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Background: Emerging evidence suggests that clinical prediction models that use repeated (time-varying) measurements within each patient may have higher predictive accuracy than models that use patient information from a single measurement., Objective: To determine the breadth of the published literature reporting the development of clinical prediction models in children that use time-varying predictors., Data Sources: MEDLINE, EMBASE and Cochrane databases., Eligibility Criteria: We included studies reporting the development of a multivariable clinical prediction model in children, with or without validation, to predict a repeatedly measured binary or time-to-event outcome and utilizing at least one repeatedly measured predictor., Synthesis Methods: We categorized included studies by the method used to model time-varying predictors., Results: Of 99 clinical prediction model studies that had a repeated measurements data structure, only 27 (27%) used methods that incorporated the repeated measurements as time-varying predictors in a single model. Among these 27 time-varying prediction model studies, we grouped model types into nine categories: time-dependent Cox regression, generalized estimating equations, random effects model, landmark model, joint model, neural network, K-nearest neighbor, support vector machine and tree-based algorithms. Where there was comparison of time-varying models to single measurement models, using time-varying predictors improved predictive accuracy., Conclusions: Various methods have been used to develop time-varying prediction models in children, but there is a paucity of pediatric time-varying models in the literature. Incorporating time-varying covariates in pediatric prediction models may improve predictive accuracy. Future research in pediatric prediction model development should further investigate whether incorporation of time-varying covariates improves predictive accuracy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate how psychological and behavioural factors change from the first to the last half of pregnancy., Methods: In this prospective cohort study, we assessed the changes in psychological and behavioural factors across 10 domains among 445 women (mean age = 30.9 years) in Ontario, Canada. We collected data using 2 standardized questionnaires administered at <21 and 32-36 weeks of gestation. We computed intraclass correlation coefficients, percentages of no change, decrease, and increase, and mean differences between the 2 surveys., Results: Most psychological and behavioural factors had intraclass correlation coefficients < 0.50 between the first and the second half of pregnancy, suggesting remarkable changes over the course of pregnancy. We observed significant decreases in self-efficacy, compensatory health beliefs, guilt regarding binge eating, emotional eating, dietary restriction, pregnancy-related nausea and food cravings, sleep duration, and physical activity. We also found increases in anxious and depressive symptoms and the tendency to accept friends' and family's beliefs regarding pregnancy., Conclusions: In the first prospective analysis, we found that many psychological and behavioural factors changed significantly over pregnancy., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Masticatory myofascial pain is a musculoligamentous syndrome that can mimic odontogenic pain. Pain referral to odontogenic structures can be traced to hyperirritated myofascial trigger points (MTrPs). This pragmatic study evaluated the concordance between ultrasonography and palpation in detecting MTrPs in the masseter and temporalis muscles., Methods: Fifty-seven patients suspected to have temporomandibular disorder were included. MTrPs were palpated manually by expert clinicians. Ultrasonography was then performed by a blind sonographer. The quantity of MTrPs and the involved muscle sections, the pain occurrence, and the location of the MTrPs within the muscle sections were compared using the mean difference (MD) and concordance statistics (Cohen κ and the interclass correlation coefficient [ICC]) as applicable., Results: Ultrasonography located MTrPs as 2.1 ± 1.3 mm 2 hypoechoic nodules at a depth of 7 ± 3.3 mm. Ultrasonography moderately agreed with palpation on the quantity of MTrPs per patient (MD = 1; 95% confidence interval [CI], 0.06-1.9; ICC = 0.56; 95% CI, 0.32-0.72). Palpation detected marginally more involved muscle sections per patient (MD = 0.7; 95% CI, 0.06-1.34.05; ICC = 0.64; 95% CI, 0.44-0.77) with more pain occurrence per patient (MD = 1.4; 95% CI, 0.56-2.28; ICC = 0.13; 95% CI, -0.26 to 0.41). There was a discordance in the location of the MTrPs within the muscle sections per patient (κ = -0.46; 95% CI, -0.77 to -0.14)., Conclusions: Ultrasonography and palpation concurred moderately to substantially on the quantity of MTrPs and the involved muscle sections but disagreed on the location of the MTrPs within the muscle sections. Ultrasonography has the potential as a chairside diagnostic aid to help clinicians determine an accurate diagnosis, enhance patient experience during examination, and avoid unnecessary treatments that can mitigate the risk of iatrogenic damage., (Copyright © 2022 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Dietary recommendations and policies should be guided by rigorous systematic reviews. Reviews that are of poor methodological quality may be ineffective or misleading. Most of the evidence in nutrition comes from nonrandomized studies of nutritional exposures (usually referred to as nutritional epidemiology studies), but to date methodological evaluations of the quality of systematic reviews of such studies have been sparse and inconsistent., Objectives: We aimed to investigate the quality of recently published systematic reviews and meta-analyses of nutritional epidemiology studies and to propose guidance addressing major limitations., Methods: We searched MEDLINE (January 2018-August 2019), EMBASE (January 2018-August 2019), and the Cochrane Database of Systematic Reviews (January 2018-February 2019) for systematic reviews of nutritional epidemiology studies. We included a random sample of 150 reviews., Results: Most reviews were published by authors from Asia (n = 49; 32.7%) or Europe (n = 43; 28.7%) and investigated foods or beverages (n = 60; 40.0%) and cancer morbidity and mortality (n = 54; 36%). Reviews often had important limitations: less than one-quarter (n = 30; 20.0%) reported preregistration of a protocol and almost one-third (n = 42; 28.0%) did not report a replicable search strategy. Suboptimal practices and errors in the synthesis of results were common: one-quarter of meta-analyses (n = 30; 26.1%) selected the meta-analytic model based on statistical indicators of heterogeneity and almost half of meta-analyses (n = 50; 43.5%) did not consider dose-response associations even when it was appropriate to do so. Only 16 (10.7%) reviews used an established system to evaluate the certainty of evidence., Conclusions: Systematic reviews of nutritional epidemiology studies often have serious limitations. Authors can improve future reviews by involving statisticians, methodologists, and researchers with substantive knowledge in the specific area of nutrition being studied and using a rigorous and transparent system to evaluate the certainty of evidence., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objective: Our objective was to systematically review randomized and quasi-randomized trials on the neonatal and maternal effects of lower doses of antenatal corticosteroids (<24 mg of betamethasone or dexamethasone) compared with standard double doses of antenatal corticosteroids (24 mg of betamethasone or dexamethasone) administered to women at risk of preterm delivery., Data Sources: Medline, Embase, CINAHL, Web of Science, Cochrane CENTRAL, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, and the Australia New Zealand Clinical Trials Registry were searched from inception to December 8, 2019., Study Selection: A total of 2401 titles, abstracts, and protocols were independently screened by two reviewers, and subsequently 113 full-text articles were reviewed., Data Extraction: Our primary outcomes were perinatal death and severe respiratory distress syndrome., Data Synthesis: We identified one large in-progress trial comparing 11.4 mg versus 22.8 mg betamethasone and one published randomized controlled trial that compared a lower dose of dexamethasone (16 mg) to a standard dose of betamethasone (24 mg). The only relevant data from the published trial suggests minor changes in fetal heart rate variability between baseline and 24- to 48-hour follow-up between the two groups. Data for other outcomes had to be excluded due to the administration of weekly courses of antenatal corticosteroids., Conclusions: Randomized trial data comparing lower doses of antenatal corticosteroids to standard double doses are scarce. Given concerns regarding current antenatal corticosteroids dosing patterns, there is an urgent need for randomized controlled trials examining lower versus standard double doses of antenatal corticosteroids., (Copyright © 2020 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Introduction: Several strategies have been investigated for achieving successful pulpal anesthesia during endodontic treatment of mandibular molars with symptomatic irreversible pulpitis. However, comprehensive evaluation and identification of the most efficacious and safe intervention are lacking. We aimed to determine this using network meta-analysis., Methods: MEDLINE, Embase, Cochrane Central, CINAHL, and Scopus databases were searched. Study selection and data extraction were performed in duplicate. Eligible randomized controlled trials were meta-analyzed to estimate the treatment effects (odd ratios [ORs]; 95% credible interval (CrI) and surface under the cumulative ranking curve (SUCRA)]. CINeMA software (University of Bern, Bern, Switzerland) was used to assess the quality of results., Results: Thirty-seven interventions from 46 studies were identified. Compared with the common practice of an inferior alveolar nerve block with 2% lidocaine, a supplemental intraosseous injection was ranked the most efficacious with very low to moderate confidence (2% lidocaine + preoperative nonsteroidal anti-inflammatory drugs [NSAIDs] + acetaminophen [OR = 74; 95% CrI, 15-470; SUCRA = 97%], 2% lidocaine + preoperative NSAIDs [OR = 46; 95% CrI, 8-420; SUCRA = 94%], 2% lidocaine [OR = 33; 95% CrI, 14-80; SUCRA = 93%], 2% lidocaine + preoperative opioids + acetaminophen [OR = 20; 95% CrI, 4.4-98; SUCRA = 86%], and 4% articaine [OR = 20; 95% CrI, 6.3-96; SUCRA = 87%]) followed by supplemental buccal and lingual infiltrations using 4% articaine + preoperative NSAIDs (OR = 18; 95% CrI, 6-56; SUCRA = 86%; very low confidence). No major safety concerns were reported., Conclusions: Very low- to moderate-quality evidence suggests intraosseous injection using 2% lidocaine with 1:100,000 epinephrine or 4% articaine with 1:100,000 epinephrine or buccal and lingual infiltrations of 4% articaine with 1:100,000 epinephrine are superior strategies to achieve pulpal anesthesia during endodontic treatment of mandibular molars with symptomatic irreversible pulpitis. Preoperative NSAIDs or opioids with or without acetaminophen may increase the efficacy of these injections., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of the study was to develop a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) summary of findings (SoF) table format that displays the critical information from a network meta-analysis (NMA)., Study Design and Setting: We applied a user experience model for data analysis based on four rounds of semistructured interviews., Results: We interviewed 32 stakeholders who conduct or use MA. Four rounds of interviews produced six candidate NMA-SoF tables. Users found a final NMA-SoF table that included the following components highly acceptable: (1) details of the clinical question (PICO), (2) a plot depicting network geometry, (3) relative and absolute effect estimates, (4) certainty of evidence, (5) ranking of treatments, and (6) interpretation of findings., Conclusion: Using stakeholder feedback, we developed a new GRADE NMA-SoF table that includes the relevant components that facilitate understanding NMA findings and health decision-making., (Copyright © 2019. Published by Elsevier Inc.)

