Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis.

OBJECTIVE: To evaluate the relative efficacy and safety of different oral anticoagulant agents (OACs) for patients with atrial fibrillation (AF) and chronic kidney disease (CKD). STUDY DESIGN: Systematic review and pairwise and Bayesian network meta-analysis. SETTING & STUDY POPULATIONS: Adult patients with AF and CKD stages 3-5D who received OACs. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials (RCTs) and observational studies that reported the efficacy and safety outcomes of subgroups with a glomerular filtration rate (GFR)<60mL/min. DATA EXTRACTION: Two reviewers independently abstracted data, assessed study quality, and rated the strength of evidence (SOE). ANALYTICAL APPROACH: Random-effects models using restricted maximum-likelihood methods were fit for the pairwise meta-analyses as well as a network meta-analysis within a Bayesian framework. RESULTS: Pairwise meta-analysis including 8 RCTs and 46 observational studies showed that direct OACs (DOACs) were superior to warfarin in preventing thromboembolic events (hazard ratio [HR], 0.86 [95% CI, 0.78-0.95]), without heterogeneity (I2=10.5%), and in reducing the risk of bleeding events (HR, 0.81 [95% CI, 0.66-0.99]), with substantial heterogeneity (I2=69.8%), in patients with AF and a GFR of 15-60mL/min. Bayesian network meta-analysis including 8 RCTs showed that dose-adjusted apixaban and a 15-mg dose of edoxaban were superior to the other OAC regimens in reducing bleeding events. Dose-adjusted apixaban was more effective than edoxaban in preventing thromboembolic events for patients with AF and GFR in the range of 25-50 or 30-50mL/min. In dialysis recipients with AF, the use of OACs increased the risk of bleeding events by 28% (HR, 1.28 [95% CI, 1.03-1.60]) without significant beneficial effects versus not using anticoagulants. LIMITATIONS: Low SOE and heterogeneity in most comparisons. CONCLUSIONS: This study suggests that DOACs are superior to warfarin for the prevention of thromboembolic events and reduction in bleeding risk in patients with AF and mild to moderate kidney disease. However, the low SOE limits the conclusions that can be drawn about the preferred DOAC. Notably, the use of OACs may increase bleeding risk without significant benefits in dialysis recipients with AF. REGISTRATION: Registered at PROSPERO with identification number CRD42018090896.

Two kinds of rare light chain cast nephropathy caused by multiple myeloma: case reports and literature review.

BACKGROUND: Light chain cast nephropathy (LCCN) is the most common renal disease caused by multiple myeloma (MM). In addition to ordinary light chain protein casts, there are a few rare casts with unique shapes, including light chain amyloid casts (LCAC) and light chain crystal casts (LCCC). CASE PRESENTATIONS: Here, we report two patients. Patient 1 is a 72-year-old man who was clinically diagnosed with MM and acute kidney injury (AKI). Pathological examination of a renal biopsy revealed that there were many amyloid casts in the distal tubules that had a lightly-stained central area and a deeply-stained burr-like edge. The marginal zone of the cast was positive for Congo red staining and contained numerous amyloid fibers, as observed by electron microscopy. No systemic amyloidosis was found. The patient received 4 courses of bortezomib-based chemotherapy, and then, his MM achieved partial remission. Patient 2 is a 57-year-old man who was also clinically diagnosed with MM and AKI. Pathological examination of a renal biopsy showed that there were many crystalline casts in the distal tubules that were fully or partially composed of crystals with different shapes, including rhomboid, needle, triangle, rectangle and other geometric shapes. Congo red staining was negative. Crystals were also detected in the urine of this patient. After 9 courses of treatment with a bortezomib-based regimen, his MM obtained complete remission and his renal function returned to normal. CONCLUSIONS: LCAC and LCCC nephropathy caused by MM are two rare types of LCCN, and both have their own unique morphological manifestations. LCAC nephropathy may not be accompanied by systemic amyloidosis. The diagnosis of these two unique LCCNs must rely on renal biopsy pathology, and the discovery of urine crystals is of great significance for indicating LCCC nephropathy.

