Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU ...biomarkers (phenylalanine, glutamyl‐phenylalanine, glutamyl‐glutamyl‐phenylalanine, N‐lactoyl‐phenylalanine, N‐acetyl‐phenylalanine, the dipeptides phenylalanyl‐phenylalanine and phenylalanyl‐leucine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well‐defined PKU patient‐COBESO cohort and a healthy control group. Serum samples of 35 PKU adults and 20 healthy age‐ and sex‐matched controls were analyzed using ultra‐high performance liquid chromatography quadrupole time‐of‐flight mass spectrometry. Group differences were tested using the Mann–Whitney U test. Multiple linear regression analyses were performed with these biomarkers as predictors of (neuro‐)cognitive functions working memory, sustained attention, inhibitory control, and mental health. Compared to healthy controls, phenylalanine, glutamyl‐phenylalanine, N‐lactoyl‐phenylalanine, N‐acetyl‐phenylalanine, phenylalanine–hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate were significant elevated in PKU adults (p < 0.001). The remaining three were below limit of detection in PKU and controls. Both phenylalanine and N‐lactoyl‐phenylalanine were associated with DSM‐VI Attention deficit/hyperactivity (R2 = 0.195, p = 0.039 and R2 = 0.335, p = 0.002, respectively) of the ASR questionnaire. In addition, N‐lactoyl‐phenylalanine showed significant associations with ASR DSM‐VI avoidant personality (R2 = 0.265, p = 0.010), internalizing (R2 = 0.192, p = 0.046) and externalizing problems (R2 = 0.217, p = 0.029) of the ASR questionnaire and multiple aspects of the MS2D and FI tests, reflecting working memory with R2 between 0.178 (p = 0.048) and 0.204 (p = 0.033). Even though the strength of the models was not considered strong, N‐lactoyl‐phenylalanine outperformed phenylalanine in its association with working memory and mental health outcomes.
Background
Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other aetiologies. In recent years, procalcitonin (PCT), a ...blood marker for bacterial infections, has emerged as a promising tool to improve decisions about antibiotic therapy (PCT‐guided antibiotic therapy). Several randomised controlled trials (RCTs) have demonstrated the feasibility of using procalcitonin for starting and stopping antibiotics in different patient populations with ARIs and different settings ranging from primary care settings to emergency departments, hospital wards, and intensive care units. However, the effect of using procalcitonin on clinical outcomes is unclear. This is an update of a Cochrane review and individual participant data meta‐analysis first published in 2012 designed to look at the safety of PCT‐guided antibiotic stewardship.
Objectives
The aim of this systematic review based on individual participant data was to assess the safety and efficacy of using procalcitonin for starting or stopping antibiotics over a large range of patients with varying severity of ARIs and from different clinical settings.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE, and Embase, in February 2017, to identify suitable trials. We also searched ClinicalTrials.gov to identify ongoing trials in April 2017.
Selection criteria
We included RCTs of adult participants with ARIs who received an antibiotic treatment either based on a procalcitonin algorithm (PCT‐guided antibiotic stewardship algorithm) or usual care. We excluded trials if they focused exclusively on children or used procalcitonin for a purpose other than to guide initiation and duration of antibiotic treatment.
Data collection and analysis
Two teams of review authors independently evaluated the methodology and extracted data from primary studies. The primary endpoints were all‐cause mortality and treatment failure at 30 days, for which definitions were harmonised among trials. Secondary endpoints were antibiotic use, antibiotic‐related side effects, and length of hospital stay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable hierarchical logistic regression adjusted for age, gender, and clinical diagnosis using a fixed‐effect model. The different trials were added as random‐effects into the model. We conducted sensitivity analyses stratified by clinical setting and type of ARI. We also performed an aggregate data meta‐analysis.
Main results
From 32 eligible RCTs including 18 new trials for this 2017 update, we obtained individual participant data from 26 trials including 6708 participants, which we included in the main individual participant data meta‐analysis. We did not obtain individual participant data for four trials, and two trials did not include people with confirmed ARIs. According to GRADE, the quality of the evidence was high for the outcomes mortality and antibiotic exposure, and quality was moderate for the outcomes treatment failure and antibiotic‐related side effects.
Primary endpoints: there were 286 deaths in 3336 procalcitonin‐guided participants (8.6%) compared to 336 in 3372 controls (10.0%), resulting in a significantly lower mortality associated with procalcitonin‐guided therapy (adjusted OR 0.83, 95% CI 0.70 to 0.99, P = 0.037). We could not estimate mortality in primary care trials because only one death was reported in a control group participant. Treatment failure was not significantly lower in procalcitonin‐guided participants (23.0% versus 24.9% in the control group, adjusted OR 0.90, 95% CI 0.80 to 1.01, P = 0.068). Results were similar among subgroups by clinical setting and type of respiratory infection, with no evidence for effect modification (P for interaction > 0.05). Secondary endpoints: procalcitonin guidance was associated with a 2.4‐day reduction in antibiotic exposure (5.7 versus 8.1 days, 95% CI ‐2.71 to ‐2.15, P < 0.001) and lower risk of antibiotic‐related side effects (16.3% versus 22.1%, adjusted OR 0.68, 95% CI 0.57 to 0.82, P < 0.001). Length of hospital stay and intensive care unit stay were similar in both groups. A sensitivity aggregate‐data analysis based on all 32 eligible trials showed similar results.
Authors' conclusions
This updated meta‐analysis of individual participant data from 12 countries shows that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic‐related side effects. Results were similar for different clinical settings and types of ARIs, thus supporting the use of procalcitonin in the context of antibiotic stewardship in people with ARIs. Future high‐quality research is needed to confirm the results in immunosuppressed patients and patients with non‐respiratory infections.
