Participants with antibody levels below these technical cut-offs were considered as antibody negative; however, as this is not a clinical cut-off, they were not considered true negatives. Functional antibodies against the 10 serotype-specific PS-conjugates of PHiD-CV were measured by a pneumococcal killing assay (OPA) with an opsonic titer cut-off of 8, as described previously

[20]. Safety analyses were performed on primary and booster total vaccinated cohorts (TVC). Immunogenicity analyses were performed on primary and booster according-to-protocol (ATP) cohorts for immunogenicity, comprising participants who met all eligibility criteria, complied with protocol-defined procedures, and with pre- and post-vaccination results available for at Selleckchem ISRIB least one assay. All objectives were descriptive. The target sample size of the primary vaccination study was 156 participants: 12 for dPly-10; 24 for the remaining

groups. With this sample size, the percentage of participants with grade 3 and related symptoms that would lead to a significant difference between groups with 80% power is 4% in the control group and 39.7% in the investigational formulation groups. Incidences of solicited and unsolicited AEs were calculated with exact 95% confidence intervals (CIs). Antibody geometric mean concentrations (GMCs), OPA geometric mean titers (GMTs) and seropositivity rates were calculated with their 95% CIs. GMCs and GMTs were calculated BTK signaling inhibitor by taking the anti-log10 of the mean of the log10 antibody concentration or titer transformations. Antibody concentrations/titers below assay cut-offs

were given an arbitrary value of half the cut-off for the purpose of GMC/GMT calculation. Analyses were performed with Statistical Analysis System (SAS® Institute Inc., Cary, NC). Of 156 vaccinated adults, 146 completed the primary vaccination study. 43 adults who had received two primary doses of dPly/PhtD-10 or dPly/PhtD-30 completed the booster vaccination study (Fig. 2). Demographic characteristics of the groups are shown in Table 1. Pain was the most commonly reported solicited local symptom in all groups, reported by 41.7%–100% of participants post-dose 1 and 71.4%–95.2% post-dose 2 for investigational formulation groups, and 91.7% post-dose 1 and 4.3% (one participant) post-dose 2 for the control group Bumetanide (Fig. 3A–C). Grade 3 local symptoms were reported by up to three participants (0.0%–12.5%) post-dose 1 and up to one participant (0.0%–4.8%) post-dose 2 in groups receiving an investigational formulation, and by one participant (4.2%) post-dose 1 and none of the participants post-dose 2 (placebo) in the control group (Fig. 3A–C). The most frequently reported solicited general symptoms were fatigue and headache in the investigational groups and fatigue in the control group. Fever was reported by 0.0%–8.3% of participants post-dose 1 and 0.0%–10.0% of participants post-dose 2 in the investigational groups, and by 4.2% post-dose 1 and 0.

, 2007, Sajdyk et al., 2008 and Berube

et al., 2013). In fact, a comprehensive analysis of neuronal activation across the entire brain in hamsters exposed to social stress indicates Fulvestrant nmr that distinct brain regions are activated to varying degrees in dominant versus submissive animals (Kollack-Walker et al., 1997). The following sections of this review report evidence from clinical and preclinical social stress studies highlighting putative neural substrates of resilience or vulnerability to social stress. a. Corticotropin-releasing factor There are several stress-sensitive biological molecules that have pro-depressive or anxiogenic effects and are dysregulated following chronic stress in susceptible individuals. One potential biomarker is corticotropin-releasing factor (CRF). This neuropeptide is considered the “hallmark” of the stress response as it is the initiating hormone in the hypothalamic–pituitary–adrenal axis (Vale et al., 1981). In extrahypothalamic regions of the brain such as the amygdala, locus coeruleus (LC) and dorsal raphe CRF receptor activation is involved in stress-related emotionality and produces

behavioral features of the stress response (Dunn and Swiergiel, 2008, Wood and Woods, 2007, Ayala et al., 2004, Valentino et al., 2009, Hammack et al., 2003 and Heinrichs et al., selleck chemical 1992). Given CRF’s pervasive influence, it plays a central role in the behavioral, neuroendocrine and cardiovascular limbs of the stress response. Like many elements of the stress response

