Davide Gori

Probiotics for prevention of atopic diseases in infants: systematic review and meta‐analysis

Growing evidence underlines the pivotal role of infant gut colonization in the development of the immune system. The possibility to modify gut colonization through probiotic supplementation in childhood might prevent atopic diseases. The aim of the present systematic review and meta‐analysis was to evaluate the effect of probiotic supplementation during pregnancy and early infancy in preventing atopic diseases. PubMed, Embase and Cochrane Library were searched for randomized controlled trials evaluating the use of probiotics during pregnancy or early infancy for prevention of allergic diseases. Fixed‐effect models were used, and random‐effects models where significant heterogeneity was present. Results were expressed as risk ratio (RR) with 95% confidence interval (CI). Seventeen studies, reporting data from 4755 children (2381 in the probiotic group and 2374 in the control group), were included in the meta‐analysis. Infants treated with probiotics had a significantly lower RR for eczema compared to controls (RR 0.78 [95% CI: 0.69–0.89], P = 0.0003), especially those supplemented with a mixture of probiotics (RR 0.54 [95% CI: 0.43–0.68], P < 0.00001). No significant difference in terms of prevention of asthma (RR 0.99 [95% CI: 0.77–1.27], P = 0.95), wheezing (RR 1.02 [95% CI: 0.89–1.17], P = 0.76) or rhinoconjunctivitis (RR 0.91 [95% CI: 0.67–1.23], P = 0.53) was documented. The results of the present meta‐analysis show that probiotic supplementation prevents infantile eczema, thus suggesting a new potential indication for probiotic use in pregnancy and infancy.

Early growth characteristics and the risk of reduced lung function and asthma : A meta-analysis of 25,000 children

BACKGROUND Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Maternal complications in pregnancy and wheezing in early childhood: a pooled analysis of 14 birth cohorts

BACKGROUND Evidence on the effect of maternal complications in pregnancy on wheezing in offspring is still insufficient. METHODS A pooled analysis was performed on individual participant data from fourteen European birth cohorts to assess the relationship between several maternal pregnancy complications and wheezing symptoms in the offspring. Exposures of interest included hypertension and preeclampsia, diabetes, as well as pre-pregnancy overweight (body mass index between 25 and 29.9) and obesity (body mass index ≥ 30) compared with normal weight (body mass index between 18.5 and 24.9). Outcomes included both ever and recurrent wheezing from birth up to 12-24 months of age. Cohort-specific crude and adjusted risk ratios (RR) were calculated using log-binomial regression models and then pooled using a random effects model. RESULTS The study included 85509 subjects. Cohort-specific prevalence of ever wheezing varied from 20.0% to 47.3%, and of recurrent wheezing from 3.0% to 14.3%. Adjusted pooled RR for ever and recurrent wheezing were: 1.02 (95% CI: 0.98-1.06) and 1.20 (95% CI: 0.98-1.47) for hypertensive disorders; 1.09 (95% CI: 1.01-1.18) and 1.23 (95% CI: 1.07-1.43) for preeclampsia; 1.04 (95% CI: 0.97-1.13) and 1.24 (95% CI: 0.86-1.79) for diabetes; 1.08 (95% CI: 1.05-1.11) and 1.19 (95% CI: 1.12-1.26) for overweight; 1.12 (95% CI: 1.08-1.17) and 1.16 (95% CI: 0.97-1.39) for obesity. No heterogeneity was found in RR estimates among the cohorts, except for diabetes and recurrent wheezing (P=0.027). CONCLUSIONS Preeclampsia, maternal pre-pregnancy overweight and obesity are associated with an increase risk of wheezing in the offspring.

