Three year outcomes in infants with a family history of autism and/or attention deficit hyperactivity disorder.

Background: Most research on early outcomes in infants with a family history (FH) of autism has focussed on categorically defined autism, although some have language and developmental delays. Less is known about outcomes in infants with a FH of attention deficit hyperactivity disorder (ADHD). Methods: Infants with and without a FH of autism and/or ADHD, due to a first-degree relative with either or both conditions, were recruited at 5 or 10 months. Three year outcomes were characterised using latent profile analysis (LPA) across measures of cognitive ability, adaptive functioning and autism, ADHD and anxiety traits (n = 131). We additionally ran an LPA using only autism and ADHD measures, and the broader LPA in an independent cohort (n = 139) and in both cohorts combined (n = 270). Results: A Low Developmental Level + High Behavioural Concerns class had elevated autism, ADHD and anxiety scores, low cognitive and adaptive function, and included all but one child with autism. A Low Developmental Level + Typical Behaviour class had average cognitive ability and typical behaviour but low adaptive function. A Typical Developmental Level + Some Behavioural Concerns class had average cognitive and adaptive function but slightly elevated behaviour scores. A High Developmental Level + Typical Behaviour class had above average cognitive ability and typical behaviour. All four LPAs identified classes characterised by combinations of either, or both, Low Development Level and elevated behaviour scores, as well as a typically developing class. No classes had elevated autism or ADHD traits in isolation. Conclusions: Some infants with a FH of autism or ADHD have atypical developmental and behavioural outcomes, but do not show strong autism or ADHD traits in isolation. The field needs to recalibrate aims and methods to embrace the broader transdiagnostic pattern of outcomes seen in these infants.

Parent attitudes towards data sharing in developmental science.

Background: Data sharing in developmental science is increasingly encouraged, supported by funder and publisher mandates for open data access. Data sharing can accelerate discovery, link researchers with high quality analytic expertise to researchers with large datasets and democratise the research landscape to enable researchers with limited funding to access large sample sizes. However, there are also significant privacy and security concerns, in addition to conceptual and ethical considerations. These are particularly acute for developmental science, where child participants cannot consent themselves. As we move forward into a new era of data openness, it is essential that we adequately represent the views of stakeholder communities in designing data sharing efforts. Methods: We conducted a comprehensive survey of the opinions of 195 parents on data sharing in developmental science. Survey themes included how widely parents are willing to share their child's data, which type of organisations they would share the data with and the type of consent they would be comfortable providing. Results: Results showed that parents were generally supportive of curated, but not open, data sharing. In addition to individual privacy and security concerns, more altruistic considerations around the purpose of research were important. Parents overwhelmingly supported nuanced consenting models in which preferences for particular types of data sharing could be changed over time. This model is different to that implemented in the vast majority of developmental science research and is contrary to many funder or publisher mandates. Conclusions: The field should look to create shared repositories that implement features such as dynamic consent and mechanisms for curated sharing that allow consideration of the scientific questions addressed. Better communication and outreach are required to build trust in data sharing, and advanced analytic methods will be required to understand the impact of selective sharing on reproducibility and representativeness of research datasets.

INTERSTAARS: Attention training for infants with elevated likelihood of developing ADHD: A proof-of-concept randomised controlled trial.

Attention-deficit/hyperactivity disorder (ADHD) is first diagnosed during middle childhood, when patterns of difficulty are often established. Pre-emptive approaches that strengthen developing cognitive systems could offer an alternative to post-diagnostic interventions. This proof-of-concept randomised controlled trial (RCT) tested whether computerised gaze-based attention training is feasible and improves attention in infants liable to develop ADHD. Forty-three 9- to 16-month-old infants with a first-degree relative with ADHD were recruited (11/2015-11/2018) at two UK sites and randomised with minimisation by site and sex to receive 9 weekly sessions of either (a) gaze-contingent attention training (intervention; n = 20); or (b) infant-friendly passive viewing of videos (control, n = 23). Sessions were delivered at home with blinded outcome assessments. The primary outcome was a composite of attention measures jointly analysed via a multivariate ANCOVA with a combined effect size (ES) from coefficients at baseline, midpoint and endpoint (Registration: ISRCTN37683928 ). Uptake and compliance was good but intention-to-treat analysis showed no significant differences between 20 intervention and 23 control infants on primary (ES -0.4, 95% CI -0.9 to 0.2; Complier-Average-Causal Effect ES -0.6, 95% CI -1.6 to 0.5) or secondary outcomes (behavioural attention). There were no adverse effects on sleep but a small increase in post-intervention session fussiness. Although feasible, there was no support for short-term effects of gaze-based attention training on attention skills in early ADHD. Longer-term outcomes remain to be assessed. The study highlights challenges and opportunities for pre-emptive intervention approaches to the management of ADHD.