CRF is capable of promoting healthy adaptation to stress (Vale et al., 1981), but when unabated it can lead to pathology. For example, transgenic mice engineered to over-express CRF in the brain are disposed to exhibiting a depressive- and anxiety-like phenotype these (Bangasser et al., 2013 and Vicentini et al., 2009). Furthermore, Elliott et al. (2010) demonstrated that chronic social stress in adult mice produced long-term demethylation of the CRF gene. Interestingly, demethylation was only observed in the subset of mice that displayed social avoidance as a consequence of social defeat. Using site-specific knockdown of CRF, the authors confirmed the role of methylation of the CRF gene in resilience to social stress. Moreover, social stress exposure impacts CRF levels and CRF receptor distribution and quantity in brain and pituitary (Wood et al., 2010, Wood et al., 2013a, Chaijale et al., 2013 and Wood et al., 2009). In the VBS, male subordinate rats exhibited higher CRF mRNA expression in the central amygdala as compared with dominant rats and controls and a subset of the subordinate males had higher CRF mRNA expression in the PVN (Albeck et al., 1997). Furthermore, social stress using the resident intruder paradigm shifted CRF receptor signaling in the dorsal raphe from CRF1 to CRF2 in active coping, resilient rats while this adaptation was absent in passive coping rats (Wood et al., 2013b).

3). As the patient AZD8055 concentration was well and reluctant to have orchidectomy, a conservative management approach was adopted. Ultrasound scan performed 10 weeks from the first scan showed that the lesion had significantly decreased in size confirming the diagnosis of testicular infarction (Fig. 4). BD is a progressive vasculitic disease with a relapsing and remitting course. The prevalence in North America and Europe is 1 case per 15,000–500,000 population compared with 420 cases per 100,000 population in Turkey.1 and 2 The clinical manifestations presenting in most of the patients with BD are oral and genital ulcers, uveitis, and skin lesions. Other common clinical manifestations include arthritis,

thrombophlebitis, and various neurologic syndromes. Less frequent complications include arterial thrombosis, systemic and pulmonary circulation aneurysms, colitis, epididymitis, and orchitis.3 The frequency of epididymo-orchitis in BD has geographic variation and differs between juvenile

and adult patients. The highest frequency (44%) of epididymo-orchitis has been reported in Russia and the lowest (2%) in France. Epididymo-orchitis was noted in 11.3% of adult patients and 7.7% in children. The incidence of epididymo-orchitis was 31% in Iraqi but only 6% in Turkish patients.4 Zouboulis et al5 reported prostatitis learn more and epididymo-orchitis with BD in 22% of cases. The etiology of epididymo-orchitis in patients with BD is not fully understood. Vasculitis causing inflammation has been proposed, but there is lack of histologic data. Infection has also been implicated; however, urinary cultures have consistently been negative in case series, and inflammation subsides with administration of anti-inflammatory drugs.4 and 6 Clinical presentation in different case series and reports was mainly as testicular pain, with testicular mass being less common.7, 8, 9 and 10 Testicular infarction is a rare entity, with <50 reported cases.8 Although vasculitis was reported as a cause for testicular infarction in too few cases before,

none of these patients had BD. Case reports of polyarteritis nodosa as a cause of testicular infarction are described.9 and 10 In one case, a patient had bilateral testicular infarction and orchidectomy with subsequent androgen hormone replacement. In another case report, a 19-year-old man presented with unilateral testicular swelling and pain. The initial diagnosis of epididymo-orchitis was altered to testicular neoplasm after ultrasonography. Histologic examination after orchidectomy showed testicular vasculitis.11 Furthermore, there are 2 cases series describing testicular infarction secondary to vasculitis. In one series of 19 cases of testicular infarction with associated vasculitis, 14 showed polyarteritis nodosa features with transmural necrotizing inflammation of small-medium arteries.

For the uptake in MC lower concentrations of Sicastar Red particles (6 μg/ml) showed no toxic effects on epithelial cells, and an uptake in cells was

detectable by fluorescence microscopy. In contrast, we observed a lower sensitivity of cells to Sicastar particles in the CC as indicated by the absence of toxic effects at concentrations of 60 μg/ml, which were also sufficient to detect NP uptake in the CCs. The results examining cytotoxicity (MTS and LDH) and inflammatory responses (IL-8 and sICAM) of NP-exposed H441 and ISO-HAS-1 in MC show dose-dependent cytotoxic effects for Sicastar Red, especially at higher concentrations such as 100 and 300 μg/ml. selleck compound However, for AmOrSil, no harmful effects could be observed at all end-points. According to the data for general cytotoxicity and inflammatory activation cells used in this model appeared to tolerate the AmOrSil particles, even though these were present in higher mass concentrations than the Sicastar particles. At the concentrations NVP-AUY922 datasheet used, Sicastar always provided a much larger surface compared to AmOrSil in regard to the smaller particle size, which may also explain its higher toxicity. However,

