In addition to the less complex downstream manufacturing process and higher yields, the intranasal route of administration of LAIV imitates natural infection and presents a lower risk to the recipient compared to the injectable administration of IIV, making it

the most appropriate candidate for mass immunization during a pandemic. With these considerations, SII initiated the development of IIV and also approached WHO to obtain a sub-licence for the Russian LAIV technology. We present here our activities, as one of the WHO grantees, to develop, manufacture and license both IIV and LAIV for use in the event of an influenza pandemic. Our initial objective was to gain experience and generate technical and preclinical experimental data on Regorafenib in vitro influenza vaccines in order to decide on the best options for large-scale vaccine manufacture. Most influenza vaccines are produced in embryonated eggs.

However, due to our extensive experience with production of cell-culture derived vaccines, we started by exploring the development find more of cell-based IIV to compare yields with those of egg-based vaccines. We undertook extensive work between June 2007 and June 2009 on upstream and downstream processing of egg- and tissue culture-based IIV. A developmental and an analytical laboratory were set up to establish protocols for vaccine production and analytical testing, respectively. A/PR/8/34 (H1N1) prototype strain and seasonal influenza vaccine strains A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005(H3N2) and B/Malaysia/2506/2004 were used to establish virus growth and purification methods, compare yields in eggs and tissue culture, generate trivalent seasonal influenza vaccine and carry out immunogenicity studies. The vaccine prepared using seasonal influenza strains induced an immune response

in mice comparable to that in commercially available vaccine using the same strains. The isothipendyl H5N1 NIBRG-14 strain was used to generate prototype whole and subunit pandemic vaccine and immunogenicity studies were conducted with and without adjuvants. The H5N1 whole virion inactivated vaccine induced considerable immune response using aluminium adjuvant (Fig. 1). Adequate exposure and successful handling of the NIBRG-14 strain along with promising immunogenicity data in mice provided confidence to advance the project to clinical development and large-scale manufacture of a H5N1 pandemic influenza vaccine at the beginning of 2009 [2]. The sudden outbreak of novel H1N1 pandemic influenza virus in May 2009 shifted our focus away from our comparative studies to develop a vaccine against the novel pandemic strain in the quickest possible time.

An Independent Ethics Committee approval of the protocol was obtained before enrolment; and written, informed consent was obtained from each subject or, if applicable (subjects Raf inhibition under 18 years of age), the subject’s parents or legal guardians. Study site monitoring was performed by Quintiles (Bogota,

Colombia). Healthy persons 11–18 years of age who were appropriately vaccinated against diphtheria (D), T, and pertussis (P) (i.e., had received five doses of paediatric DTP/DTaP before their seventh birthday; if the fourth dose was administered on or after their fourth birthday, the fifth dose was not required) with no prior history of sexual activity and no intention INCB018424 chemical structure of becoming sexually active during the study period, were eligible for inclusion in the study. Subjects were excluded if they had ever received meningococcal or HPV vaccine; had been vaccinated with any licensed vaccines within 1 month of enrolment; had received any investigational agents or vaccines in the 3 months before enrolment; had any serious acute, chronic, or progressive disease; or had a known or suspected impairment/alteration of immune function. A total of 1620 subjects were randomized 1:1:1 to three groups stratified by gender and age (11–14 years of age and 15–18 years of age) to receive: • Group 1 (n = 540)

MenACWY-CRM concomitantly with Tdap (Boostrix™, GlaxoSmithKline, Rixensart, Belgium) and HPV (Gardasil™, Merck & Co., NJ, USA), followed by HPV at 2 and 6 months (MenACWY-CRM + Tdap + HPV). All subjects received a single dose (0.5 ml) of each vaccine, administered intramuscularly in the right deltoid area (MenACWY-CRM), the left deltoid area (Tdap), and the upper anterolateral

