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Ellen S Koster,1 Lyda Blom,1 Marloes R Overbeeke,1 Daphne Philbert,1 Marcia Vervloet,2 Laura Koopman,2,3 Liset van Dijk2 1Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, the Netherlands; 2Netherlands Institute of Health Services Research (NIVEL), Utrecht, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands Introduction: Consumer Quality Index questionnaires are used to assess quality of care from patients’ experiences.Objective: To provide insight into the agreement about quality of pharmaceutical care, measured both by a patient questionnaire and video observations.Methods: Pharmaceutical encounters in four pharmacies were video-recorded. Patients completed a questionnaire based upon the Consumer Quality Index Pharmaceutical Care after the encounter containing questions about patients’ experiences regarding information provision, medication counseling, and pharmacy staff’s communication style. An observation protocol was used to code the recorded encounters. Agreement between video observation and patients’ experiences was calculated.Results: In total, 109 encounters were included for analysis. For the domains “medication counseling” and “communication style”, agreement between patients’ experiences and observations was very high (>90%). Less agreement (45%) was found for “information provision”, which was rated more positive by patients compared to the observations, especially for the topic, encouragement of patients’ questioning behavior.Conclusion: A questionnaire is useful to assess the quality of medication counseling and pharmacy staff’s communication style, but might be less suitable to evaluate information provision and pharmacy staff’s encouragement of patients’ questioning behavior. Although patients may believe that they have received all necessary information to use their new medicine, some information on specific instructions was not addressed during the encounter. When using questionnaires to get insight into information provision, observations of encounters are very informative to validate the patient questionnaires and make necessary adjustments. Keywords: community pharmacy, CQI, patient–provider communication, pharmaceutical care, patient perspective, video observation

Survival of children with single ventricle heart defects after the total cavopulmonary connection (TCPC) has improved, but impaired cardiac function remains a major cause of morbidity and mortality. Cardiac magnetic resonance imaging (cMRI) is the gold standard in assessing single ventricle volume and function, but high costs and limited availability hamper its routine use. A cheaper and more available alternative is echocardiography. Myocardial function can be studied in more detail using speckle tracking echocardiography (STE). The purpose of the study was to describe the association between myocardial deformation assessed by speckle tracking echocardiography (STE) and single ventricle function assessed by cMRI and to evaluate differences in myocardial deformation in children with single left and single right ventricular morphology. Cross-sectional, multicenter study in 77 children after TCPC was conducted. STE segmental and global longitudinal peak strain and systolic strain rate (SR) of the dominant ventricle were measured. Impaired SV function by cMRI was defined as ejection fraction (EF) < 45%. Mean age was 11.8 (range 9.7–14.3) years. Pearson R for cMRI EF versus global longitudinal strain and SR was − 0.25 (p = 0.06) and − 0.03 (p = 0.82), respectively. Global single ventricle longitudinal strain and SR was similar in patients after TCPC with single left and single right ventricular morphology (− 19.0 ± 3.1% vs 19.2 ± 3.2%, p = 0.94). STE myocardial deformation parameters do not correlate with single ventricle ejection fraction assessed by cMRI. [ABSTRACT FROM AUTHOR]

The hygiene hypothesis suggests that exposure to micro-organisms influences development of the immune system in children.In this study, we examined nasal immune responses in the first 2 years of life in relation to age of children and the number of viral infections they have experienced. Nasal brushes were taken during rhinovirus- (n = 20) or respiratory syncytial virus (RSV)-induced (n = 7) upper respiratory tract infections (URTI), and of controls (n = 40).The number of macrophages were higher during URTI and increased with age. The number of T lymphocytes increased with age in controls and were higher during URTI at all ages. We found an age-related decrease in the number of interleukin (IL)-4- and IL-10-positive cells in controls, while the number of IL-12-positive cells remained unchanged. Changes in T lymphocyte and IL-4 cell number were stronger related to the age of the child than to the number of respiratory infections, while the opposite was true for macrophages.In infants, we found an infection- and age-related increase respectively for nasal macrophages and T lymphocytes during URTI. Furthermore, the number of IL-4- and IL-10-positive cells decreased with age. Whether this maturation reflects a natural age-related maturation, the degree of exposure to respiratory infections, or possibly both, could not be resolved and needs further study. [ABSTRACT FROM AUTHOR]

