lacking.
Intussusception: The risk of intussusception was evaluated in 71,725 infants enrolled in phase III RotaTeq™ efficacy trials(15,58). In a large-scale safety and efficacy trial designed specifically to evaluate the risk of intussusception, six cases were observed in the RotaTeq™ group versus five cases in the placebo group (multiplicity adjusted relative risk = 1.6, 95% CI 0.4 to 6.4) within 42 days of any vaccine dose(58). This provides a ratio of 1:49 vs. 1:60 in vaccine vs. placebo recipients. No evidence of clustering of cases of intussusception was observed within a 7- or 14-day window after vaccination for any dose, the period of greatest risk for intussusception associated with Rotashield®. For the one year follow-up period after administration of the first dose, 13 cases of intussusception were observed in the RotaTeq™ group versus 15 cases in the placebo group (multiplicity adjusted relative risk: 0.9, 95% CI 0.4 to 1.9)(58).
In the US, post-marketing safety of RotaTeq™ is being monitored by the Centers for Disease Control and Prevention (CDC) and the FDA through both evaluation of reports to the Vaccine Adverse Events Reporting System (VAERS) and active surveillance using data from the Vaccine Safety Datalink (VSD). Additionally, Merck is conducting a post-marketing observational study in 44,000 infants in the US designed to monitor for occurrence of intussusception within 30 days of receipt of RotaTeq™.
As of 31 January, 2007, 3.6 million doses of RotaTeq™ had been distributed in the United States (Merck, unpublished data); the number of doses administered is not known. An assessment of a potential association between RotaTeq™ and intussusception was recently published(61). Background rates of intussusception in infants 6 to 14 weeks of age, 15 to 23 weeks of age and 24 to 35 weeks of age were determined from hospital discharge diagnoses at the VSD study sites for the period 2000-2004, before the use of RotaTeq™. The number of intussusception reports to VAERS following RotaTeq™ vaccination was then compared with the number of cases expected to occur (i.e. the background number of cases of intussusception).
From 1 February, 2006, to 15 February, 2007, VAERS received reports of 35 cases of intussusception that met the Brighton Collaboration case definition(62); 17 of these (49%) occurred within 1 to 21 days of vaccination, 11 (31%) occurred within 1 to 7 days of vaccination, and the other 18 cases occurred between 22 and 73 days after vaccination, with the exception of one case that occurred on the same day as vaccination. Of the 17 cases reported within 21 days of vaccination, nine (53%) occurred following the first dose, eight (47%) occurred following the second, and none followed the third dose. Ten infants (59%) required surgery (including five who required intestinal resection). In the remaining seven infants, intussusception resolved spontaneously or was successfully reduced by barium enema.
On the basis of VSD data for the period 2000-2004, the background rate of intussusception was 18.1 per 100,000 person years (PY) among infants 6 to 14 weeks of age, 32.5 per 100,00 PY in infants 15 to 23 weeks of age and 42.5 per 100,000 PY among infants 24 to 35 weeks of age. By applying these background intussusception rates to the estimated distributed doses per age group, an expected number of 57 cases of intussusception was calculated for the period from one to 21 days after vaccination. Seventeen of these cases would be expected to occur between one and 7 days after vaccination. In contrast, 17 intussusception cases were reported to VAERS that occurred during the period one to 21 days after vaccination, including 11 cases that occurred between one and 7 days after vaccination. Thus, VAERS reports of intussusception following RotaTeq™ vaccination have not been higher than expected according to age-adjusted background rates between one and 21 days after vaccination (relative risk [RR] 0.32, 95% CI 0.17 to 0.55) or between one and 7 days after vaccination (RR 0.61; 95% CI 0.29 to 1.18).
Between 1 February, 2006, and 15 February, 2007, a total of 28,377 doses of RotaTeq™ were distributed in VSD-monitored health maintenance organizations. No intussusception cases occurring within 30 days of RotaTeq™ vaccination have been reported, whereas eight intussusception cases were reported among approximately 240,110 infants who received vaccines other than RotaTeq™.
In summary, post-marketing surveillance following distribution of 3.6 million doses of RotaTeq™ in the US does not demonstrate or suggest an increased risk of intussusception among infants following RotaTeq™ vaccination. This is very reassuring, as the association between intussusception and Rotashield® was observed following immunization of only approximately 600,000 infants. Because VAERS is a passive reporting system, it is possible that intussusception is underreported. However, given the awareness of both providers and the public regarding the association of the previous rotavirus vaccine (i.e. Rotashield®) and intussusception, it is unlikely that significant underreporting is occurring.
The CDC and FDA will continue to monitor adverse events reported in the US following vaccination with RotaTeq™.
Hematochezia: The most comprehensive, complete and final dataset on hematochezia comes from the Safety Update Report, which is the complete safety follow-up data integrated across the three Phase III protocols(15,58) (Merck Frosst Canada, Inc.: personal communication, 2007). Among the 11,690 subjects in the detailed safety cohort of the Phase III trials, the overall incidence of hematochezia within 42 days of the first vaccine dose was 0.6% in each group (39/6,130 in the vaccine group and 34/5560 in the placebo group).
Although not significantly different, an increased rate of hematochezia was observed among negatively adjudicated intussusception cases (i.e. cases that did not meet the study case definition for intussusception) in the Phase III trials. In total, 17 cases of hematochezia were seen in the vaccine group vs. nine in the placebo group (12 cases vs. seven cases within 42 days of any dose and seven cases vs. four cases in the 42 days following dose one). The rate of hematochezia in vaccinees was 0.5% compared with 0.3% among placebo recipients following dose one. Although this difference was not statistically significant, similar differences were not observed after the second or third doses, raising the possibility of an increased risk of hematochezia after the first dose.
A total of 19 cases of hematochezia have been reported to VAERS during post-marketing surveillance in the US, representing 10% of all reports; 68% of reported episodes occurred within 3 days of vaccination, and 68% occurred in infants 2 months of age. The frequency of 19 cases of hematochezia/1.7 million doses of RotaTeq™ distributed is compared with 60 cases/1.5 million doses of Rotashield®.
Other adverse events following immunization: Serious adverse events and deaths were evaluated in 71,725 infants enrolled in phase III trials(58). Among RotaTeq™ and placebo recipients, the incidence of serious adverse events (2.4% vs. 2.6%, respectively), including deaths (< 0.1% [n = 25] vs. < 0.1% [I = 27], respectively), was similar. The most frequently reported serious adverse events were bronchiolitis (0.6% RotaTeq™ vs. 0.7% placebo), gastroenteritis (0.2% vs. 0.3 %), pneumonia (0.2% vs. 0.2 %), fever (0.1% vs. 0.1 %) and urinary tract infection (0.1% vs. 0.1 %).
No deaths were attributed to vaccination by blinded investigators. Of 52 reported deaths, the most common cause was Sudden Infant Death Syndrome (SIDS) (17/52). Deaths from SIDS were equally distributed between RotaTeq™ and placebo recipients (eight and nine, respectively).
Seizures reported as serious adverse experiences occurred in < 0.1% (27/36,150) of vaccine and < 0.1% (18/35,536) of placebo recipients. Although not statistically significantly different, the number of seizures reported among vaccine recipients was consistently higher than that reported among placebo recipients in each time interval after immunization (Table 6). As the number of febrile seizures reported was the same in both groups (five), the apparent increase in seizure frequency among vaccinees appears to be attributable to non-febrile seizures. Post-marketing surveillance will be necessary to determine whether RotaTeq™ is associated with an increased risk of seizure.
Table 6. Seizures reported by day after vaccination in relation to any dose in Phase III trials of RotaTeq™