Objective: The Global Alliance to Prevent Prematurity and Stillbirth developed a phenotypic classification for preterm birth using clinical presentation (rather than risk factors) to improve surveillance. The objective of this study was to determine distributions of preterm birth phenotypes and associations with Caesarean section, low Apgar score, and neonatal death in multiparous women, stratifying by first versus recurrent preterm births., Methods: This population-based cohort study used the Better Outcomes Registry and Network (BORN) of multiparous women giving birth in hospital with a singleton after 20 weeks in Ontario from 2012 to 2014 (Canadian Task Force Classification II-2)., Results: In multiparous women with preterm birth, 29.6% had a history of recurrence, of whom 66.2% had at least one clinical condition associated with the phenotypic model, compared with 63.5% of first preterm births. In recurrent preterm births, criteria for maternal, fetal, and placental conditions were met in 44.5%, 37.9%, and 8.2%, respectively, compared with 36.8%, 39.0%, and 10.4%, respectively, of first preterm births. Associations of preterm birth with Caesarean section, low Apgar score, and neonatal death varied across clinical conditions but were similar between first and recurrent preterm births; for example, for recurrent preterm birth, Caesarean section for maternal, fetal, and placental conditions had odds ratios of 1.66 (95% confidence interval [CI] 1.32-2.07), 1.09 (95% CI 0.80-1.49), and 3.92 (95% CI 1.98-7.78), compared with first preterm birth odds ratios of 1.21 (95% CI 1.03-1.41), 0.92 (95% CI 0.77-1.10), and 6.24 (95% CI 4.07-9.56)., Conclusion: This study provides novel evidence of the utility of the preterm birth phenotypic classification model by using stratification for previous preterm birth, a robust predictor-with variation in phenotypes in initial and recurrent preterm births., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: A classification model based on preterm birth clinical presentations (phenotypes) was proposed at the International Conference on Prematurity and Stillbirth, with calls for validation. This study sought to determine the distribution of clinical phenotypes of preterm birth among nulliparous women, their corresponding associations with maternal characteristics, and the odds ratios (ORs) of preterm Caesarean section and other adverse outcomes., Methods: A population-based cohort study was performed of all nulliparous women with singleton pregnancies (>20 weeks) who gave birth in a hospital in Ontario between 2012 and 2014. Logistic regression models were used to estimate adjusted ORs (Canadian Task Force Classification II-2)., Results: Among 113 942 nulliparous women, 6.1% delivered at <37 weeks, at a mean gestational age of 33.9 weeks. Of those women, 34.1% did not meet the criteria for the presence of any clinical phenotype; 42.3% had one maternal, fetal, or placental condition; 22.3% had two clinical conditions; and 1.3% had three clinical conditions. The most common preterm birth phenotypes were worsening of maternal diseases (24.0%), intrauterine growth restriction (23.5%), and fetal distress (23.0%). Compared with preterm births without any significant clinical phenotype, those with maternal, fetal, or placental phenotypes were associated with increased odds of Caesarean section (adjusted ORs 2.70 [95% confidence interval [CI] 2.30-3.17], 1.66 [95% CI 1.36-2.03], and 6.49 [95% CI 4.29-9.80], respectively)., Conclusion: Approximately two thirds of nulliparous preterm births were grouped into distinct clinical phenotypes. This study demonstrated that outcomes varied across phenotypes, thus providing evidence of benefit for the phenotypic classification model., (Copyright © 2019 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the impact of applying the Grading of Recommendations and Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence in a published network meta-analysis (NMA) of antidepressant therapies., Study Design and Settings: We applied the GRADE approach to rate the certainty of the evidence for two outcomes, efficacy and acceptability, in each of the 66 paired comparisons within a previously published NMA assessing the relative efficacy and acceptability of 12 new-generation antidepressants., Results: For the outcome of efficacy, of the 25 comparisons in which the 95% CrI of OR excluded 1, 18 had certainty of evidence rated high or moderate. For the outcome of acceptability, of the 13 comparisons whose 95% CrI excluded 1, 10 had certainty of evidence rated high or moderate. Of the 11 comparisons involving sertraline, the antidepressants that the authors of the NMA suggested to be best, only 3 demonstrated it to be more effective and only 3 showed better tolerance, based on a 95% CrI excluding 1 and a high or moderate rating of certainty., Conclusions: In this example, application of GRADE highlighted varying evidence certainty, led to more conservative conclusions, and potentially avoided unwarranted strong inferences based on low certainty evidence., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Missing data is a universal research problem that can affect studies examining the relationship between physical activity measured with accelerometers and health outcomes. Statistical techniques are available to deal with missing data; however, available techniques have not been synthesized. A scoping review was conducted to summarize the advantages and disadvantages of identified methods of dealing with missing data from accelerometers. Missing data poses a threat to the validity and interpretation of trials using physical activity data from accelerometry. Imputation using multiple imputation techniques is recommended to deal with missing data and improve the validity and interpretation of studies using accelerometry., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To systematically examine the evidence around the combination of interventions to prevent preterm birth., Methods: Without language restrictions, we searched clinicaltrials.gov and five electronic databases (Medline, EMBASE, CINAHL, Cochrane CENTRAL, and Web of Science) up to July 7, 2016. We included randomized and non-randomized studies where asymptomatic women at risk of preterm birth received any combination of progesterone, cerclage, or pessary compared with either one or no intervention. Primary outcomes were preterm birth <34 and <37 weeks and neonatal death. Two independent reviewers extracted data using a piloted form and assessed risk and direction of bias. We pooled data with unlikely or unclear bias using random-effects meta-analyses. Comparisons with likely bias (e.g., confounding by indication) were not pooled., Results: We screened 1335 results and assessed 154 full texts, including seven studies. In singletons, we found no differences in preterm birth <34 weeks when comparing pessary & progesterone with pessary alone (RR 1.30, 95% CI 0.70-2.42) or progesterone alone (RR 1.16, 95% CI 0.79-1.72). Similarly, we found no differences in preterm birth <37 weeks when comparing cerclage & progesterone with cerclage alone (RR 1.04, 95% CI 0.56-1.93) or with progesterone alone (RR 0.82, 95% CI 0.57-1.19) nor between pessary & progesterone and pessary alone (RR 1.04, 95% CI 0.62-1.74). No data were available for neonatal death in singletons., Conclusions: Despite being a common clinical practice, evidence to support the combined use of multiple versus single interventions for preventing preterm birth is scarce., (Copyright © 2017 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Objective: To compare results from meta-analyses for mean differences in minimal important difference (MID) units (MD MID ), when MID is treated as a random variable vs. a constant., Study Design and Setting: Meta-analyses of published data. We calculated the variance of MD MID as a random variable using the delta method and as a constant. We assessed performance under different assumptions. We compare meta-analysis results from data originally used to present the MD MID and data from osteoarthritis studies using different domain instruments., Results: Depending on the data set and depending on the values of rho and coefficient of variation of the MID (CoV MID ), estimates of treatment effect and P-values between an approach considering the MID as a constant vs. as a random variable may differ appreciably. Using our data sets, we provide examples of the potential magnitude. When rho = 0.5 and CoV MID  = 0.8, considering MID as a constant overestimated the treatment effect by 33-110% and decreased the P-value for heterogeneity from above 0.95 to below 0.08. When rho = 0.8 and CoV MID  = 0.5, the magnitude of the effects was similar., Conclusions: Considering MID as a random variable avoids unrealistic assumptions and provides more appropriate treatment effect estimates., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Purpose: Single-nucleotide polymorphism (SNP) panel tests have been proposed for use in the detection of, and prediction of risk for, prostate cancer and as prognostic indicator in affected men. A systematic review was undertaken to address three research questions to evaluate the analytic validity, clinical validity, clinical utility, and prognostic validity of SNP-based panels., Methods: Data sources comprised MEDLINE, Cochrane CENTRAL, Cochrane Database of Systematic Reviews, and EMBASE; these were searched from inception to April 2013. The gray-literature searches included contact with manufacturers. Eligible studies included English-language studies evaluating commercially available SNP panels. Study selection and risk of bias assessment were undertaken by two independent reviewers., Results: Twenty-one studies met eligibility criteria. All focused on clinical validity and evaluated 18 individual panels with 2 to 35 SNPs. All had poor discriminative ability (overall area under receiver-operator characteristic curves, 58-74%; incremental gain resulting from inclusion of SNP data, 2.5-11%) for predicting risk of prostate cancer and/or distinguishing between aggressive and asymptomatic/latent disease. The risk of bias of the studies, as assessed by the Newcastle Ottawa Scale (NOS) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tools, was moderate., Conclusion: The evidence on currently available SNP panels is insufficient to assess analytic validity, and at best the panels assessed would add a small and clinically unimportant improvement to factors such as age and family history in risk stratification (clinical validity). No evidence on the clinical utility of current panels is available.Genet Med 18 6, 535-544.