Background: Various mechanisms contribute to the loss of human leukocyte antigen (HLA) class I expression that is frequently observed in cancers. Although some single allele losses have been ascribed to mutations in HLA class I genes, direct evidence for this phenomenon in vivo is still lacking. Thus, we investigated whether HLA class I gene mutations could account for the loss of allele-specific expression in cervical carcinomas.Methods: We used polymerase chain reaction-based techniques, including sequencing, oligonucleotide hybridization, and microsatellite analysis, to identify HLA class I gene defects in two tumor-derived cell lines and to confirm the presence of these defects in the original tumors.Results: In one tumor, in exon 2 of the HLA-B15 gene, a four-nucleotide insertion resulted in a stop codon in exon 3. In the other tumor, in two duplicated copies of the HLA-A24 gene, single-point mutations resulted in stop codons in exons 2 and 5.Conclusions: To our knowledge, this is the first report of HLA class I gene mutations identified in primary tumors that lead to loss of allelic expression in tumor cells. Such tumor-specific mutations may permit the cell to escape HLA class I-restricted cytotoxic T-cell responses. [ABSTRACT FROM AUTHOR]

Background Exercise can improve physical fitness in children and adults with congenital heart disease. We hypothesized that exercise training would not lead to adverse cardiac remodelling in this population. Methods and results This multi-centre randomized controlled trial included children and young adults (10 to 25 years) with either corrected tetralogy of Fallot or Fontan circulation. The exercise-group was enrolled in a 12 week standardized aerobic dynamic exercise training program. The control-group continued their life-style and received care as usual. Both groups underwent cardiopulmonary exercise testing, cardiac magnetic resonance imaging (MRI), echocardiography and neurohormonal assessment, within 2 weeks before and 2 weeks after the intervention period. Fifty-six patients were randomized to the exercise-group and 37 to the control-group. We assessed changes between the pre- and the post-intervention period for the exercise group compared to the changes in the control-group. Peak load increased significantly in the exercise-group compared to the control-group (exercise-group 6.9 ± 11.8 W; control-group 0.8 ± 13.9 W; p = 0.047). There were no adverse events linked to the study. Ventricular systolic parameters, cardiac dimensions and neurohormonal markers during follow-up did not change in patients allocated to the exercise-group and control-group. Although there were some isolated minor changes in inflow parameters, there was no consistent pattern of changes, indicating a lack of true change in the diastolic function. Conclusion We demonstrated that no clinically relevant adverse cardiac remodelling occurred after 12 weeks of exercise training in patients with either corrected tetralogy of Fallot or Fontan circulation. [ABSTRACT FROM AUTHOR]

Educational and psychological tests with an ordered item structure enable efficient test administration procedures and allow for intuitive score interpretation and monitoring. The effectiveness of the measurement instrument relies to a large extent on the validated strength of its ordering structure. We define three increasingly strict types of ordering for the ordering structure of a measurement instrument with clustered items: a weak and a strong invariant cluster ordering and a clustered invariant item ordering. Following a nonparametric item response theory (IRT) approach, we proposed a procedure to evaluate the ordering structure of a clustered item set along this three-fold continuum of order invariance. The basis of the procedure is (a) the local assessment of pairwise conditional expectations at both cluster and item level and (b) the global assessment of the number of Guttman errors through new generalizations of the H -coefficient for this item-cluster context. The procedure, readily implemented in R, is illustrated and applied to an empirical example. Suggestions for test practice, further methodological developments, and future research are discussed., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Canadian Institutes of Health Research for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Categorical marginal models (CMMs) are flexible tools for modelling dependent or clustered categorical data, when the dependencies themselves are not of interest. A major limitation of maximum likelihood (ML) estimation of CMMs is that the size of the contingency table increases exponentially with the number of variables, so even for a moderate number of variables, say between 10 and 20, ML estimation can become computationally infeasible. An alternative method, which retains the optimal asymptotic efficiency of ML, is maximum empirical likelihood (MEL) estimation. However, we show that MEL tends to break down for large, sparse contingency tables. As a solution, we propose a new method, which we call maximum augmented empirical likelihood (MAEL) estimation and which involves augmentation of the empirical likelihood support with a number of well-chosen cells. Simulation results show good finite sample performance for very large contingency tables., (© 2023. The Author(s).)