area of the thigh (HPV). Each subject was observed Electron transport chain for 30 min post-vaccination for local or systemic reactions, or anaphylaxis. Oral temperature was recorded, and the subject, or the parents or legal guardians, where applicable, were given diary cards to record any local (pain, erythema, and induration) or systemic (chills, nausea, malaise, myalgia, arthralgia, headache, and rash) reactions that occurred between Day 1 and Day 7. Any adverse events (AEs) requiring medical attention were recorded for 1 month post-vaccination, and any medically significant and serious AEs (SAEs) were recorded for 6 months post-vaccination. Blood samples (20 ml) were obtained at the first visit, before vaccination, and 1 month post-vaccination with MenACWY-CRM and/or Tdap, and 1 month following the final dose of HPV. Immunogenicity of the MenACWY-CRM vaccine was evaluated by serum bactericidal assay using human complement (hSBA) to Neisseria meningitidis serogroups A, C, W-135, and Y.

These dramatic clinicopathologic findings show that vitreomacular attachments most likely are needed for transmitting intense acceleration–deceleration forces throughout the eye. The characteristic pathology of the perimacular ridge, described as a “dome-like lesion” filled as a

“traumatic bloody cavity” at the macula with fibrin deposition and an elevated, peeled ILM, is the logical consequence of these traumatic forces.27 Observing these findings in their abusive head trauma “cases” but not “controls” is again consistent with our histopathology. Perimacular ridge formation is often minimized as an unreliable finding in abusive head trauma, partially because of its presence in 2 seemingly accidental

cases,11 and 12 rather than considering them as outliers that deviate from the norm.28 Though learn more it may not be pathognomonic, it is important to emphasize the perimacular ridge in diagnosing abusive head trauma, by recognizing the vitreomacular traction involved this website in its formation. Every perimacular ridge in our study, like the cherry hemorrhage, was found in association with an ILM tear. Roughly half of all ILM tears were associated with perimacular ridge formations, and still, the majority of cherry hemorrhages were found concurrently with a perimacular ridge and an ILM tear. This evidence points strongly towards a linked mechanism of vitreoretinal traction for creating the perimacular ridge and cherry hemorrhage. Vitreomacular attachments become weaker by as early as 20 years of age.29, 30 and 31 Furthermore, clinically relevant effects of this diminishing vitreomacular connection may be seen at as early as 1 and 2 years of age, based on our results. Specifically, retinal hemorrhages, hemorrhages extending to the ora, perimacular ridges, and ILM tears all occurred more frequently in infants less than 16 months of age compared to those older than 16 months. While controlling for other confounding variables may be necessary,

it seems most plausible that the ever age-related change in the vitreomacular interface plays at least some part in this proportional difference in findings between 1- and 2-year-old abused children. Thus, the youngest eyes may be the most vulnerable to violent forces. Our 2 cases of “survivor” abusive head trauma after inflicted trauma 2 years prior to death demonstrate unique histopathologic features. The remarkable optic nerve cupping and atrophy with macular ganglion cell scarcity, in addition to the perpetually torn ILM, demonstrate the long-term consequences of ocular changes in previously shaken infants. The lack of hemorrhage and the negative iron stain may both indicate that blood and hemosiderin alike had long been resorbed earlier during the 2-year period.

The questionnaire was pre-tested by 15 pediatricians and subsequently mTOR kinase assay posted to all eligible members, accompanied by a cover letter and one-page background information on Bexsero® and MenB IMD epidemiology in Germany. Returned questionnaires were

double-entered electronically using EpiData version 3.1 (EpiData Association, Denmark). A descriptive analysis was performed, including calculation of proportions and 95% confidence intervals (CI). Demographic data on participants were compared to available BVKJ-member information. Due to Germany’s geographical size and historical differences, we performed regional analyses. We explored associations using the Chi-squared Test and univariate logistic regression, followed by stratification for duration in private practice, sex and region to estimate odds ratios (ORs) with 95% CIs. Statistical analysis was performed using Stata® version 13 (StataCorp, Texas, USA). Of the 5677 questionnaires sent out, 3107 (55%) were returned. Respondents’