MANAGEMENT OF ENDOCRINE DISEASE: Long-term outcomes of the treatment of central precocious puberty

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Drug-Free Interventions to Reduce Pain or Opioid Consumption After Total Knee Arthroplasty: A Systematic Review and Meta-analysis

Importance There is increased interest in nonpharmacological treatments to reduce pain after total knee arthroplasty. Yet, little consensus supports the effectiveness of these interventions. Objective To systematically review and meta-analyze evidence of nonpharmacological interventions for postoperative pain management after total knee arthroplasty. Data Sources Database searches of MEDLINE (PubMed), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Web of Science (ISI database), Physiotherapy Evidence (PEDRO) database, and ClinicalTrials.gov for the period between January 1946 and April 2016. Study Selection Randomized clinical trials comparing nonpharmacological interventions with other interventions in combination with standard care were included. Data Extraction and Synthesis Two reviewers independently extracted the data from selected articles using a standardized form and assessed the risk of bias. A random-effects model was used for the analyses. Main Outcomes and Measures Postoperative pain and consumption of opioids and analgesics. Results Of 5509 studies, 39 randomized clinical trials were included in the meta-analysis (2391 patients). The most commonly performed interventions included continuous passive motion, preoperative exercise, cryotherapy, electrotherapy, and acupuncture. Moderate-certainty evidence showed that electrotherapy reduced the use of opioids (mean difference, −3.50; 95% CI, −5.90 to −1.10 morphine equivalents in milligrams per kilogram per 48 hours; P = .004; I2 = 17%) and that acupuncture delayed opioid use (mean difference, 46.17; 95% CI, 20.84 to 71.50 minutes to the first patient-controlled analgesia; P < .001; I2 = 19%). There was low-certainty evidence that acupuncture improved pain (mean difference, −1.14; 95% CI, −1.90 to −0.38 on a visual analog scale at 2 days; P = .003; I2 = 0%). Very low-certainty evidence showed that cryotherapy was associated with a reduction in opioid consumption (mean difference, −0.13; 95% CI, −0.26 to −0.01 morphine equivalents in milligrams per kilogram per 48 hours; P = .03; I2 = 86%) and in pain improvement (mean difference, −0.51; 95% CI, −1.00 to −0.02 on the visual analog scale; P < .05; I2 = 62%). Low-certainty or very low-certainty evidence showed that continuous passive motion and preoperative exercise had no pain improvement and reduction in opioid consumption: for continuous passive motion, the mean differences were −0.05 (95% CI, −0.35 to 0.25) on the visual analog scale (P = .74; I2 = 52%) and 6.58 (95% CI, −6.33 to 19.49) opioid consumption at 1 and 2 weeks (P = .32, I2 = 87%), and for preoperative exercise, the mean difference was −0.14 (95% CI, −1.11 to 0.84) on the Western Ontario and McMaster Universities Arthritis Index Scale (P = .78, I2 = 65%). Conclusions and Relevance In this meta-analysis, electrotherapy and acupuncture after total knee arthroplasty were associated with reduced and delayed opioid consumption.

DNA methylation in childhood asthma: an epigenome-wide meta-analysis

BACKGROUND DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. METHODS We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4-5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4-16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2-56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1-79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. FINDINGS 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p<1·14 × 10-7) after meta-analysis. Consistently lower methylation levels were observed at all associated loci across childhood from age 4 to 16 years in participants with asthma, but not in cord blood at birth. All 14 CpG sites were significantly associated with asthma in the second replication study using whole-blood DNA, and were strongly associated with asthma in purified eosinophils. Whole-blood transcriptional signatures associated with these CpG sites indicated increased activation of eosinophils, effector and memory CD8 T cells and natural killer cells, and reduced number of naive T cells. Five of the 14 CpG sites were associated with asthma in respiratory epithelial cells, indicating cross-tissue epigenetic effects. INTERPRETATION Reduced whole-blood DNA methylation at 14 CpG sites acquired after birth was strongly associated with childhood asthma. These CpG sites and their associated transcriptional profiles indicate activation of eosinophils and cytotoxic T cells in childhood asthma. Our findings merit further investigations of the role of epigenetics in a clinical context. FUNDING EU and the Seventh Framework Programme (the MeDALL project).