Objective: Patients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis., Methods: Twenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls., Results: A total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5-16.3). Mean LVMI before start of ERT was increased 292.3 g/m 2 (95% CI: 202.8-381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m 2 (CI: 67.5-107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<-16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls., Conclusion: Cardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years., Competing Interests: Declaration of Competing Interest Prof. dr. Ans T. van der Ploeg and dr. J M.P. (Hannerieke) van den Hout participated in advisory boards and received consultancy fees and/or research grants of Sanofi/Genzyme, Amicus, Denali, Spark Therapeutics, GSK, Biomarin, Takeda and others under agreements between these industries and Erasmus University Medical Center, Rotterdam, The Netherlands., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Cardiac surgery may cause temporarily impaired ventricular performance and myocardial injury. We aim to characterise the response to perioperative injury for patients undergoing repair or pulmonary valve replacement (PVR) for tetralogy of Fallot (ToF)., Methods: We enrolled children undergoing ToF repair or PVR from four tertiary centres in a prospective observational study. Assessment-including blood sampling and speckle tracking echocardiography-occurred before surgery (T1), at the first follow-up (T2) and 1 year after the procedures (T3). Ninety-two serum biomarkers were expressed as principal components to reduce multiple statistical testing. RNA Sequencing was performed on right ventricular (RV) outflow tract samples., Results: We included 45 patients with ToF repair aged 4.3 (3.4 - 6.5) months and 16 patients with PVR aged 10.4 (7.8 - 12.7) years. Ventricular function following ToF repair showed a fall-and-rise pattern for left ventricular global longitudinal strain (GLS) (-18±4 to -13±4 to -20±2, p < 0.001 for each comparison) and RV GLS (-19±5 to -14±4 to 20±4, p < 0.002 for each comparison). This pattern was not seen for patients undergoing PVR. Serum biomarkers were expressed as three principal components. These phenotypes are related to: (1) surgery type, (2) uncorrected ToF and (3) early postoperative status. Principal component 3 scores were increased at T2. This increase was higher for ToF repair than PVR. The transcriptomes of RV outflow tract tissue are related to patients' sex, rather than ToF-related phenotypes in a subset of the study population., Conclusions: The response to perioperative injury following ToF repair and PVR is characterised by specific functional and immunological responses. However, we did not identify factors relating to (dis)advantageous recovery from perioperative injury., Trial Registration Number: Netherlands Trial Register: NL5129., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Ventricular performance is temporarily reduced following surgical atrial septal defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention. Methods and Results In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2-weeks follow-up), and 1-year postintervention (1-year follow-up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty-three patients (median age, 4.1 [interquartile range, 3.1-6.1] years) were included. Forty-three patients underwent surgery. At 2-weeks follow-up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (-17.6±4.1 versus -27.1±3.4; P <0.001). A smaller decrease was noted for left ventricular global longitudinal strain at 2-weeks follow-up for the surgical group (surgical versus percutaneous, -18.6±3.2 versus -20.2±2.4; P =0.040). At 1-year follow-up, left ventricular performance returned to baseline, whereas right ventricular performance improved, but did not reach preintervention levels. Eight biomarkers relating to cardiovascular and immunological processes differed across study time points. Of these biomarkers, only NT-proBNP (N-terminal pro-B-type natriuretic peptide) correlated with less favorable left ventricular global longitudinal strain at 2-weeks follow-up. Conclusions Right, and to a lesser degree left, ventricular performance was reduced early after surgical atrial septal defect closure. Right ventricular performance at 1-year follow-up remained below baseline levels. Several biomarkers showed a pattern over time similar to ventricular performance. These biomarkers may provide insight into the processes that affect ventricular function. Registration URL: https://www.trialregister.nl/; Unique identifier: NL5129.