mean age was 53 years (all BVKJ-members: 54 years), 52% were male (all members: 50%), and response ranged from 53–58% per region. Mean duration in pediatric practice was 16 years, and 99% (n = 3070) were board-certified pediatricians. Participants’ responses are summarized in Table 1. The majority (79.1%) stated they would recommend MenB vaccination. The most common reasons given for not recommending the vaccine were a concern that the schedule would become overcrowded XAV-939 molecular weight and insufficient

data on potential rare adverse events. Children ≤24 months were most frequently specified as target groups for MenB vaccination, in keeping with the highest incidence at these ages. Two thirds of participants believed that parents would be acceptant next of an official STIKO recommendation. Of two possible licensed vaccine schedules integrating MenB vaccination into the current German routine immunization schedule, vaccination at month 6, 8 and 12 of age (Option 2, Fig. 1) was preferred by 66.7% of physicians (95%CI 65.0–68.3; n = 2070), whereas vaccination at month 2, 3, 4 and 12 (Option 1, Fig. 1) was favored by only 13.4% (95%CI 12.2–14.6; n = 416). Neither schedule was chosen by 14% (95%CI 13.0–15.5; n = 441). Of these, 59.6% (95%CI 54.9–64.3%; n = 263) indicated they would vaccinate in the first 6 months of life but at different time points than in Option 1. In keeping with the strong preference for Option 2, only 31.3% of all respondents thought MenB vaccination should be administered concomitantly with other standard vaccinations. Similarly, >70% of all participants objected in principle to the simultaneous administration of 3 vaccines; 19.7% among those favoring Option 1 and 81.8% among those favoring Option 2 (p < 0.005). The most common reason given for objection was lack of parental acceptance ( Table 1).

We will also extend the process to include a step to serve parties that

prefer split over whole virus pandemic vaccine and those interested in seasonal vaccine production. A major challenge of the hub model is its sustainability. The need to secure NVI’s international role in building capacity for common public goods such as those described here have led to other initiatives and innovative approaches that will be introduced into the curriculum. For instance, we plan to develop and introduce cell-culture based technology modules for viral vaccine production. Developing countries may thereby enhance their capacity to manufacture RG7204 datasheet not only influenza, but also other vaccines of high public health relevance, such as rabies or rotavirus. In addition, we serve as a training partner within the recently launched Y-27632 research buy project for the technology transfer

of an oil-in-water adjuvant for pandemic influenza vaccines in developing countries. The first years of operation have shown the International Technology Platform for Influenza Vaccines to be a highly successful capacity-building tool. The egg-based pilot-scale process established is robust, consistent and meets all international specifications. The technology is easy to scale up and has proven suitable for transfer to developing country manufacturers. The training and technology transfer objectives have been met, since participants at the fully booked generic courses are successfully using the technology and

know-how gained in their facilities, and two bilateral consultancy agreements for follow-up activities have been signed. The generic hub approach to technology transfer can thus be seen as complementary to the bilateral partnerships for domestic influenza vaccine production reported by the International Federation of Pharmaceutical Manufacturers & Associations, which usually focus on fill/finish activities.1 In conclusion, technology transfer from the public domain to emerging developing country second manufacturers and regulators will increase global and equitable access to vaccines of high public health relevance. The hub approach is thus meeting a critical international need, and may be worth considering for other vaccines needed in low- and middle-income countries [12]. The authors state they have no conflict of interest. “
“In 2000, the Ministry of Health decided to provide influenza vaccination free of charge to individuals over 60 years of age, patients with chronic diseases, and health-care personnel. The Instituto Butantan – an arm of the São Paulo Office of Health – was charged to develop, produce and register the seasonal vaccine needed to implement this policy decision. The yearly demand for seasonal influenza vaccine was estimated at 25 million doses, to be deployed at 25 000 health centres across the country.

Social pressure was associated with a change in intention suggesting that the intervention accomplished exactly what it was supposed to do: preparing children for secondary school.

