CR formulations provide certain advantages when compared to their

CR formulations provide certain advantages when compared to their IR counterparts. CR formulations can reduce peak to trough fluctuations in the plasma concentration–time profile (compared to multiple-dose administration of an IR product), hence reducing fluctuation-related side effects and/or sub-therapeutic concentrations. CR formulations can increase the exposure over time of drugs with a short elimination half-life, and can be used to target delivery into distal regions

Lapatinib price of the intestine (e.g. colon), or where there is a need for targeted delivery for the treatment of a specific disease, such has Crohn’s disease (Langer, 1990, Rubinstein, 2005 and Thombre, 2005). This can lead to an increased patient compliance. Furthermore, CR formulations can be of use in drug CT99021 development when the standard IR formulation is not an alternative due to unfavourable pharmacokinetic properties of the drug candidate (Langer, 1990, Rubinstein, 2005 and Thombre, 2005). One of the main goals when developing a CR formulation of a marketed drug is

to achieve, at least, the same exposure as the equivalent dose of their IR counterpart. In general however the relative bioavailability of a CR formulation compared to its IR counterpart is expected to be less than 100% (European Medicines Agency, 2013). Several physiological factors can influence the observed Suplatast tosilate differences in systemic exposure between IR and CR. A CR formulation is intended to release its drug content within 12–24 h, in contrast the small intestinal transit time is around 2–5 h (Davis et al., 1986, Fallingborg et al., 1989 and Yu et al., 1996). Therefore a majority of the dose should be released into distal regions of the small intestine and the colon, where the residence time in the colon is about 12–24 h (Coupe et al., 1992, Davis et al., 1986 and Fallingborg et al., 1989). The extended release may limit the absorption potential for a drug formulated as CR as, in

general, the distal regions of the intestine provide a less favourable environment for drug absorption. For instance, the reduced surface area available for absorption in the distal region of the GI tract may limit the absorption for poorly permeable compounds (Tannergren et al., 2009 and Watts and Lllum, 1997), the intestinal pH increases towards the distal portion of the intestine consequently limiting the aqueous solubility of basic compounds (Fallingborg et al., 1989). Finally, the lack of bile salts, less fluid volume in the colon, differences in the regional permeability and possible degradation by colonic microflora can also have a negative impact on the drug absorption of CR formulations (Lennernas, 2014a, Schiller et al., 2005, Sutton, 2009 and Tannergren et al., 2009).

Low levels of health literacy have been documented in people with

Low levels of health literacy have been documented in people with COPD (Press et al 2011) which may impact on the effectiveness of written information. However, it has recently been demonstrated that even when high quality, specific information about pulmonary rehabilitation is delivered, using current best practice regarding information presentation and terminology, there may

not Selleck 3-deazaneplanocin A be improvements in COPD care (Harris et al 2009). This suggests that information alone is insufficient to change behaviours. Data from this study suggest that there is a group of patients who see pulmonary rehabilitation as of minimal value who also have low expectations regarding their future health status, and thus may not consider that the potential benefits of rehabilitation might apply to them. Further consideration is needed of how best to convey the potential benefits of pulmonary rehabilitation to those who are eligible to attend. Such strategies could include utilising Cobimetinib clinical trial peer support and education delivered

by others with COPD who have personal experience of the program. More than half of the participants in this study indicated that difficulty in getting to the pulmonary rehabilitation venue affected their decision to participate, despite the fact that the vast majority lived less than 10 km from the hospital. Both the availability and the cost of transport were cited as barriers to attendance. Over half of the participants lived alone and many relied on public transport or family and friends

to attend pulmonary rehabilitation. Although a volunteer driver program was in place at the hospital where the pulmonary rehabilitation program took place, this had limited capacity and was clearly insufficient to overcome the burden of travel. These results are consistent with previous reports examining attendance at pulmonary rehabilitation (Fischer et al 2007, Taylor et al 2007, Young et al 1999). Current pulmonary rehabilitation guidelines do not else make strong recommendations regarding transport, recognising the cost implications for clinical services (British Thoracic Society 2001). Other guidelines suggest that patients with limited access to transport undergo pulmonary rehabilitation as an inpatient (Nici et al 2006), however this is not available in many settings – including our own. Given the consistency with which travel and transport have been reported as barriers to attendance, this issue requires attention in future program models. A number of participants who did not complete the pulmonary rehabilitation program expressed a preference for programs conducted in the home environment. This was related to both the challenges of travel and the greater feeling of security associated with being at home.