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single-center trials yield systematically larger effects than multi-center trials., Study Design and Setting: We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs., Results: We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%)., Conclusions: Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses)., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Obesity is a risk factor for developing several diseases, and although dietary pulses (nonoil seeds of legumes such as beans, lentils, chickpeas, and dry peas) are well positioned to aid in weight control, the effects of dietary pulses on weight loss are unclear., Objective: We summarized and quantified the effects of dietary pulse consumption on body weight, waist circumference, and body fat by conducting a systematic review and meta-analysis of randomized controlled trials., Design: We searched the databases MEDLINE, Embase, CINAHL, and the Cochrane Library through 11 May 2015 for randomized controlled trials of ≥3 wk of duration that compared the effects of diets containing whole dietary pulses with those of comparator diets without a dietary pulse intervention. Study quality was assessed by means of the Heyland Methodologic Quality Score, and risk of bias was assessed with the Cochrane Risk of Bias tool. Data were pooled with the use of generic inverse-variance random-effects models., Results: Findings from 21 trials (n = 940 participants) were included in the meta-analysis. The pooled analysis showed an overall significant weight reduction of -0.34 kg (95% CI: -0.63, -0.04 kg; P = 0.03) in diets containing dietary pulses (median intake of 132 g/d or ∼1 serving/d) compared with diets without a dietary pulse intervention over a median duration of 6 wk. Significant weight loss was observed in matched negative-energy-balance (weight loss) diets (P = 0.02) and in neutral-energy-balance (weight-maintaining) diets (P = 0.03), and there was low evidence of between-study heterogeneity. Findings from 6 included trials also suggested that dietary pulse consumption may reduce body fat percentage., Conclusions: The inclusion of dietary pulses in a diet may be a beneficial weight-loss strategy because it leads to a modest weight-loss effect even when diets are not intended to be calorically restricted. Future studies are needed to determine the effects of dietary pulses on long-term weight-loss sustainability. This protocol was registered at clinicaltrials.gov as NCT01594567., (© 2016 American Society for Nutrition.)