One question is whether the transition to a different school instead of the intervention is responsible for the difference between the intervention and control students. Other findings indicated, among others, that students are more likely susceptible to smoking if they have two or more close friends who smoke, attend a school with a relatively high smoking rate among the older students or a school with less (endorsed) smoking restrictions (Leatherdale et al., Olaparib research buy 2006 and Wakefield et al., 2000). If a larger part of the control students went to schools with a higher smoking rate, this change in school instead of the intervention might have caused the difference in smoking. Although we could not verify this school transition effect properly, we do not think that the effect of the transition Androgen Receptor Antagonist to secondary school differs for intervention or control

students. First, in each participating region, we have randomized schools to the intervention or control group, meaning that an important part of the students in both conditions went to the same regional secondary schools. Secondly, there were no important differences in perceived non-smoking policies between the intervention and control group. The largest effect of the intervention is found in girls. Other studies already have shown that there are gender differences in smoking uptake in adolescence and that smoking is more prevalent Adenosine in girls than in boys (Rodham et al., 2005 and de Vries et al., 2003). Moreover, Mercken et al. (2010) found that particularly girls are influenced to smoke by their peers concluding that an intervention preparing girls to resist peer pressure might be more effective in girls than in boys. This might explain the larger effect of the present intervention among girls. The schools were randomly assigned to the intervention and control group

in order to reduce the chance of selection bias. In spite of the randomization procedure, differences between the groups at baseline were found. Chance confounding, due to randomization at school level, may explain these differences, so we adjusted for this in our analysis. Loss to follow-up was somewhat selective but seemed to have a limited effect on the results, while there were no significant differences in smoking behavior between the non-response of intervention and control condition. Moreover, intention-to-treat analyses by carrying the last observation of smoking behavior forward did not have different effects on smoking behavior. The response rate also did not differ between groups. Therefore, it is highly unlikely that selective response has affected the impact of the intervention. All measurements were self-reports, meaning that information bias could have occurred, especially in the intervention group.

Other reviews have also shown that the extent of thyroidectomy, hyperthyroidism, thyroid

resection for malignancy and re-operative surgery do not reliably predict those most at risk of developing a haematoma [3], [11] and [26]. A higher incidence of haematomas requiring evacuation in thyroid re-operations Selleckchem Cobimetinib compared with primary procedures, and re-operative hyperthyroid patients compared to euthyroid has been shown [19], [24] and [27]. Swedish registry and Promberger’s data suggest that older age and male gender are risk factors [11] and [24]. Promberger also showed that the risk of postoperative haematoma was increased two fold by extent of resection and bilateral procedure and as much as seven fold between surgeons of variable experience. Assuming a 1–2% risk of postoperative bleeding [4], [10], [11], [12], [13], [14], [15], [18] and [26] and recognising that bleed prediction is unreliable ensuring Vismodegib price safe management of this complication is paramount. In day case surgery, it is the timing and severity of the bleed that is most important. Provided the necessary resources

are available, an early bleed recognized and dealt with before discharge is no different to the patient treated as an in-patient. Early bleeds are perceived to be more dangerous than a later bleed, as is the severity of haemorrhage between hemi- and total thyroidectomy. Mirnezami’s review of 1571 cases suggested that all patients with significant haemorrhage display signs of bleeding within the first few hours, and those with potential airway obstruction within 4 hours [2]. Promberger’s series [24] showed 81% of postoperative haematomas occurred within 6 hours of thyroidectomy, 17% between 6 and 24 hours and only 2% after 24 hours. However, Leyre et al.’s retrospective review of nearly

7000 thyroidectomies performed in Poitier, France reporting 70 haematomata (1%) showed only 37 (53%) occurred within 6 hours [3]. The rest occurred after 6 hours (i.e.: post-discharge for the day case patient) with 26 (37%) between 7 and found 24 hours from surgery and 7 (10%) after 24 hours. Likewise, Burkey’s large series found only 43% occurring within 6 hours, 37% between 7–24 hours and 19% over 24 hours [25]. Lang et al. reported 70% within 6 hours, the rest between 6 and 24 hours [19]. These retrospective reviews are unselected patients and, as commented by Lo Gerfo et al., do not consider symptoms or the possibility that intervention in those with early symptomatic haematomas may alleviate the risk of obstruction [28]. Using decision model analysis on earlier US thyroidectomy mortality data, Schwartz et al. estimated 94 haemorrhage-related deaths per 100,000 could be prevented by observation for 24 hrs (i.e., advocating a 23-hour stay) as opposed to 6 hours [29]. It appears the bleeding risk after 23 hours is generally acceptable [2], [19] and [24].