Antineutrophil cytoplasmic antibody and/or antiglomerular basement membrane antibody associated crescentic glomerulonephritis in combination with IgG4-related tubulointerstitial nephritis.

OBJECTIVES: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder and is characterised by elevated serum IgG4 concentrations and dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells. IgG4-related tubulointerstitial nephritis (IgG4-TIN) is the most common manifestation of IgG4-related kidney disease (IgG4-RKD). We report four cases of kidney injury with concurrent IgG4-TIN and crescentic glomerulonephritis confirmed by renal pathology. METHODS: The medical charts of four patients were reviewed to collect clinical and laboratory data at the time of diagnosis, treatment and outcomes after 6-36 months. Two of them are cases of IgG4-TIN with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and the other two cases are rare IgG4-TIN with antiglomerular basement membrane (anti-GBM) glomerulonephritis coexistent with ANCA-positive serum. RESULTS: Compared with IgG4-TIN, IgG4-TIN combined with AAV or anti-GBM glomerulonephritis is less associated with other organ injuries, and the clinical manifestations, treatment effects and prognosis were consistent with that of crescentic glomerulonephritis. CONCLUSIONS: IgG4-TIN concurrent with anti-GBM glomerulonephritis and positivity in serum has more severe clinical features and a worse renal prognosis than IgG4-TIN coexistent with AVV.

Effect of antiplatelet therapy on cardiovascular and kidney outcomes in patients with chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: The benefits and risks of antiplatelet therapy for patients with chronic kidney disease (CKD) remain controversial. We undertook a systematic review and meta-analysis to investigate the effects of antiplatelet therapy on major clinical outcomes. METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library for trials published before April 2019 without language restriction. We included rrandomized controlled trials that involved adults with CKD and compared antiplatelet agents with controls. RESULTS: Fifty eligible trials that included at least one event were identified, providing data for 27773patients with CKD, including 4518 major cardiovascular events and 1962 all-cause deaths. Antiplatelet therapy produced a 15% (OR, 0.85; 95% CI 0.74-0.94) reduction in the odds of major cardiovascular events (P = 0.002), a 48% reduction for access failure events (OR, 0.52; 95% CI, 0.31-0.73), but had no significantly effect on all-cause death (OR, 0.87; 95% CI, 0.71-1.01) or kidney failure events (OR, 0.87; 95% CI, 0.32-1.55). Adverse events were significantly increased by antiplatelet therapy, including major (OR, 1.33; 95% CI, 1.11-1.59) or minor bleeding (OR, 1.66; 95% CI, 1.27-2.05). Among every 1000 persons with CKD treated with antiplatelet therapy for 12 months, 23 major cardiovascular events will be prevented while nine major bleeding events will occur. CONCLUSIONS: Major prevention with antiplatelet agents (cardiovascular events and access failure), might outweigh the risk of bleeding, and there seemed to be an overall net benefit. Individual evaluation and careful monitoring are required.

Derivation and validation of a prediction score for acute kidney injury secondary to acute myocardial infarction in Chinese patients.

BACKGROUND: Acute kidney injury (AKI) is a major complication of acute myocardial infarction(AMI), which can significantly increase mortality. This study is to analyze the related risk factors and establish a prediction score of acute kidney injury in order to take early measurement for prevention. METHODS: The medical records of 6014 hospitalized patients with AMI in Beijing Anzhen Hospital from January 2010 to December 2016 were retrospectively analyzed. These patients were randomly assigned into two cohorts: one was for the derivation of prediction score (n = 4252) and another for validation (n = 1762). The criterion for AKI was defined as an increase in serum creatinine of ≥ 0.3 mg/dL or ≥ 50% from baseline within 48 h. On the basis of odds ratio obtained from multivariate logistic regression analysis, a prediction score of acute kidney injury after AMI was built up. RESULTS: In this prediction score, risk score 1 point included hypertension history, heart rate > 100 bpm on admission, peak serum troponin I ≥ 100 µg/L, and time from admission to coronary reperfusion > 120 min; risks score 2 points included Killip classification ≥ class 3 on admission; and maximum dosage of intravenous furosemide ≥ 60 mg/d; risks score 3 points only included shock during hospitalization. In addition, when baseline estimated glomerular filtration rate (eGFR) was less than 90 ml/min·1.73 m2, every 10 ml/min·1.73 m2 reduction of eGFR increased risk score 1 point. Youden index showed that the best cut-off value for prediction of AKI was 3 points with a sensitivity of 71.1% and specificity 74.2%. The datasets of derivation and validation both displayed adequate discrimination (an area under the ROC curve, 0.79 and 0.81, respectively) and satisfactory calibration (Hosmer-Lemeshow statistic test, P = 0.63 and P = 0.60, respectively). CONCLUSIONS: In conclusion, a prediction score for AKI secondary to AMI in Chinese patients was established, which may help to prevent AKI early.