a direct comparison of the cytotoxicity of the two different silica-based particles should not merely base on their mass concentration due to their different size, mass and particle density. Thus, using the same administered mass of the NPs leads on the one hand to a different applied particle number and particle surface area and on the other hand it may lead to different cellular doses (compared to the administered

dose on the cells) due to different particokinetics (diffusion, gravitational settling, agglomeration) of the particles [16]. In addition, different endocytotic pathways, that NPs may follow, might lead to differential toxicological effects. Beside size and shape, the cytotoxic effect of silica nanoparticles can primarily be associated to the reactivity of the nanoparticle surface which interfaces with the biological milieu. As reviewed Bumetanide by Napierska et. al., the hydrophilicity which is due to surface silanol groups is linked to cellular toxicity [1]. Since Sicastar Red is a hydrophilic amorphous silica nanoparticle with a plain/unfunctionalized surface it exerted a higher cytotoxicity. No obvious toxicity was observed for the organically modified and hydrophobic poly(organosiloxane) particle AmOrSil, whose silanol groups are mostly condensed into siloxane bonds. Furthermore, AmOrSil is coated with poly(ethylene oxide) (PEO) to achieve a water-solubility. Coating of NPs with poly(ethylene glycol) (PEG) or as in our case poly(ethylene oxide) (PEO) is widely applied in research concerning nanoparticles generated for biomedical applications.

In order to verify the bioactivity of the rIL-5 protein and thus the authenticity of the

vaccine, we tested the ability of rIL-5 to induce proliferation of BCL-1 cells. As shown in Fig. 1A, rIL-5 induced proliferation of BCL-1 cells in a concentration dependent manner. The highest proliferation rate was induced with 10 ng/ml of rIL-5. This activity was similar to commercially acquired IL-5 (cIL-5). This result demonstrates that rIL-5 was correctly folded and that the His-tag and the Cys-containing linker did not adversely affect the protein. Murine r-eotaxin 1 with a hexa-histidine tag and a cysteine containing linker at its C-terminus was expressed and purified. It has been previously demonstrated that the number of eosinophils circulating in selleck products the blood increases in response to administration of eotaxin and the accumulation of eosinophils in response to eotaxin was more selleck chemical pronounced in mice that had been sensitized with OVA [30]. To verify the bioactivity of r-eotaxin, we tested its chemo-attractant activity towards eosinophils in vivo. OVA immunized BALB/c

mice (n = 5) were injected with either PBS or 0.5 μg of r-eotaxin i.v. The number of eosinophils in the blood was assessed 30 min after the injection. As shown in Fig. 1B, the number of eosinophils in the blood doubled in mice which had been treated with r-eotaxin. This results shows that r-eotaxin was efficient Cell press at inducing the accumulation of eosinophils in the blood and was thus expressed in an authentic manner. In order to produce Qβ-IL-5 and Qβ-Eot vaccines, rIL-5 and r-eotaxin were both chemically coupled to VLPs derived from bacteriophage Qβ via a heterobifunctional cross-linker. The Coomassie-stained SDS-PAGE demonstrates the presence of rIL-5 (lane 2 of the left panel of Fig. 1C), r-eotaxin (lane 4 of the left panel of Fig. 1D), monomeric (14 kDa) and multimeric Qβ subunits (lane 3 of the left panel of Fig. 1C and lane 2 of the left panel of Fig. 1D). Coupling products whose molecular masses correspond to rIL-5 or r-eotaxin covalently

linked to one or more Qβ monomers are shown in lane 4 of the left panel of Fig. 1C and lane 3 of the left panel of Fig. 1D, respectively. Western blot analysis with either anti-His (middle panels of 1C and D) or anti-Qβ antibodies (right panels of 1C and D) demonstrated the same bands reacted with both antibodies, confirming the covalent attachment of rIL-5 or r-eotaxin to Qβ. In contrast, anti-Qβ antibody did not react with either rIL-5 or r-eotaxin (lane 1 of the right panel of Fig. 1C and lane 3 of the right panel of Fig. 1D, respectively). Analysis of the coupling efficiency by densitometry showed that 47% or 15% of Qβ monomers were cross-linked to rIL-5 or r-eotaxin, respectively. This corresponds to about 80–90 rIL-5 and 25-30 r-eotaxin molecules displayed per VLP.