|Day after vaccination, range
|RotaTeq™ n = 36,150
|Placebo n = 35,536
|1-42 (total)
Kawasaki disease occurred in 5/36,150 infants who received RotaTeq™ and 1/35,536 infants who received placebo during the Phase III clinical trials. This difference was not statistically significant. Additionally, three cases of Kawasaki disease have been reported to VAERS since vaccine licensure in the US in February 2006, following distribution of approximately 6 million doses. One case of Kawasaki disease occurring within 30 days of RotaTeq™ vaccination (65,000 doses administered to children < 1 year) has been observed in the VSD Project. The reported cases of Kawasaki disease following immunization with RotaTeq™ do not represent an increased risk over what would be expected to occur among children < 1 year of age who did not receive the vaccine. There is not a known cause-and-effect relationship between receiving RotaTeq™, or any other vaccine, and the occurrence of Kawasaki disease. The FDA and CDC will continue to monitor cases of Kawasaki disease reported following vaccination with RotaTeq™.
A subset of 11,722 infants were studied in detail to assess other potential adverse experiences. Overall, 47.0% of infants given RotaTeq™ experienced an adverse event following vaccination compared with 45.8% of infants given placebo(15). The most commonly reported adverse experiences that occurred more frequently with RotaTeq™ than with placebo were pyrexia (20.9%), diarrhea (17.6%) and vomiting (10.1%). In the 7-day period after vaccination, vaccinees had a small, but statistically significant, increased rate of diarrhea after every dose (10% vs. 9% following dose one, 9% vs. 6% following dose two, 18% vs. 15% following dose three)(15). Vaccinees also had a small, but statistically significant, greater rate of vomiting (12% vs. 10% following any dose). In the 42-day period after vaccination, vaccinees had a small but significantly greater rate of vomiting (15% vs. 14%), diarrhea (24% vs. 21%), nasopharyngitis (7% vs. 6%), otitis media (15% vs. 13%) and bronchospasm (1.1% vs. 0.7%). Among RotaTeq™ and placebo recipients, the incidence of reported episodes of fever (43% vs. 43%) was the same. The incidence of fever and irritability during the 7-day period after any vaccine dose was similar among RotaTeq™ and placebo recipients.
Safety in pre-term infants: RotaTeq™ or placebo was administered to 2,070 pre-term infants (25 to 36 weeks' gestational age, median 34 weeks) according to their chronological age in the Phase III trials. All pre-term infants were followed for serious adverse experiences, and a subset of 308 infants was monitored for all adverse experiences. There were four deaths throughout the study, two in vaccine recipients (one SIDS and one motor vehicle accident) and two in placebo recipients (one SIDS and one unknown cause). No intussusception cases were reported. Serious adverse experiences occurred in 5.5% of vaccine and 5.8% of placebo recipients. The most common serious adverse experience was bronchiolitis, which occurred in 1.4% of vaccine and 2.0% of placebo recipients. The frequencies of vomiting, diarrhea and irritability were not higher among pre-term infants than term infants within 7 days after administration of RotaTeq™.
Shedding and transmission of vaccine virus: Fecal shedding of vaccine virus was evaluated in a sub-study of 134 infants within REST by viral culture with use of a plaque assay and RNA electropherotyping; a single stool sample was obtained during days 4 to 6 following each vaccination(58). Fecal shedding occurred in 12.7% after the first dose; no shedding was documented after the second or third dose. In a smaller, end-of-shelf-life study(17), all stool samples found to be RV positive by enzyme immunoassay were tested by reverse transcriptase PCR (polymerase chain reaction), and shedding of viable vaccine reassortants was evaluated by plaque assay and RNA electropherotyping. Only one was identified as positive after the first dose. Overall, during Phase III studies, vaccine virus was shed in 8.9% (95% CI 6.2% to 12.3%) of infants after the first dose, none (95% CI 0% to 1.5%) after the second dose and 0.3% (95% CI < 0.1% to 1.4%) after the third dose(17). Shedding occurred from 1 to 15 days after a dose. The potential for horizontal transmission of vaccine virus has not been evaluated.
Dosage and schedule
RotaTeq™ is given as three separate 2 mL oral doses. Correct timing of administration is critical given the apparent age-associated risk of intussusception observed with Rotashield® and the lack of safety data in infants outside the recommended age range. As detailed earlier (see "Rotavirus vaccines") the risk of intussusception associated with Rotashield® appears to have been age-dependent, the risk increasing with increased age at vaccination, particularly with receipt of the first dose after 3 months of age. Eighty percent of intussusception cases reported occurred in infants who were ≥ 90 days at the time of administration of the first vaccine dose(53). Because of concerns arising from the experience with Rotashield®, clinical trials with RotaTeq™ have strictly adhered to schedules providing the first dose of vaccine at 6 to 12 weeks of age and completing the vaccination series by 32 weeks of age. Thus, data on the safety of administering the vaccine to infants outside of this age range are lacking.
The first dose of RotaTeq™ vaccine should be administered between 6 and 12 weeks (13 weeks minus a day) of age. The first dose should not be given after 12 weeks of age. Following the initial dose, subsequent doses should be administered at an interval of 4 to 10 weeks between each dose. All doses should be administered by 32 weeks of age.
In the absence of safety data regarding administration of RotaTeq™ in the home setting and given concerns about maintenance of the cold chain, the Committee recommends that all doses be given in a clinic/office setting under the direction of a health care provider.
Interrupted vaccine schedules
If, for any reason, an incomplete dose is administered (e.g., the infant spits or regurgitates the vaccine), a replacement dose is not recommended.
For infants in whom the first dose of RotaTeq™ vaccine is inadvertently administered off label at age ≥ 13 weeks, the rest of the RotaTeq™ vaccination series should be completed with a minimum of 4 weeks between each dose. All doses should be administered by 32 weeks of age.
Previous RV infection
Infants who have had RV gastroenteritis before receiving the full course of RV vaccinations should still initiate or complete the three-dose schedule, because the initial infection frequently provides only partial immunity(60).
Infants who are being breastfed can receive RV vaccine. The efficacy of RV vaccine is similar among breastfed and non-breastfed infants(60).
Intercurrent illness
Like other vaccines, RV vaccine can be administered to infants with transient mild illnesses and to those with or without fever(60). See "Precautions" below for guidance on vaccine administration to infants with acute gastroenteritis.
Premature infants (< 37 weeks gestation)
Currently available evidence demonstrates that RotaTeq™ is safe and effective in premature infants, although a relatively small number of pre-term infants have been evaluated. Because premature infants have lower levels of maternal antibodies against RV, they may theoretically be at increased risk of both severe, naturally occurring RV gastroenteritis and of adverse reactions to the rotavirus vaccine. Premature infants who are between 6 and 32 weeks of chronological age can receive RotaTeq™. The first dose of RotaTeq™ vaccine should be administered between 6 and 12 weeks (13 weeks minus 1 day). All doses should be administered by 32 weeks of age.
Exposure of immunocompromised persons or pregnant women to vaccinated infants
Vaccine virus may be shed by up to 13% of recipients of RotaTeq™ between 1 and 15 days after immunization, and this is most likely to occur following the first dose. The potential for horizontal transmission of vaccine virus has not been evaluated. However, the benefit of protecting immunocompromised household contacts from naturally occurring RV by immunizing infants is believed, by most experts, to outweigh the theoretical risk of transmitting vaccine virus. Thus, infants living in households with persons who have or are suspected to have immunosuppressive conditions or who are receiving immunosuppressive medications can be vaccinated. To minimize the risk of transmission of vaccine virus, careful handwashing should be used after contact with the feces of the vaccinated infant (i.e., after changing a diaper).
