The expiratory flow retardation created find more by the distal end produces positive back pressure on the airway. The expiratory pressure induced by resistance of the conical-PEP is flow dependent; the greater the expiratory flow the greater the back pressure (Mitchell 2007, Weng 1984). It produces a positive mouth pressure of 4.2–10.9 cmH2O at expiratory flows of 0.06− 0.41 L/s at rest and 4–20 cmH2O at flow rates of 0.09–0.51 L/s during exercise. This pressure range has been reported to be optimal for retarding airway collapse in patients with chronic obstructive pulmonary disease (O’Donnell et al 1988, Petrof

et al 1990, Plant et al 2000). Exercise was terminated when one of the following symptoms occurred: breathlessness ≥ 5/10 on the modified Borg scale, leg discomfort, or any other unpleasant symptoms such as dizziness. The control intervention was normal breathing during exercise. Lung function was measured as inspiratory capacity and slow vital capacity in litres according to ATS/ERS taskforce guidelines (Miller et al 2005) with a portable automated spirometera. The volume sensor was calibrated before each test. The duration

of exercise and the reasons for exercise termination were collected. Breathlessness was measured using the modified Borg scale (0 to 10) where 0 is no breathlessness and leg discomfort was measured using a 0–10 visual analogue scale Palbociclib datasheet where 0 is no discomfort. Cardiorespiratory function was also measured. SpO2 was measured by finger pulse oximeter and end tidal pressure of carbon dioxide (PETCO2) was measured in a side-stream of Histone demethylase expired air with a capnometerb. Electrocardiogram, expiratory mouth pressure and expiratory flow rate were continuously recorded on a PC with an A/D converterc. The flow and pressure sensors were calibrated before each data collection. Tidal volume, respiratory rate, inspiratory time, expiratory time and ratio (I:E ratio) were determined from the flow signal. Minute ventilation was calculated for the last minute of exercise. A pilot study

of two elderly participants without lung disease showed a between-intervention difference of 150 ml (SD 130) for inspiratory capacity. Therefore, we needed 11 participants to have a 90% power to detect between intervention difference of 150 mL at p = 0.05. Student’s paired t tests showed no evidence of either period effects or intervention-period interaction of the primary outcome and, therefore, the data for the two tests in each intervention were averaged to provide a single value for each participant. Statistical significance was considered at p < 0.05, therefore mean between-intervention differences (95% CI) are presented. Forty-three patients with moderate-severe stages of chronic obstructive pulmonary disease were screened and 17 (40%) agreed to participate in the study. Of these, 4 (24%) withdrew prior to randomisation for reasons that were unrelated to the procedures of the study.

In the present study all compounds AZD2281 molecular weight were treated as neutral and therefore regional differences in the intestinal pH, which are accounted for in the ADAM model, did not affect intestinal solubility

of the compounds. This may in particular lead to an overestimation of colonic solubility of basic compounds, whereas an opposite situation can occur for acidic compounds, for which the solubility is higher in the upper regions of the GI tract. There are also many in vivo factors that might contribute to the possible under/overestimation of drug dissolution and solubility within the GI tract. For instance the over-simplified composition of the small intestinal and colonic fluids in available PBPK absorption models, as well as the actual fluid volumes available to dissolve the drug might affect such estimations ( Sjogren et al., 2014). Furthermore, several biopharmaceutical and physicochemical properties, known to influence drug absorption, were not taken into account in this study, i.e. particle size and its distribution; excipients; and in particular the drug release mechanism, which was oversimplified in this study; just to name a few

(Martinez and Amidon, 2002). Consideration of such factors would have significantly increased the number of simulations to be performed, thus Z-VAD-FMK mw complicating any subsequent analysis. Those simulations were out of the scope of this work. One of the main goals of this work was to identify the parameter space in which a drug, formulated as CR, would display higher relative bioavailability than the corresponding IR formulation. The above results clearly indicated absorption – fa – to be reduced for all the CR formulation as compared to the IR formulations. Still, in the case of the simulated CYP3A4 substrates, the reduction in fa seemed to be compensated by an increase in FG ( Figs. 3B and S1B–S3B), that is, a reduction in the CYP3A4-mediated first pass intestinal metabolism. For some of the simulated compounds, this compensation was translated into similar exposure levels of CR formulations as compared to IR. The Bay 11-7085 proposed explanation is based on