Purpose: Mokken scale analysis (MSA) is an attractive scaling procedure for ordinal data. MSA is frequently used in health-related quality of life research. Two of MSA's prime features are the scalability coefficients and the automated item selection procedure (AISP). The AISP partitions a (large) set of items into scales based on the observed item scores; the resulting scales can be used as measurement instruments. There exist two issues in MSA: First, point estimates, standard errors, and test statistics for scalability coefficients are inappropriate for clustered item scores, which are omnipresent in quality of life research data. Second, the AISP insufficiently takes sampling fluctuation of Mokken's scalability coefficients into account., Methods: We solved both issues by providing point estimates and standard errors for the scalability coefficients for clustered data and by implementing a Wald-based significance test in the AISP algorithm, resulting in a test-guided AISP (T-AISP), that is available for both nonclustered and clustered test scores., Results: We integrated the T-AISP into a two-step, test-guided MSA for scale construction, to guide the analysis for nonclustered and clustered data. The first step is performing a T-AISP and select the final scale(s). For clustered data, within-group dependency is investigated on the final scale(s). In the second step, the strength of the scale(s) is determined and further analyses are performed. The procedure was demonstrated on clustered item scores obtained from administering a questionnaire on quality of life in schools to 639 students nested in 30 classrooms., Conclusions: We developed a two-step, test-guided MSA for scale construction that takes into account sample fluctuation of all scalability coefficients and that can be applied to item scores obtained by a nonclustered or clustered sampling design., (© 2021. The Author(s).)

Two-level Mokken scale analysis is a generalization of Mokken scale analysis for multi-rater data. The bias of estimated scalability coefficients for two-level Mokken scale analysis, the bias of their estimated standard errors, and the coverage of the confidence intervals has been investigated, under various testing conditions. It was found that the estimated scalability coefficients were unbiased in all tested conditions. For estimating standard errors, the delta method and the cluster bootstrap were compared. The cluster bootstrap structurally underestimated the standard errors of the scalability coefficients, with low coverage values. Except for unequal numbers of raters across subjects and small sets of items, the delta method standard error estimates had negligible bias and good coverage. Post hoc simulations showed that the cluster bootstrap does not correctly reproduce the sampling distribution of the scalability coefficients, and an adapted procedure was suggested. In addition, the delta method standard errors can be slightly improved if the harmonic mean is used for unequal numbers of raters per subject rather than the arithmetic mean., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

For the construction of tests and questionnaires that require multiple raters (e.g., a child behaviour checklist completed by both parents) a novel ordinal scaling technique is currently being further developed, called two-level Mokken scale analysis. The technique uses within-rater and between-rater coefficients to assess the scalability of the test. These coefficients are generalizations of Mokken's scalability coefficients. In this paper we derived standard errors for the two-level coefficients and for their ratios. The coefficients, the estimates, the estimated standard errors and the software implementation are discussed and illustrated using a real-data example, and a small-scale simulation study demonstrates the accuracy of the estimates., (© 2019 The British Psychological Society.)

Objective: The objectives of this study were to, first, describe the information exchanged between pharmacy staff and patients about prescribed medication at the community pharmacy counter, and second, to investigate to what extent this met professional medication counselling guidelines., Methods: Pharmaceutical encounters were videotaped in four community pharmacies in the Netherlands. Patients were included if they collected a prescription for their own use. An observation protocol, including the MEDICODE checklist, was used to analyse the video recordings. A distinction was made between first and repeat prescriptions., Key Findings: One hundred fifty-three encounters were videotaped. When dispensing first prescriptions, pharmacy staff provided most information on instructions how to use the medication (83.3%), form of the medication (71.4%) and treatment duration (42.9%). Topics for repeat prescriptions (such as the effects of the medication and the incidence of observed adverse effects) were rarely discussed. Pharmacy staff rarely encouraged patients to ask questions., Conclusions: Pharmacy staff members provided little medication-related information at the counter, especially for repeat prescriptions, did not encourage active patient participation, and thereby did not adhere to the guidelines of their professional organisation. Further research is needed to understand the reasons for this., (© 2015 Royal Pharmaceutical Society.)

