13-valent Conjugate Vaccine Research Articles

Immune Response to the 23-Valent Polysaccharide Pneumococcal Vaccine (PPV23) after the 7-Valent Conjugate Vaccine (PCV7) in Allogeneic Stem Cell Transplant (SCT) Recipients: Results of the EBMT IDWP01 Trial

Background: Pneumococcal infections are causes of death after SCT. The IDWP01 trial compared early (E) vs late (L) pneumococcal immunization after allogeneic SCT, starting either at 3, or at 9 months post-transplant with 3 doses of PCV7 given at 1 month intervals,. This study has shown that the early immunization was not inferior in the proportion of responders one month after the last PCV7 dose. In addition, all patients received one dose of PPV23 after the 3 doses of PCV7 at 12 months and 18 months in the E and L groups, respectively. The goal of this supplementary analysis was to look at the immune response to the PPV23 according to the time of its administration.Methods: 158 patients were randomized in the IDWP01 trial, 75 in the E, and 83 in the L group, of whom 109 received the PPV23 (56 in the E, and 53 in the L group, respectively) and 86 (44 in the E, and 42 in the L group) were followed up to 24 months after SCT. The immune response to PPV23 was assessed by the antibody (Ab) titres, measured by ELISA to pn1 and pn5, which are both included in PPV23 but not in PCV7. Pn1 and pn5 Ab titres were assessed before, and one month after the PPV23 dose, and at 24 months post-SCT. Two cut-off levels for protection were considered for each antigen: □ .15 μg/ml and □ .5 μg/ml. The geometric mean concentrations (GMC) were also analyzed. Additionally, all Ab titres to the 7 PCV7 antigens were measured in parallel.Results: Ab titres to pn1 and pn5 before the PPV23 were not significantly different in the E (at 12 mo post-SCT) and in the L (at 18 mo post-SCT) group. Whatever the cut-off used to evaluating the response, the percentage of responders one month after the PPV23 was not significantly different in both groups: For pn1: □ .15μg/ml: E: 80% vs L: 87%; □ .5μg/ml: E: 42% vs L: 60%; For pn5: □ .15μg/ml: E: 84% vs L: 94%; □ .5μg/ml: E: 62% vs L: 74%). The GMC were not significantly different in the E vs. the L group for pn1. The GMC were significantly higher in the L vs. the E group for pn5 (P=.02). At 24 months post-SCT, there was no significant difference in the GMC of pn1 and pn5 Ab titres but there was a tendency for higher titres in the L group for both antigens. Additionally, among 36 non-responders to the PCV7 at the time of PPV23 administration, 21 remained non-responders, but 15 (42%) responded to all the seven PCV7 antigens 1 month later.Conclusion: Although there was a tendency for a better response rate and for higher GMC for pn1 and pn5 according to the timing of immunization with PPV23 (12 vs. 18 months) in favour of the L group, these differences were not significant. Additionally, PPV23 increase the response rate to the serotypes included in the PCV7. Therefore, we recommend starting PCV7 vaccination early after SCT (3 PCV7 from 3 months). A dose of PPV23 after 3 doses of PCV7 broadens the immune response to pneumococci as well as increases the response rate to the serotypes included in the PCV7 and should therefore be considered at 12 months after SCT.The authors are grateful to the Safety committee: D Engelhard, P Reusser, and P Reinert

The effect of 23-valent pneumococcal polysaccharide vaccine on immunological priming induced by 7-valent conjugate vaccine in asplenic subjects with β-thalassemia

The effect of the 23-valent pneumococcal polysaccharide vaccine (PPV) on the 7-valent conjugate (PCV) vaccine-induced priming was evaluated in 35 splenectomised β-thalassemics [median (range) age: 30 (12–41) years] vaccinated with either PCV/PPV or two PCVs 1 month apart, followed by a PPV booster 12 months later. 28/35 had already received 1–3 PPVs in the past. Different schedules induced similar anamnestic responses; however priming for 3/5 serotypes induced by one or two PCVs, was inferior in subjects who had received ≥2 PPVs in the past when compared with 23 aged-matched PPV-naïve β-thalassemics. One PPV following PCV does not affect PCV priming; multiple PPVs induce hyporesponsiveness for some serotypes in splenectomised subjects with β-thalassemia.