the distribution of the CYP3A abundance along the GI tract. As discussed previously in this manuscript, the CYP3A enzymes decrease towards the distal regions of the human GI tract ( Berggren et al., 2007, Paine et al., 1997 and Zhang et al., 1999), this pattern is taken into account in the ADAM model. As a result, when a CR formulation releases its drug content into the distal regions of the intestine, the drug would encounter less CYP3A enzymes on its way towards the portal circulation, thus reducing the CYP3A-mediated intestinal first pass metabolism. In this study the impact on the AUC was however only noticeable for highly permeable (BCS classes 1 or 2) and highly cleared drugs (CLint,CYP3A4 ⩾ 250 μL/min/mg).

This blood was left to clot in the monovette for 30–60 min at room temperature, followed by centrifugation at 1500 g for 10 min. The serum was then transferred to a polypropylene tube and if the analysis was not performed immediately, the samples were

frozen and maintained at −20 °C until thawed and analyzed. Albumin was determined using commercially available kits from Spectrum Company. Bilirubin was measured using commercially available kits from dp International company. Serum alanine transaminase (ALT) was analyzed using commercially available kits from Bio Adwic Company. Alpha fetoprotein was analyzed by the chemiluminescence technique by Centor Ribociclib cost apparatus (Bayer, Germany). Dermatan sulfate was measured using the method described by Berry.12 Sialic CAL-101 cell line acid was measured using the method described by Bhavanandan and Sheykhnazari.13 Glucosamine was measured using the method described by Elson and Morgan.14 Serum glucuronic acid was measured using the method described by Mosher.15 β-Glucuronidase and β-N-Acetylglucosaminidase was measured using the method described by Mack. 16 Data were analyzed on a personal computer running IBM SPSS Statistics for Windows (Statistical Package for

Social Scientists) Release16. For descriptive statistics of qualitative variables, the frequency of distribution procedure was run with a calculation of the number of cases and percentages. For descriptive statistics of quantitative variables, the mean, range, standard deviation and standard error (SE) were used to describe central tendency and dispersion. For a comparison between two groups student t-test was calculated. Statistical significance was predefined as P < 0.05. Correlations between variables were determined by Pearson's correlation coefficient. The patients' characteristics

are shown in Table 1. The study was carried out on 75 consecutive patients Resminostat with HCC, 40 patients with liver cirrhosis and 30 healthy subjects as a control. The mean age ± SE was 57.30 ± 5.61, 61.30 ± 7.31, and 48 ± 7.2 years, respectively. As shown in Table 2, patients with HCC and cirrhosis showed a significant decrease in their serum levels of albumin (P < 0.05) and a significant increase in their serum levels of ALT and AFP compared with the control group. Among the 75 studied cases of HCC, only three patients were fit for surgery (4.0%), five patients (6.6%) for local ablative therapy by radio-frequency ablation. On the other hand, forty-two (56.0%) patients were treated with a subcutaneous injection of 30 mg of viscum fraxini-2 as two ampoules once weekly in addition to the best supportive care. Repeated AFP and radiological study were used to follow up and for monitoring of those patients. The response to treatment is illustrated in Fig. 1. In non-responding cases, a dose escalation was advised and recommended to be 45 mg weekly (3 ampoules) but this failed also to achieve further objective responses.

(6f) 5-(4-methoxy phenyl)-4-methyl-3yl- (Imidazolidin-1ylmethyl, 2-ylidene nitro imine)isoxazole IR: νmax 3354, 1553, 1412 cm−1, 1H NMR: δ 3.9 (s, 3H, –OCH3), 5.5 (s, 2H, –CH2–N–), 2.4 (s, 3H, isoxazole–CH3),2.0 (brs, 1H, –NH), 2.65–3.1 (m, 4H), 7.0 (d, 2H, Ar.H), 7.3–7.4 (m, 2H, Ar.H), EI mass (m/z) 331 (M+), 262, 180. (6g) 5-(2-chlorophenyl)-4-methyl-3yl-(Imidazolidin-1ylmethyl, 2-ylidene nitro imine) isoxazole IR: νmax: 3318, 1587, 1410, 1310 cm−1, 1H NMR: δ 5.5 (s, 2H, –CH2N–), 2.4 (s, 3H, isoxazole–CH3), 2.2 (brs,1H,–NH), BGB324 concentration 2.7–3.0 (m,