Carbimazole et thiamazole ont une durée d’action proche de 4 à 6 heures et une meilleure concentration intrathyroïdienne (gradient thyroïde/plasma proche de 1/100). Ceci autorise leur prescription en une prise quotidienne. De plus, les ATS s’accumulent dans la thyroïde, ce qui explique la durée prolongée de l’activité antithyroïdienne qui persiste plusieurs jours ou plusieurs semaines après l’interruption du traitement. Les dérivés du thiouracile ont une affinité de liaison plus forte pour les protéines plasmatiques et une demi-vie plus courte. Ils sont plutôt prescrits en 2 ou 3 prises quotidiennes,

au moins en début de traitement. La tolérance des ATS est bonne. Néanmoins, peuvent s’observer des épigastralgies, arthralgies, réactions fébriles (tableau II). Les signes d’intolérance ne sont pas nécessairement dépendants de la dose. Dans une série cumulative récente de 31 cohortes, ils étaient présents Dasatinib cost chez 13 % des patients, plus fréquents

avec le thiamazole surtout pour les manifestations cutanées, tandis que les altérations hépatiques étaient observées principalement avec le propylthiouracile. La survenue d’une éruption érythémateuse ou urticarienne (souvent vers la deuxième semaine) n’impose Selleck Baf-A1 pas absolument l’interruption du traitement, car elle est parfois transitoire, résolutive sous traitement antihistaminique. Cependant, sa prolongation conduit à utiliser un autre antithyroïdien, car il n’y a pas nécessairement d’allergie croisée entre imidazolines et dérivés du thiouracile. Le risque majeur est hématologique : soit leuco-neutropénie progressive, dépistée par les hémogrammes recommandés tous les 8 à 10 jours durant les deux premiers mois du traitement, ou lors de sa reprise ; soit agranulocytose aiguë toxo-allergique, rare mais d’une extrême sévérité, reconnue à l’occasion d’un état fébrile, d’altérations des muqueuses (pharyngite). L’agranulocytose est parfois précédée par la neutropénie progressive, mais peut aussi survenir brutalement : la surveillance des hémogrammes est insuffisante Histone demethylase pour

dépister toutes les agranulocytoses. Le risque hématologique est précoce, survenant presque toujours lors des 3 premiers mois du traitement ou de sa reprise ; il est analogue sous imidazolines et dérivés du thiouracile ; il semble dépendant de la posologie utilisée pour l’antithyroïdien. En cas de leuco-neutropénie survenant sous un antithyroïdien, il est possible d’envisager la substitution par une autre médication : imidazolines ou dérivés du thiouracile. En revanche, la survenue d’une agranulocytose condamne définitivement le recours à un ATS, quel qu’il soit. Les altérations des fonctions hépatiques sont de type plutôt rétentionnel sous imidazolines, et plutôt cytolytique sous dérivés du thiouracile.

Of note, the sample sizes are clearly smaller also under alternative (d), in which efficacy for non-common

(“new”) serotypes is estimated. Some pneumococcal serotypes are only rarely found in carriage despite causing a significant proportion of disease. This is particularly true for the invasive disease outcomes with so called ‘epidemic’ types (e.g. 1 and 5), since they are carried either very briefly or Z-VAD-FMK molecular weight as minor populations in the nasopharynx. One possible approach in such a case is to conduct a colonisation study in pneumonia patients to estimate VEcol. It would then be based on rates of acquisition weighted according to the case-to-carrier ratios (i.e. probabilities of disease per episode of carriage) for each of the target serotypes, reflecting more directly the distribution of serotypes causing 3-MA mw disease. The set of reference states of colonisation should again exclude any states with VT colonisation (cf. Section 4 in [1]). Apart from the fact that the uncolonised study subjects can be included in the reference set of the analysis, this study design is equivalent to the indirect cohort method. The indirect effects of large-scale vaccination with current PCVs in the whole population follow after a relatively short time-lag. Usually such changes are seen in VT colonisation. Therefore, it may be of concern that data collected in vaccine studies conducted in restricted areas may be affected by indirect