Cross-Sectional Study of Nasopharyngeal Carriage of Streptococcus pneumoniae in Human Immunodeficiency Virus-Infected Adults in the Conjugate Vaccine Era

Human immunodeficiency virus (HIV)-infected patients have an increased rate of pneumococcal infections. Within the HIV-infected population, patients with low CD4(+) cell counts have a higher rate of pneumococcal infection. The purpose of our study was to determine pneumococcal carriage and to examine the serotypes carried by HIV-infected patients after the introduction of the conjugate vaccine. Nasopharyngeal swabs were obtained from patients during routine clinic visits. Samples were cultured on blood agar plates with gentamicin and screened for alpha-hemolysis, optochin sensitivity, and bile solubility. Capsular serotypes were determined by multiplex PCR, multibead assay, or latex agglutination. Antibiotic susceptibility was determined by the Etest method. Multilocus sequence typing was also performed. Of the 175 patients enrolled, 120 patients had absolute CD4(+) cell counts above 200/mm(3) and 55 had counts below 200/mm(3). A total of six (3.4%) patients carried pneumococci. All but one of these patients had received the 23-valent pneumococcal vaccine within the previous 5 years. Five of the isolates were serotypes that are not included in the 7-valent conjugate vaccine. Immunization with the pneumococcal polysaccharide vaccine does not prevent colonization in HIV-infected patients; however, the observation of carriage of serotypes not included in the conjugate vaccine may be due to herd immunity and serotype replacement effects in the general population.

Incidence of invasive pneumococcal disease in the Czech Republic and serotype coverage by vaccines, 1997–2006

We studied the incidence of invasive pneumococcal disease (IPD) in the Czech Republic by analysing two sources of data. The incidence of pneumococcal meningitis based on routine notification data varied between 0.4 and 0.6/100 000 population between 1997 and 2006. The incidence of IPD based on laboratory surveillance varied between 2.3 and 4.3/100 000 population between 2000 and 2006. The annual IPD incidence remained stable during the study period. Estimates of absolute IPD case-load in the entire country varied from 235 to 437 per year. The age-specific incidence was highest in the <1 year age group, reaching 4.3/100 000 for pneumococcal meningitis in routine notification and 15.7/100 000 for IPD in laboratory-based surveillance data, respectively. A total of 1236 Streptococcus pneumoniae isolates from cerebrospinal fluid and sterile body sites were investigated. The most frequent serotypes causing IPD in all ages were 3, 4, 14, 8 and 19F, accounting for 41.5% of all isolates. The most frequent serotypes by age group were: <1 year (6B and 19F); 1-4 years (14, 6B and 23F); 40-64 years (3, 8 and 4), and > or = 65 years (3, 4, 9N and 14). The coverage of serotypes in all age groups by pneumococcal vaccines ranged from 41.5% for 7-valent conjugate vaccine to 67.9% for 13-valent conjugate vaccine. The coverage of serotypes causing IPD is significantly different between infants/children and adults/elderly. PCV-7 coverage by age group was: <1 year (66.0%), 1-4 years (65.1%), 40-64 years (34.4%) and > or = 65 years (39.3%). Similar age differences between infants/children and adults/elderly were found in coverage by PCV-9, PCV-11 and PCV-13. The distribution of serotypes in the total population and individual age groups was stable during the period 2000-2006.