Hospital Deaths Increased After Reforms Regardless of Dementia Status: An Interrupted Time-Series Analysis.

OBJECTIVES: Dying in a hospital is highly stressful for older adults and families. Persons with dementia who are hospitalized are particularly vulnerable to negative outcomes. The objective of this study is to fill an evidence gap on whether the 2015 Dutch long-term care reforms were effective in increasing deaths at home while avoiding increases in hospital deaths for the total population aged ≥65 years and by dementia status. DESIGN: We used annual cross-sectional, nationally representative data from 2012 to 2017. We performed an interrupted time-series analyses to evaluate changes in location of death after the implementation of the Dutch long-term reforms. SETTING AND PARTICIPANTS: Dutch population aged ≥65 years (N = 727,519) who died between 2012 and 2017 using data from Statistics Netherlands. METHODS: The primary outcome was death in a long-term care facility (LTCF), home, hospital, or elsewhere. RESULTS: After adjusting for seasonality and sex, we found significantly increased adjusted relative risk ratios (aRRRs) for the total older adult population having a death at home [aRRR 1.17, 95% confidence interval (CI) 1.12.-1.23] and hospital (1.09, 1.04-1.15) compared to deaths in an LTCF after the reforms. For persons with dementia (N = 81,373), hospital deaths increased (2.03, 1.37-3.01) compared with long-term care deaths after the implementation of the long-term care reforms; however, there was no change in the aRRR for death at home. For people without dementia (N = 646,146), we found increased aRRR for death at home (1.21, 1.16-1.28) and death at hospital (1.12, 1.07-1.19) vs LTCF deaths following the reforms. CONCLUSIONS AND IMPLICATIONS: Hospital and home deaths increased for the total population. Hospital deaths increased for persons with dementia after the long-term care reforms despite evidence of negative outcomes associated with end-of-life hospitalizations. The Netherlands may have overlooked the merits of home care and LTCFs, particularly for people with dementia.

Effectiveness of an e-health tennis-specific injury prevention programme: randomised controlled trial in adult recreational tennis players.

BACKGROUND: Despite reported injury rates of up to 3 per 1000 hours exposure, there are no evidence-based prevention programmes in tennis. PURPOSE: To evaluate the effectiveness of an e-health prevention programme for reducing tennis injury prevalence. STUDY DESIGN: Two-arm, researcher-blinded randomised controlled trial. METHODS: Adult tennis players of all playing levels were randomised in an unsupervised programme lasting 12 weeks (TennisReady group or control group). The primary outcome was the overall injury prevalence over a 16-week period, measured at 2 weekly intervals with the Oslo Sports and Trauma Research Centre questionnaire. Estimates for the primary outcome and associated 95% CIs were obtained using generalised estimating equation models. Secondary outcome scores included prevalence of substantial injuries, overall incidence, adherence and time-loss injuries. RESULTS: A total of 579 (83%) (TennisReady n=286, control n=293) participants were included in the primary analysis. The mean injury prevalence was 37% (95% CI 33% to 42%) in the TennisReady vs 38% (95% CI 34% to 42%) in the control group (adjusted p-value 0.93). The prevalence of substantial injuries was 11% (95% CI 9% to 14%) in the TennisReady vs 12% (95% CI 9% to 15%) in the control group (p value of 0.79). Analysis of the secondary outcome scores showed no difference between groups. The mean prevalence rates between high (8%) and low (92%) adherent groups were 32% (95% CI 23% to 44%) and 37% (95% CI 33% to 42%), respectively (p value 0.36). CONCLUSION: Providing an unsupervised e-health tennis-specific exercise programme did not reduce the injury rates and should not be implemented. TRIAL REGISTRATION NUMBER: NTR6443.

Diminutive Polyps With Advanced Histologic Features Do Not Increase Risk for Metachronous Advanced Colon Neoplasia.