Of the five known dopamine receptors, D1A and D2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in ...the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D1A receptors expressed by direct output neurons and D2 receptors expressed by indirect output neurons. To further examine the interaction of D1A and D2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D1A receptors (D1A-/-). D1A-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D1A receptor binding was absent in striatal sections from D1A-/- mice. Striatal neurons normally expressing functional D1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D2 receptors, are unaffected. These findings show that D1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.
The European Pediatric Pulmonary Vascular Disease Network is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in ...all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles that include pediatric data were searched using the term "pulmonary hypertension" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle- and low-income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.
In patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the ...effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.
Blood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).
BH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.
BH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.
Livestock-caused rangeland degradation remains a major policy concern globally and the subject of widespread scientific study. This concern persists in part because it is difficult to isolate the ...effects of livestock from climate and other factors that influence ecosystem conditions. Further, degradation studies seldom use multiple plant and soil indicators linked to a clear definition of and ecologically grounded framework for degradation assessment that distinguishes different levels of degradation. Here, we integrate two globally applicable rangeland degradation frameworks and apply them to a broad-scale empirical data set for the country of Mongolia. We compare our assessment results with two other recent national rangeland degradation assessments in Mongolia to gauge consistency of findings across assessments and evaluate the utility of our framework. We measured livestock-use impacts across Mongolia’s major ecological zones: mountain and forest steppe, eastern steppe, steppe, and desert steppe. At 143 sites in 36 counties, we measured livestock-use and degradation indicators at increasing distances from livestock corrals in winter-grazed pastures. At each site, we measured multiple indicators linked to our degradation framework, including plant cover, standing biomass, palatability, species richness, forage quality, vegetation gaps, and soil surface characteristics. Livestock use had no effect on soils, plant species richness, or standing crop biomass in any ecological zone, but subtly affected plant cover and palatable plant abundance. Livestock effects were strongest in the steppe zone, moderate in the desert steppe, and limited in the mountain/forest and eastern steppes. Our results aligned closely with those of two other recent country-wide assessments, suggesting that our framework may have widespread application. All three assessments found that very severe and irreversible degradation is rare in Mongolia (1–18% of land area), with most rangelands slightly (33–53%) or moderately (25–40%) degraded. We conclude that very severe livestock-induced rangeland degradation is overstated in Mongolia. However, targeted rangeland restoration coupled with monitoring, adaptive management and stronger rangeland governance are needed to prevent further degradation where heavy grazing could cause irreversible change. Given the broad applicability of our degradation framework for Mongolia, we suggest it be tested for application in other temperate grasslands throughout Central Asia and North America.
In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This ...meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings.
Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects.
We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 9% deaths in 3336 procalcitonin-guided patients vs 336 10% in 3372 controls; adjusted odds ratio OR 0·83 95% CI 0·70 to 0·99, p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days 95% CI −2·71 to −2·15, p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 95% CI 0·57 to 0·82, p<0·0001).
Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance.
National Institute for Health Research.
Objective To quantify the overall effects of bariatric surgery compared with non-surgical treatment for obesity.Design Systematic review and meta-analysis based on a random effects model.Data sources ...Searches of Medline, Embase, and the Cochrane Library from their inception to December 2012 regardless of language or publication status.Eligibility criteria Eligible studies were randomised controlled trials with ≥6 months of follow-up that included individuals with a body mass index ≥30, compared current bariatric surgery techniques with non-surgical treatment, and reported on body weight, cardiovascular risk factors, quality of life, or adverse events.Results The meta-analysis included 11 studies with 796 individuals (range of mean body mass index at baseline 30-52). Individuals allocated to bariatric surgery lost more body weight (mean difference −26 kg (95% confidence interval −31 to −21)) compared with non-surgical treatment, had a higher remission rate of type 2 diabetes (relative risk 22.1 (3.2 to 154.3) in a complete case analysis; 5.3 (1.8 to 15.8) in a conservative analysis assuming diabetes remission in all non-surgically treated individuals with missing data) and metabolic syndrome (relative risk 2.4 (1.6 to 3.6) in complete case analysis; 1.5 (0.9 to 2.3) in conservative analysis), greater improvements in quality of life and reductions in medicine use (no pooled data). Plasma triglyceride concentrations decreased more (mean difference −0.7 mmol/L (−1.0 to −0.4) and high density lipoprotein cholesterol concentrations increased more (mean difference 0.21 mmol/L (0.1 to 0.3)). Changes in blood pressure and total or low density lipoprotein cholesterol concentrations were not significantly different. There were no cardiovascular events or deaths reported after bariatric surgery. The most common adverse events after bariatric surgery were iron deficiency anaemia (15% of individuals undergoing malabsorptive bariatric surgery) and reoperations (8%).Conclusions Compared with non-surgical treatment of obesity, bariatric surgery leads to greater body weight loss and higher remission rates of type 2 diabetes and metabolic syndrome. However, results are limited to two years of follow-up and based on a small number of studies and individuals. Systematic review registration PROSPERO CRD42012003317 (www.crd.york.ac.uk/PROSPERO).
Dried blood spot succinylacetone (SA) is often used as biomarker for newborn screening (NBS) for Tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also ...be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D.
We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of 9 referred newborns (2 TT1, 7 false-positive), 8 genetically confirmed MAAI-D children and 66 controls.
Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the 3 available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n=66), and from 0.95-192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n=10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the 2 newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA.
MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1. This article is protected by copyright. All rights reserved.
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