Serotype-Specific Immune Unresponsiveness to Pneumococcal Conjugate Vaccine following Invasive Pneumococcal Disease

Following the introduction of the pneumococcal 7-valent conjugate vaccine (PCV7) into the routine infant immunization schedule in England, Wales, and Northern Ireland, pneumococcal serotype-specific immunoglobulin G (IgG) antibody testing was offered as a clinical service to all children within the program with invasive pneumococcal disease (IPD) to confirm an adequate antibody response to PCV7. As of March 2008, serum samples taken within 14 to 90 days of vaccination had been submitted from 107 children who had received one or more doses in the second year of life. Sera were assayed by a multiplexed microsphere assay incorporating both cell wall polysaccharide and serotype 22F adsorption. A protective serotype-specific antibody level was defined as a concentration of > or = 0.35 microg/ml. Eight children failed to develop a response to their infecting serotype (6B [n = 4], 18C [n = 2], 4 [n = 1], and 14 [n = 1]), despite receiving at least three doses of PCV7 in the second year of life or two doses in the second and two or three in the first year of life. A further two children were nonresponsive to a serotype (6B) different than that causing disease. None of the 10 children had a clinical risk factor for IPD. Two had marginally low levels of total serum IgG but mounted adequate responses to the other six PCV serotypes. This serotype-specific unresponsiveness may reflect immune paralysis due to large pneumococcal polysaccharide antigen loads and/or a potential genetic basis for nonresponse to individual pneumococcal serotypes.

Editorial Commentary:Changing Epidemiology of Invasive Pneumococcal Disease: A Complicated Story

jugate vaccine into the WMA population in Arizona. This study is very beneficial to our understanding of the dynamics of pneumococcal epidemiology in general and of the impact, both positive and negative, that vaccine introduction may have in a population. The study performed by Lacapa et al. [2] was an observational study and compared rates of disease in the time period before vaccine introduction with rates in the time period after vaccine introduction. One of the key observations of the study was that the incidence of invasive disease due to the 7 serotypes covered in the vaccine was reduced substantially in this highrisk population. The observed 92% reduction in the rate of infectious pneumococcal disease among high-risk children aged !5 years is consistent with the reductions observed in other studies. However, the rate of disease among vaccinated WMA children still remains higher than that among the general population. There are 2 reasons for this. First, given the higher initial rate of disease, a 92% reduction in the rate of disease still leaves a substantial disease burden in the population. Second, prior to vaccine introduction, the proportion of overall invasive disease due to the 7 serotypes covered in the vaccine was only 56.2% among WMA children, compared with ∼90% in the general population. The reasons for this difference are not known, but the difference is consistent with both the variability of coverage of the 7-valent conjugate vaccine globally and with changes in serotype distribution observed over time in the Native American population and other populations globally. Although other vaccines that contain 10 and 13 pneumococcal serotypes are in development and would provide broader coverage, until we better understand the reasons that serotype distributions vary geographically and over time, strategic vaccine design will be hampered.

Serotypes and susceptibility of Streptococcus pneumoniae strains isolated from children in Mexico

To identify serotypes and susceptibility of S. pneumoniae strains from 48 children with invasive infections and 50 carriers. Typing was performed by the Quellung reaction and susceptibility by Kirby-Bauer and Etest according to CLSI standards. Of 31 meningeal strains, serotypes 19F, 3, 6B, 14 and 23F were predominant. Resistance to penicillin and STX was 16 and 58%, respectively; of 17 invasive non-meningeal strains, serotypes 19F and 3 were predominant and resistance to penicillin and SXT was 0 and 82%, respectively; of carrier strains, serotypes 6A, 6B, 19F and 23F were predominant. A 10-valent conjugate vaccine could offer a better coverage for meningeal strains.

Economic impact of pneumococcal conjugate vaccination in Brazil, Chile, and Uruguay

To evaluate the economic impact of vaccination with the pneumococcal 7-valent conjugate vaccine (PCV7) in Brazil, Chile, and Uruguay. A decision analytic model was constructed to compare pneumococcal vaccination of children 0-5 years old with no vaccination in Brazil, Chile, and Uruguay. Costs and health outcomes were analyzed from the societal perspective. Vaccine, demographic, epidemiologic, and cost data were incorporated into this economic analysis. At the rate of diphtheria-tetanus-pertussis (DTP) vaccine coverage and a vaccine price of US$ 53 per dose, PCV7 was projected to prevent 23 474 deaths per year in children under 5 years old in the three countries studied, thus averting 884,841 disability-adjusted life years (DALYs) yearly. To vaccinate the entire birth cohort of the three countries, total vaccine costs would be US$ 613.9 million. At US$ 53 per dose, the cost per DALY averted from a societal perspective would range from US$ 664 (Brazil) to US$ 2019 (Chile). At a cost of US$ 10 per dose, vaccine cost is lower than the overall cost of illness averted (US$ 125,050,497 versus US$ 153,965,333), making it cost effective and cost-saving. The results of this study demonstrate that the incorporation of PCV7 vaccine at US$ 53 per dose confers health benefits at extra costs. It is unclear whether vaccinatfon at the current price is affordable to these countries.