Objective: To investigate whether analysis of the modified intention-to-treat (mITT) population with postrandomization exclusion of patients from analysis is associated with biased estimates of treatment effect compared to the conservative intention-to-treat (ITT) population., Study Design and Setting: Placebo-controlled, blinded randomized trials on biological or targeted interventions for rheumatoid arthritis were identified through a systematic search. Two authors independently extracted data. A random-effects meta-analysis was used to combine odds ratios as an expression of treatment effect and stratify according to the different analysis populations., Results: Seventy-two randomized trials were included and analyzed (23,842 patients). Thirty trials analyzed the ITT population, 37 analyzed an mITT population, and 5 trials had an unclear analysis population. The treatment effect of active intervention compared to control, when based on mITT, was comparable to ITT (odds ratio 3.76 [95% confidence interval 3.09, 4.57], and 3.47 [2.77, 4.34]; comparison P = 0.60)., Conclusion: We found no difference in the treatment effect between randomized trials using ITT and mITT analyses populations. This suggests that the mITT approach in rheumatoid arthritis trials investigating biological or targeted interventions does not introduce bias compared to ITT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The role of sugar-sweetened beverages (SSBs) that contain free or bound fructose in the pathogenesis of hypertension remains unclear., Objective: We conducted a systematic review and meta-analysis of prospective cohort studies to quantify the association between fructose-containing SSBs and risk of hypertension., Design: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane registry were searched from conception through 11 November 2014. Two independent reviewers extracted data and assessed the quality of studies (with the use of the Newcastle-Ottawa Scale). Risk estimates of extreme quantiles of SSB intake (lowest compared with highest) for hypertension incidence were generated with the use of generic inverse-variance methods with random-effects models and expressed as risk ratios with 95% CIs. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I(2) statistic., Results: Six prospective cohort studies (n = 240,508) with 79,251 cases of hypertension observed over ≥3,197,528 person-years of follow-up were included. SSB consumption significantly increased the risk of developing hypertension by 12% (risk ratio: 1.12; 95% CI: 1.06, 1.17) with evidence of significant heterogeneity (I(2) = 62%, P = 0.02) when highest [≥1 serving (6.7, 8, or 12 oz)/d] and lowest (none) quantiles of intake were compared. With the use of a dose-response analysis, a significant 8.2% increase in risk of every additional SSB per day from none to ≥1 SSB/d (β = 0.0027, P < 0.001) was identified. Limitations include unexplained heterogeneity and residual confounding. The results may also have been subject to collinearity effects from aspects of a Western dietary pattern., Conclusions: SSBs were associated with a modest risk of developing hypertension in 6 cohorts. There is a need for high-quality randomized trials to assess the role of SSBs in the development of hypertension and its complications. This study was registered at clinicaltrials.gov as NCT01608620., (© 2015 American Society for Nutrition.)

Objective: One half of women's gestational weight gain (GWG) exceeds the recommended amount. In attempting to prevent this, randomized trials targeting diet and/or exercise have been generally unsuccessful. In response, study of psychological factors has been called for. We aimed to determine the feasibility of a full-scale prospective cohort study examining psychological and other factors affecting GWG and to obtain prospective pilot data., Methods: We conducted a prospective cohort feasibility study in seven clinics in southwestern Ontario. Women with a singleton pregnancy were recruited between May and September 2013 and subsequently completed a questionnaire. GWG was abstracted from medical records and was categorized as below, within, or above guideline-recommended limits., Results: All clinics and 89.7% of women approached (n = 525) agreed to participate, and 514 were eligible for analysis. For the prospective analysis, we included participants enrolled during their first or second trimester (27%), because only 11% were less than 21 weeks' gestation. Planning GWG predicted excess GWG (adjusted RR [aRR] 9.44; 95% CI 2.64 to 33.80), as did binge eating (aRR 6.51; 95% CI 1.03 to 41.18). Dietary restraint was not significantly associated with excess GWG (aRR 2.74; 95% CI 0.67 to 11.22) or inadequate GWG (aRR 3.86; 95% CI 0.82 to 18.11)., Conclusion: This prospective pilot study demonstrated the feasibility of a full-scale study and identified a need for additional strategies to permit recruitment before 21 weeks, such as a longer recruitment period and involvement of more clinics. Previously identified knowledge factors, particularly planned weight gain, were predictive of excess GWG. However, psychological factors identified in this study, especially binge eating (which was found to be independently predictive for the first time) and dietary restraint, are areas requiring further study.