BACKGROUND & AIMS: With advances in endoscopic imaging, it is possible to differentiate adenomatous from hyperplastic diminutive (1-5 mm) polyps during endoscopy. With the optical Resect-and-Discard strategy, these polyps are then removed and discarded without histopathology assessment. However, failure to recognize adenomas (vs hyperplastic polyps), or discarding a polyp with advanced histologic features, could result in a patient being considered at low risk for metachronous advanced neoplasia, resulting in an inappropriately long surveillance interval. We collected data from international cohorts of patients undergoing colonoscopy to determine what proportion of patients are high risk because of diminutive polyps advanced histologic features and their risk for metachronous advanced neoplasia. METHODS: We collected data from 12 cohorts (in the United States or Europe) of patients undergoing colonoscopy after a positive result from a fecal immunochemical test (FIT cohort, n = 34,221) or undergoing colonoscopies for screening, surveillance, or evaluation of symptoms (colonoscopy cohort, n = 30,123). Patients at high risk for metachronous advanced neoplasia were defined as patients with polyps that had advanced histologic features (cancer, high-grade dysplasia, ≥25% villous features), 3 or more diminutive or small (6-9 mm) nonadvanced adenomas, or an adenoma or sessile serrated lesion ≥10 mm. Using an inverse variance random effects model, we calculated the proportion of diminutive polyps with advanced histologic features; the proportion of patients classified as high risk because their diminutive polyps had advanced histologic features; and the risk of these patients for metachronous advanced neoplasia. RESULTS: In 51,510 diminutive polyps, advanced histologic features were observed in 7.1% of polyps from the FIT cohort and 1.5% polyps from the colonoscopy cohort (P = .044); however, this difference in prevalence did not produce a significant difference in the proportions of patients assigned to high-risk status (0.8% of patients in the FIT cohort and 0.4% of patients in the colonoscopy cohort) (P = .25). The proportions of high-risk patients because of diminutive polyps with advanced histologic features who were found to have metachronous advanced neoplasia (17.6%) did not differ significantly from the proportion of low-risk patients with metachronous advanced neoplasia (14.6%) (relative risk for high-risk categorization, 1.13; 95% confidence interval 0.79-1.61). CONCLUSION: In a pooled analysis of data from 12 international cohorts of patients undergoing colonoscopy for screening, surveillance, or evaluation of symptoms, we found that diminutive polyps with advanced histologic features do not increase risk for metachronous advanced neoplasia.

Statistical analysis plan for the Healthy Hands Project; single centre cluster-randomised clinical trial of a skin care program for the prevention of contact dermatitis in health care workers.

BACKGROUND: The Healthy Hands Project (HHP) is a randomised clinical trial aiming to determine the effectiveness of an intervention program in the prevention of hand dermatitis in healthcare workers (HCWs). The intervention is comprised of placing dispensers with hand creams on wards combined with continuous electronic monitoring of cream consumption and regular feedback to HCWs. The clinical severity (HECSI score) was used as the primary outcome and natural moisturising factor (NMF) levels as the secondary outcome. The study protocol for the cluster-randomised controlled trial of HHP was published in Trials in 2017. This article describes the detailed statistical analysis plan for the HHP trial. METHODS/DESIGN: The HHP is a single-centre, cluster-randomised controlled trial with two parallel groups and blinded outcome assessment. This update article presents (1) the descriptive statistics of the primary and secondary outcomes, (2) the statistical models used for the analysis of the main outcomes, (3) sensitivity analyses on the effect of observed exposure to wet work, (4) handling of missing data including sensitivity analysis and (5) an updated power calculation. This statistical analysis plan was written prior to unblinding of the study. DISCUSSION: This paper presents a comprehensive statistical analysis plan for the data resulting from the HHP trial. It supports transparency in reporting by clarifying differences between the previously published protocol and the proposed actual statistical analyses. TRIAL REGISTRATION: Netherlands Trial Register (NTR), identification number NTR5564 . Registered on 2 November 2015.

Rabies Antibody Response After Booster Immunization: A Systematic Review and Meta-analysis.