The reliance on big pharma alone to develop new vaccines is chang

The reliance on big pharma alone to develop new vaccines is changing with the emergence of public–private partnerships. These partnerships, which engage public health institutions, donor agencies

and academia, as well as the pharmaceutical industry, have the potential to create a new era for vaccine development. The PATH Malaria Vaccine Initiative is a successful demonstration of a partnership between an NGO, industry, academia, donors and government. It encompasses the development DAPT price of RTS,S malaria vaccine candidates, translational research and demonstration projects. The vaccine investment strategy that has been undertaken by GAVI to evaluate the feasibility and cost effectiveness of introducing malaria vaccine within the next 5 years gives the partnering pharmaceutical companies an indication of the kind of advance market commitment that can be generated through GAVI support. Another example

of a successful partnership is the Meningitis Vaccine Project that involved WHO and PATH with support from the Bill and Melinda Gates Foundation. Not only did the scientists develop an effective and safe MenA conjugate vaccine, but the commitment of African governments within the meningitis belt to roll out the vaccine resulted in a dramatic reduction of Group A meningitis infections to almost negligible levels within a three year period. With Alisertib their confidence boosted by this success, the countries involved are now aiming to eliminate Group A meningitis Cediranib (AZD2171) infection across the Meningitis Belt. The GVAP calls for the use of a new model to assist decision-makers in prioritising investments in new vaccine; the model is based on health, economic, demographic,

programmatic, and social impact criteria as well as scientific, technical and business opportunities. The data presented to the WHO’s STI Vaccine Consultation critically evaluated the potential for the development of vaccines to prevent infection from five common STI pathogens, namely herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum, or Trichomonas vaginitis and/or the diseases they cause. The data unequivocally showed that development of vaccines to prevent all five infections could be justified using the GVAP criteria. Significant scientific advances have been made towards the development of vaccines for these five infections, development in herpes and chlamydial vaccine being the most advanced. Furthermore, the pharmaceutical industry has demonstrated interest in investing in the field.

It is linked to the onset of psychological problems such as depre

It is linked to the onset of psychological problems such as depression (Carroll et al., 2003) and is also a major cause of work absence, leading to substantial economic consequences (Wynne-Jones et al., 2008). LBP is therefore a significant public health problem. Although many LBP sufferers do not recover completely (Hestbaek et al., 2003), fewer than one-third seek healthcare (Carey et al., 1996 and McKinnon et al., 1997). As LBP is so common, this means 6–9% of adults seek healthcare for LBP annually (Croft et al., 1998, Dunn and Croft, 2005 and Royal College of General Practitioners,

1995). It is therefore a considerable burden on primary care, where Navitoclax in vivo most LBP management occurs, and several studies have investigated prognosis in primary care (Lanier and Stockton, 1988, Von Korff et al., 1993, Coste et al., 1994, Klenerman et al., 1995, Croft et al., 1998, van den Hoogen et al., 1998, Reis et al., 1999, Schiøttz-Christensen et al., 1999, Carey et al., 2000, Nyiendo et al., 2001, Burton et al., 2004, Jones et al., 2006 and Mallen et

al., 2007). These studies have focused on prognostic ability, including factors measuring pain intensity and widespreadness, disability and psychological status, but have not investigated the proportion of poor prognosis that is related to each factor. Population attributable fractions (PAFs) are used in aetiological research to estimate the public health impact of removing a putative cause of disease from a population. They depend on the strength

of association between cause and effect, and on the population prevalence of the causal factor – because smoking JNJ-26481585 mw is common, the proportion of lung cancer attributed to it is high and the effect of removing smoking on lung cancer occurrence is substantial. This is an advantage over presentation of relative risks (RRs), as rare exposures with high RRs may not present good population intervention targets. Such calculations can also be applied to prognostic factors in presenting illness or established disease – the population in this case is everyone with the illness, and the calculation refers to outcome rather than disease onset. When identifying sub-groups for treatment targeting, factors identifying high-risk patients are not necessarily causal, and therefore standard PAF interpretation – that the relationship being quantified is causal – might not apply. Oxymatrine However, the PAF calculation itself provides useful information on prognostic markers, or groups in which to target interventions, and gives clear methods for comparing the impact of new interventions. For example, if two prognostic indicators have similar associations with outcome, but one is common and the other rare, intervening on the common factor would have greater public health impact. We therefore aimed to determine the risk factors for poor prognosis – and their relative contributions to outcome – in adults consulting with LBP in primary care.

