This measure asks adolescents how many vehicles and computers their family owns, whether they have a bedroom to themselves

and how many holidays they have had with their family in the past year. Items were summed to give an overall family affluence score (range 0–10), which was split into tertiles: ‘low’ (scores of 0–4), ‘medium’ (scores of 5–6) and ‘high’ (scores of 7–10). Participants were asked whether they smoked (yes/no). Sexual experience was assessed by asking participants ‘Have you ever had vaginal sex?’ (yes/no); this question was adapted from the ‘National Survey Caspase activation of Sexual Attitudes and Lifestyles’ [17]. Expectation of having sex in the next year was also assessed using two items adapted from Sheeran and Orbell [36]: ‘I expect I will have sex this year’ and ‘I think I will have sex this year’ (5-point scale: ‘strongly disagree’ to ‘strongly agree’, scored from 1 to 5). These items correlated highly (r = 0.97) and were summed to give an overall score which was split into tertiles: ‘no expectation’ (scores of 2), ‘low expectation’ find more (3–5) and ‘high expectation’ (6–10)

of having sex in the next year. Intention to attend cervical screening in the future was assessed using similar items: ‘When I am older and am invited to go for a smear (Pap) test, I intend to go’ and ‘When I am older and am invited to go for a smear (Pap) test, I will try to go’ (with a 5-point response scale as before). The items correlated highly (r = 0.89) and were summed to give an overall screening intention score which was split into secondly tertiles: ‘low intention’ (scores of 2–6), ‘medium intention’ (7–8) and ‘high intention’ (9–10). Other measures in the questionnaire that are not reported here have been described elsewhere [34]. After reading a brief description of the HPV vaccine (see Box 1) participants were asked to indicate their vaccine status (response options: ‘I have had all 3 doses of the HPV vaccine’; ‘I have had 1 or 2 doses of the HPV vaccine’; ‘I have been offered the HPV vaccine but I haven’t had it’; ‘I have not been offered the HPV vaccine’;

‘I don’t know’). Human papillomavirus (HPV) is a very common infection involved in most cervical cancer. It is transmitted via skin-to-skin contact, most commonly during sexual activity. A vaccine was developed that protects against this infection. You should have been offered the HPV (cervical cancer) vaccine in Year 8. It involved having three injections over about 6 months. Logistic regression analyses, clustering by school and cohort, were used to examine the association between HPV vaccine status (fully vaccinated versus un-/under-vaccinated) and other risk factors for cervical cancer. It is necessary to adjust for clustering of data within schools and cohorts in order to obtain unbiased tests of significance. Analyses were performed using the Complex Samples function in SPSS v.20 [37].

Encapsulation efficiency of all batches was in between 90% and 100% w/w. One of the objectives of non-aqueous emulsion technique was to entrap maximum amount of metformin HCl. As discussed earlier the major drawback of other techniques (aqueous phase) was drug leakage occurred during solidification of nanoparticles. But in oil in oil method there was not a phase where metformin can leak out. Due to polymer saturated solvent and methanol immiscible with oil, polymeric matrix was immediately precipitate

out as solvent start to evaporate and gives maximum encapsulation efficiency.14 Secondly the high concentration of polymer increases viscosity of the solution and hindrance the drug diffusion within the polymer droplets. Drug-polymer ratio do not significantly see more increased the encapsulation efficiency of metformin HCl in all three ethylcellulose polymers (p < 0.05). The encapsulated drug in all nanoparticles was already high. In EC100 and EC300 at 1:3 and 1:6 ratios encapsulation was increased slightly by 3–4% than EC45 but at 1:9 there was no significant difference in encapsulation all three polymers because nominal effect of viscosity on entrapment was concentrated at this ratio. There were also slight differences in drug content and percentage yield within same ratios of different ethylcellulose polymers. As percentage of polymers increased the drug content was also decreased.