Population structure of invasive Streptococcus pneumoniae isolates in Italy prior to the implementation of the 7-valent conjugate vaccine (1999–2003)

A total of 773 pneumococcal isolates were collected from a nationwide surveillance of invasive pneumococcal diseases during 1999-2003 prior to the implementation of the 7-valent conjugate vaccine (PCV7) in Italy. The isolates included vaccine serotypes (VS, 393 isolates), vaccine-related serotypes (VRS, 93), and nonvaccine serotypes (NVS, 279). The ten most prevalent serotypes were: 14 (16.4%), 3 (8.4%), 23F (8%), 19F (7.4%), 4 (5.9%), 7F (5.8%), 9V (5.3%), 6B (4.9%), 19A (4.7%), and 1 (3.7%). VRS or NVS isolates showed a lower rate of penicillin or drug resistance than VS. Representative isolates of the major VS, VRS, and NVS were genotyped by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The isolates examined were found to belong to 18 international clones and to eight newly described clones. VS isolates sharing clonal groups with VRS or NVS were also detected. Evidence of a past history of capsular switching events was observed in five clones.

Factors Associated with Pneumococcal Carriage in Healthy Dutch Infants: The Generation R Study

To study the prevalence, risk factors, and dynamics of pneumococcal carriage in infancy. In a population-based prospective cohort study conducted in Rotterdam, the Netherlands between June 2003 and November 2006, nasopharyngeal swabs were obtained from children at age of 1.5, 6, and 14 months. Data on risk factors were obtained from midwives, hospital registries, and questionnaires. The prevalence of pneumococcal carriage increased from 8.3% at age 1.5 months (n = 627) to 31.3% at age 6 months (n = 832) and 44.5% at age 14 months (n = 757). The prevalence of serotypes covered by the 7-valent conjugate increased from 3.0% to 16.2% and 27.7% at these respective ages. Having siblings (adjusted odds ratio [aOR] = 4.33; 95% confidence interval [CI] = 1.22 to 15.35) and day care attendance (aOR = 3.05, 95% CI = 1.88 to 4.95 at 6 months; aOR = 2.78, 95% CI 1.= 70 to 4.55 at 14 months) were associated with pneumococcal carriage. Pneumococcal carriage at age 6 months was associated with pneumococcal carriage at age 14 months (aOR = 2.43; 95% CI = 1.50 to 3.94). Pneumococcal carriage was not associated with sex, maternal smoking, maternal educational level, or breast-feeding. The prevalence of serotypes covered by the 7-valent conjugate vaccine increased in the first year of life. Siblings, day care attendance, and previous pneumococcal carriage were independent factors associated with pneumococcal carriage.

The effect of the 7-valent conjugate vaccine (PCV7) on the incidence of pneumococcal infections world-wide

The effect of the 7-valent conjugate vaccine (PCV7) on the incidence of pneumococcal infections world-wide

Invasive pneumococcal disease in children in Ireland—the anticipated benefit of conjugate pneumococcal vaccination

Streptococcus pneumoniae is an important cause of childhood illness. Recently a safe and effective 7-valent conjugate pneumococcal vaccine for children has been licensed in the EU. To calculate the incidence of invasive pneumococcal disease (IPD) in children in Ireland, to estimate the burden of disease and to anticipate the protective effect of the conjugate vaccine. Retrospective review of data from children with IPD. Ninety-six cases of IPD in 95 children including two related deaths were identified. All childhood IPD incidence was estimated at 10.6/100,000. We anticipate that the 7-valent conjugate vaccine could prevent up to 90% of sepsis and up to 82.5% of meningitis cases. IPD is an important cause of mortality and morbidity in children in Ireland. Routine use of conjugate pneumococcal vaccine would have a significant impact on pneumococcal disease, especially in vaccinated children but also in unvaccinated children and older adults.