Infants living in households with pregnant women can be vaccinated. Because most women of childbearing age have pre-existing immunity to RV through natural exposure, the risk of infection and disease from vaccine virus is low. Additionally, rotavirus infection during pregnancy is not known to pose a risk to the fetus.
Storage and handling
RotaTeq™ should be protected from light, stored and transported refrigerated at 2° C to 8° C and should not be frozen. The vaccine should be used before the expiration date and has a shelf life of 2 years when stored under the appropriate conditions. Vaccine should be administered as soon as possible after removal from refrigeration, but administration may be delayed for up to 4 hours if the vaccine has been maintained at temperatures at ≤ 25° C.
Simultaneous administration with other vaccines
When RotaTeq™ was administered concomitantly with other routine infant vaccines in clinical trials it was well tolerated. When administered simultaneously, a three-dose series of RotaTeq™ does not diminish the immune response to Haemophilus influenzae type b conjugate (Hib) vaccine, inactivated poliovirus vaccine (IPV), hepatitis B vaccine, pneumococcal conjugate vaccine, or the diphtheria and tetanus antigens in diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) (Merck, unpublished data, 2005). A reduction in response to pertussis pertactin was observed in the REST clinical trial (Rotavirus Efficacy and Safety Trial)(58). However, subsequent analysis of antibody responses to pertussis antigens in a larger sample of subjects receiving concomitant RotaTeq™ and DPT-IPV-Hib confirmed a reduction in geometric mean titres to pertactin in the original sample studied from the REST trial, but failed to demonstrate a difference in geometric mean titre to pertactin in the additional subjects studied or in the total sample(63). No data have been provided to indicate that RotaTeq™ can be administered with conjugated meningococcal C vaccine. Nonetheless, it is felt that RotaTeq™ may be administered concomitantly with all routinely recommended infant vaccines.
RotaTeq™ cannot be administered with oral polio vaccine, as concomitant administration of the two vaccines has not been studied, but this is irrelevant in Canada, where IPV is used exclusively.
Persons who are hypersensitive to RotaTeq™ or to any of its ingredients or any components of the container should not receive the vaccine, and individuals who experience symptoms suggestive of hypersensitivity after receiving a dose of RotaTeq™ should not receive further doses.
History of intussusception: No association between RotaTeq™ and intussusception has been demonstrated in large-scale safety trials involving over 70,000 infants or through post-marketing surveillance following distribution of 3.6 million doses of vaccine in the US. However, because of the previously documented association of Rotashield® with increased rates of intussusception, incomplete understanding of the pathogenic mechanisms underlying this increased risk and the possibility that infants with a history of intussusception are at increased risk of subsequent episodes, infants with a history of intussusception should not be given RotaTeq™ until further post-licensure safety data are available.
Immunocompromise: Infants known or suspected to be immunocompromised should not receive RotaTeq™. There are no safety or efficacy data available for its administration to immunocompromised patients, as these patients were excluded from clinical trials.
Administration of blood transfusions or blood products, including immunoglobulins, within 42 days before administration of RotaTeq™ may be associated with decreased vaccine efficacy. However, this has not been studied.
Acute gastroenteritis: The immunogenicity and efficacy of RotaTeq™ has not been studied in infants with concurrent gastroenteritis. However, in these infants, as is the case with oral polio vaccine, the immunogenicity and effectiveness of the vaccine may theoretically be reduced(64). Therefore, in infants with moderate to severe gastroenteritis, rotavirus vaccine should be deferred until the condition improves, unless deferral will result in scheduling of the first dose at ≥ 13 weeks of age. Infants with mild gastroenteritis can be vaccinated.
Pre-existing chronic gastrointestinal conditions: The safety and efficacy of RotaTeq™ has not been established in children with pre-existing chronic gastrointestinal conditions. However, infants with chronic gastrointestinal disease who are not receiving immunosuppressive therapy are likely to benefit from rotavirus vaccination and therefore can be vaccinated.
Although the limited available Canadian data demonstrate a high prevalence of illness associated with RV gastroenteritis among Canadian children, with an estimated 1/62 to 1/312 children < 5 years of age experiencing an RV-associated hospitalization lasting an average of 2 to 3 days, the disease is typically self-limited and only very rarely associated with long-term sequelae or death. However, it is associated with a noteworthy societal disruption when time off work for caregivers is considered.
Because RV causes only approximately 20% of all diarrheal illness in Canadian children, even a highly effective vaccine will appear ineffective to the general public. Insufficient data about the strain distribution of RV in Canada, and geographic and seasonal trends in distribution make prediction of the absolute impact of a universal RV vaccine program difficult. It must be recognized that vaccine effectiveness may be lower than the vaccine efficacy reported in clinical trials. Using the burden of disease estimated by the Rotavirus Gastroenteritis Cohort Model (Table 3) and the observed vaccine efficacy in clinical trials (Tables 4 and 5), and assuming that approximately 94% of RV disease in Canada is caused by RV strains contained in RotaTeq™, implementation of universal immunization of all Canadian infants could be expected to prevent as many as 56,000 cases of RV gastroenteritis, 33,000 physician visits, 15,000 emergency department visits and 5,000 hospitalizations annually. If the hospitalization rate is actually lower than that estimated by the Rotavirus Gastroenteritis Cohort Model, as suggested by the limited published Canadian data demonstrating hospitalization rates as low as 320/100,000, universal immunization may prevent as few as 1,000 hospitalizations annually. Prospective surveillance data from IMPACT will soon be available to provide better RV epidemiologic data regarding burden of illness and RV strain distribution in Canada.
Canadian epidemiology suggests that individual infants and their families are likely to benefit from immunization with RotaTeq™. The vaccine has been approved for use in infants 6 to 32 weeks of age and should be offered to infants whose parents/guardians wish to reduce the risk of rotavirus. The first dose must be given within 12 weeks of age. Adherence to recommendations regarding the timing of administration of RotaTeq™ should be ensured, as the safety of its administration outside of these age recommendations is not known (see earlier section, Dosage and Schedule).
The decision to include RotaTeq™ in universal, publicly funded provincial and territorial programs will depend upon other factors, such as detailed cost-benefit evaluation and assessment of other elements of the Erikson and DeWals analytic framework for immunization programs in Canada(65).
Some outstanding questions about RotaTeq™ that will influence the overall impact of the vaccine can only be determined in post-licensure studies. These include the following:
†Members: Dr. J. Langley (Chairperson), Dr. T. Tam (Executive Secretary), Dr. K. Laupland, Dr. S. Dobson, Dr. B. Duval, Ms. A. Hanrahan, Dr. J. Kellner, Dr. A. McGeer, Dr. S. McNeil, Dr. M-N Primeau, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan, Dr. B. Warshawsky.
Liaison Representatives: Dr. P. Hudson (CPHA), Dr. B. Bell (CDC), Dr. D. Money (SOGC), Ms. K. Pielak (CNCI), Dr. B. Larke (CCMOH), Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE), Dr. P. Orr (AMMI Canada).
Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. RM. Ramsignh (FNIHB), Dr. P. Laforce (DND), Dr. B. Law (IRID), Ms. R. Hickey (TMP).
† †This statement was prepared by Dr. Shelly McNeil, and approved by NACI and the Public Health Agency of Canada.