5 million Swiss residents

5 million Swiss residents learn more aged ≥16 years were diagnosed with an IPD per year in mean (i.e. 14.2/100,000). It was possible to link approximately 90% of reported IPD cases with a corresponding pneumococcal isolate. Therefore, the completeness of this linkage was very high indicating a very high participation

of involved laboratories. During 2007–2010, incidence of IPD cases with known serotype has changed significantly in adults overall and in those ≥65 years in Switzerland. In addition, this study shows a changing serotype distribution of invasive S. pneumoniae isolates from 2003 to 2012. This has been described for the PCV7 versus non-PCV7 serotypes recently [9] but our study additionally shows the single serotype epidemiology

in Switzerland. The sharp increase of the non-PCV7 serotype 19A is remarkable and has also been observed in other countries [6], [23], [24] and [25]. However, it is not clear if the introduction of PCV7 is exclusively responsible for this observation [26] and [27]. A significant increase of other non-PCV7 serogroups/serotypes was detected which countered the drop of vaccine serotypes to a certain extent. Increasing numbers of isolates of serotypes 19A, 22F and 6C but not of serogroup 35 have also been described Ixazomib purchase in a study performed at the University Hospitals in Cleveland during 1999–2007 [28]. It is well known that IPD incidence rates increase with advancing age and with various comorbidities like immunosuppression, underlying respiratory diseases and chronic diseases [29]. Hence PPV23 vaccination was recommended for persons with increased risk for IPD (i.e. for those aged 65 years and older and those older than 2 years with known risk

factors for IPD) in Switzerland. However, despite the broad vaccine usage, the efficacy of PPV23 is generally described as being poor at least in preventing pneumonia [14]. These issues secondly cannot be confirmed or dismissed with our data but in those with a known PPV23 vaccination history, vaccinated patients had a lower proportion of IPD due to PPV23 serotypes, whereas the non-PPV23 serotype 6A was associated with previous PPV23 vaccination. This study identified individual serotypes which mainly caused IPD in elderly adults and/or in adults with comorbidities. Unfortunately, a few of those serotypes/serogroup are not covered, by PCV13 e.g. serogroups 15, 20 and 35. The latter showed an increasing trend from 2007 to 2010 and may therefore become more important in the future. Our study also illustrates that the serotype was related to the clinical manifestations which was also investigated in a previous study in the Netherlands [30]. A recent population based study from Denmark demonstrated that patients aged 5 years and older infected with serotypes/serogroups 31, 11A, 35F, 17F, 3, 16F, 19F, 15B or 10A more often died than those infected with serotype 1, from 1977 to 2007 [20].

An illustration of practical application of the method to the Erb

An illustration of practical application of the method to the ErbB2/3 network model is given in Section 3. To create local sensitivity spectrum of our model parameters, each nominal parameter Pi was incremented and decremented by 1% of its value (dpi) and the normalised sensitivity coefficient for the area under the pAkt time course profile was calculated as follows ( Zi et al., 2008): CipAkt=SpAkt(Pi+dPi)-SpAkt(Pi-dPi)SpAkt(Pi)2dPiPi The construction and calibration of the ErbB2/3 model was carried out with the use of the DBsolve package for kinetic CCI-779 manufacturer modelling (Gizzatkulov et al., 2010 and Goryanin

et al., 1999). All GSA-related computations were run on Edinburgh University ECDF cluster: 10 nodes were used to run simulations of ODE system for 120,000 Sobol’s points; 200 nodes were used to calculate PRCC indexes for sensitivity analysis. Thus an average analysis took 20 h for model simulation and two hours for sensitivity analysis. ODE system was solved using CVODE solver from SUNDIALS package (Hindmarsh et al., 2005), sensitivity analysis was performed with the package ‘sensitivity’ Rucaparib in vivo ( in R environment ( PE04 and OVCAR4 cells were