First trimester human decidua is composed of decidual cells, CD56(bright)CD16(-) decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell-derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell-recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-γR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56(bright)CD16(-) pNK cells and intermediate CXCR3 levels on the majority of CD56(dim)CD16(+) pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age-matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To find ways to improve response rates of medical and health surveys. We investigated whether a prenotification letter instead of a second reminder and varying senders of the questionnaires would affect response rates., Study Design and Setting: We present the results of two studies. In the first study, four groups were compared that either received a prenotification letter (group 1 and 2) or a second reminder letter (group 3 and 4); received the questionnaire from either a research institute (group 1 and 3) or a health insurance company (HIC; group 2 and 4). In the second study, we compared two groups that received the questionnaire sent by either a HIC or a hospital. Response rates, response speed, respondent characteristics, item nonresponse, and mean scores on quality aspects and global ratings were compared., Results: Response rates did not differ significantly between groups. Prenotification groups returned their questionnaires faster. No other significant differences were found for response speed, respondent characteristics, item nonresponse, or mean scores., Conclusion: A prenotification letter does only increase initial response speed and does not increase total response rates. A prenotification letter should be considered when quick response is desirable. Varying senders had no effect on response rates., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The Internet is increasingly considered to be an efficient medium for assessing the quality of health care seen from the patients' perspective. Potential benefits of Internet surveys such as time efficiency, reduced effort, and lower costs should be balanced against potential weaknesses such as low response rates and accessibility for only a subset of potential participants. Combining an Internet questionnaire with a traditional paper follow-up questionnaire (mixed-mode survey) can possibly compensate for these weaknesses and provide an alternative to a postal survey., Objective: To examine whether there are differences between a mixed-mode survey and a postal survey in terms of respondent characteristics, response rate and time, quality of data, costs, and global ratings of health care or health care providers (general practitioner, hospital care in the diagnostic phase, surgeon, nurses, radiotherapy, chemotherapy, and hospital care in general)., Methods: Differences between the two surveys were examined in a sample of breast care patients using the Consumer Quality Index Breast Care questionnaire. We selected 800 breast care patients from the reimbursement files of Dutch health insurance companies. We asked 400 patients to fill out the questionnaire online followed by a paper reminder (mixed-mode survey) and 400 patients, matched by age and gender, received the questionnaire by mail only (postal survey). Both groups received three reminders., Results: The respondents to the two surveys did not differ in age, gender, level of education, or self-reported physical and psychological health (all Ps > .05). In the postal survey, the questionnaires were returned 20 days earlier than in the mixed-mode survey (median 12 and 32 days, respectively; P < .001), whereas the response rate did not differ significantly (256/400, 64.0% versus 242/400, 60.5%, respectively; P = .30). The costs were lower for the mixed-mode survey (€2 per questionnaire). Moreover, there were fewer missing items (3.4% versus 4.4%, P = .002) and fewer invalid answers (3.2% versus 6.2%, P < .001) in the mixed-mode survey than in the postal survey. The answers of the two respondent groups on the global ratings did not differ. Within the mixed-mode survey, 52.9% (128/242) of the respondents filled out the questionnaire online. Respondents who filled out the questionnaire online were significantly younger (P < .001), were more often highly educated (P = .002), and reported better psychological health (P = .02) than respondents who filled out the paper questionnaire. Respondents to the paper questionnaire rated the nurses significantly more positively than respondents to the online questionnaire (score 9.2 versus 8.4, respectively; χ²₁ = 5.6)., Conclusions: Mixed-mode surveys are an alternative method to postal surveys that yield comparable response rates and groups of respondents, at lower costs. Moreover, quality of health care was not rated differently by respondents to the mixed-mode or postal survey. Researchers should consider using mixed-mode surveys instead of postal surveys, especially when investigating younger or more highly educated populations.

K-ras mutations occur frequently in epithelial cancers. Using short hairpin RNAs to deplete K-Ras in lung and pancreatic cancer cell lines harboring K-ras mutations, two classes were identified-lines that do or do not require K-Ras to maintain viability. Comparing these two classes of cancer cells revealed a gene expression signature in K-Ras-dependent cells, associated with a well-differentiated epithelial phenotype, which was also seen in primary tumors. Several of these genes encode pharmacologically tractable proteins, such as Syk and Ron kinases and integrin beta6, depletion of which induces epithelial-mesenchymal transformation (EMT) and apoptosis specifically in K-Ras-dependent cells. These findings indicate that epithelial differentiation and tumor cell viability are associated, and that EMT regulators in "K-Ras-addicted" cancers represent candidate therapeutic targets.