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HomeTrust Bancshares Technical Analysis (NASDAQ:HTBI)
Technical analysis is based on the study of past price and volume movements of a security with the help of technical stock charts or trading charts. Just by looking at the HomeTrust Bancshares stock price one can't take a trading decision. A trader needs to find a chart pattern, which is a clear cut pattern formation on the HTBI stock chart which creates a trading signal.
You can view Simple Moving Average (SMA 20 day, 50 day & 100 day), Exponential Moving Average (EMA 20 day, 50 day & 100 day) charts, and Bollinger Bands for HomeTrust Bancshares. The technical analysis form of HomeTrust Bancshares stock analysis tries to understand the market by studying the stock market trend itself as opposed to other aspects like the company's fundamentals.
HomeTrust Bancshares Moving Average:
HTBI stock price movements can be forecasted by using triggers based on moving averages, which are also some of the simplest technical indicators. The way the averages are calculated in each of the 2 popular cases, that is SMA and EMA varies, however the interpretation of HomeTrust Bancshares chart patterns after the calculations remain the same. The 100 day moving average of 24.3 is below the last closing price of 24.45. Moving averages can be used for HTBI trend identification. A rising moving average shows that stock prices are generally increasing.
HomeTrust Bancshares Bollinger Bands:
Bollinger bands comprise of a center line usually HTBI SMA, and two HTBI stock price bands above and below it. The stock is considered over brought when the price starts moving closer towards the upper band, and is considered oversold as stock price moves closer towards the lower band. Currently the stock price of $24.45 is in the lower range of HomeTrust Bancshares bollinger bands.
HomeTrust Bancshares Moving Average Convergence Divergence or MACD:
Two important concepts with respect to moving average convergence divergence or MACD are: crossovers and divergence. When the MACD rises above the signal line, it typically indicates a bullish trend and most likely the stock prices will go up. The HomeTrust Bancshares MACD indicator can be used to identify bullish and bearish trends for the stock.
HomeTrust Bancshares Relative Strength Index:
This technical indicator compares the relative strength or weakness of a stock. It measures the magnitude of rise or fall in stock price movements . The relative strength index of HTBI stock is 44.9. .