4H),6.9 (m, 1H, Ar.H) 7.3–7.6 (m, 3H, Ar.H),7.9(m, J = 8.25, 1H, Ar.H), EI (m/z) 335(M+),263,135. (6h) 5-(2-methoxyphenyl)-4-methyl-3yl-(Imidazolidin-1ylmethyl, 2-ylidene nitro imine) isoxazole IR: νmax: 3350,

1550, 1415, 1298 cm−1, 1H NMR: δ 3.9 (s, 3H, –OCH3), 4.6 (s,2H, –CH2N–), 2.3(s, 3H, isoxazole–CH3),2.1 (brs, 1H, –NH), 2.6–3.0 (m, 4H), 7.0 (d, J = 8.3Hz, 2H, Ar.H), 7.1 (t,J = 7.6Hz, 1H, Ar.H), 7.4(t, J = 7.4 Hz, 1H, Ar.H),7.8 (d, J = 7.6 Hz, 1H, Ar.H), EI mass (m/z) 331 (M+),265, 170. (6i) 5-(3-methoxyphenyl)-4-methyl-3yl-(Imidazolidin-1ylmethyl,2-ylidenenitroImine) isoxazole. IR: νmax: 3330, 1567, 1410 cm−1, 1H NMR: δ 3.8 (s, 3H, OCH3), 5.5 (s, 2H, –CH2–N), 2.35 (s, –CH3, isoxazole), 2.2 (brs, 1H, –NH), 2.7–3.1 (m, 4H), 6.9 (m, 1H, Ar.H), 7.2–7.4 (m, 3H, ArH), EI mass (m/z) 331 (M+), 264, 175. (6j) 5-(3-chlorophenyl)-4-methyl-3yl-(Imidazolidin-1-ylmethyl, 2-ylidene nitro imine)

isoxazole IR: νmax: 3304, Smad inhibitor GBA3 1589, 1428, 1312 cm−1, 1H NMR : δ5.6(s, 2H, –CH2–N), 2.35(s, –CH3, isoxazole), 2.1 (brs, 1H, –NH), 2.64 (t, 2H, N–CH2), 2.8–3.1 (m, 4H), 7.4 (m, 2H, ArH) 7.7 (m, 1H, ArH),7.8 (m, 1H, ArH), EI mass (m/z) 335 (M+), 260, 171. (6k) 5-(2,4 di methoxyphenyl)-4-methyl-3yl-(Imidazolidin-1ylmethyl, 2-ylidene nitro imine) isoxazole IR: νmax: 3331, 1555, 1418 cm−1, NMR: δ 3.8 (s, 3H, OCH3), 3.9 (s, 3H, OCH3), 5.4 (s, 2H, –CH2–N), 2.38 (s, CH3, isoxazole), 2.1 (brs, NH), 2.8–3.0 (m, 4H), 6.45 (d, 1H, ArH, J = 3.0 Hz), 6.55 (dd, 1H, Ar.H, J = 8.4 and 3.0), 7.8 (d, 1H, ArH), EI mass (m/z) 361 (M+), 267, 105, 77. In the present study we found that the exclusive formation of one isomer methyl-5-(phenyl/substituted phenyl)-3-isoxazole-carboxylate. A rigorous study on the direction of enolisation of disubstituted β-ketones was reported.15 When the substituents are not the electronically very different the separation of the 3,5 disubstituted isomers is difficult.

Importantly, the interest in combating pandemic influenza at national and regional levels, with the assistance of WHO grants to stimulate local production, has resulted in a variety of indigenous financing mechanisms

that will dramatically improve the supply of influenza vaccines in the future. Moreover, interest in influenza seems to have rekindled interest in the local production of essential vaccines in several countries. This could have a major impact on the future health of populations in these countries. Conflict of Interest Statement: The authors state they have no conflict of interest. “
“Due to the increasing number of human deaths since 2004 during the regional expansion in Asia of the H5N1 influenza strain, concern was high that this virus would become transmissible between humans. Indeed, many articles by prominent scientists and public health officials warned that this virus could Crizotinib in vitro cause a devastating pandemic resulting in high mortality. In response, the United States published the National Strategy for Pandemic Influenza [1], followed by an