Fig. 1 illustrates the morphology of nanoparticles of EC45, click here EC100 and EC300. All particles were spherical in nature, uniform size and have tough surface texture. EC300 nanoparticles were less porous than other two polymeric nanoparticles. Smoothness of surface was due to polymer saturated internal organic phase. Fast diffusion of organic phase in

continuous phase before stable nanoparticles development can cause aggregation. 8 But in this preparation method methanol is not diffused in oil phase therefore aggregation of particles was not observed. After confirmed the physical characteristics of nanoparticles whether drug and polymer interact chemically to at processing conditions was tested by infrared spectroscopy. Actually negated drug-polymer interaction was studied before development of nanoparticles but processing conditions of nanoparticles development may affect on its chemical stability. The IR spectra of metformin HCl, ethylcellulose and drug loaded nanoparticles shown in Fig. 2. Pure metformin HCl illustrates two typical bands at 3371 cm−1 and 3296 cm−1 due to N–H primary stretching vibration and a band at 3170 cm−1 due to N–H secondary stretching. Characteristic bands at 1626 cm−1, 1567 cm−1 allocate to C N stretching. FTIR of EC showed principal peaks between 1900 cm−1 to 3500 cm−1. Of these 2980.12 cm−1 and 2880 cm−1 peaks were due to C–H stretching and a broad band at 3487.42 cm−1 was due to O–H stretching.

Loss of these sources on discharge from the course may negatively impact on selfefficacy, which arguably could diminish further during an exacerbation. Ongoing peer support for exercise was viewed as particularly influential in our study; a finding corroborated by research in older adults showing that exercise-focused social support promotes long-term adherence to exercise, mediated via self-efficacy (McAuley et al 2003).

Our data also support the more specific theory that maintaining physical activity self-efficacy for people with COPD is important for sustained engagement in physical activity after pulmonary rehabilitation. Various maintenance interventions have been tested in clinical trials as strategies are sought to effectively maintain pulmonary rehabilitation benefits longitudinally. Conclusions from this work so far are equivocal. Spencer and colleagues’ (2010) randomised trial demonstrated no additional Selleckchem Y 27632 benefit of once-weekly supervised maintenance over unsupervised home exercise. Interestingly, exercise capacity and quality of life were maintained one year after pulmonary rehabilitation in both strategies. Limitations of this well conducted study

are worthy of consideration. First, regular contact with the pulmonary rehabilitation physiotherapist in the unsupervised group may have unduly biased adherence to long-term exercise. Second, it is possible that the study cohort was an atypical, highlyfunctioning subgroup of people with COPD, with mean sixminute walk MEK inhibitor Carnitine dehydrogenase distances of 464 m and 527 m before and after pulmonary rehabilitation, respectively. This is substantially higher than the typical

six-minute walk distance of 388 m in people with COPD (Casanova et al 2007). Distances around 500 m have been reported for healthy age-matched controls (Casanova et al 2011). Therefore, the generalisability of the results of Spencer et al (2010) is debatable. The quantitative data showing that maintenance programmes have limited efficacy contrasts with patients’ perspectives expressed both in our study and in similar work (Lewis and Cramp, Toms and Harrison 2002, Wilson et al 2007). However, we acknowledge that our study did not include patient views concerning different modes of maintenance. Given the known health and economic benefits of regular physical activity in COPD (Garcia-Aymerich et al 2006), further research is warranted to improve our understanding of potentially cost-effective activity promotion strategies for this population. For example, a trial could examine whether referral to independent group exercise sessions in a community hall with remote access to a pulmonary rehabilitation specialist promotes greater long-term participation in physical exercise than no ongoing support. We acknowledge some limitations of our study.