subset: commoncrawl


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A 41-year-old white man presented with a 7-year history of erythematous papules, livedo reticularis, swelling, myalgias, arthralgias, Raynaud phenomenon, and very large, painful and progressive ulcers on the lower part of both legs (Figure 1). A skin biopsy specimen revealed polyarteritis nodosa (PAN) with fibrinoid necrosis of medium-sized vessels. The patient fulfilled 4 of the criteria for PAN (ie, weight loss >4 kg, livedo reticularis, myalgias, and characteristic histological picture).1 Also, he had an elevated erythrocyte sedimentation rate, leukocyte count (Figure 2), CD3+ cell count (pan-T cells) (3.5 × 109/L), CD3+CD4+ T-cell count (T-helper cells) (2.7 × 109/L), and antinuclear antibody titer (1:640, speckled pattern). Systemic prednisone therapy administered at dosages as high as 100 mg/d had little, if any, effect. The patient's intense pain could only be controlled with morphine derivatives.
Polyarteritis nodosa with extended ulcers on the lower part of the leg before low-dose methotrexate treatment.
Synopsis of leukocyte counts and polyarteritis nodosa (PAN) activity during low-dose methotrexate therapy with more than 56 months of follow-up (0 indicates no visible lesions; 1, few nodules, livedo reticularis, and no ulcer; 2, abundant nodules, small to medium-sized ulcer(s), livedo reticularis, and pain; and 3, abundant nodules, medium-sized to large ulcers without tendency to heal, livedo reticularis, and severe pain).
Polyarteritis nodosa is a necrotizing vasculitis of small and medium-sized arteries with a chronic course that needs effective long-term treatment with a favorable benefit-risk ratio, and our patient failed to respond to prednisone treatment.
Treatment consisting of intravenous injections of methotrexate (25 mg/wk) was initiated. The skin lesions improved and the patient's pain ceased, so the morphine treatment could be discontinued. The ulcers completely healed within 6 months. The methotrexate therapy was not discontinued, but the dosage was adjusted based on disease activity (range, 10-35 mg/wk). The initial remission lasted for 15 months, at which time the patient again developed ulcers on the lower part of both legs despite ongoing methotrexate therapy (10-25 mg/wk), but the ulcers were much smaller, less deep, and not as painful as they were before methotrexate therapy was begun. To achieve rehealing, the dosage was adjusted (25-35 mg/wk). After 13 months, all the new ulcers had completely disappeared, and after 7 months the patient remained free of ulcers at a dosage of less than 25 mg/wk (Figure 3).
Scars and livedo reticularis but no visible ulcers on the lower part of the leg after a total methotrexate dose of 5491 mg.
Routine laboratory parameters and lymphocyte subsets as determined by flow cytometry were regularly monitored once a week to once a month. Initially, the PAN-associated leukocytosis decreased during methotrexate therapy (Figure 2). Despite ongoing methotrexate treatment, the number of leukocytes increased after 18 months and was accompanied by worsening of the clinical picture (Figure 2). The treatment neither induced pathologic alterations of routine laboratory findings nor decreased circulating T-lymphocyte subsets. Histological examination of a liver biopsy specimen obtained after a cumulative methotrexate dose of 2.5 g revealed no hepatic abnormalities. An ultrasonogram of abdominal organs showed no hepatic fibrosis or cirrhosis. Dynamic hepatic scintigraphy after cumulative doses of 3.8 and 5.2 g revealed normal findings. With single weekly intravenous doses ranging from 10 to 35 mg, methotrexate therapy has controlled the patient's PAN for more than 56 months. Despite a total cumulative dose of 5.5 g, the therapy was well tolerated, and we did not find any methotrexate-associated adverse effects.
Methotrexate has been successfully used in the treatment of different types of vasculitides, eg, Wegener granulomatosis,2 Takayasu arteritis,3 and giant cell arteritis,4 and has rarely been reported in patients with PAN.5,6 This article represents the first report of long-term low-dose methotrexate therapy in a case of severe cutaneous PAN.
There is evidence that an anti-inflammatory mechanism rather than immunosuppression is responsible for the effectiveness of the low-dose methotrexate regimen.7 This theory is supported by the lack of immunocompetent cell depression,8 which was confirmed in our case by the results of long-term monitoring of leukocytes and circulating T-cell subsets. The fact that a wide spectrum of vascular diseases, including PAN, demonstrate improvement during low-dose methotrexate therapy leads to the assumption that methotrexate may control a crucial inflammatory step or factor. Since the report of Segal et al,9 one of the major effects of low-dose methotrexate therapy seems to be the inhibition of interleukin 1 (IL-l) activity without alteration of either IL-1 synthesis or IL-1 secretion, a finding that has been confirmed by other researchers.10,11 Previously, we demonstrated in an in vitro assay that methotrexate inhibited IL-1β binding to its cell surface receptor.12 Interleukin 1 plays a central role in inflammatory events and vasculitides. It activates endothelial cells to express adhesion molecules and to produce other pro-inflammatory cytokines, such as IL-6 and IL-8, and stimulates the chemotactic activity of neutrophils. Moreover, methotrexate inhibits leukotriene B4– and/or C5a–induced neutrophil and macrophage chemotaxis13 and reduces platelet activation factor–induced leukocyte–endothelial cell adhesion.14
The case presented herein is interesting in several respects: (1) as has been established in cases of psoriasis and rheumatoid arthritis, our case shows that methotrexate therapy also has short- and long-term efficacy in PAN; (2) short-term treatment involves a low risk for the development of adverse effects, but even during long-term follow-up (>56 months) of methotrexate treatment, our patient did not develop immunosuppression or any other adverse reaction; and (3) disease activity runs in parallel with absolute peripheral blood leukocyte counts (Figure 2).
We presume that the clinical improvement noted was mediated by methotrexate's anti-inflammatory properties. Therefore, low-dose methotrexate therapy appears to represent an interesting alternative treatment strategy for managing this complex disease. Clinical trials will be necessary to confirm this observation in a larger group of patients.
Accepted for publication November 15, 1999.
Corresponding author: Ingrid Boehm, MD, Department of Dermatology, University of Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany.
Boehm I, Bauer R. Low-Dose Methotrexate Controls a Severe Form of Polyarteritis Nodosa. Arch Dermatol. 2000;136(2):167-169. doi:10.1001/archderm.136.2.167
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Students with a GPA below 2.5—either cumulatively or in the most recent semester—are automatically placed on Academic Oversight. Academic Oversight is not the same as Academic Probation or Satisfactory Academic Progress. If a student is on Academic Probation, the information on this page is not applicable.
Students on Academic Oversight are in good academic standing. The purpose of Academic Oversight is to help students achieve their maximum academic potential. A student on Academic Oversight will be assigned an "Academic Advisor," either the Director or the Associate Director of the Academic Achievement Program (AAP). The AAP at Miami Law has been especially created to provide resources to students seeking to improve their academic performance. Academic Advisors have extensive experience helping students meet the challenge of maintaining their GPA above the 2.5 level.
The Academic Achievement Program sponsors numerous programs and workshops, which are open to all students. Students on Academic Oversight are expected to fully participate in this programming, and take advantage of all the resources sponsored by the AAP. If a student is on Oversight, his or her Advisor will provide details about such programs. Note also that if one's GPA is below 2.3, special conditions may apply. For detailed information about Academic Oversight, please see the Student Handbook.
Course Registration Procedures for Students on Academic Oversight
Below are specific guidelines regarding Academic Oversight course registration. So long as course selections satisfy these guidelines, a student may enroll in the courses of his or her choice via CaneLink, without prior approval from an Advisor. However, if course selections do not meet these criteria, a student may be administratively dropped from certain courses and added to other courses deemed more appropriate.
1) 2L students on Academic Oversight are required to complete at least one writing requirement during their 2L year. This rule applies for the entire 2L year, even if a student is only on Academic Oversight for one semester.
2) Students on Academic Oversight should not elect pass/fail status in any classes where a letter grade is normally awarded. It is to your benefit to raise your GPA by taking all graded courses. While you are not prohibited from taking classes that are mandatory pass/fail for all students (such as Litigation Skills), you should focus on graded courses where you can demonstrate your ability and improve your GPA, so as to be off academic oversight as soon as possible.
3) All students on Academic Oversight are required to register for at least 2 classes for next semester from the list below:
·Business Associations
Registration Dates and Times: The registrar will assign a registration date and time pursuant to normal procedures, based upon class year and other standard policies. However, students on oversight have a limited "open registration" period, to choose classes (including adding or dropping), and to place themselves on waitlists. When the open registration period ends, an administrative hold will be placed on a student's CaneLink account. Advisors will provide more information about this process, including the exact dates of the open registration period.
Adding and Dropping Courses: During the open registration period, a student may add or drop courses via CaneLink, as long as his or her overall schedule remains compliant with the registration guidelines listed below. If a student wishes to add or drop a course after the open registration period, he or she must complete the following form, which is subject to approval by an Advisor: Academic Oversight Add/Drop Form.
Instructions to use this form:
- You must use Firefox or Internet Explorer.
- Your username is your full law school student email address (e.g., email@example.com). Do not use your canelink username.
- Your password is the password that you use to access your law school email account.
- Access the form here: Academic Oversight Add/Drop Form.
- Please send an email to your academic advisor (firstname.lastname@example.com or email@example.com) immediately after submitting the form, so we can confirm that it was completed properly.
- Forms will be reviewed during business hours and are typically resolved within 2 business days.
Waitlists: Students may add and remove themselves from waitlists during the open registration period. If a seat becomes available during the open registration period, a student will automatically be added to that class (including any designated course swaps). However, once the open registration period ends, it is no longer possible to add or remove oneself from waitlists and enter classes from waitlists. Students should use every effort to ensure that they are satisfied with their schedule by the end of open registration, without requiring a waitlisted seat.
Difficulty Obtaining a Seat: If a student is unable to comply with the Academic Oversight Registration guidelines listed below, because no seats are available in his or her desired course, or he or she is on a waitlist after the open registration period ends, please contact one's Academic Advisor.
Graduation Requirements: Please remember that, in order to graduate, all students must fulfill the general graduation requirements for JDs – see the Student Handbook for details. It is each student's responsibility to ensure that he or she is on track to fulfill these requirements before graduation.
Joint Degree Students: For joint degree students on Academic Oversight, please consult with one's Academic Advisor and the advisor of the joint degree program before course enrollment.