HHS implementation plan [2], both of which stated a clear commitment to supporting international pandemic preparedness. Diseases do not respect national borders so increasing the capacity to make and use influenza vaccines in more countries can help every country reduce the spread of the influenza virus. The US government included a commitment in its strategy to implement the World Health old BAY 73-4506 clinical trial Assembly resolution WHA58.5 which specifically called for increased influenza vaccine manufacturing capacity in developing countries. In Vietnam, in particular, concern was high that the close connection between backyard poultry kept by a large percentage of the population and limited rural medical infrastructure would produce ideal conditions for development of a “bird flu” pandemic. Thus, initial efforts at vaccine capacity-building took the form of an HHS grant to the state-owned company in Hanoi, VABIOTECH, to enhance its capacity to produce influenza vaccine produced under current Good Manufacturing Practice (cGMP). Further international support followed as a component

of legislation that appropriated funding through the Public Health and Social Services Emergency Fund [3]. This funding has been made available on a regular basis from 2005 to 2011. Such capacity building activities were noted recently as one of seven prioritized to support global pandemic preparedness [4]. BARDA realized that support and maintenance of bilateral cooperative agreements with developing countries and their varying relationships would require a level of personnel beyond its capacity. Given that WHO was specifically coordinating an initiative to support influenza vaccine capacity-building as a component of the 2006 The Global Action Plan (GAP) to increase supply of pandemic influenza vaccines (http://www.who.int/vaccines-documents/DocsPDF06/863.

Rhesus monkeys are refractory until the first menses, and squirrel monkeys were dependent on estrus. Naturally occurring trichomonads are a conflicting factor for the use of monkeys as a disease model or vaccination

model. However, the pigtailed macaque is still useful since it naturally hosts lactobacilli, MAPK inhibitor has a vaginal pH of 5.5–8.0, sustains infection up to 2 weeks, responds to metronidazole treatment, signs of pathogenesis have been documented (erythema), and has been used as a disease model for C. trachomatis [71]. Determining the appropriate components of a vaccine can be problematic. Whole cell Tv vaccines are an attractive option due to the cheap manufacturing costs associated with culturing Tv and formulating a vaccine. We recently used this approach following the previously established mouse model that used FCA/FIA immunization. However, we used a FDA approved adjuvant, Alhydrogel, formulated with live, whole cell Tv. Vaccination with either Freund’s or Alhydrogel was found to significantly reduce incidence of infections on day 7 post-infection (incidence) and significantly improved clearance by day 28 post-infection

(resolution) compared to unvaccinated controls [Smith and Garber, unpublished data]. The simplicity and cost effectiveness of a whole cell vaccine are the predominant Bumetanide advantages. An intramuscular route of immunization is also relatively noninvasive and easy to administer. A single dose injection is preferred to overcome dropout rates in Dasatinib vaccination schedules, but human testing would be required to determine the necessity of boosters. On the other hand, a subunit vaccine could be a more targeted approach and safer with regards

to possible autoimmunity that could result from multiple antigens evoking molecular mimicry in host defense [50]. Since the draft genome sequence of Tv by Carlton and colleagues, [72] genomic and proteomic studies have been able to contribute valuable information for identification of unique and hypothetical Tv proteins that with further study could be potential vaccine targets. Hirt [73] reviews genomic and proteomic approaches and their contribution to identification of Tv surface protein antigens that could be pivotal virulence factors. The identification of antigen targets that will be effective against multiple isolates will require study of genetic diversity of Tv isolates and additional genome sequences. Meade and Carlton [74] suggest a unified approach to use microsatellite genotyping and multilocus sequence typing of T. vaginalis. So far, the use of random amplification of polymorphic DNA (RAPD) has been successful at identifying an association of Tv genotype and metronidazole resistance.

The sole participation of MDR1 in digoxin net secretory transport in Calu-3 layers could not be demonstrated and the contribution of an ATP-independent transporter such as a basolaterally located member of the OATP find more family was therefore hypothesised. Identification of this unknown transporter might provide a better understanding of the distribution of drugs in the pulmonary tissue. This work was carried out under the Targeted