[Application of Immunohistochemistry and Immunofluorescence Staining in Detection of Phospholipase A2 Receptor on Paraffin Section of Renal Biopsy Tissue].

OBJECTIVE: To evaluate the application of immunohistochemistry and fluorescence staining method in the detection of phospholipase A2 receptor (PLA2R) on paraffin section of renal biopsy tissue,and to find an accurate and fast method for the detection of PLA2R in renal tissue. METHODS: The PLA2R of 193 cases were detected by immunohistochemical staining,and the antigen was repaired by the method of high pressure cooker (HPC) hot repair plus trypsin repair. The 193 samples including 139 cases of idiopathic membranous nephropathy (IMN), 15 cases of membranous lupus nephritis, 8 cases of hepatitis B virus associated membranous nephropathy, 18 cases of IgA nephropathy, and 13 cases of minimal change diseases. To compare the dyeing effects, 22 paraffin sections of renal biopsy tissue of IMN cases with positive PLA2R were stained by using 4 different. METHODS: of antigen repairing,which included HPC hot repair, HPC hot repair plus trypsin repair, water bath heat repair, and water bath heat repair plus trypsin repair. To compare the dyeing effects, 15 paraffin sections of renal biopsy tissue of IMN cases with positive PLA2R were stained by using 3 different. METHODS: of antigen repairing,which included water bath heat repair plus trypsin repair, protease K digestion repair, and pepsin digestion repair. RESULTS: In 193 cases, the positive rate of PLA2R in IMN cases was 90.6% (126/139), and the other 54 patients without IMN were negative. Twenty-two IMN patients were positive for PLA2R by using the HPC heat repair plus trypsin repaire or the water bath heat repair plus trypsin repair;while only a few cases of 22 IMN cases were positive by using the HPC hot repair alone or water bath heat repair alone. Fifteen IMN patients were positive for PLA2R by using water bath heat repair plus trypsin repair,protease K digestion repair,and pepsin digestion repair, but the distribution of positive deposits and the background were different. CONCLUSIONS: PLA2R immunohistochemical staining can effectively identify IMN and secondary MN. For immunohistochemical staining and immunofluorescence staining, the preferred method of antigen repair is water bath heat repair plus trypsin repair.

Derivation and validation of a risk score for contrast-induced nephropathy after cardiac catheterization in Chinese patients.

BACKGROUND: To derive and validate a risk score for prediction of contrast-induced nephropathy (CIN) in the Chinese patients undergoing cardiac catheterization. METHODS: The hospital medical records of 3945 patients undergoing coronary angiography or percutaneous coronary intervention were reviewed. Patients were randomly assigned into two cohorts: one was for derivation of risk score (n = 2764) and another for validation (n = 1181). The CIN was defined as an increase of serum creatinine level ≥44.2 µmol/L or ≥25 % and beyond its upper limit of normal value within 72 h following the procedure. On the basis of the odds ratio obtained from multivariate logistic regression, risk score of CIN was built up. The discrimination of the risk score was assessed using the area under the receiver operating characteristic curve and the calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The incidences of CIN in the derivation and validation cohorts were 4.6 and 4.2 %, respectively. Independent predictors included age >60 years, hypertension, acute myocardial infarction, heart failure, use of intra-aortic balloon pump, decreased glomerular filtration rate and contrast volume >100 mL. The incidence of CIN was increased with increment of risk score. Both the derivation and validation cohorts showed adequate discrimination (an area under the ROC curve, 0.76 and 0.71, respectively) and good calibration (Hosmer-Lemeshow statistic test, P = 0.50 and P = 0.54, respectively). CONCLUSION: A simple risk score for prediction of CIN development after cardiac catheterization in Chinese patients was built up by this study. Use of this risk score may help clinicians to perform early preventative strategies to minimize the risk of CIN.