Indeed, during the second year of follow-up, 96 cases of severe RVGE were detected. During the second year of follow-up the point estimate of vaccine

efficacy was 19.2%. We surmise that if a similarly intense and culturally compatible surveillance selleck inhibitor system had also been utilized through the first year of follow-up, the number of cases of severe RVGE detected would have been greatly increased due to the higher burden of severe rotavirus GE in the first year of life. Thus, the estimate of vaccine efficacy may have been higher. The composite of experiences in poorer developing countries in Africa and Asia now provides convincing evidence that the level of efficacy of oral RV vaccines measured in individual subject-randomized,

double-blind, controlled field trials (approximately 50–65% efficacy) is lower [7], [8] and [24] than the efficacy of vaccine documented in controlled field trials in industrialized Antidiabetic Compound Library supplier and transitional countries [3] and [4]. The reduced immunogenicity and efficacy of both live and non-living oral vaccines in populations in developing countries has been previously described with multiple vaccines, such as oral polio vaccine, cholera vaccine and Shigella vaccines [25], [26], [27], [28], [29], [30], [31], [32], [33] and [34] and is the subject of much discussion and research to understand the basis of this phenomenon. Possibilities include potential vaccine factors, such as restricted immunogenicity or host factors such as gut enteropathy, and co-morbidities as described elsewhere [35], [36] and [37] This has led some to become discouraged about what live oral RV vaccines can accomplish in the world’s least developed countries (where RV vaccines are most needed) and to propose

starting afresh on new vaccine strategies such as parenterally administered inactivated ADAMTS5 vaccines [38] and [39]. On the other hand, there are also clear reasons for optimism. The immunogenicity in Mali was comparable to that in Ghana and Kenya, where sufficient numbers of cases were captured to yield site-specific efficacies of 65.0% and 83.4%, respectively, through the first year of life [4] and [40]. Moreover, it is likely that the actual impact of widespread immunization of infants in Mali with live oral RV vaccine would result in an impact far greater than anticipated based just on the estimate of vaccine efficacy because of indirect protection and a herd immunity effect. Experiences in the U.S.A. [41], [42], [43] and [44], Australia [45], [46] and [47], and Latin America [48] show an unequivocal herd immunity effect wherein the observed fall in rotavirus disease far exceeds the expectation based just on estimates of direct vaccine efficacy and immunization coverage.

4C), amygdala (F(3–16) = 2.451; find more p = 0.10 Fig. 4C) and hippocampus (F(3–13) = 10.168; p = 0.001 Fig. 4C) with imipramine at the dose of 30 mg/kg and in the amygdala (F(3–14) = 10.512; p = 0.001 Fig. 4C) with all treatments, but did not alter in the prefrontal cortex (F(3–15) = 4.175; p > 0.05 Fig. 4C) and in the hippocampus

(F(3–13) = 10.168; p > 0.05 Fig. 4C). The acute administration increased MK-2206 manufacturer the mitochondrial complex IV activity in the hippocampus (F(3–13) = 18.471; p < 0,001 Fig. 4D) with all treatments, compared with saline, but did not alter in the prefrontal cortex (F(3–12) = 0.828; p = 0.50 Fig. 4D) and amygdala (F(3–11) = 4,514; p = 0,27 Fig. 4D). The chronic treatment did not alter the mitochondrial complex IV activity in the prefrontal cortex (F(3–13) = 0.689; p = 0.57 Fig. 4D), amygdala (F(3–16) = 3.666; p = 0.35 Fig. 4D) or hippocampus (F(3–11) = 2.317; p = 0.13 Fig. 4D). The acute treatment decreased the Bcl-2 protein levels in the

prefrontal cortex (F(3–12) = 106.818; p < 0,001 Fig. 5A) and in the hippocampus (F(3–12) = 265,226; p < 0,001 Fig. 5A) with imipramine at the dose of 30 mg/kg and lamotrigine at the dose of 20 mg/kg, and also in the amygdala (F(3–12) = 87.304; p < 0.001 Fig. 5A) with all treatments, compared with saline. The chronic treatment decreased the Bcl-2 protein levels in the prefrontal cortex (F(3–12) = 310.093; p < 0.001 Fig. 5A), amygdala (F(3–12) = 238.818; p < 0.001