Objective: Given that planning to gain gestational weight categorized as above the national guidelines is associated with actually gaining above the guidelines, we sought to identify physical, lifestyle, knowledge, and psychological factors associated with planned weight gain., Methods: Using a piloted, self-administered questionnaire, a cross-sectional study of women with singleton pregnancies was conducted. Women's plans for weight gain were categorized as above, within, or below the guidelines. Univariate and multivariate analyses were performed., Results: The response rate was 90.7% (n = 330). Compared with women whose plans to gain weight were within the guidelines, women whose plans to gain were above the guidelines were more likely to be older (adjusted odds ratio [aOR] 1.09 per year; 95% CI 1.03 to 1.16), to have a greater pre-pregnancy BMI (aOR 1.17 per unit of BMI; 95% CI 1.10 to 1.25), to drink more than one glass of soft drink or juice per day (aOR 2.73; 95% CI 1.27 to 5.87), and to report receiving a recommendation by their care provider to gain weight above the guidelines (aOR 5.46; 95% CI 1.56 to 19.05). Women whose plans to gain weight were categorized as below the guidelines were more likely to eat lunch in front of a screen (aOR 2.27; 95% CI 1.11 to 4.66) and to aspire to greater social desirability (aOR 2.51; 95% CI 1.01 to 6.22)., Conclusion: Modifiable factors associated with planned gestational weight gain categorized as above the guidelines included soft drink or juice consumption and having a recommendation from a care provider, while planned weight gain categorized as below the guidelines was associated with eating lunch in front of a screen and social desirability.

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

In this study, we conducted a systematic review of the literature to re-evaluate the role of C4d in the diagnosis of acute antibody-mediated rejection of kidney allografts. Electronic databases were searched until September 2013. Eligible studies allowed derivation of diagnostic tables for the performance of C4d by immunofluorescence or immunohistochemistry with comparison to histopathological features of acute antibody-mediated rejection and/or donor-specific antibody (DSA) assays. Of 3492 unique abstracts, 29 studies encompassing 3485 indication and 868 surveillance biopsies were identified. Assessment of C4d by immunofluorescence and immunohistochemistry exhibited slight to moderate agreement with glomerulitis, peritubular capillaritis, solid-phase DSA assays, DSA with glomerulitis, and DSA with peritubular capillaritis. The sensitivity and specificity of C4d varied as a function of C4d and comparator test thresholds. Prognostically, the presence of C4d was associated with inferior allograft survival compared with DSA or histopathology alone. Thus, our findings support the presence of complement-dependent and -independent phenotypes of acute antibody-mediated rejection. Whether the presence of C4d in combination with histopathology or DSA should be considered for the diagnosis of acute antibody-mediated rejection warrants further study.

Background: In the absence of consistent clinical evidence, concerns have been raised that fructose raises postprandial triglycerides., Purpose: A systematic review and meta-analysis was conducted to assess the effect of fructose on postprandial triglycerides., Data Sources: Relevant studies were identified from MEDLINE, EMBASE, and Cochrane databases (through September 3, 2013)., Data Selection: Relevant clinical trials of ≥ 7-days were included in the analysis., Data Extraction: Two independent reviewers extracted relevant data with disagreements reconciled by consensus. The Heyland Methodological Quality Score (MQS) assessed study quality. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean differences (SMD) with 95% confidence intervals (CI). Heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic)., Data Synthesis: Eligibility criteria were met by 14 isocaloric trials (n = 290), in which fructose was exchanged isocalorically for other carbohydrate in the diet, and two hypercaloric trials (n = 33), in which fructose supplemented the background diet with excess energy from high-dose fructose compared with the background diet alone (without the excess energy). There was no significant effect in the isocaloric trials (SMD: 0.14 [95% CI: -0.02, 0.30]) with evidence of considerable heterogeneity explained by a single trial. Hypercaloric trials, however, showed a significant postprandial triglyceride raising-effect of fructose (SMD: 0.65 [95% CI: 0.30, 1.01])., Limitations: Most of the available trials were small, short, and of poor quality. Interpretation of the isocaloric trials is complicated by the large influence of a single trial., Conclusions: Pooled analyses show that fructose in isocaloric exchange for other carbohydrate does not increase postprandial triglycerides, although an effect cannot be excluded under all conditions. Fructose providing excess energy does increase postprandial triglycerides. Larger, longer, and higher-quality trials are needed., Protocol Registration: ClinicalTrials.gov identifier, NCT01363791., (Copyright © 2013 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Objective: Excess weight gain during pregnancy is associated with increased risks of overweight and obesity in both women and their children. Conversely, inadequate weight gain can predispose to growth restriction, which is also associated with childhood obesity. Because most pregnant women now gain more weight than is recommended in guidelines and a substantial portion gain less than the recommended amounts, we sought to determine factors associated with inappropriate weight gain, including physical, lifestyle, knowledge, and particularly psychological factors., Methods: We conducted a self-administered cross-sectional survey of English-speaking women with a live, singleton gestation. Biologically relevant variables significant at P < 0.10 were included in multiple logistic regression., Results: Three hundred thirty women completed the survey, a response rate of 90.7%. Gaining weight above the amount recommended in guidelines was associated with planning to do so (adjusted OR [aOR] 11.18; 95% CI 4.45 to 28.06), bedtime television (aOR 2.38; 95% CI 1.08 to 5.23), and higher emotional instability scores (aOR 1.26; 95% CI 1.10 to 1.44). Inadequate weight gain was associated with less satisfaction with body weight (aOR 4.84; 95% CI 1.56 to 15.02) and bedtime television (aOR 3.92; 95% CI 1.50 to 10.30), while self-efficacy towards healthy weight was protective (aOR 0.91; 95% CI 0.83 to 0.99)., Conclusion: Planned weight gain was most strongly associated with excess gestational weight gain, followed by bedtime television watching and emotional instability, while inadequate gain was associated with less satisfaction with body weight and bedtime television watching. Better characterization of psychological and other factors that predict inappropriate gain will be critical for providing a basis for interventions.