grown as monolayer cultures in RPMI supplemented with 10% heat-inactivated foetal calf serum (FCS) and penicillin/streptomycin (100 IU/mL) in a humidified atmosphere of 5% CO2 at 37 °C. Time course experiments were set up by plating cells into 10 cm diameter petri dishes and leaving for 24 h. Cells were then briefly washed in PBS before transferring to phenol red-free DMEM containing 5% double aminophylline charcoal-stripped serum supplemented with penicillin/streptomycin (100 IU/mL) and glutamine (0.3 mg/mL) for a further 48 h prior to treatment. Cells were treated with UCN-01 (protein kinase inhibitor; Calbiochem #539644; final concentration of 1 μM), LY294002 (PI3 kinase

inhibitor; Calbiochem #440204; final concentration 20 μM), Pertuzumab (ErbB2 inhibitor; final concentration 100 nM) and stimulation by Heregulin (R&D Systems; 396-HB-CF) was at final concentration of 1 nM. Cells were treated for 15 min with the aforementioned drugs as appropriate immediately followed by the addition of heregulin-β (1 nM). The concentrations of drugs used in the experiments corresponded to the dose causing 50% inhibition of cell growth. Samples were collected at time points of 1, 5, 30, and 60 min after initiation of heregulin treatment, washed in PBS, and immediately lysed in ice-cold isotonic lysis buffer [50 mM Tris–HCl (pH 7.5), 5 mM EGTA (pH 8.5), 150 mM NaCl, 1% Triton X-100] supplemented with aprotinin (10 μg/mL), phosphatase inhibitor cocktail A (Sigma, P2850), phosphatase inhibitor cocktail B (Sigma, P5726) and a protease inhibitor cocktail (Roche, 11836153001). Lysates were centrifuged for 6 min at 13,000g and protein concentrations of supernatants subsequently determined using the BCA assay (Sigma, BCA-1).

g whether nanoparticles remain internalised or readily ‘escape’)

g. whether nanoparticles remain internalised or readily ‘escape’) it is important to understand the relationship between the production technique and the structure of the resulting product. The aim of the work described in this paper was to explore the production of NIMs using

a method based on traditional ‘double emulsion’ techniques that are conventionally employed to make drug-loaded microparticles. The distribution of nanoparticles within PR-171 datasheet the resulting NIM formulations was investigated, drawing on evidence from imaging of the emulsion systems and the final particle products and also through characterisation of drug loading/release profiles. As stated earlier, NIMs have the broad range of potential pharmaceutical uses. In this work, we had the application of chemoembolisation click here in mind, where the inner nanoparticles are drug delivery vehicles and the outer microparticles act as embolisation agents for cutting off the blood supply to tumours. Poly(ε-caprolactone) (PCL), hydrocortisone acetate (HA), poly(vinyl alcohol) (PVA), SPAN 80 and Nile red were purchased from Sigma–Aldrich, UK. 50:50 poly(lactic-co-glycolic) acid (PLGA), isomeric poly(l-lactic acid) (PLLA) and poly(dl-lactic acid) (PDLA)

were purchased from SurModic Pharmaceutical Inc., USA. Dichloromethane (DCM), ethyl acetate (EA), acetonitrile (MeCN), acetone, fluorescein, sodium acetate (NaOAc), sodium chloride, citric acid, sodium hydroxide and acetic acid glacial were purchased from Fisher Scientific, UK. PCL nanoparticles loaded with HA were prepared

for the study as follows: A solution of PCL in acetone (1% w/w) was prepared to which HA was added, producing a drug-to-polymer mass ratio of 1:2. 5 mL of the drug/polymer solution was then emulsified in 200 mL of 1% w/w PVA solution. The stirring was continued for 4 h for the particles to solidify. After that, the particles Phosphoprotein phosphatase were collected by centrifugation, and the supernatant decanted off. Before the resultant nanoparticles (N) were further used in the production of NIMs, they were either resuspended in 1 mL of 1% PVA solution to produce a slurry of wet nanoparticles (Nslurry), or oven-dried at 40 °C to produce dry nanoparticles (Ndried). For visualisation studies, Nile red was used in the place of HA. Two formulations were produced; NIMs formulated either with the oven-dried nanoparticles (NIMdried) or with the wet slurry nanoparticles (NIMslurry). For the NIMdried formulation, 40 mg of Ndried was homogenised in 0.5 mL of 1% w/w PVA solution ([w1]), and then homogenised (IKA Ultra-Turrax® T25 Digital homogeniser, Janke & Kunkel GMBH & Co. KG., Germany) in 3 mL of 1% w/w 50:50 PLGA solution dissolved in EA (i.e. [o]) with 0.02 g of SPAN 80. The [Ndried/w1/o] primary emulsion was then added dropwise to 200 mL of 0.5% w/w PVA solution (i.e. [w2]) under continuous magnetic stirring to form the double emulsion.