protection, thus complicating the interpretation of any estimates of direct vaccine efficacy. Theoretical results based on a simple VT/NVT split indicate that prevalence-based estimates of vaccine efficacy are less prone to bias when indirect protection occurs simultaneously in vaccinees and controls [15]. One problem requiring further investigation is the possibility no of an interaction (effect modification) between the current colonisation (at the time of vaccination) and the subsequent vaccine effect. Such an effect of current carriage on the vaccine-induced serotype-specific antibody

response has been recently shown [16]. A somewhat different question relates to the potential interaction of the vaccine effect and the current carriage (yes/no) at the time of acquisition of (secondary) serotypes. Protection induced by a vaccine may be heterogeneous across individuals. A general discussion of the estimation of vaccine efficacy under heterogeneity is provided in an article by Halloran et al. [17]. Most importantly, the account of VEcol in the present article is based on the assumption of a leaky vaccine effect, i.e. that vaccinees would benefit from the vaccination through a reduced target serotype acquisition rate, rather than through a portion of vaccinees being completely protected against pneumococcal colonisation (and the rest remaining unprotected). Ideally, investigations of the impact of vaccination on the dynamics of colonisation should be based on longitudinal data.

The activity PD0325901 cost of the extract was more profound than quercetin – an important antioxidant flavonoid. There are no reports available on lipophilic antioxidants in this plant. The fatty acid/lipid autooxidation or metal dependent oxidant generation in cells lead to the formation of peroxyl free radicals (ROO.). The half life of ROO∙ radicals are relatively longer

than any other oxygen derived free radicals present in normal cells and are present at high steady state concentrations. Therefore, these free radicals are also of utmost importance in pathological conditions and tumor initiation.26 Therefore, lipid peroxidation inhibition capacity of the extract was assessed by TBARS assay, which is useful in quantifying the capacity of antioxidants to inhibit peroxidation. The activity http://www.selleckchem.com/products/VX-809.html of the extract was comparable to that of quercetin and better than previously reported in H. japonicum from Nilgiris, India. 9 Hydroxyl free radicals degrade the deoxyribose of the DNA molecule releasing purine and pyrimidine bases.27 This may yield the mutagenic sites, which is one of the most important mechanisms in the initiation of cancer.16 In the present study, the extract effectively reduced the oxidative damage of the DNA. The hydroxyl free radical scavenging activity of the extract could be due to the ferrous ion chelating activity, by which it reduces the generation of hydroxyl radicals.

The phenolic profiling of the methanolic extract by HPLC had revealed the

presence of various vital phenolic acids such as chlorogenic acid, ferulic acid, gallic acid, p-coumaric acid, phloroglucinol, vanillic acid, 4-hydroxy benzoic acid; and flavonoids such as, quercetin and epicatechin. The antioxidant and antimicrobial activity of these phenolics and flavonoids are well documented and the Electron transport chain presence of which, substantiates the antioxidant activity of the extract. There are a few reports on flavonoids profiling of H. japonicum. But no comprehensive reports are available on phenolic profile of the plant except a report on quality evaluation of H. japonicum extracts, which showed the presence of quercetin, 3,4-dihydroxy benzoic acid and phluoroglucinols. 28 The methanolic extract of H. japonicum from Western Ghats of India was rich in total phenol and flavonol contents with moderate antimicrobial and significant antioxidant activities. The extract had shown hydrogen donation capacity, quenching of peroxyl and hydroxyl free radicals and metal chelation capacity. As discussed before, these radicals are involved in the tissue damage during normal and pathological conditions with varying degree of affects. Therefore, the plant could be a rich source for dietary antioxidants and a candidate for the extraction of vital phenolic and flavonoids in pharmaceutical industries. All authors have none to declare.