text: Bravo to Bill O'Reilly for taking note of Caroline Kennedy's phrase "as a Catholic woman" before she attacked pro-life laws passed around the country in legislatures controlled by Republicans. O'Reilly recognized this as a direct attack on the Catholic Church. Of course this is all part of the Democrat party's attempt to promote a de facto schism in the Church in America for political advantage. As I have noted many times this isn't merely an election year for American Catholics. This is an Elijah on Mount Carmel year. A time of choosing is upon us.


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Investment in the stock market has been yielding great results to earn more or to acquire a good position of power in a company. Trading in stock market is at times a very complicated process because it requires many smart ways of thinking in order to find the best shares to be invested in. Anyone who plans to invest in the stock market has to consider various criteria so as to find the stocks of a company that meets the individual's requirement.
Need for Stock Screeners
In general, a person will have to go through a vast amount of data about companies, stock prices, market situation, the profitability of shares and much more so as to discover the best stocks for investment. It is a very cumbersome process and many people also find it very difficult to make the analysis. Finding the right stock which favors the investor's requirement is like finding a needle in a haystack. It is in these situations that stock screeners come to save the day. Stock screeners play a commendable role in helping people to find the shares of their choice with ease. Basically, stock screening is a procedure that involves finding stocks which are relevant to the selection criteria of the investor.
Functions of Stock screeners
A Stock screener can be considered as an instrument that acts as a wonderful searching tool which helps to filter the stocks according to the conditions placed by the investors. It helps to identify stocks that are according to the need of the investor based on certain fundamental factors like market capitalization, price, dividend yield, return on investment, price change percentage, balance sheet ratio, average volume, P/E ratio, etc. Some stock screeners also permit the users to screen based on technical indicator data in order to filter stocks according to their relative strength index, above 200-day moving average etc.
Usually, stock screener comprises of three primary components namely, a database of companies, a set of variables, and a screening engine. Once an investor enters the data with the requirements of the stock, the stock screener identifies the companies which fulfill the needs of the variables that are entered by the investor and then produces the list matching the specifications. Thus, it carries out a detailed quantitative analysis of the stocks for the sake of the investor.
Bond between Stock Screeners and Trading Technologies
The link between Stock Screeners and Trading Technologies is unbreakable. A stock screener can perform exceptionally only with the help of trading technologies. Many advanced software programs and online subscription services give rise to stock screeners which perform complicated Stock Analysis just within a short period of time for the user. The trading technologies enable stock screeners to carry out screening of stocks by utilizing many factors and advanced mathematical calculations. These Artificial Intelligence stock trading technologies facilitate to compare fundamental and technical features of stocks to analyze the stock performance in the past and estimate the expected return from such stocks in the future. These trading technologies also offer Stock Price Variables which can be helpful for day traders. The technologies are so sophisticated that they use about 20 predetermined screens encompassing a plethora of investment strategies.
Benefits of Stock screeners with Trading technologies
Trading technologies aid the stock screeners to allow the user to witness technical analysis, trading strategies that lead them to the stocks which meet the criteria described. With the advancement in technology, the users also have an option to use customized screeners through which they can decide the factors of input that are to be considered for stock screening.
The technology helps to massively cut down the time taken to find the right stocks because it presents reliable results with great accuracy in just a few minutes. Over the course of time, these Artificial Intelligence engines have been proven to give good market predictions and thorough analysis of stocks. These trading technologies have been garnering immense prominence from the investors due to the simplified approach, ease of usage, and user-friendly interface. Stock screeners with high-end trading technologies have become popular because the results that they provide are accurate, efficient and are of impartial nature.
The process of stock screening has become majorly dependent on artificial Intelligence and hence it is a valid fact that no stock screeners exist without high-end trading technologies.


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Newegg.com - A great place to buy computers, computer parts, electronics, software, accessories, and DVDs online. With great prices, fast shipping, and top-rated customer service - once you know, you Newegg.
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This review is from: Philips Norelco Series 4000 AT810/41HP PowerTouch with Aquatec electric razor with bonus Neutrogena Men Sensitive Skin Shave Cream 5.1 oz, Neutrogena Men Triple Protect Face Lotion 1.7 oz with sunscre
Pros: cuts well, umm yeah
Cons: easy to get razor burn, the trimmers are not good at cutting
Other Thoughts: it cuts very well. I get razor burn easy and this is my first electric razor so I decided to do it in the shower without cream... not a good idea. a few days later used it with the cream and it was great. kind of hard to get used to but have been shaving with a 3 or 5 blade for a while now so I expect the irritation. gets better with every use and is definately a good razor to use. just make sure u use the gel that it comes with for a great shave !READ FULL REVIEW
This review is from: HooToo® HT-UH010 7-Port USB 3.0 Hub with 2 Smart-Charging Ports for iPad, iPhone, Smart Phones & Tablets (Latest VIA VL812 Chipset, 12V/5A Power Adapter, 3.3ft USB Data Cable)
Pros: It can power almost anything I throw at it USB wise. Windows picks it up and there seems to be great transfer ( I did not test the transfer rate though). recognized USB 3 hard drive and transferred movies without much time
Cons: No really big cons other than I did have some trouble getting it to recognize when first plugged in but I feel that this is due to my motherboard. I have been having problems with usb 3 with other peripherals before I purchased this item. after a fresh boot all was well and everything I threw at it worked fine
Other Thoughts: I originally purchased this product to work with my Rasp Pi CGminer bitcoin miner that I have built. Though Rasp Pi will not recognize it, I decided to hard solder the 12V in to a C{U cooler to cool the GPUs and the accessory USB port to power the Pi.It works like a champ and has more than enough juice and a stable power supply for the fan. Wish it would have work with the Pi, but that is due ot limitations of the Pi not accepting usb 3.0READ FULL REVIEW