Objectives: To determine predictors of the development of asymptomatic middle ear effusion (MEE) in children with acute otitis media (AOM) and to assess the effect of antibiotic therapy in preventing the development of MEE in these children., Data Sources: A systematic literature search was performed using PubMed, EMBASE, the Cochrane databases, and the proceedings of international otitis media symposia., Study Selection: A trial was selected if the allocation of participants to treatment was randomized, children aged 0 to 12 years with AOM were included, the comparison was between antibiotic therapy and placebo or no (antibiotic) treatment, and MEE at 1 month was measured., Data Extraction: Data from 5 randomized controlled trials were included in the meta-analysis of individual patient data (1328 children aged 6 months to 12 years). We identified independent predictors of the development of asymptomatic MEE and studied whether these children benefited more from antibiotic therapy than children with a lower risk. The primary outcome was MEE (defined as a type B tympanogram) at 1 month., Data Synthesis: The overall relative risk of antibiotic therapy in preventing the development of asymptomatic MEE after 1 month was 0.9 (95% confidence interval, 0.8-1.0; P =.19). Independent predictors of the development of asymptomatic MEE were age younger than 2 years and recurrent AOM. No statistically significant interaction effects with treatment were found., Conclusion: Because of a marginal effect of antibiotic therapy on the development of asymptomatic MEE and the known negative effects of prescribing antibiotics, including the development of antibiotic resistance and adverse effects, we do not recommend prescribing antibiotics to prevent MEE.

Objectives: To determine whether individual patient data meta-analyses (IPDMA) are used to perform subgroup analyses and to study whether the analytical methods regarding subgroup analyses differ between IPDMA and conventional meta-analyses (CMA)., Study Design and Setting: IPDMA were identified with a comprehensive literature search, subsequently, CMA on similar research questions were traced. Methods for studying subgroups were compared for IPDMA and CMA that were matched with respect to domain, type of treatment, and outcome measure., Results: Of all 171 identified IPDMA and 102 CMA, 80% and 45% presented subgroup analyses, respectively. For 35 IPDMA and 37 "matched" CMA, subgroup analytic methods could be compared. The number of performed subgroup analyses did not differ between IPDMA and CMA. Both IPDMA and CMA often do not report adequate information on methods of analyses. Interaction tests were often not performed in IPDMA (69%) and individual patient data was often not directly modelled (74%)., Conclusion: Many IPDMA performed subgroup analyses, but overall treatment effects were more emphasized than subgroup effects. To study subgroups, a wide variety of analytical methods was used in both IPDMA and CMA. In general, the use and reporting of appropriate methods for subgroup analyses should be promoted. Recommendations for improvement of methods of analyses are provided.

Cervical squamous cell carcinomas are composed histologically of tumour cell islands surrounded by varying amounts of tumour stroma, the amount and composition of which are influenced by local TGF-beta(1). TGF-beta(1) is secreted in an inactive complex with latency-associated peptide (LAP). Both LAP and the extracellular matrix (ECM) protein fibronectin are important ligands for the integrin receptor alpha v beta 6. While alpha v beta 6 is only weakly expressed by normal epithelia, it is up-regulated in different carcinomas where it generally reflects a more aggressive phenotype. In cervical cancer, the expression of alpha v beta 6 has not thus far been investigated. Given the ability of alpha v beta 6 both to activate TGF-beta(1) and to interact with fibronectin, we studied correlations between the expression of these components and disease parameters in a large cohort of cervical cancer specimens. We analysed alpha v beta 6 expression using immunohistochemistry in primary cervical squamous carcinomas of FIGO stage IA to IIB patients and correlated the findings with formerly investigated fibronectin and TGF-beta(1) expression and clinico-pathological parameters. alpha v beta 6 expression was also examined in cervical intra-epithelial neoplasia (CIN) and lymph node metastases. alpha v beta 6 was only weakly expressed in normal epithelium but clearly up-regulated in CIN lesions. In carcinomas, strong expression of alpha v beta 6 in tumour cells correlated with different clinico-pathological parameters and with worse overall and disease-free survival. Furthermore, alpha v beta 6 expression correlated positively with TGF-beta(1) mRNA expression as well as with fibronectin expression. Overexpression of alpha v beta 6 in cervical squamous carcinomas is an unfavourable prognostic factor. This might reflect an increased capacity of alpha v beta 6-expressing tumour cells to migrate in a fibronectin-rich ECM and/or to activate TGF-beta(1) at the tumour/stroma interface, both of which processes may contribute to cervical cancer progression., (Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)