Derivation and validation of a prediction score for acute kidney injury in patients hospitalized with acute heart failure in a Chinese cohort.

AIMS: Acute kidney injury (AKI) is a common complication among patients hospitalized for acute heart failure (AHF), and is associated with increased mortality. The goal of this study was to derive and validate a prediction score for AKI in AHF patients. METHODS: The hospital medical records of 1709 patients with AHF were reviewed. AKI was defined as an increase in serum creatinine (SCr) of ≥26.4 µmol/L or ≥50% within 48 h. A multivariate logistic regression analysis was undertaken to develop a new prediction score. The area under the receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow goodness-of-fit statistic test were calculated to assess the discrimination and calibration of the prediction score, respectively. RESULTS: Acute kidney injury developed in 32.2% of patients with AHF. Factors independently associated with the risk of AKI included: ≥70 years of age, ≥3 previous hospital admissions for AHF, systolic blood pressure <90 mmHg, serum sodium <130 mmol/L, heart functional class IV, proteinuria, SCr ≥104 µmol/L and intravenous furosemide dose ≥80 mg/day. A prediction score for AKI was derived based on the ß coefficients of each risk factor. Patients with ≥8 points would be considered at high risk for development of AKI (55.1% incidence vs 18% in those with <8 points, P < 0.001). Both the derived and validated datasets showed adequate discrimination (area under ROC curve was 0.76 in both datasets) and calibration (Hosmer-Lemeshow statistic test, P = 0.98 and 0.13, respectively). CONCLUSION: The newly derived and validated clinical prediction score may effectively predict AKI in the patients hospitalized with AHF.

Effectiveness of Growing-Up Milk Containing Only A2 ß-Casein on Digestive Comfort in Toddlers: A Randomized Controlled Trial in China.

BACKGROUND: Emerging clinical evidence indicates the potential gastrointestinal (GI) benefits of milk containing only A2 ß-casein, but data from randomized controlled trials is sparse among pediatric populations. We aimed to evaluate the effectiveness of growing-up milk (GUM) containing only A2 ß-casein on GI tolerance in toddlers. METHODS: A total of 387 toddlers aged 12-36 months were recruited in Beijing, China, and randomized in a 1:1:1 ratio to consume one of two commercially available A2 GUMs (combined in the analysis as A2 GUM) or continue their current feeding regimen of conventional milk for 14 days. The primary outcome was the total Gut Comfort Score (GCS) (range: 10-60; higher values indicate greater GI distress) derived from a 10-item (score range: 1-6 per item) parent-reported questionnaire, reflecting GI tolerance. RESULTS: The GCS (mean ± SD) was comparable between the A2 GUM and conventional milk groups on day 7 (14.7 ± 5.0 vs. 15.0 ± 6.1, p = 0.54) and day 14 (14.0 ± 4.5 vs. 14.3 ± 5.5, p = 0.51). Parents reported less constipation in those consuming A2 GUM vs. conventional milk on day 14 (1.3 ± 0.6 vs. 1.4 ± 0.9, p = 0.020). Among 124 participants with minor GI distress at baseline (GCS ≥ 17, top tertile range 17-35), GCS was significantly lower in those consuming A2 GUM on day 7 (18.2 ± 5.1 vs. 21.2 ± 6.8, p = 0.004) and day 14 (17.1 ± 5.3 vs. 19.6 ± 6.3, p = 0.026), as were individual GI symptoms (all p < 0.05). In the toddlers without GI issues at baseline (GCS < 17), a low GCS was maintained throughout the study period after switching to A2 GUM (mean values range 10-13). CONCLUSIONS: Growing-up milk containing only A2 ß-casein were well-tolerated and associated with lower parent-reported constipation scores after two weeks when compared to conventional milks. In healthy toddlers with minor GI distress, A2 GUM improved overall digestive comfort and GI-related symptoms within one week.