However, flaviviruses belonging to the tick-borne encephalitis virus complex are on this list. Construction of infectious flaviviruses, involving DNA synthesis, cloning, assembly into larger PFI-2 chemical structure units, in vitro transcription and transfection steps, is a complex task and can be done in a professional environment only. A recent review on synthetic viruses discusses the dual use concerns in more detail [24]. For vaccine manufacturing,

the most important advantage of using primary seed virus stocks derived by gene synthesis is the exclusion of potential contamination with unknown and known adventitious agents – including the transmissible spongiforme encephalopathy agents – which maybe co-isolated from animal-derived viruses or their host cells. Furthermore, this approach renders passaging, plaque purifications and other steps to achieve satisfactory purity of seed viruses from animal sources unnecessary. Our study demonstrates the feasibility of generating the flavivirus WNV in a completely synthetic approach. Synthetic biology is therefore a valuable alternative to obtain viral seed stocks free from the adventitious agents that might accompany recovery from vertebrate or insect cells. We thank Helga

Savidis-Dacho and her team Sorafenib for performing the animal experiments, Kathrin Janecki, Marie-Luise Zips and Petra Cech for expert technical assistance and the Geneart team for providing the cloning strategy and the six genomic plasmids. “
“Kaposi’s sarcoma-associated herpesvirus (KSHV) was identified as a causative agent of Kaposi’s sarcoma (KS) in 1994 [1]. Since KSHV has been detected in all cases of KS, there is no doubt about the association between KS pathogenesis and KSHV infection [2]. More than 15 years after the discovery of KSHV, KS is still an important complication in AIDS patients. KS occurs frequently among human immunodeficiency Fossariinae virus (HIV)-infected men who have had sex with men (MSM), suggesting that homosexual behavior in males is an important risk factor for KS and KSHV infection [3]. Although vaccine is available for other

herpes viruses, such as varicella zoster virus, KSHV vaccine is not available so far. There are several reasons why KSHV vaccine has not yet been developed. First, most HIV-infected MSM are already infected with KSHV [3]. For example, an epidemiological study revealed that about 60% of HIV-infected MSM were positive for serum antibody to KSHV in Japan, suggesting widespread KSHV infection among MSM [4]. Immunodeficiency condition may cause some problems for vaccine to work in HIV-infected individuals [5]. However, vaccination of influenza vaccine to asymptomatic HIV-infected patients showed similar antibody production to uninfected group [6], suggesting possibility of vaccine strategy for KSHV in HIV-infected adults.

A WHO consultation on NP sampling and testing for pneumococcus was held in March selleck inhibitor 2012. The review will update the existing recommendations for pneumococcal NP sampling methods and detection of multiple serotype carriage. When a protein or conjugate-protein vaccine candidate is ready

for clinical evaluation, it may be advantageous for interested partners and the manufacturer to engage the WHO and national regulatory agencies early to get input on the acceptability of NP carriage data for meeting pre-qualification and licensure criteria, respectively. PneumoCarr has laid some of the groundwork and advanced the case for the trial design specifications and technical points in quantifying VE-col as a surrogate endpoint for pneumococcal disease. KOB: research grant support from Pfizer, and GlaxoSmithKline and has served on pneumococcal external expert committees convened by Merck, Aventis-pasteur, and GlaxoSmithKline. KPK: research grant support from Pfizer and has served on pneumococcal external expert committees convened by Pfizer, Merck, Aventis-pasteur, and GlaxoSmithKline. RD: grants/research support from Berna/Crucell, Wyeth/Pfizer, MSD, Protea; has been a scientific consultant