Probiotics and Time to Achieve Full Enteral Feeding in Human Milk-Fed and Formula-Fed Preterm Infants: Systematic Review and Meta-Analysis.

Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta-analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD −3.15 days (95% CI −5.25/−1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management.

Impact of Procedure Volumes and Focused Practice on Short-Term Outcomes of Elective and Urgent Colon Cancer Resection in Italy

Background The relationship between hospital volumes and short-term patients’ outcomes of colon cancer (CC) surgery is not well established in the literature. Moreover, evidence about short-term outcomes of urgent compared with elective CC procedures is scanty. The aims of this study are 1) to determine whether caseloads and other hospital characteristics are associated with short-term outcomes of CC surgery; 2) to compare the outcomes of urgent and elective CC surgery. Methods A total of 14,200 patients undergoing CC surgery between 2005 and 2010 in the General Surgery Units (GSUs) of the hospitals of Emilia-Romagna region, Northern Italy, were identified from the hospital discharge records database. The outcomes of interest were 30-day in-hospital mortality, re-intervention and 30-day re-admission. Using multilevel analysis, we analyzed the relationship of GSU volumes and focused practice, defined as the percentage of CC operations over total operations, with the three outcomes. Results High procedure volumes were associated with a lower risk of 30-day in-hospital mortality, after adjusting for patients’ characteristics [aOR (95% CI) = 0.51 (0.33–0.81)]. Stratified analyses for elective and urgent surgery showed that high volumes were associated with a lower 30-day mortality for elective patients [aOR (95% CI) = 0.35 (0.17–0.71)], but not for urgent patients [aOR (95% CI) = 0.72 (0.42–1.24)]. Focused practice was an independent predictor of re-intervention [aOR (95% CI) = 0.67 (0.47–0.97)] and re-admission [aRR (95% CI) = 0.88 (0.78–0.98)]. Conclusions The present study adds evidence in support of the notion that patients with CC undergoing surgery at high-volume and focused surgical units experience better short-term outcomes.

Probiotics Prevent Late-Onset Sepsis in Human Milk-Fed, Very Low Birth Weight Preterm Infants: Systematic Review and Meta-Analysis

Growing evidence supports the role of probiotics in reducing the risk of necrotizing enterocolitis, time to achieve full enteral feeding, and late-onset sepsis (LOS) in preterm infants. As reported for several neonatal clinical outcomes, recent data have suggested that nutrition might affect probiotics’ efficacy. Nevertheless, the currently available literature does not explore the relationship between LOS prevention and type of feeding in preterm infants receiving probiotics. Thus, the aim of this systematic review and meta-analysis was to evaluate the effect of probiotics for LOS prevention in preterm infants according to type of feeding (exclusive human milk (HM) vs. exclusive formula or mixed feeding). Randomized-controlled trials involving preterm infants receiving probiotics and reporting on LOS were included in the systematic review. Only trials reporting on outcome according to feeding type were included in the meta-analysis. Fixed-effects models were used and random-effects models were used when significant heterogeneity was found. The results were expressed as risk ratio (RR) with 95% confidence interval (CI). Twenty-five studies were included in the meta-analysis. Overall, probiotic supplementation resulted in a significantly lower incidence of LOS (RR 0.79 (95% CI 0.71–0.88), p < 0.0001). According to feeding type, the beneficial effect of probiotics was confirmed only in exclusively HM-fed preterm infants (RR 0.75 (95% CI 0.65–0.86), p < 0.0001). Among HM-fed infants, only probiotic mixtures, and not single-strain products, were effective in reducing LOS incidence (RR 0.68 (95% CI 0.57–0.80) p < 0.00001). The results of the present meta-analysis show that probiotics reduce LOS incidence in exclusively HM-fed preterm infants. Further efforts are required to clarify the relationship between probiotics supplementation, HM, and feeding practices in preterm infants.

Long-term outcomes of the treatment of central precocious puberty

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.