Although fatal once symptomatic, rabies is preventable by administration of pre- and post-exposure vaccines. International guidelines suggest lifelong protection by a pre-exposure vaccination scheme followed by timely post-exposure vaccines. Rapidity and magnitude of the antibody recall response after booster inoculation are essential, as many people have been previously immunized a long time ago. The objective of this study was therefore to systematically review the evidence on the boostability of rabies immunization to date. We included 36 studies, of which 19 studies were suitable for meta-analysis. Reduced antibody levels were found after intradermal primary schedules as compared to intramuscular schedules. However, responses after booster immunization were adequate for both routes. Although studies showed that antibody levels decline over time, adequate booster responses were still retained over long time intervals indicating that post-exposure treatment is effective without extra measures after long periods of time.

Analysis of clinical data to determine the minimum number of sensors required for adequate skin temperature monitoring of superficial hyperthermia treatments.

PURPOSE: Tumor response and treatment toxicity are related to minimum and maximum tissue temperatures during hyperthermia, respectively. Using a large set of clinical data, we analyzed the number of sensors required to adequately monitor skin temperature during superficial hyperthermia treatment of breast cancer patients. METHODS: Hyperthermia treatments monitored with >60 stationary temperature sensors were selected from a database of patients with recurrent breast cancer treated with re-irradiation (23 × 2 Gy) and hyperthermia using single 434 MHz applicators (effective field size 351-396 cm2). Reduced temperature monitoring schemes involved randomly selected subsets of stationary skin sensors, and another subset simulating continuous thermal mapping of the skin. Temperature differences (ΔT) between subsets and complete sets of sensors were evaluated in terms of overall minimum (Tmin) and maximum (Tmax) temperature, as well as T90 and T10. RESULTS: Eighty patients were included yielding a total of 400 hyperthermia sessions. Median ΔT was <0.01 °C for T90, its 95% confidence interval (95%CI) decreased to ≤0.5 °C when >50 sensors were used. Subsets of <10 sensors result in underestimation of Tmax up to -2.1 °C (ΔT 95%CI), which decreased to -0.5 °C when >50 sensors were used. Thermal profiles (8-21 probes) yielded a median ΔT < 0.01 °C for T90 and Tmax, with a 95%CI of -0.2 °C and 0.4 °C, respectively. The detection rate of Tmax ≥43 °C is ≥85% while using >50 stationary sensors or thermal profiles. CONCLUSIONS: Adequate coverage of the skin temperature distribution during superficial hyperthermia treatment requires the use of >50 stationary sensors per 400 cm2 applicator. Thermal mapping is a valid alternative.

Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): statistical analysis plan.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth with short-term and long-term adverse consequences. Although the glucocorticoid dexamethasone has been proven to be beneficial for the prevention of BPD, there are concerns about an increased risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. The aim of the Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (SToP-BPD) trial is to assess the efficacy and safety of postnatal hydrocortisone administration for the reduction of death or BPD in ventilator-dependent preterm infants. METHODS/DESIGN: The SToP-BPD study is a multicentre, double-blind, placebo-controlled hydrocortisone trial in preterm infants at risk for BPD. After parental informed consent is obtained, ventilator-dependent infants are randomly allocated to hydrocortisone or placebo treatment during a 22-day period. The primary outcome measure is the composite outcome of death or BPD at 36 weeks postmenstrual age. Secondary outcomes are short-term effects on pulmonary condition and long-term neurodevelopmental sequelae assessed at 2 years corrected age. Complications of treatment, other serious adverse events and suspected unexpected serious adverse reactions are reported as safety outcomes. This pre-specified statistical analysis plan was written and submitted without knowledge of the unblinded data. TRIAL REGISTRATION: Netherlands Trial Register, NTR2768 . Registered on 17 February 2011. EudraCT, 2010-023777-19. Registered on 2 November 2010.

Guidelines on constructing funnel plots for quality indicators: A case study on mortality in intensive care unit patients.

Funnel plots are graphical tools to assess and compare clinical performance of a group of care professionals or care institutions on a quality indicator against a benchmark. Incorrect construction of funnel plots may lead to erroneous assessment and incorrect decisions potentially with severe consequences. We provide workflow-based guidance for data analysts on constructing funnel plots for the evaluation of binary quality indicators, expressed as proportions, risk-adjusted rates or standardised rates. Our guidelines assume the following steps: (1) defining policy level input; (2) checking the quality of models used for case-mix correction; (3) examining whether the number of observations per hospital is sufficient; (4) testing for overdispersion of the values of the quality indicator; (5) testing whether the values of quality indicators are associated with institutional characteristics; and (6) specifying how the funnel plot should be constructed. We illustrate our guidelines using data from the Dutch National Intensive Care Evaluation registry. We expect that our guidelines will be useful to data analysts preparing funnel plots and to registries, or other organisations publishing quality indicators. This is particularly true if these people and organisations wish to use standard operating procedures when constructing funnel plots, perhaps to comply with the demands of certification.