The changing epidemiology of pneumococcal pulmonary disease in the era of the heptavalent vaccine

Since the pediatric pneumococcal 7-valent conjugate vaccine was licensed in the United States, dramatic changes have taken place in the occurrence of pneumococcal disease among children and adults. Incidence of invasive pneumococcal disease including bacteremic pneumonia has declined, but changes in noninvasive pulmonary disease have been more difficult to assess. This paper reviews evidence of the epidemiologic features of invasive pneumococcal disease and community-acquired pneumonia among children and adults since 2000. Despite some increases in non-vaccine-type disease, its use has resulted in major reductions in incidence of invasive pneumococcal disease in all age groups, particularly that of antibiotic-resistant disease and of pediatric pneumococcal pneumonia. Several studies show that changes in circulating pneumococcal strains may be producing differential changes in disease incidence and disease presentation in several populations, including HIV-infected individuals and Alaska Natives.

Population Snapshot of EmergentStreptococcus pneumoniaeSerotype 19A in the United States, 2005

Serotype 19A invasive pneumococcal disease (IPD) increased annually in the United States after the introduction of the 7-valent conjugate vaccine (PCV7). To understand this increase, we characterized serotype 19A isolates recovered during 2005. IPD cases during 1998-2005 were identified through population-based surveillance. We performed susceptibility testing and multilocus sequence typing on 528 (95%) of 554 serotype 19A isolates reported in 2005. The incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P < .05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P < .05). Simultaneously, the incidence of IPD due to penicillin-resistant 19A isolates increased from 6.7% to 35% (P < .0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan(19F)-14. The remaining penicillin-resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple-isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone. PCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States.

Emergence and spread of antibiotic-resistant Gram-positive bacterial pathogens

Development of multiple resistances to antibiotics in staphylococci, enterococci and pneumococci became a health threat during the past 20 years, not only with respect to nosocomial infections. This resistance development is based on acquisition of resistance genes by predominant epidemic subpopulations (clonal complexes). Although emergence and spread of methicillin-resistant Staphylococcus aureus is associated with a limited number of epidemic clones which have been widely disseminated, acquisition of SCC mec elements by susceptible ancestors has taken place at different times and at different locations. Among Staphylococcus epidermidis and Enterococcus faecium, one clonal complex, which had acquired resistance genes at several occasions, is widely disseminated in hospitals. Also in Streptococcus pneumoniae, antibiotic resistance is preferentially associated with clonal lineages which have a capacity for spreading. They became, however, more rare after introduction of the 7-valent conjugate vaccine.

Streptococcus pneumoniaeSerotype 19A in Children, South Korea

Despite the concern of replacement disease, notably by serotype 19A after 7-valent conjugate vaccine (PCV7) use, serotype 19A was increasingly recognized in Korean children before the introduction of PCV7. To understand the dynamics of serogroup 19 prevalence from 1991-2006, we serotyped 538 pediatric pneumococcal isolates. Serogroup 19 isolates (n = 126) were characterized by antimicrobial drug susceptibility, presence of mefA/ermB, and multilocus sequence typing. Overall, the proportion of serotype 19A isolates increased but serotype 19F decreased. Among children <5 years of age, the proportion of serotype 19A isolates in invasive pneumococcal disease increased from 0% in 1991-1994 to 8%-10% in 1995-2000, reached 26% in 2001-2003, and remained at 20% in 2004-2006 when vaccine coverage did not exceed 25% (p = 0.005 for trend). This study demonstrates that the expansion of multidrug-resistant ST320 was responsible for the increase in serotype 19A before PCV7 use.