Fig. 5A) and hippocampus (F(3–12) = 557.669; p < 0.001 Fig. 5A) with all treatments. The acute treatment Rutecarpine increased the AKT protein levels in the prefrontal cortex (F(3–12) = 49.088; p = 0.000 Fig. 5B) with imipramine at the dose of 30 mg/kg, in the amygdala (F(3–12) = 70.335; p < 0.001 Fig. 5B) with lamotrigine at the dose of 20 mg/kg and in the hippocampus (F(3–12) = 21.011; p = 0.009 Fig. 5B), with imipramine at the dose of 30 mg/kg and with lamotrigine at the dose of 20 mg/kg, compared with saline. The acute treatment also decreased the AKT protein levels in the amygdala with imipramine at the dose of 30 mg/kg (F(3–12) = 70.335; p = 0.04 Fig. 5B) and in the hippocampus with lamotrigine at the dose of 10 mg/kg (F(3–12) = 21.011; p = 0.04 Fig. 5B). The chronic treatment increased the AKT protein levels in the prefrontal cortex (F(3–12) = 121.938; p < 0,001 Fig. 5B), amygdala (F(3–12) = 83.853; p < 0.001 Fig. 5A) and hippocampus (F(3–12) = 58.262; p < 0,001 Fig. 5B) after all treatments. The acute treatment decreased the GSK-3 protein levels in the prefrontal cortex with imipramine at the dose of 30 mg/kg and lamotrigine at the dose of 20 mg/kg (F(3–12) = 126.185; p < 0.001 Fig.

The expected seroconversion was based on published data with Rotarix vaccine, which showed 58% seroconversion in Indian children given two doses of vaccine at eight and 12 weeks of age [23]. Variables were assessed using descriptive statistics, dispersion for continuous variables, frequency counts and marginal percentages with 95% confidence intervals for categorical variables. Comparisons between the two groups were done using t-tests for normally distributed variables (or non-parametric tests

for non-normally distributed variables) and chi-square tests for categorical variables. All differences Tanespimycin in vitro were considered statistically significant if the two-tailed p-value was <0.05. A total of 118 infants were assessed for enrollment and 28 infants (five did not meet the http://www.selleckchem.com/products/PD-0332991.html inclusion criteria, 17 refused

participation, six were unavailable for the follow up period) were excluded. Of the 90 infants who were enrolled, 45 were randomized into the three dose arm and 45 into the five-dose arm (Fig. 1). Demographic details for infants recruited in both arms of the study were similar (data not shown) and all children received the vaccine by 17 and 26 weeks of age in the three and five dose arms, respectively. Sera at 4 weeks post third and fifth dose were obtained from 88 of 90 infants, with one child lost to follow up in each arm. Of the enrolled infants, 66% (29/44 infants) from the three dose group and 50% (22/44) infants from the five dose group were seropositive at baseline (Fig. 2). Of the 51 infants seropositive prior to immunization, 13 (25.5%) showed a >4 fold and 12 (23.5%) showed a three or two fold increase in RV specific IgA four weeks post last dose of vaccination; 26 (51%) infants did not show any rise or fall in antibody levels. Of the 37 infants

who were seronegative at baseline, 10 (27%) had a >4-fold and seven (19%) had a three or two fold increase in RV specific IgA. second Twenty (54%) infants had no rise or fall in antibody levels and remained seronegative even after three or five doses of vaccination. The GMCs of IgA pre- and post-vaccination are shown in Table 1, stratified by baseline seropositivity in the three and five dose arms. The Wilcoxon signed rank test showed that there was a significant difference (p-value < 0.001) between the pre- and post-vaccination GMCs of the 88 infants taken together and separately as the three dose arm (p = 0.029) and the five dose arm (p < 0.001). However, with three doses, in baseline seropositive children the difference between pre- and post-GMCs did not reach statistical significance (p = 0.086). Of the 88 infants, 42 (47.7%) responded to three or five doses of vaccination. When the proportion of children seroconverting and the GMCs were compared between the three and five dose arms ( Table 2A and Table 2B), there was no significant difference in the post vaccination rotavirus specific serum IgA levels between them (p-value = 0.894, Mann–Whitney 0.