Is patient length of stay associated with intensive care unit characteristics?

PURPOSE: We described the association between Intensive care units (ICU) characteristics and ICU Length of stay (LoS), after correcting for patient characteristics. We also compared the predictive performances of models including either patient and ICU characteristics or only patient characteristics. MATERIALS AND METHODS: We included all admissions of 38 ICUs participating in the Dutch National Intensive Care Evaluation registry (NICE) between 2014 and 2016. We performed mixed effect regression including, one ICU characteristic in each model and a random intercept per ICU. Furthermore, we developed a prediction model containing multiple ICU characteristics and patients characteristics. RESULTS: We found negative associations for the number of hospital beds; number of ICU beds; availability of fellows in training for intensivist; full-time equivalent ICU nurses; and discharged in a shift with 100% bed occupancy. Furthermore, we found a U-shaped association with the nurses to patient ratio as spline function. The performance based on R2 was between 0.30 and 0.32 for both the model containing only patient characteristics and the model also containing ICU characteristics. CONCLUSION: After correcting for patient characteristics, we found statistically significant associations between ICU LoS and six ICU characteristics, mainly describing staff availability. Furthermore, we conclude that including ICU characteristics did not significantly improve ICU LoS prediction.

Diabetes Is Not Associated With Increased 90-Day Mortality Risk in Critically Ill Patients With Sepsis.

OBJECTIVES: To determine the association of pre-existing diabetes, hyperglycemia, and hypoglycemia during the first 24 hours of ICU admissions with 90-day mortality in patients with sepsis admitted to the ICU. DESIGN: We used mixed effects logistic regression to analyze the association of diabetes, hyperglycemia, and hypoglycemia with 90-day mortality (n = 128,222). SETTING: All ICUs in the Netherlands between January 2009 and 2014 that participated in the Dutch National Intensive Care Evaluation registry. PATIENTS: All unplanned ICU admissions in patients with sepsis. INTERVENTIONS: The association between 90-day mortality and pre-existing diabetes, hyperglycemia, and hypoglycemia, corrected for other factors, was analyzed using a generalized linear mixed effect model. MEASUREMENTS AND MAIN RESULTS: In a multivariable analysis, diabetes was not associated with increased 90-day mortality. In diabetes patients, only severe hypoglycemia in the absence of hyperglycemia was associated with increased 90-day mortality (odds ratio, 2.95; 95% CI, 1.19-7.32), whereas in patients without pre-existing diabetes, several combinations of abnormal glucose levels were associated with increased 90-day mortality. CONCLUSIONS: In the current retrospective large database review, diabetes was not associated with adjusted 90-day mortality risk in critically ill patients admitted with sepsis.

Thermal Skin Damage During Reirradiation and Hyperthermia Is Time-Temperature Dependent.

PURPOSE: To investigate the relationship of thermal skin damage (TSD) to time-temperature isoeffect levels for patients with breast cancer recurrence treated with reirradiation plus hyperthermia (reRT + HT), and to investigate whether the treatment history of previous treatments (scar tissue) is a risk factor for TSD. METHODS AND MATERIALS: In this observational study, temperature characteristics of hyperthermia sessions were analyzed in 262 patients with recurrent breast cancer treated in the AMC between 2010 and 2014 with reirradiation and weekly hyperthermia for 1 hour. Skin temperature was measured using a median of 42 (range, 29-82) measurement points per hyperthermia session. RESULTS: Sixty-eight patients (26%) developed 79 sites of TSD, after the first (n=26), second (n=17), third (n=27), and fourth (n=9) hyperthermia session. Seventy percent of TSD occurred on or near scar tissue. Scar tissue reached higher temperatures than other skin tissue (0.4°C, P<.001). A total of 102 measurement points corresponded to actual TSD sites in 35 of 79 sessions in which TSD developed. Thermal skin damage sites had much higher maximum temperatures than non-TSD sites (2.8°C, P<.001). Generalized linear mixed models showed that the probability of TSD is related to temperature and thermal dose values (P<.001) and that scar tissue is more at risk (odds ratio 0.4, P<.001). Limiting the maximum temperature of a measurement point to 43.7°C would mean that the probability of observing TSD was at most 5%. CONCLUSION: Thermal skin damage during reRT + HT for recurrent breast cancer was related to higher local temperatures and time-temperature isoeffect levels. Scar tissue reached higher temperatures than other skin tissue, and TSD occurred at lower temperatures and thermal dose values in scar tissue compared with other skin tissue. Indeed, TSD developed often on and around scar tissue from previous surgical procedures.