for Berna/Crucell, GlaxoSmithKline, Novartis, Wyeth/Pfizer, http://www.selleckchem.com/products/MK-2206.html Protea, MSD and a speaker for Berna/Crucell, GlaxoSmithKline, Wyeth/Pfizer; he is a shareholder of Protea/NASVAX. AS: has received research grant support from GSK and travel and accommodation support to attend a meeting convened by Merck. MA: no conflicts of interest. SAM: research grant support from GlaxoSmithKline anmd Pfizer, and has served on pneumococcal external committees convened by Pfizer, Amisulpride MERCK and GlaxoSmithKline. KA: no conflicts of interest. DG: has received honoraria for participation in external expert advisory committees on pneumococcal vaccines convened by Pfizer, GSK, Sanofi Pasteur and Merck. His laboratory performs contract research for Merck,

Sanofi Pasteur and GSK. HK: no conflicts of interest. MGL: Has served as speaker in several GSK conferences and as member of two GSK advisory board meetings for the past three years. HN: has served on pneumococcal vaccination external expert committees convened by GlaxoSmithKline, Pfeizer, and sanofi-pasteur. Works in a department which holds a major research grant from GlaxoSmithKline on phase IV evaluation of a pneumococcal conjugate vaccine. Fig. 1: Reproduced from Expert Review of Vaccines, July 2012, Vol.11, No. 7, pages 841–855 with permission of Expert Reviews Ltd. This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the World Health Organization.

These areas were rebiopsied 1 and 3 years after the initial biopsy, without significant change in the pathologic findings. Four years after initial presentation, the patient was again taken to the operating room for cystoscopy and biopsy. On this examination, multiple papillary tumors were noted and biopsied. The largest was approximately 5 cm in diameter with several satellite Buparlisib mw lesions. Representative biopsy revealed squamous papillomas. After counseling the patient regarding these findings, we recommended continuing follow-up with cystoscopy and periodic rebiopsy. A review of the urologic literature reveals

only 12 reported cases of squamous papilloma. Current literature suggests that although the appearance and presentation may mimic urothelial carcinoma, squamous papilloma is benign and not thought to be a risk factor for bladder cancer.2 Extensive keratinization of the bladder has been associated with bladder contracture and risk

of development of metachronous bladder cancer.4 For this reason, we suggest that it is prudent to continue surveillance with periodic rebiopsy in patients with keratinizing squamous metaplasia that does not resolve with conservative therapy. To our knowledge, this is the first published case of keratinizing squamous metaplasia with melanotic deposits of an unknown material with synchronous development of squamous papilloma. “
“Primary signet ring cell adenocarcinoma of the urinary bladder, also called linitis plastica urinary bladder, is rare, accounting for only 0.24% of all ABT-263 datasheet malignant tumors of the urinary bladder.1 A 72-year-old patient consulted for intermittent painless total gross hematuria, urgency, and pollakiuria. The medical and familial histories were unremarkable. Physical examination was normal. The abdominal and pelvic ultrasound showed a bilateral hydroureteronephrosis with thickening of the urinary bladder wall. Cystoscopy visualized a solid mass in the left-side wall of the urinary bladder. Histologic examination of cystoscopic biopsy showed a proliferation Ketanserin of

round-cell aspect of signet ring. An immunohistochemical study demonstrated positivity for cytokeratin 7 and negativity for cytokeratin 20. The diagnosis of signet ring cell adenocarcinoma of the bladder was established. Abdominal computed tomography (CT) showed no locoregional lymph nodes, metastases, or a primary tumor in other abdominal or pelvic organs. We performed a complete gastrointestinal endoscopic evaluation to exclude an extravesical primary tumor site, but no other primary site was found. The tumor was therefore treated as a primary signet ring cell carcinoma (SRCC) of the urinary bladder. The patient underwent a radical cystoprostatectomy. The intraoperative examination found a budding tumor inserted to the left-side wall. Histologic examination concluded to a signet ring cell adenocarcinoma with a colloid component estimated about 40%.