Pale yellow color amorphous powder, UV (MeOH) nm: 345; IR (KBr) cm−1: 3450 (hydroxyl),1705 (carbonyl), 1630 and characteristic signals; EIMS m/z: 410 [M]+; 1H NMR (400 MHz, CDCl3): δ 1.58 (3H, s, H-24), 1.67 (3H, s, H-23), 1.80 (3H, s, H-25), 2.08 (4H, m, H-19 & 20), 3.0 (2H, m, H-9), 3.12 (2H, m, H-8), 3.42 (2H, d, J = 6.7 Hz, H-16), 5.04 (1H, t, J = 6.7 Hz, H-21), 5.16 (1H, t, J = 6.7 Hz, H-17), 6.37 (1H, dd, J = 2.1, 8.7 Hz, H-5), 6.38 (1H, d, J = 2.1 Hz, H-3), 6.68 (1H, d, J = 8.2 Hz, H-11), 6.74 (1H, d, J = 8.2 Hz, H-12), 7.60 (1H, d, J = 8.7 Hz, H-6), 12.8 (1H, s, OH-2); 13C NMR (100 MHz, CDCl3): δ 16.2 (C-25), 17.7 RG 7204 (C-24), 25.7 (C-23), 25.9 (C-16), 26.3 (C-20), 27.8 (C-9), 39.6 (C-19), 39.7 (C-8), 103.6 (C-3), 107.8 (C-5), 112.8 (C-12), 113.7 (C-1), 121.4 (C-11), 121.7 (C-17), 123.7 (C-21), 126.0 (C-15), 131.1

(C-10), 132.2 (C-6), 132.3 (C-22), 138.9 (C-18), 142.4 (C-14), 142.8 (C-13), 162.6 (C-4), 165.2 (C-2), 204.0 (C-1); EIMS m/z (rel. The compound was obtained as pale yellow color amorphous Selleckchem SAHA HDAC powder from fraction.2. It was readily recognized as chalcone derivative based on its spectral data. Its molecular formula has been fixed as C25H30O5 on the basis of mass, M+ 410. Its UV spectrum showed lambda max value is 345 nm indicating that the molecule is having conjugation. Its IR spectrum showed specific absorption bands at 3450 (hydroxyl), 1705 (carbonyl) and 1630 (aromatic) cm−1. The 1H NMR spectrum (Fig. 1) clearly showed the presence of three double bonded methyls at δ 1.58, 1.67 and 1.80

each as singlet, four allylic methylene Thiamine-diphosphate kinase groups at δ 2.08 as multiplet and another methylene group α – to the carbonyl group at δ 3.12 as multiplet. Further, the spectrum also showed two benzylic methylene groups at δ 3.00 (m) and 3.42 (d, J = 6.7 Hz). The second benzylic group showed doublet indicates that this methylene group coupled with only one neighbouring proton. Additionally, the spectrum showed two olefinic protons at δ 5.16 (t, J = 6.7 Hz) and 5.04 (t, J = 6.7 Hz) coupled with methylenic protons, two ortho coupled aromatic protons at δ 6.68 and 6.74 each as doublet (J = 8.2 Hz) belongs to one phenolic ring and three more additional aromatic protons at δ 6.38 (d, J = 2.1 Hz), 6.37 (dd, 2.1 & 8.7 Hz) and 7.60 (d, J = 8.7 Hz) belongs another tri-substituted phenolic ring. The carbon spectrum clearly showed twenty-five carbons. Of which, three methyl carbons, five methylene carbons, four olefinic carbons, twelve aromatic carbons and one ketonic carbon at δ 203.8.