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Berkeley County Schools
August 27, 2011 by USA Post
Berkeley County Schools, All schools in the Dorchester School District 4 will close at 1 pm today and the teachers and staff will go after all the children are gone. All afternoon and evening programs are closed.
Berkeley Schools close early. Check the schedule for free time for your child's school. Dorchester School District 2 and 4 have announced that they will close schools early today, too.
In Dorchester 2, Givhans Alternative School will close at 10 am, primary schools will close at 11 am, high schools will close at noon; Rollings Middle School of the Arts will close at 12:20 pm; other schools half will be closed at 12: 45 pm Child development is closed but extended day programs will be open until 3 pm For more information visit the school district.
Dorchester 4 has not yet announced what time school will be announced.
Charleston County School District officials have been watching Hurricane Irene days, but did not know the parents until 21:30 Thursday that the school would be canceled today.
And about 8 o'clock this morning, the Berkeley County schools announced they would move to a part-time schedule.
"Due to bad weather imminent, Berkeley County Emergency Management has advised the Berkeley County School District to operate on a schedule of noon today," said a press release in the morning.
Late at night, Charleston County's decision left many struggling to arrange child care, but school officials said they were acting with members of staff and student safety in mind.
"We felt we could bring (students) safely, but the problem is, can we get home safely?" Said Nancy McGinley Superintendent. "We err on the side of caution rather than creating all this chaos in the middle of the day. We try to go as fast as we could."
School leaders have been in close communication with the Emergency Operations Centre County, and the last one I received was at 5:30 pm At 5 pm, the National Hurricane Center lifted the advisory for the coast of South Carolina from a tropical storm watch to a warning, that is, tropical storm conditions could be expected within 36 hours.
District officials spent the next hour reviewing information from various sources and realized at about 7 pm as the deadline for winds could begin collecting could create some security problems, said Jeff Scott, director of the district facility security and emergency preparedness.
Strong winds can cause a problem for students traveling home, especially those who ride in buses over bridges, he said. The winds are expected to exceed 30 miles per hour.
The wind at first was not going to get worse until 4 or 5 hours, but this time changed to noon and school leaders.
"We were worried about the storm accelerating," said Scott.
School officials then began talking about what to do. They came to the district transportation director, the company that provides services of buses, the Emergency Operations Center, a meteorologist, its chief financial officer, the Deputy Superintendent for communication and the superintendent.
"It took us a while to get input from everyone," said Scott.
Once the superintendent's decision to cancel school, parents were notified within 15 minutes, he said.
The school district buses run three routes each, so it takes time to get mobilized and transported all the students home, McGinley said. She said she acknowledged that parents were notified at a late hour, but could have created a bigger problem to allow students to attend school in the morning, he said.
Parents had mixed reactions. Some said they preferred to stay home with their children to be in a dangerous situation.
"It's better to be safe than sorry and cancel it does not," wrote Caroline snoots bleach in a post on the page and courier Facebook.
Others said the late decision left struggling to make child care plans for today.
"I would like not going to wait until 9:30 pm to make the call!" Beth Hunter Baldwin wrote in another post.
The city of Charleston scheduled to continue preparations for the hurricane today and do regular business, said Barbara Vaughn, a spokesman for the city government.
"Employees should call the human resources information, if you have questions," he said.
Please feel free to send if you have any questions regarding this post , you can contact on
Disclaimer: The views expressed on this site are that of the authors and not necessarily that of U.S.S.POST.


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Video - Plans to revamp Barcelona's Nou Camp are breathtaking
Barcelona have unveiled plans for the revamp of their iconic Nou Camp home, with the four-year project set to transform the stadium into Europe's most lavish sporting arena.
Plans to expand the Nou Camp to stadium to a venue that will hold more than 100,000 spectators were outlined last month, with the club officially launching the project with the help of the current first team squad on Thursday morning.
Barcelona's home ground is already the largest capacity stadium in Europe, with the revenue stream from match days set to expand with improved facilities put in place in a project that is expected to be completed in time for the 2021-22 season.
🔊 Andrés Iniesta: "The Club is taking an important step in its history. The #NouCampNou will be a reference point" pic.twitter.com/O2fyHcQJ24— FC Barcelona (@FCBarcelona) April 21, 2016
The project is expected to cost around £500m and club chiefs hope it was turn the Nou Camp into "an iconic symbol for the City of Barcelona", with Japanese architects Nikken Sekkei completing the work alongside Catalan firm Pascual i Ausio Arquitectes.
"The proposal presents a very subtle attempt to intervene in the environment to facilitate circulation and achieve diverse urban usage in the Barca Campus and guarantees a clear and safe construction," read a club statement.
"In short, it is a unique solution, reproducing the characteristic vision of the grandstand and canopy, from the inside out, a silent and powerful tribute to the stadium built by Francesc Mitjans in 1957."
Football will continue to be played at the venue throughout the redevelopment work and in this video, Barcelona chiefs have outlined how the Nou Camp experience will feel for paying customers.
Check out the model of the #NouCampNou. Força Barça!— FC Barcelona (@FCBarcelona) April 21, 2016
This video looks at how the Nou Camp will be restructured, with the final images confirming a complete transformation will be unveiled by the time building work concludes:
The #NouCampNou, a dream open to the world. This is what Barça's new stadium will look like https://t.co/zr2vn5RtTt— FC Barcelona (@FCBarcelona) April 21, 2016


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You are here: Entertainment Options » Christmas Themed Events » Christmas Entertainers for Hire » Christmas Walkabout Entertainers » Human Box for Hire
The Human Box
Curiosity is awoken by the arrival of a muted clown alongside a box. Despite his size somehow the clown climbs into the box and shuts the lid as the audience awaits to find out what will happen next. The Human Box extends its legs and leaps to life and begins to scurry off.
Our walkabout box comes complete with a comedic security guard for good measure. The box itself has different decorations to choose from. It can come as a Christmas present or in corporate branding.
The Human Box is a unique entertainment option to hire for Christmas-themed events, product launches, corporate events and much more.
Watch it Here!
Watch as this entrancing Human Box scurries around an event, amazing people as he goes. Our Human Box is truly a site to behold. The Human Box is available to book for a wide range of events including; shopping centre events, Christmas-themed events, corporate events and much more.