Hyperuricemia is linked to gout and features of metabolic syndrome. There is concern that dietary fructose may increase uric acid concentrations. To assess the effects of fructose on serum uric acid concentrations in people with and without diabetes, we conducted a systematic review and meta-analysis of controlled feeding trials. We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials (through August 19, 2011). Analyses included all controlled feeding trials ≥ 7 d investigating the effect of fructose feeding on uric acid under isocaloric conditions, where fructose was isocalorically exchanged with other carbohydrate, or hypercaloric conditions, and where a control diet was supplemented with excess energy from fructose. Data were aggregated by the generic inverse variance method using random effects models and expressed as mean difference (MD) with 95% CI. Heterogeneity was assessed by the Q statistic and quantified by I(2). A total of 21 trials in 425 participants met the eligibility criteria. Isocaloric exchange of fructose for other carbohydrate did not affect serum uric acid in diabetic and nondiabetic participants [MD = 0.56 μmol/L (95% CI: -6.62, 7.74)], with no evidence of inter-study heterogeneity. Hypercaloric supplementation of control diets with fructose (+35% excess energy) at extreme doses (213-219 g/d) significantly increased serum uric acid compared with the control diets alone in nondiabetic participants [MD = 31.0 mmol/L (95% CI: 15.4, 46.5)] with no evidence of heterogeneity. Confounding from excess energy cannot be ruled out in the hypercaloric trials. These analyses do not support a uric acid-increasing effect of isocaloric fructose intake in nondiabetic and diabetic participants. Hypercaloric fructose intake may, however, increase uric acid concentrations. The effect of the interaction of energy and fructose remains unclear. Larger, well-designed trials of fructose feeding at "real world" doses are needed.

Objective: Many women have high gestational weight gain (GWG), but potential neonatal consequences are not yet well quantified. We sought to determine the relationship between high GWG and preterm birth (PTB) and low birth weight (LBW) in singleton births., Data Sources: We searched Medline and Embase and reference lists., Study Selection: Two assessors independently performed all steps. We selected studies assessing high total or weekly GWG on PTB (< 37 weeks) and LBW (< 2500 grams)., Data Extraction and Synthesis: Thirty-eight studies, 24 cohort and 14 case-control, were included involving 2 124 907 women. Most contained unadjusted data. Women with high total GWG had a decreased risk overall of PTB < 37 weeks (relative risk [RR] 0.75; 95% CI 0.60 to 0.96), PTB 32 to 36 weeks (RR 0.70; 95% CI 0.70 to 0.71), and < 32 weeks (RR 0.87; 95% CI 0.85 to 0.90). High GWG was associated with lower risk of LBW (RR 0.64; 95% CI 0.53 to 0.78). Women with the highest GWG had lower risks of LBW (RR 0.55; 95% CI 0.32 to 0.94) than women with moderately high GWG (RR 0.73; 95% CI 0.60 to 0.89). Women with the highest weekly GWG had greater risks of PTB (RR 1.51; 95% CI 1.47 to 1.55) than women with moderately high weekly GWG (RR 1.09; 95% CI 1.05 to 1.13). Women with high weekly GWG were at increased risk of PTB 32 to 36 weeks (RR 1.14; 95% CI 1.10 to 1.17 and < 32 weeks (RR 1.81; 95% CI 1.73 to 1.90)., Conclusion: Although women with high total GWG have lower unadjusted risks of PTB and LBW, high weekly GWG is associated with increased PTB, and more adjusted studies are needed, as are more studies in obese women. Potential benefits of high GWG for the infant must be balanced against maternal risks and other known infant risks such as high birth weight.

Background: In some centers, outpatient management for cancer patients with low-risk febrile neutropenia (FN) has been implemented into routine clinical practice. Our objective was to evaluate the current level of evidence before supporting widespread adoption of outpatient management for this population., Methods: We systematically reviewed randomized controlled trials evaluating efficacy and safety of outpatient management of FN., Results: From 1448 reviewed articles, 14 studies were included for meta-analysis. (i) Inpatient versus outpatient setting (6 studies) was not significantly associated with treatment failure [risk ratio 0.81; 95% confidence interval (CI) 0.55-1.19; P = 0.28]. Death occurred in 13 of 742 FN episodes with no difference between the two groups (risk ratio 1.11; 95% CI 0.41-3.05; P = 0.83). (ii) Outpatient oral versus outpatient parenteral antibiotics (8 studies) were similarly efficacious with no association between route of drug administration and treatment failure (risk ratio 0.93; 95% CI 0.65-1.32; P = 0.67). No death occurred in 857 FN episodes., Conclusion: Based on the current literature, outpatient treatment of FN is a safe and efficacious alternative to inpatient management. Variation between studies in terms of time to discharge, choice of antibiotic class, and age of study population may limit the interpretation of the data.