Therapeutics, Centre for Doctoral Training at the University of Nottingham (Grants EP/D501849/1 and EP/I01375X/1) and AstraZeneca. The authors would like to thank AstraZeneca, the Engineering and Physical Science Research Council (EPSRC, UK) and the University of Nottingham for their financial support. “
“Active pharmaceutical ingredients (API) commonly exist in various crystalline forms, known as polymorphs, with different molecular arrangements and/or conformations. Multi-component crystals, where one or more additional compounds are incorporated into the crystal lattice, may also be formed and include salts, co-crystals, and solvates. A widely observed solvate is the hydrate, where water molecules have been incorporated into the API’s crystal lattice. Single and multi-component API solids may also exist in a higher energy, disordered amorphous form. The solid-state

form www.selleckchem.com/products/Metformin-hydrochloride(Glucophage).html of an API is an important parameter in the development of oral dosage formulations. It has an effect on the chemical and physical stability, processibility, solubility, dissolution rate, and potentially bioavailability of the API. In dynamic environments, solid-state changes in pharmaceutical materials are common: there have been numerous reports on solid-state forms undergoing changes during processing [1], [2] and [3]

and storage and dissolution [4], [5] and [6]. Solid-state changes that occur during dissolution when a metastable form (higher solubility) converts to a stable form (lower solubility) through precipitation from a supersaturated solution are called solvent-mediated phase transformations [7]. The kinetics of a solvent-mediated phase transformation are determined by the relative rates of dissolution and growth of the two phases [7] and [8]. Solution-mediated transformations of APIs are well documented. whatever Murphy et al. [5] studied the conversion of carbamazepine (CBZ) form III to the dihydrate form in samples undergoing dissolution testing. They found that the conversion time depended on grinding and storage conditions of the form III [5]. Savolainen et al. [9] studied the dissolution of amorphous indomethacin (IMC) and compared this to the dissolution of α and γ forms of IMC. As expected, they found that the initial intrinsic dissolution rate for amorphous IMC was faster than for either crystalline form. However, the dissolution rate decreased as the sample surfaces began to crystallize to α-IMC during dissolution. Aaltonen et al.

Secondary outcomes: Outcomes used to describe physical activity levels included steps per day, time spent in upright activities per day (minutes), time spent walking per day (minutes), and time spent inactive per day (hours). The Functional Independence Measure (FIM) was used to assess the amount of assistance required to complete activities Adriamycin clinical trial of daily living at baseline and on discharge ( Hamilton and Granger 1994). The FIM consists of 18 items in two domains: motor (13 items) and cognitive (5 items). Each item is rated on a 7-point scale, where 1 reflects complete dependence and 7 reflects complete independence. Scores range from 18 (lowest function) to 126 (highest function).

The FIM mobility score refers to items 9 through 13 which relate to transfers, walking, and stairs. Co-morbidities were recorded using the Charlson Co-morbidities Index ( Charlson et al 1994), the 10-metre walk test ( Hollman et al 2008) was used to calculate cadence at baseline (steps per minute), and length of stay in inpatient rehabilitation (days) was recorded. A uniaxial accelerometer-based activity monitora was used to provide an objective AZD5363 supplier measure of physical activity.

Activity monitors were attached to the participant’s nonaffected lower limb on the mid-anterior thigh at the earliest convenient time after admission and remained in place for five days (the middle three days of recording were used to ensure that three complete days were drawn on for analyses). To allow for continuous monitoring (including showering) the monitor was taped inside a zip-lock bag and affixed to the skin with a water-proof DNA ligase medical dressing. The activity monitor used is a valid and reliable measure of walking

in healthy adults (Ryan et al 2006) and community dwelling older adults (Grant et al 2008), and is a valid measure of activity or inactivity for the long-term monitoring of older adults with impaired function (Taraldsen et al 2011) and of steps taken at slower walking speeds (Kanoun 2009). The number of participants meeting activity guidelines was described. For normally distributed data the mean and standard deviation (SD) were reported. For skewed data the median and inter-quartile range (IQR) were reported. Bivariate correlations examined the relationships between steps taken per day, length of stay and FIM. One hundred and nine orthopaedic patients were admitted to the ward during the study period. Only patients who were available to have the activity monitors applied early in the week (Monday or Tuesday) were screened for eligibility to participate because three uninterrupted days of monitoring were needed before the weekend. Therefore 51 patients were not eligible because they were admitted later in the week. A further 4 patients were excluded due to cognitive impairment.