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Mr. Stark says that Pacer is one of the most flexible 3PLs and can expand and contract as Yamaha's requirements change. He also notes that Yamaha has long been one of Pacer's key strategic business partners "and we work frequently with them to develop customizable solutions to expand their business." As one example, Mr. Stark cites an account management process that Pacer recently implemented with Yamaha. "We look forward to helping Yamaha Motor Corp. continue to grow its business," he says.About Yamaha Motor Corp., U.S.A. Yamaha Motor Corporation, U.S.A., (YMUS), is a leader in the motorsports market. The company's ever-expanding product offerings include ATVs and Side-by-Side vehicles, motorcycles, outboard motors, personal watercraft, snowmobiles, boats, outdoor power equipment, accessories, apparel and much more. YMUS products are sold through a nationwide network of dealers in the United States. Headquartered in Cypress, Calif., since its incorporation in 1976, Yamaha also has facilities in Wisconsin and Georgia, as well as factory operations in Tennessee and Georgia. For more information on Yamaha, visit www.yamaha-motor.com About Pacer ( www.pacer.com ) Pacer International, a leading asset-light North American freight transportation and logistics services provider, offers a broad array of services to facilitate the movement of freight from origin to destination through its intermodal and logistics operating segments. The intermodal segment offers container capacity, integrated local transportation services, and door-to-door intermodal shipment management. The logistics segment provides truck brokerage, drayage, warehousing and distribution, international freight forwarding, and supply-chain management services. Pacer specializes in designing integrated supply chain solutions for its customer base. For more information on Pacer International visit www.pacer.com The Pacer Distribution Services logo is available at http://www.globenewswire.com/newsroom/prs/?pkgid=14690
CONTACT: Media Contact: Melissa Bradley 928-208-9300 email@example.com


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| This article doesn't have a proper headlining picture.
You can help American Girl Wiki by locating a catalog picture, scanning an image or illustration, or taking a picture and uploading it. Please follow our Good Article Images Guidelines.
The Holiday Sweater Set I is a Just Like You outfit released in 2009 and retired the same year. It was sold as a Purchase With Purchase at American Girl Stores.


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Eco-friendly fashion is both trendy and good for the environment. Over the past couple years, garments made from bamboo, organic cotton, hemp and recyclable materials have been popping up in boutiques from Coast to Coast. Smartglass Recycled Jewelry is handmade in Atlanta and fashioned from beer and soda bottles. I own the eye catching green circle necklace made from a recycled Coke bottle on a sterling silver chain, $72.
More information: http://www.hotmamadaily.com


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Hey there,
this code crashes the EA with the message: Access violation write to 0x00000020 in '(...)EA.ex4'. WTF?
string filename=NULL; string search="*"; long handle=FileFindFirst(search,filename,FILE_COMMON); while (handle!=INVALID_HANDLE) { handle=FileFindNext(handle,filename); } FileFindClose(handle);
When FileFindNext() is executed 3rd time, the debugger stops. It happens with every search mask. I cannot trace the problem.
Of course I reported this to the service desk, but my last answer there is 3 months ago. Senseless in most cases. Maybe someone had the same problem and has an idea.
Thanks in advance


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|Property type
|Minimum Stay
|5 nights
A relaxing vacation in the Valdichiana countryside. Two pleasant apartments. IL POMO and LA PALMA, have been carefully made from part of an old country house with views across to the soft hills and old villages of Val di Chiana. The apartments each have their own entrance and outside area equipped with garden furniture, are furnished with taste and include all modern comforts for those who are looking for the peace of the countryside in a welcoming environment.
The well kept garden, the pool and all the services. There is a large well kept garden with table tennis, play ground for children, barbecue and beautiful 9x18 m swimming pool (depth m 0,75-2,20) used by guests and the owners of the house, who live next door.
Distance from shops km 4,00
Distance from main cities Firenze km 90,00, Siena km 50,00, Arezzo km 30,00, Roma km 185,00, Perugia km 65,00
Total number of apartments composing the property: 2
Apartment on the first floor reached by an inside staircase comprising sitting room with fireplace, dining room with kitchenette, double bedroom, single bedroom, twin bedroom, bathroom with jacuzzi and shower.
EQUIPMENT: Satellite Tv, washing machine, dishwasher, oven, microwave, freezer, moka coffee maker, filter coffee maker, toaster, Wi-Fi Internet access.
The pool is open from 29/5 to 25/9
Wonderful location, beautiful garden and swimmingpool. Close to lovely Lucignano. Only remark: barking dogs in neughbourhood who wake you up at 6AM
Lots of space, clean appartment, quiet and typical Tuscany region, big pool, friendly people


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|Named Person:
|Pedro de Castañeda de Nájera; Francisco Vásquez de Coronado; Alvar Núñez Cabeza de Vaca; Pedro de Castañeda de Nájera; Francisco Vásquez de Coronado; Alvar Núñez Cabeza de Vaca
|Document Type:
|Archival Material
|All Authors / Contributors:
Adolph Francis Alphonse Bandelier; Frederick Webb Hodge; Ralph Emerson Twitchell; Huntington Free Library.
|OCLC Number:
|The work was published in the "New Mexico historical review", volume 4, number 4, 1929, and volume 5, number 1, 1930.
Forms part of the Native American Collection. (NAC).
|137 p.
Typed manuscript. Covers history of New Mexico in the 1500s including the Spanish conquest and observations from explorers. Cover states "Copy sent to me by Ralph E. Twitchell, it is signed FWH, Frederick Webb Hodge. Inside is other writing by Hodge.".
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Related Subjects:(19)
- Castañeda de Nájera, Pedro de, -- active 16th century.
- Coronado, Francisco Vásquez de, -- 1510-1554.
- Núñez Cabeza de Vaca, Alvar, -- active 16th century.
- Indians of Mexico.
- Indians of North America.
- Indians of North America -- New Mexico.
- Acoma Indians.
- Pueblo Indians.
- Tiwa Indians.
- Zuni Indians.
- Cibola (Ariz.)
- Colorado River (Colo.-Mexico) -- Discovery and exploration.
- New Mexico -- History.
- Rio Grande (Colo.-Mexico and Tex.)
- Discoveries in geography.
- Arizona -- Cibola.
- New Mexico.
- North America -- Colorado River.
- North America -- Rio Grande.
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- The Southwest, history, Bandelier, Adolph(117 items)
by rdheinritz updated 2008-07-27


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Reshaping Societies HIV/Aids And Social Change1 edition - first published in 2000
Children on the brink1 edition - first published in 1997
HIV/AIDS orphans and NGOs in Zambia1 edition - first published in 1997
AIDS in America1 edition - first published in 2006 DAISY
Children of AIDS patients, AIDS (Disease), AIDS (Disease) in children, Accessible book, Acquired Immunodeficiency Syndrome, Care, Children's rights, Community health services, Congresses, Epidemiology, Family relationships, Non-governmental organizations, Orphans, Protected DAISY, Services for, Sida
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History Created April 1, 2008 · 2 revisions
|September 8, 2008
|Edited by RenameBot
|fix author name
|April 1, 2008
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