Despite representing only a small percentage of ICU patients, those who fail to wean from ventilation consume a disproportionate share of

healthcare resources (Sprague and Hopkins, 2003) with an increase in mortality, morbidity, and ICU length of stay (Choi et al 2008, Epstein, 2009, Gosselink et al 2008). Weakness or fatigue of the diaphragm and the accessory muscles of inspiration is widely recognised as a cause of failure to wean from mechanical ventilation (Choi et al 2008, Petrof et al 2010). learn more There is also some evidence to suggest that mechanical ventilation may adversely affect diaphragmatic structure and function. These alterations, known as ventilator-induced diaphragmatic dysfunction, involve changes in myofibre length and rapid atrophy (Petrof et al 2010). Patients who undergo prolonged periods of ventilation also demonstrate decreases in respiratory muscle endurance (Chang et al 2005). Inspiratory muscle training is a technique click here that loads the diaphragm and accessory inspiratory muscles with the aim of increasing their strength and endurance. Theoretically, mechanically ventilated patients could

undertake inspiratory muscle training in several ways: isocapnic/normocapnic hyperpnoea training, the application of devices that impose resistive or threshold loads, or adjustment of the ventilator sensitivity settings, such that patients need to generate greater negative intrathoracic pressures to initiate inspiratory flow (Hill et al 2010, Caruso et al 2005, Bissett and Leditschke, 2007). Inspiratory muscles respond to What is already known on this topic: Inspiratory

muscle weakness in critically ill patients appears to contribute to slow or unsuccessful weaning from mechanical ventilation. Several trials of inspiratory muscle training to facilitate weaning in intensive care have been performed, with inconsistent results. What this review adds: Pooled data from randomised trials confirm that inspiratory muscle training increases inspiratory muscle strength, but it is not yet clear whether it shortens the mechanical ventilation Unoprostone period, improves weaning success, or improves survival. As no systematic appraisal of studies investigating the effect of inspiratory muscle training on weaning from mechanical ventilation has been indexed on the PEDro website or in PubMed, we undertook such a review, which aimed to answer the following specific research questions: 1. Does inspiratory muscle training improve inspiratory muscle strength and endurance in adults receiving mechanical ventilation? In addition to registration on PROSPERO, a more detailed protocol for conducting this review was submitted for peer review and publication (Moodie et al 2011) prior to commencing the review process. Five electronic databases were searched (PEDro, PubMed, CENTRAL, EMBASE, and CINAHL) from the earliest available date until April 2011.

They must also declare conflicts at each meeting of a WG. Any single conflict, real or apparent, may serve to disqualify a participant from participating in a WG. WG members may receive confidential and proprietary information from the FDA or others to assist C646 them in their discussions. When appropriate, they are therefore required to fulfill confidentiality requirements and, when required, sign non-disclosure forms prior to receiving such information. If, despite

all these safeguards, a conflict exists, limited waivers allow members to participate in committee discussions on condition that they are prohibited from voting on matters involving the specific or competing vaccine manufacturers. A member who develops an important conflict of interest during the 4-year term is required to resign from the ACIP. External consultants may participate despite conflicts of interest if they bring specific expertise, as long as their conflicts are declared and recorded at the selleck inhibitor beginning of each meeting. No special interest or lobbying groups provide any funding or any other

material support to ACIP or its members. Preparatory work for the in-person committee meetings involves two areas of ongoing activity. The ACIP WGs (currently numbering 14) meet regularly – at least once a month – to undertake an extensive, in-depth review of all relevant data and to prepare draft policy recommendations for consideration by the full ACIP in open meetings (see Section 8.1, below). The ACIP Secretariat is responsible for meeting preparations, which involves facilitation of WG proceedings; compilation of in-depth background technical background material that is published in a bound document distributed at least 2 weeks in advance of the meeting; and compilation of a Briefing Book, comprising concise (1–2 page) summaries of the key issues coming up for consideration or vote, which is distributed to the CDC Director, the ACIP membership and key Center/Division Directors at CDC. The Secretariat also is responsible for logistical preparations for each meeting, during i.e. meeting hall arrangements,

hard-copy handouts for the public, and audio-visual arrangements (including web-casting meetings in full, since July 2009). The Executive Secretary of ACIP, the Assistant to the Director for Immunization Policy and the ACIP Committee Management Specialist comprise the Secretariat, which was established in 2004 (prior to 2004 the work of ACIP was managed by the Executive Secretary alone). All three positions reside within CDC at the National Center for Immunization and Respiratory Diseases (NCIRD). Responsibility for reviewing and replying to inquiries from practitioners, members of the public, academics and others regarding the overall functioning of ACIP or about specific vaccine recommendations resides in the Secretariat as well.