For chiral drug molecules only one enantiomer (the eutomer)

For chiral drug molecules only one enantiomer (the eutomer)

will fit properly into this receptor, resulting in the desired therapeutic effect. The other enantiomer (the distomer) can either not interact or can interact less intense with the receptor, which generally causes a lower effect. Occasionally the distomer interacts with other receptors, causing side or even toxic effects. As a consequence, the enantiomers of drug candidates must be subjected to supplementary investigations during development see more processes: the eutomer has to be distinguished from the distomer during identification and impurity determinations of the drug substance. For drug products, it should be confirmed that the eutomer is present in the required dose while the distomer level should be analyzed as impurity, as prescribed in the guidelines imposed by the International Conference on Harmonisation (ICH), more precisely in guideline Q6A (decision tree number 5).3 and 4 According to the regulatory authorities, an enantioselective HPLC method should be able to separate the optically Selleckchem ZVADFMK active drug substance from the enantiomeric impurity and other potential organic impurities. Potential organic impurities include chiral and/or achiral starting materials, intermediates and by-products from the drug substance manufacturing

process. Enantiomers are strictly similar in structure to the active product ingredient (API). So, a chemo-and enantioselective HPLC purity appears a critical step in the development of high-quality manufacturing processes and quality-control methods. Sodium butyrate Sitagliptin Phosphate is chemically 7-[(3R)-3-amino-1-oxo-4-(2,4,5 trifluorophenyl) butyl]-5,6,7,8-tetrahydo-3-(trifluoromethyl)-1,2,4-Triazolo

[4,3-a] pyrazine phosphate (1:1) monohydrate (Fig. 1),an oral anti-diabetic agent that blocks dipeptidylpeptidase-4 (DPP-4) activity. Currently it is available in the market under the brand name of Januvia. Januvia is an orally-active inhibitor of the dipeptidylpeptidase-4 (DPP-4) enzyme. The DPP-4 enzyme inactivates incretin hormones, which are involved in the physiologic regulation of glucose homeostasis. By inhibiting DPP-4, Januvia increases and prolongs active incretin levels. This in turn increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Januvia is specifically indicated for the improvement of glycemic control in patients with type II diabetes mellitus as monotherapy or combination therapy with metformin or a peroxisome proliferator activated receptor gamma (PPAR) agonist (e.g., thiazolidinediones) when the single agent does not provide adequate glycemic control. Several HPLC methods are reported for determination of sitagliptin phosphate in tablet dosage and combination with other drugs in pharmaceutical formulation, and plasma.

4(a)) The reason for this is that if very old adults cannot be b

4(a)). The reason for this is that if very old adults cannot be boosted then reduction in varicella incidence (reduced exposure to VZV) will have little effect on their risk of developing zoster. Thirdly, more effective vaccines (or effective programs) against varicella will produce the greatest increases in zoster cases (Fig. BYL719 mw 4(b)). However, in the long-term the worst vaccines will produce a higher zoster incidence as more people will be infected with varicella

and therefore will have the possibility of reactivation (Fig. 4(b)). Finally, age-specific effective mixing can largely influence the impact of varicella on zoster. If older adults have very little contact with varicella cases (e.g. low contact rates with infected children) then reduction in varicella incidence following vaccination will only have a small impact on zoster (see England and Wales mixing scenario ( Fig. 4(c)). The expected increase in zoster predicted by the model is directly related to estimates of the force of infection in adults; the force