A red color with sodium amalgam and HCl acid. The flavone glycoside RS-2 was found to be soluble in water, ethanol and acetone and crystallized from methanol. RS-2 analyzed for molecular formula C29H34O13, m.p. 285–286° and M+ 590 (CIMS). The wavelengths of maximum absorption as observed with various shift reagents were at; λmax (MeOH) 270, 347 nm, λmax (NaOMe) 287, 395 nm, λmax (AlCl3) 278, 389, 405 nm, λmax (AlCl3 + HCl) 277, 389, 405 nm, and λmax (NaOMe) 272, 348 nm as depicted in Graph 2. The characteristic band observed in the IR spectrum of RS-2

and the structural assignments made with the help of available literature1, 2, 3 and 4 are described below: 3396.3 cm−1 (Hydrogen bonding intermolecular stretching), 2864.5 cm−1 (CH3 stretching of CH3), 1637.9 cm−1 (α,β-unsaturated C O), 1461.5 cm−1 (Aromatic ring system), 1219.0 cm−1 (C–O–C– stretching Osimertinib vibration), and 771 cm−1 (C–H out of plane bending) as portrayed in Graph 1. Significant band at Vmax (KBr) 3396.3 cm−1 as mentioned in Graph 1 in the IR spectrum of the glycoside (RS-2) indicated the presence of hydroxyl group(s) in it. The glycoside (RS-2) was acetylated with Ac2O/Pyridine to give an acetylated product having molecular formula, C41H46O19, m.p. 204–205° and M+ 842 (CIMS). The estimation of percentage of the

acetyl group (31.04%) in the acetylated derivative was given by Weisenberger method5 UMI-77 as described by Belcher and Godbert6 which showed that there were six acetylable hydroxyl groups in the glycoside (RS-2). The appearance of band in IR spectrum of the acetyl derivative at Vmax (KBr) 1725.4 cm−1 with disappearance of band at Vmax (KBr) 3396.3 cm−1 confirmed that the acetylation of all the hydroxyl groups present

in the glycoside RS-2 was complete. 7 and 8 The IR absorption spectrum of the flavone glycoside (RS-2) displayed important band at Vmax (KBr) 2925.9 cm−1 indicating the presence of methoxyl group(s) in it. The methoxyl group estimation (16.05%) was done by Zeisel’s method 9 which confirmed the presence of three methoxyl groups in RS-2. The 1H NMR spectrum Metalloexopeptidase of the flavonoidal glycoside (RS-2) showed three singlets at δ 4.0, δ 3.97 and δ 3.80 as depicted in Graph 3 each of these integrating for three protons, thereby suggesting the presence of three methoxyl groups in RS-2. Characteristic band at Vmax (KBr) 1461.5 cm−1 in the IR spectrum of glycoside RS-2 showed the presence of C C ring stretching. The structure of the glycoside (RS-2) was elucidated by its acid hydrolysis and identifying the components of hydrolyzate and the aglycone respectively. The glycoside (RS-2) on its acid hydrolysis with 7% alcoholic H2SO4 yielded an aglycone RS-2(A) as a solid residue and sugar moiety(ies) in the filtrate. They were separated by filtration and studied separately. The aglycone RS-2(A) was found to be homogenous on TLC examination (EtOAc–MeOH–H2O, 3:2:1). It crystallized from MeOH.

The total number of hilar neurons per hippocampus computed

in the present study (39.200 ± 3.882) compares closely to the number reported by Jiao and Nadler (2007) (37.580 ± 1.594), Buckmaster and Dudek (1997) (41.093 ± 1.284), who used essentially the same optical disector approach, and by Miki et al., 2005 (35.200 ± 1.600), who used a physical disector approach. The similarity of our results with previously reported values demonstrates high precision in the stereological estimates of neuronal number. Previous studies on pilocarpine model showed that cell death occurs by necrosis or apoptosis (Fujikawa, 1996, Fujikawa, 2005, Fujikawa et al., 2000, Fujikawa et al., 2002, Fujikawa et al., 2007 and Henshall, 2007). In contrast to acute cell death, which occurs in the first 24–48 h and is predominantly necrotic, secondary or delayed neuronal cell death occurring XAV-939 mw at later stages has been identified to be predominantly

apoptotic (Kermer and Klocker, 1999, Snider et al., 1999 and Weise et al., 2005). Caspases are considered the common apoptosis execution pathway, and its activation raises structural alterations that characterize apoptosis (Henkart and Gristein, 1996). In the present investigation, we evaluated two types of caspases: caspase-1, related with inflammatory process, and caspase-3, which executes the apoptosis (Earnshaw et al., 1999 and Henkart and Gristein, 1996). As previously demonstrated in the pilocarpine model (Persike et al., 2008) we also observed Vorinostat solubility dmso an increased activity of caspases-1 and -3 seven days after SE. Treatment with Pyr and/or