Emergence of Invasive Pneumococcal Disease Caused by Nonvaccine Serotypes in the Era of 7-Valent Conjugate Vaccine

Little is known about the epidemiology of invasive pneumococcal disease (IPD) after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in Spain and other European countries. We performed a 10-year prospective study including all children with culture-proven IPD admitted to Sant Joan de Deu Hospital, a children's center in the southern area of Barcelona, Catalonia, Spain. PCV7 was introduced in June 2001, and the current estimate of PCV7 coverage is 45%-50%. Comparing the prevaccine period (1997-2001) with the vaccine period (2002-2006), among children aged <2 years, the rate of IPD increased from 32.4 episodes per 100,000 population to 51.3 episodes per 100,000 population (an increase of 58%; 95% confidence interval, 2%-145%), and among children aged 2-4 years, the rate increased from 11.3 episodes per 100,000 population to 26.5 episodes per 100,000 population (an increase of 135%; 95% confidence interval, 31%-320%). At clinical presentation, the rate of pneumonia and/or empyema among children aged <5 years increased from 3.6 episodes per 100,000 population to 15.1 episodes per 100,000 population (an increase of 320%; 95% confidence interval, 98%-790%). These increased rates of IPD were caused by non-PCV7 serotypes, which represented 38% and 72% of infecting serotypes in the prevaccine and vaccine periods, respectively (P=.001). Penicillin resistance decreased from 48% in the prevaccine period to 27% in the vaccine period (P=.005). In the vaccine period, there was an emergence of previously established virulent clones of non-PCV7 serotypes 1 and 5. There was also an increase in the prevalence of serotypes 19A and 6A expressed with different clonal types, including Spain(23F)-1 and Spain(6B)-2. Since the introduction of PCV7 for children, there has been an emergence of IPD caused by virulent clones of non-PCV7 serotypes that has been associated with significant clinical changes and a decrease in antibiotic resistance.

Trends and geographical variation in invasive pneumococcal infections in Finland

We evaluated regional variation and trends in invasive pneumococcal infections (IPI) in Finland by using data from national, population-based laboratory surveillance and number of blood and cerebrospinal fluid (CSF) cultures performed by all microbiology laboratories during 1995-2002. The overall annualized IPI incidence was 10.6/100,000 (range by region, 7.9 15.1): 9.9 for bacteraemias (range 7.3-14.2) and 0.6 for meningitis (range 0.4-1.1). The rate in children aged <5 y was 23.5/100,000. Regional pneumococcal bacteraemia rates were correlated with blood culture sampling rates (p =0.015), but meningitis rates did not correlate with CSF culture rates. During 1995-2002, the overall annual IPI rate increased by 35.1%, from 8.2 to 11.5/100,000 (p<0.001). The annual blood culturing rate increased by 29.6% (p=0.015 for the correlation with IPI rate). Temporal increase and higher regional IPI rates were significantly associated with higher blood culturing rates. Pneumococcal serotypes included in the 7- and 10-valent conjugate vaccines caused 69.8% and 85.2% of IPIs among children aged <5 y and 49.5% and 59.3% in adults, respectively. The true incidence of pneumococcal bacteraemia in Finland may be higher than previously estimated. Introduction of universal childhood pneumococcal conjugate immunization would provide substantial health benefits to Finnish children and adults.

Multiresistant Pneumococci in Otitis Media

Multiresistant Pneumococci in Otitis Media

CME QUESTIONS

CME Questions| January 01 2008 CME QUESTIONS AAP Grand Rounds (2008) 19 (1): 11–12. https://doi.org/10.1542/gr.19-1-11 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation CME QUESTIONS. AAP Grand Rounds January 2008; 19 (1): 11–12. https://doi.org/10.1542/gr.19-1-11 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: education, medical, continuing, asthma, acute, hypothermia, natural, otitis media, pneumococcal 7-valent conjugate vaccine, prednisolone, vaccines, vomiting The following continuing medical education questions cover the content of the January 2008 issue of AAP Grand Rounds. Please keep this issue. Each year’s material is worth up to 18 AMA PRA Category 1 Credit(s)TM. You do not currently have access to this content.