of infection in 25–44 years olds for the base case, England and Wales, Finland and Germany are 0.06, 0.03, 0.04 and 0.04 per person-year, respectively. Fig. 5 shows the impact of 2-dose varicella vaccination programs on varicella and zoster. The base model predicts that a 2-dose varicella vaccination program will significantly reduce varicella incidence under the three strategies investigated (Infant, Pre-school and Grade 4 ( Fig. 5)). Of note, our results suggest that giving the second Histamine H2 receptor dose in Grade 4 could help avoid the predicted epidemic of varicella 10 years into the 1-dose program by acting as: (1) catch-up vaccination in those yet to be immunised with a first dose and (2) a booster dose in vaccinees whose protection

will have waned. The main benefit of the second dose is its effectiveness at reducing breakthrough varicella (Fig. 5(b)). However, the short to medium term increase in zoster incidence (Fig. 5(c)) is predicted to be slightly higher under a 2-dose program (compared to 1-dose) because of its greater effectiveness at preventing varicella. Fig. 6 illustrates the incremental benefits of adding a second dose for different vaccine efficacy, mixing matrix and boosting assumptions. The base case model (range: min; max) predicts that adding a second dose will reduce varicella and zoster cases by an additional 22% (0%; 82%) and 6% (0%; 14%) over 80-years, respectively. Importantly, although the incremental benefit of adding the second dose is highly sensitive to assumptions regarding vaccine efficacy and mixing, the overall effectiveness of a 2-dose strategy at preventing varicella is not (Fig. 6). A 2-dose infant strategy (90% coverage) is predicted to reduce varicella cases by 72%–97%.

One four-arm trial (Itoh et al 2007) compared traditional Chinese

One four-arm trial (Itoh et al 2007) compared traditional Chinese acupuncture with acupuncture directed at ‘trigger points’, acupuncture directed to regions adjacent to ‘trigger points’, and sham acupuncture. The three acupuncture groups in this trial were combined to create a single pair-wise comparison. Pooled outcomes

from five trials (Itoh et al 2007, Nabeta and Kawakita 2002, Petrie and Hazleman 1986, Vas et al 2006, White et al 2004) showed no significant difference in pain outcomes between acupuncture and control at the conclusion of a course of treatment (WMD –12, 95% CI –23 to 0.1). Pooled results from the three trials (Petrie and Hazleman 1986, Vas et al 2006, White et al 2004) that reported

medium-term pain outcomes showed acupuncture to be no more selleck chemicals effective GSK126 supplier than control (WMD –4, 95% CI –15 to 7), consistent with the single trial (White et al 2004) that reported long-term pain outcomes (MD –4, 95% CI –13 to 7). Pooled outcomes from five trials (Itoh et al 2007, Petrie and Hazleman 1986, Vas et al 2006, White et al 2004, Witt et al 2006) showed a significant but small difference in disability outcomes in favour of acupuncture at the conclusion of treatment (WMD –8, 95% CI –13 to –2). Pooled outcomes from the three trials (Petrie and Hazleman 1986, White et al 2004, Witt et al 2006) that reported medium-term disability outcomes Non-specific serine/threonine protein kinase demonstrated that acupuncture was not more effective than control (WMD –1, 95% CI –2 to 0.3), consistent with the single trial (White et al 2004) that reported long-term disability outcomes (MD –4, 95% CI –10 to 2). Exercise: Five trials investigated exercise for non-specific neck pain. One three-arm trial ( Kjellman and Oberg 2002)

compared McKenzie exercise with general exercise and with sham ultrasound. Four trials compared various exercise approaches with minimal intervention. The exercise approaches included ‘proprioceptive’ exercises ( Revel et al 1994), a combined program of neck stabilisation, relaxation, eye fixation, behavioural support, and posture training ( Taimela et al 2000), group gymnastic exercises ( Takala et al 1994), and muscle strengthening ( Viljanen et al 2003). Pooled outcomes from three trials (Kjellman and Oberg 2002, Revel et al 1994, Taimela et al 2000) showed significant reduction in pain at the conclusion of a course of specific exercises (WMD –12, 95% CI –22 to –2). The single trial that reported medium- (MD –6, 95% CI –17 to 5) and long-term (MD 1, 95% CI –12 to 14) pain outcomes for specific exercise programs did not demonstrate similar benefit (Kjellman and Oberg 2002). One trial (Kjellman and Oberg 2002) showed no significant difference in disability at the conclusion of a course of specific exercises (MD –3, 95% CI –10 to 4) and medium- (MD –3, 95% CI –11 to 5) and long-term (MD 2, 95% CI –6 to 10) follow-up.