Oxa did not prevent the increase of caspases activation, but it was significantly less pronounced (only for caspase-1) when rats were treated with Oxa or Pyr + Oxa. This result suggests that early Glu scavenging did not prevent late apoptotic neuronal cell death. In fact, Weise else et al. (2005) observed that significant neuronal cell loss occurred in brain regions that showed activated caspase-3 expression. Areas with the highest levels of activated caspase-3 expression displayed the most extensive neuronal cell loss (Weise et al., 2005). In the present work, the increase of caspase-3 activity was not modified by Pyr and/or Oxa administration 30 min after SE. Nevertheless, it remains to be determined if late or prolonged Glu scavenging prevents SE-induced caspase activation and late neuronal cell loss. Blood glutamate scavenging has been demonstrated to be neuroprotective in terms of neurological outcome. Zlotnik and colleagues tested the hypothesis that Pyr- or Oxa-mediated blood Glu scavenging causes neuroprotection in a rat model of closed head injury (CHI), in which there is a well established deleterious increase of Glu in brain fluids.

3, Table 2). Evidence on indirect impact in low-coverage (<70%) settings

is mixed, with significant impact seen in some populations and not others. Data on indirect effect of PCV on AT–IPD showed a trend toward increasing impact with time (median decrease: 33%; IQR: 7–42%), though CP-690550 clinical trial with lower overall impact compared to that on VT-IPD (Appendix B.3, Table 3). This impact on AT-IPD was observed in all non-target age-groups (Fig. 5) and is also noted in pneumococcal pneumonia [10] and [29]. Data from mixed target and non-target groups show a greater decrease in VT-IPD rates than that in pure non-targeted groups, reflecting a mix of direct and indirect effect (Appendix B.3, Table 4). However, studies with 1-dose coverage data suggest a vaccine impact on VT-IPD that cannot be entirely accounted for by direct effect. Data were available for six unique populations: Australian aboriginals, Alaska Natives, American Indians, Gambians, Israelis and Portuguese E7080 (Appendix B.3, Table 5). Studies in children were primarily RCTs; those in adults were primarily observational. The median decrease

in VT-carriage prevalence (among either the study sample or, rarely, the subset who were carriers of any pneumococcal strain) was 77% (IQR 64–80%). Data points did not span a sufficient time range to evaluate time-related trends. The majority of carriage data is drawn from high-risk populations. Few additional supporting data points were identified for NP carriage. Supporting data are listed for pre- vs. post-introduction all-type NP in non-target groups and pre- vs. post-introduction VT-carriage in mixed groups in Appendix B.3, Tables 6 and 7; a discussion is provided in Appendix B.4. A relevant data point not eligible for inclusion due to publication

date comes from an observational study including Native American adults shortly after PCV introduction Calpain (2001–2002) and subsequently (2006–2008), finding a relative decrease of 97.5% and an absolute reduction of 4.0% in VT-NP [46]. Most individual data points were categorized as low or very-low quality by GRADE criteria because nearly all data were from observational studies, and over half the primary evidence sources were further downgraded for including only high-risk populations, but few for methodological issues (Appendix B.5). While GRADE methodology categorizes observational studies as ‘low quality’, the GRADE system was designed to assess individual patient treatments, not to assess public health benefit. Furthermore, only observational, or community randomized studies can assess population-level post-introduction effects. An additional 14 studies published after the PCV Dosing Landscape Review search met primary evidence inclusion criteria.