The Secretariat maintains the technical content of the ACIP website, including updating ACIP recommendations, meeting minutes, current immunization schedules for children and adults [4] and [5] and other key information. The Secretariat (primarily the Assistant to the Director for Immunization Policy) is responsible for the overall guidance of ACIP WGs, particularly the CDC Lead and the ACIP WG Chair for each WG. This ensures a cohesive, standardized approach on the part of each WG in terms of policies and procedures. The ACIP Steering Committee, which has responsibility BI 2536 supplier for

general operating policy, procedures, and related matters affecting the ACIP as a whole, comprises 15 members who represent the three CDC Centers that have activities related to vaccines and immunization, as well as the current ACIP Chair and

a representative from FDA. Four meetings of the ACIP Steering Committee are organized annually by the Secretariat: three for the development of ACIP meeting agendas and one for the selection of new members. The Secretariat provides comprehensive orientation and training to new ACIP members once they are selected and also fields requests for the appointment of new liaison organizations, preparing justification for their inclusion (or exclusion) to present to the ACIP Steering Committee. These requests are then submitted to the Secretary check details of HHS if the organization is deemed appropriate for official designation as a liaison; final selection and appointment of liaison organizations is made by the Secretary of HHS. ACIP meeting agendas are

prepared by the ACIP Secretariat following deliberation by the ACIP Steering Committee. Approximately 10 weeks prior to an upcoming meeting, suggestions for meeting topics are solicited from the ACIP WGs, ACIP members, ex officio members and liaison representatives, and academic consultants. Meeting topics may include items that do not require a vote but are presented for informational purposes, such as data on vaccine-preventable disease epidemiology, vaccine efficacy, and updates on outbreaks of vaccine-preventable diseases. Presentation of data on new vaccines typically occurs at ACIP meetings starting at least 2 years in advance of vaccine licensure STK38 by the FDA; this allows committee members to be fully informed about all aspects of the vaccine at the time a vote is taken following licensure. Agenda items are reviewed by the ACIP Secretariat and discussed in depth at a meeting of the ACIP Steering Committee held 7 weeks before the ACIP meeting, with finalization and distribution of the meeting agenda 6 weeks before each meeting. The Secretariat prepares material concerning new initiatives (e.g., standardization of the approach to presentation of economic analyses, development of an explicit evidence-based format to be used for ACIP recommendations) to present to the ACIP Steering Committee and CDC leadership.

Thus

these studies are not likely to be a primary strategy to detect the impact of PCVs and when undertaken are at risk of being confounded by changes in pneumonia burden or mortality trends unrelated to pneumococcal disease (e.g. respiratory viral epidemics, malaria). The assessment of carriage of vaccine type and non-vaccine type pneumococci is a direct, pathogen-specific selleck chemicals measure of PCV impact that is an indicator of the success or failure of a PCV rollout program [129]. Cross sectional studies of carriage in the target age group of PCV, as well as in older children and adults, will give a measure of herd protection. Detection of important serotypes in developing countries (such as type 1) may still be done in carriage studies if the subjects are carefully chosen, by including the detection of carriage in subjects with pneumonia on arrival at health care facilities. Detection of such rarely carried types in pneumonia patients may reflect an etiological role of those types in pneumonia [137]. Carriage studies focused on young children with respiratory illness will identify the group at risk for pneumococcal disease but also provide access to older siblings who are often transmitters of the pathogen, and mothers who may be key to measurement

of herd protection in adults. Cross sectional studies may detect changes Lonafarnib in the distribution of vaccine type carriage as soon as a year post PCV introduction if sample size is sufficient, with detection of profound changes in distribution and herd protection, if present, by 3–4 years post PCV [138]. While carriage studies will not likely be a direct measure of reduction in disease burden due to PCV, they offer a direct measure of program effectiveness and the nature of replacing pathogens, including an assessment of the impact of PCV on the NP microbiome. There are emerging data suggesting that quantitative detection of carriage using microbiological methods,

but also more easily by quantitative PCR, may be diagnostic of pneumonia in adults [139]. These methods may also reflect co-infection with respiratory viruses in children [140] which may be a significant risk for pneumonia hospitalization [141]. The antimicrobial susceptibility profile of carried pneumococci may be used to inform treatment algorithms for pneumococcal disease secondly in developing countries [142]. Quantitative molecular methods may increase the sensitivity of detection of pneumococcal carriage, and may also detect more easily than culture an impact of PCV on density of carriage. The detection of serotypes in carriage can be used together with the global distribution of those types in IPD [143] to develop an invasiveness index that may be predictive of the likelihood of invasive disease replacement due to emerging types detected in carriage. There are advances in work linking the NP and IPD post-PCV impact results, thereby providing a means to predict IPD impact using NP carriage [147].