Objective: To examine the quality of reporting and predictors of reporting in randomized clinical trials (RCTs) of herbal medicine interventions., Study Design and Setting: We searched Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and Academy of Microscope Enhanced Dentistry up to December 2007 for any English language RCT of 11 commonly used herbal medicine interventions. Two individuals separately and independently assessed all trials using the Consolidated Standards of Reporting Trials (CONSORT) checklist for herbal medicines interventions. We randomly selected 100 of these trials, extracted a set of potential predictor variables identified through a literature search and consultation with experts, and performed a conceptually driven stepwise elimination regression analyses for predictor variables., Results: The 406 trials reported on average 38% of the information suggested in the checklist. Regression analyses revealed better overall reporting in trials with a participant flow diagram (P=0.008), those of Panax quinquefolius (P=0.018), and those published in more recent years (P=0.02)., Conclusion: Our results indicate that RCTs of herbal medicine interventions frequently do not report important characteristics of the intervention. Trialists should refer to the CONSORT for herbal medicines when reporting their trials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Meta-analyses of continuous outcomes typically use mean differences (MDs) or standardized mean differences (SMDs) (MD in pooled standard deviation units). Ratio of means (RoM) is an alternative effect measure that performs comparably in simulation. We compared treatment effects and heterogeneity for RoM, MD, and SMD using empiric data., Study Design and Setting: From the Cochrane Database (2008, issue 1), we included systematic reviews reporting continuous outcomes, selected the meta-analysis with the most (and ≥five) trials, and calculated MD (where possible), SMD, and RoM. For each pair of effect measures, we compared P-values separately for treatment effect and heterogeneity and assessed asymmetry of discordant pairs (statistically significant result for only one of two measures)., Results: Two hundred thirty-two of 5,053 reviews were included. Measures demonstrated similar treatment effects, with ≤6% discordant pairs and no asymmetry. A 0.5 SMD increase corresponded to 22 (95% confidence interval: 19, 24)% increase using RoM. There was less heterogeneity in RoM vs. MD (n=143, P=0.007), SMD vs. RoM (n=232, P=0.005), and SMD vs. MD (n=143, P=0.004). Comparing discordant pairs, fewer meta-analyses showed significant heterogeneity with SMD vs. RoM (P=0.04), consistent with the known bias of SMD., Conclusion: Empiric data from diverse meta-analyses demonstrate similar treatment effects and no large differences in heterogeneity of RoM compared with difference-based methods., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: The study evaluated the power of the randomized placebo-phase design (RPPD)-a new design of randomized clinical trials (RCTs), compared with the traditional parallel groups design, assuming various response time distributions. In the RPPD, at some point, all subjects receive the experimental therapy, and the exposure to placebo is for only a short fixed period of time., Study Design and Setting: For the study, an object-oriented simulation program was written in R. The power of the simulated trials was evaluated using six scenarios, where the treatment response times followed the exponential, Weibull, or lognormal distributions. The median response time was assumed to be 355 days for the placebo and 42 days for the experimental drug., Results: Based on the simulation results, the sample size requirements to achieve the same level of power were different under different response time to treatment distributions. The scenario where the response times followed the exponential distribution had the highest sample size requirement. In most scenarios, the parallel groups RCT had higher power compared with the RPPD., Conclusion: The sample size requirement varies depending on the underlying hazard distribution. The RPPD requires more subjects to achieve a similar power to the parallel groups design., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: This study evaluated the statistical distribution of time to treatment response in patients with rheumatic diseases., Study Design and Setting: The study used a secondary data analysis design. Data from the trial of etanercept and methotrexate with radiographic patient outcomes were used to model the response times for etanercept (ETN), methotrexate (MTX), and combined ETN+MTX in patients with rheumatoid arthritis. The German etanercept registry was used to evaluate the response time distributions in patients with juvenile idiopathic arthritis., Results: For MTX, the lognormal distribution was considered to be the best model for the outcome American College of Rheumatology (ACR20), lognormal, generalized gamma, and log-logistic distributions for ACR50, and lognormal and generalized gamma for ACR70. For ETN, the lognormal model was best for ACR20, the generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For combined treatment, the best model was the log-logistic distribution for ACR20, generalized gamma for ACR50, and both lognormal and generalized gamma distributions for ACR70. For the German etanercept registry, the lognormal distribution was the best model for all three outcomes of pediatric ACR30, ACR50, and ACR70 without interval censoring., Conclusion: Study designs might be more efficient if the response distributions are taken into consideration during planning., (Crown Copyright © 2010. Published by Elsevier Inc. All rights reserved.)

Background: p-values are ubiquitous in medical research, but are often misunderstood. In addition to being misused or perhaps even abused at post-statistical analysis stage of making scientific inference and interpretations, p-values can also be a source of confusion at the design stage., Methods: Application of standard test statistic on observed data may result in a small p-value which in turn may give the impression that a new study that has the same sample size as the observed data, perhaps even smaller, would have adequate power. We used re-sampling method and computed statistical power to illustrate the fallacy of this conclusion. We have also calculated power using analytical formulae., Results: We analyzed data consisting of two group comparisons with binary as well as continuous outcome variables. For the binary outcome, the event rates for the outcome of interest in the illustrative data were 15/43 (35%) and 22/34 (65%), respectively (p-value=0.0093). Using these data, a bootstrap-based empirical power was estimated to be 75.4%. One random sample with only two-third of the original data had a p-value of 0.0066, but only an empirical power of 57.4%. Similar results were observed for a continuous outcome., Conclusion: Our results show that the number of zeros after the decimal point in a p-value from an observed sample cannot and should not be used to gauge the adequacy of sample size for a future study that is expected to have sufficient power to detect an effect as big as the observed.

Background: In a typical clinical trial treatment effects will not be expected to be the same on all of the study participants. As a result, investigators are often tempted to look at the effects of a given treatment in subgroups of patients in order to determine who will benefit the most or the least, especially when the treatment effect in the total sample is insignificant or borderline. This paper aims at demonstrating the application of random effect models as one approach to identify subpopulations suitable for subgroup analysis in a longitudinal study., Methods: Data collected from a double-blind randomized controlled trial were used to demonstrate how multilevel modeling using random effects can be used to identify subgroups of postmenopausal women who benefit the most from nonhormonal treatment (gabapentin) of their hot flashes., Results: We estimated subject-specific treatment effects and correlated these effects with patient characteristics at baseline. We found that women with a higher severity of hot flashes score at baseline were more likely to have the greatest reduction in hot flashes score from the treatment. Also, women who had a serum creatinine level higher than the median level at baseline demonstrated a greater response to gabapentin compared to the placebo group., Conclusion: Our proposed method can help researchers identify patient factors that are associated with differential effect. Those factors are potential areas for further clinical investigation or for constructing subgroups for sub-analysis.

Background: Approximately 10% of infants admitted to a Neonatal Intensive Care Unit (NICU) are at risk for Neurological Impairment (NI). While we have limited knowledge on the influence of NI risk on pain responses, we have no knowledge of how these responses change over time., Objective: To compare physiological and behavioural pain responses of infants at three levels of NI risk during the NICU neonatal period (Session 1) and at 6 months of age (Session 2)., Design/methods: Prospective observational design with 149 preterm and term infants at high (Cohort A, n=54), moderate (Cohort B, n=45) and mild (Cohort C, n=50) risks for NI from 3 Canadian tertiary level NICUs. Infants were observed in the NICU during 3 standardized phases of a heel lance: baseline, stick and return-to-baseline. At 6 months, infants were observed during the same three phases during an intramuscular immunization injection. Physiological (heart rate, oxygen saturation) and behavioural (9 facial actions, cry) responses were continuously recorded., Results: A significant interaction of Phase by Session was found with less total facial activity observed during Session 2 (all p values<0.04). A significant interaction for Session by Cohort was found, showing that infants in Cohort A had significantly more change from baseline-to-stick phase for brow bulge, eye squeeze, nasolabial furrow and open lips between sessions with less facial actions demonstrated at Session 2 (all p<0.02). There were significantly lower mean and minimum heart rate (all p<0.02) and higher minimum and maximum oxygen saturation (p<0.04) at Session 2. Significantly higher mean and minimum fundamental cry frequencies (pitch) in Cohort B (p<0.04) were found in Session 1. Cohort A had significantly longer cry durations, but no significant differences in cry dysphonation., Conclusions: Behavioural and physiological infant pain responses were generally diminished at 6 months of age compared to those in the neonatal period with some differences between NI risk groups in cry responses. Future exploration into the explanation for these differences between sessions and cohorts is warranted.