Variation in rates of ICU readmissions and post-ICU in-hospital mortality and their association with ICU discharge practices.

BACKGROUND: Variation in intensive care unit (ICU) readmissions and in-hospital mortality after ICU discharge may indicate potential for improvement and could be explained by ICU discharge practices. Our objective was threefold: (1) describe variation in rates of ICU readmissions within 48 h and post-ICU in-hospital mortality, (2) describe ICU discharge practices in Dutch hospitals, and (3) study the association between rates of ICU readmissions within 48 h and post-ICU in-hospital mortality and ICU discharge practices. METHODS: We analysed data on 42,040 admissions to 82 (91.1%) Dutch ICUs in 2011 from the Dutch National Intensive Care Evaluation (NICE) registry to describe variation in standardized ICU readmission and post-ICU mortality rates using funnel-plots. We send a questionnaire to all Dutch ICUs. 75 ICUs responded and their questionnaire data could be linked to 38,498 admissions in the NICE registry. Generalized estimation equations analyses were used to study the association between ICU readmissions and post-ICU mortality rates and the identified discharge practices, i.e. (1) ICU discharge criteria; (2) bed managers; (3) early discharge planning; (4) step-down facilities; (5) medication reconciliation; (6) verbal and written handover; (7) monitoring of post-ICU patients; and (8) consulting ICU nurses. In all analyses, the outcomes were corrected for patient-related confounding factors. RESULTS: The standardized rate of ICU readmissions varied between 0.14 and 2.67 and 20.8% of the hospitals fell outside the 95% control limits and 3.6% outside the 99.8% control limits. The standardized rate of post-ICU mortality varied between 0.07 and 2.07 and 17.1% of the hospitals fell outside the 95% control limits and 4.9% outside the 99.8% control limits. We could not demonstrate an association between the eight ICU discharge practices and rates of ICU readmissions or post-ICU in-hospital mortality. Implementing a higher number of ICU discharge practices was also not associated with better patient outcomes. CONCLUSIONS: We found both variation in patient outcomes and variation in ICU discharge practices between ICUs. However, we found no association between discharge practices and rates of ICU readmissions or post-ICU mortality. Further research is necessary to find factors, which may influence these patient outcomes, in order to improve quality of care.

Systematic Review and Meta-analysis of Intelligence Quotient in Early-Treated Individuals with Classical Galactosemia.

INTRODUCTION: Cognitive impairment is a well-known complication of classical galactosemia (CG). Differences in patient characteristics and test methods have hampered final conclusions regarding the extent of intellectual disabilities in CG. The primary aim of this systematic review was to assess intellectual performance in early-treated (≤4 weeks of life) individuals with confirmed CG (defined by absent or barely detectable GALT enzyme activity and/or the presence of two null or severe missense variations), assessed with comparable test instruments. The full-scale IQ (FSIQ) was the variable of interest. METHODS: A clinical librarian developed search strategies, and two independent investigators performed the study selection, risk of bias assessment and data extraction. Individual patient data were pooled for meta-analysis using linear mixed-effect models with a random intercept per study and including covariates (age or gender) as fixed effects where appropriate. RESULTS: Four articles were included in this meta-analysis. Data of 87 individuals (median age 13 years, range 3-38 years) were used to assess mean FSIQ in CG. The FSIQ ranged from 47 to 122, and the mean score was 87 (95% CI, 81-94). Forty-five percent of individuals attained scores <85, almost 40% attained scores of 85-100, and a minority (15%) attained scores above 100. There was no significant correlation between FSIQ and age. CONCLUSIONS: Results from this meta-analysis fortify conclusions from previous studies that early-treated individuals with CG are at risk for having impaired cognitive abilities. However, IQ varies considerably between affected individuals.

Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis.

BACKGROUND: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. METHODS: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. FINDINGS: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%. INTERPRETATION: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities. FUNDING: ERA-EDTA and ESPN.

Which Models Can I Use to Predict Adult ICU Length of Stay? A Systematic Review.

OBJECTIVE: We systematically reviewed models to predict adult ICU length of stay. DATA SOURCES: We searched the Ovid EMBASE and MEDLINE databases for studies on the development or validation of ICU length of stay prediction models. STUDY SELECTION: We identified 11 studies describing the development of 31 prediction models and three describing external validation of one of these models. DATA EXTRACTION: Clinicians use ICU length of stay predictions for planning ICU capacity, identifying unexpectedly long ICU length of stay, and benchmarking ICUs. We required the model variables to have been published and for the models to be free of organizational characteristics and to produce accurate predictions, as assessed by R across patients for planning and identifying unexpectedly long ICU length of stay and across ICUs for benchmarking, with low calibration bias. We assessed the reporting quality using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies. DATA SYNTHESIS: The number of admissions ranged from 253 to 178,503. Median ICU length of stay was between 2 and 6.9 days. Two studies had not published model variables and three included organizational characteristics. None of the models produced predictions with low bias. The R was 0.05-0.28 across patients and 0.01-0.64 across ICUs. The reporting scores ranged from 49 of 78 to 60 of 78 and the methodologic scores from 12 of 22 to 16 of 22. CONCLUSION: No models completely satisfy our requirements for planning, identifying unexpectedly long ICU length of stay, or for benchmarking purposes. Physicians using these models to predict ICU length of stay should interpret them with reservation.

Effect of fructose consumption on insulin sensitivity in nondiabetic subjects: a systematic review and meta-analysis of diet-intervention trials.

BACKGROUND: High fructose consumption has been suggested to contribute to several features of metabolic syndrome including insulin resistance, but to our knowledge, no previous meta-analyses have investigated the effect of fructose on insulin sensitivity in nondiabetic subjects. OBJECTIVE: We performed a systematic review and meta-analysis of controlled diet-intervention studies in nondiabetic subjects to determine the effect of fructose on insulin sensitivity. DESIGN: We searched MEDLINE, EMBASE, and the Cochrane Library for relevant trials on the basis of predetermined eligibility criteria. Two investigators independently performed the study selection, quality assessment, and data extraction. Results were pooled with the use of the generic inverse-variance method with random effects weighting and were expressed as mean differences (MDs) or standardized mean differences (SMDs) with 95% CIs. RESULTS: Twenty-nine articles that described 46 comparisons in 1005 normal-weight and overweight or obese participants met the eligibility criteria. An energy-matched (isocaloric) exchange of dietary carbohydrates by fructose promoted hepatic insulin resistance (SMD: 0.47; 95% CI: 0.03, 0.91; P = 0.04) but had no effect on fasting plasma insulin concentrations (MD: -0.79 pmol/L; 95% CI: -6.41, 4.84 pmol/L; P = 0.78), the homeostasis model assessment of insulin resistance (HOMA-IR) (MD: 0.13; 95% CI: -0.07, 0.34; P = 0.21), or glucose disposal rates under euglycemic hyperinsulinemic clamp conditions (SMD: 0.00; 95% CI: 20.41, 0.41; P = 1.00). Hypercaloric fructose (∼25% excess of energy compared with that of the weight-maintenance control diet) raised fasting plasma insulin concentrations (MD: 3.38 pmol/L; 95% CI: 0.03, 6.73 pmol/L; P < 0.05) and induced hepatic insulin resistance (SMD: 0.77; 95% CI: 0.28, 1.26; P < 0.01) without affecting the HOMA-IR (MD: 0.18; 95% CI: -0.02, 0.39; P = 0.08) or glucose disposal rates (SMD: 0.10; 95% CI: -0.21, 0.40; P = 0.54). Results may have been limited by the low quality, small sample size, and short duration (mostly <60 d) of included trials. CONCLUSIONS: Short-term fructose consumption, in isocaloric exchange or in hypercaloric supplementation, promotes the development of hepatic insulin resistance in nondiabetic adults without affecting peripheral or muscle insulin sensitivity. Larger and longer-term studies are needed to assess whether real-world fructose consumption has adverse effects on insulin sensitivity and long-term outcomes.