Background: To date, there are over 40 infant pain measures. Despite this plethora of measures, only 8 have included preterm infants and only 2 have included Extremely Low Gestational Age (ELGA; infants <28 weeks GA) in their development. Without reliable, valid and clinically useful indicators for procedural pain in ELGA infants, clinicians have no means to interpret the responses from an immature infant who may respond differently from infants of older GA., Objective: To examine the physiological, behavioural and biochemical responses to painful and non-painful procedures in ELGA infants and the influence of GA and sex., Design/methods: A prospective crossover design with 50 ELGA infants from one Canadian tertiary level NICU was conducted. Infants were assessed in random order during standardized painful (heel lance) and non-painful (diaper change) procedures. Physiological (heart rate, oxygen saturation) and behavioural (facial and body movement) indicators were continuously collected during 4 phases of the procedures. Biochemical (salivary cortisol) indicators were collected immediately before and 20 min following the procedures., Results: Four facial actions (brow bulge, eye squeeze, nasolabial furrow, vertical mouth stretch) increased immediately following the heel lance. There were no specific changes in physiological, body movement or cortisol indicators following the heel lance. ELGA infants demonstrated greater body movements during the diaper change, which may reflect immature motor coordination. No differences in pain responses were found for infants born between 23-25 6/7 weeks GA and those between 26-28 weeks GA. Similarly, no gender differences were found., Conclusions: Changes in 4 facial actions were the most sensitive indicators of pain in ELGA infants. This finding is consistent with existing measures where facial actions are the most prominent pain indicators. Specific body movements such as those included in NIDCAP, may provide more information about pain in ELGA infants. Movements such as hand-on-face, finger splaying, fisting, arching or yawning need to be examined in future research.

Objective: Uncontrolled studies suggest that in vitro fertilization twins have increased rates of preterm birth and low birth weight and would warrant increased antenatal monitoring. The objective of this meta-analysis was to determine whether the incidence of poor obstetric outcomes is higher for in vitro fertilization twins than for spontaneously conceived twins who were matched for maternal age., Study Design: Medline and EMBASE were searched with comprehensive search strategies. Case-control and cohort studies of twins who were conceived by in vitro fertilization or in vitro fertilization/intracytoplasmic sperm injection, with the transfer of fresh embryos or cryopreserved (frozen) in women with infertility, and/or whose partners were subfertile or infertile, compared with naturally (spontaneously) conceived twins who were matched for maternal age (case-control studies) or which were controlled for it (cohort studies). Two reviewers independently assessed titles, abstracts, and study quality and extracted the data. Statistical analysis was performed with commercial statistical software. Dichotomous data were meta-analyzed with odds ratios as measures of effect size, and continuous data was meta-analyzed with mean differences. Interstudy variation was incorporated with the assumption of a random effects model for the treatment effect., Results: Compared with spontaneously conceived twins who were matched for maternal age, in vitro fertilization twins have an increased risk of preterm birth between 32 and 36 weeks of gestation (odds ratio, 1.48; 95% CI, 1.05-2.10), and an elevated risk of preterm birth at <37 weeks of gestation when parity is also matched for an odds ratio of 1.57 (95% CI, 1.01-2.44). There was an increased rate of cesarean delivery among in vitro fertilization twins (odds ratio, 1.33; 95% CI, 1.06-1.67). There were no significant differences in incidences of perinatal death, low birth weight infants, or congenital malformations., Conclusion: In vitro fertilization twins have increased rates of preterm birth compared with spontaneously conceived twins who were matched for maternal age, despite the fact that their outcomes would be expected to be better because of the decreased proportion of monochorionic twins.

Objective: To determine whether the incidence of adverse obstetric outcomes is higher in singleton pregnancies achieved by in vitro fertilization (IVF) than in spontaneously conceived singletons matched for maternal age., Methods: We used comprehensive search strategies to search MEDLINE and EMBASE databases. We selected case-control and cohort studies that compared singleton pregnancies conceived by IVF or intracytoplasmic sperm injection (ICSI) with spontaneously conceived singletons (matched for maternal age [case-control studies] or controlled for maternal age [cohort studies]). Two reviewers independently assessed titles, abstracts, and study quality and extracted data. Statistical analysis was performed with Review Manager for Windows (Version 4.2, Oxford, UK). We performed meta-analysis of dichotomous data, using odds ratios (ORs) as measures of effect size, with a random effects model. We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines for meta-analysis of observational studies., Results: Singleton pregnancies resulting from IVF have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age, with increases in perinatal mortality (OR 2.40; 95% confidence interval [CI] 1.59-3.63), preterm birth at < 33 weeks' gestation (OR 2.99; 95% CI 1.54-5.80), preterm birth at < 37 weeks' gestation (OR 1.93; 95% CI 1.36-2.74), very low birth weight (< 1500 g) (OR 3.78; 95% CI 4.29-5.75), small for gestational age (OR 1.59; 95% CI 1.20-2.11), and congenital malformations (OR 1.41; CI 1.06-1.88)., Conclusions: IVF singleton pregnancies have increased rates of poor obstetric outcome, compared with spontaneously conceived singletons matched for maternal age.

Objective: Our aim was to study the hemodynamic effects of betamethasone on fetuses with intrauterine growth restriction (IUGR) with absent or reversed end-diastolic (ARED) umbilical artery flow., Study Design: Color/pulsed Doppler waveforms were obtained before and after intramuscular injections of betamethasone in 19 consecutive fetuses with IUGR/ARED and 6 control fetuses. Peak velocities and pulsatility index (PI) values were obtained from the umbilical (UA) and middle cerebral (MCA) arteries and intrahepatic umbilical vein (UV)., Results: Ten ARED fetuses developed transient positive umbilical end-diastolic flow after steroids, whereas nine fetuses showed persistent ARED. The persistent ARED subgroup demonstrated increased UA and UV peak velocities after steroids, which may indicate fetal hypertension. Fetal death (n=2) and severe acidosis (n=2) were confined to the subgroup with persistent ARED., Conclusion: Preterm IUGR/ARED fetuses exhibit divergent cardiovascular responses to prenatal steroids. Intensive Doppler-based fetal monitoring may identify a subset of fetuses prone to decompensation after maternal steroid administration.