JNK-dependent AP-1 activation is required for aristolochic acid-induced TGF-ß1 synthesis in human renal proximal epithelial cells.

Chronic aristolochic acid nephropathy (CAAN) is a chronic and progressive tubulointerstitial nephropathy characterized by extensive interstitial fibrosis. Aristolochic acid (AA) could induce overexpression of transforming growth factor-ß1 (TGF-ß1) in a human renal proximal tubule epithelial cells line (HKC), which has been implicated in the pathogenesis of CAAN. The present studies in HKC cells showed 1) AA could activate JNK in time- and dose-dependent manners and JNK inhibitor SP600125 could inhibit AA-induced TGF-ß1 promoter activity and TGF-ß1 synthesis; 2) AA-induced JNK activation and TGF-ß1 synthesis were significantly inhibited by kinase-inactive mutants of MEKK4, MKK4, or MKK7; 3) AA could upregulate luciferase activity derived by a wild-type TGF-ß1 promoter, but not by an AP-1 binding-deficient TGF-ß1 promoter; and 4) AA could upregulate expression of c-Fos, phospho-c-Jun, and phospho-ATF2. The above data suggest AA-induced TGF-ß1 overexpression in HKC cells may be mainly mediated by the JNK signaling pathway. Both the upstream kinases of JNK including MEKK4, MKK4, and MKK7, and the downstream transcription factor of JNK, AP-1, may also participate in this process.

Determination of normal value of glomerular size in Chinese adults by different measurement methods.

AIM: Identification of glomerulomegaly is a prerequisite for diagnosis of obesity-related glomerulopathy, so measurement of glomerular size is of critical importance. METHODS: A total 100 cases pathologically diagnosed as minor glomerular abnormalities or thin basement membrane nephropathy with normal body mass index and blood glucose level were selected as the normal value measurement group of glomerular size. The mean value of diameters of capillary tuft on the glomerular maximum profile was determined using the direct method and indirect method with the Motic Med 6.0 digital medical image analysis system. Meanwhile, 80 cases of different glomerular disease with normal body mass index and blood glucose level were also collected. Their glomerular diameters were measured and compared with those in the normal value measurement group. RESULTS: The measurement results showed that gender and age had no effects on glomerular diameter. The normal value ranges of the diameter on glomerular maximum profile were as follows. (i) Pole-containing glomerulus (the glomerulus with vascular pole or/and urinary pole): direct method, 101.3-184.9 µm; indirect method, 100.3-183.5 µm. (ii) Pole-containing glomerulus plus non-pole glomerulus (the glomerulus without poles, the maximum profile of which was larger than that in the smallest pole-containing glomerulus): direct method, 108.3-185.9 µm; indirect method, 107.4-185.4 µm. The glomerular diameters of the 80 cases with different glomerular disease were all within the aforementioned normal value ranges. CONCLUSIONS: Both methods used in the present study are feasible to measure the glomerular diameter and the normal value range of glomerular diameter in Chinese adults is established.

Comparative efficacy and safety of oral anticoagulants for the treatment of venous thromboembolism in the patients with different renal functions: a systematic review, pairwise and network meta-analysis.

OBJECTIVES: To compare the efficacy and safety of direct oral anticoagulants (DOACs) in patients with venous thromboembolism (VTE) and different renal functions. DESIGN: Systematic review containing pairwise and Bayesian network meta-analysis of randomised controlled trials (RCTs). DATA SOURCES: MEDLINE, EMBASE and Cochrane Library. ELIGIBILITY CRITERIA: RCTs reporting the efficacy and safety outcomes of DOACs in different creatinine clearance (CrCl) subgroups. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment were undertaken by two independent reviewers. Data were pooled using the DerSimonian-Laird method in pairwise meta-analysis. Network meta-analysis within a Bayesian framework was conducted. RESULTS: Data from 10 RCTs were included. In the treatment of acute VTE, DOACs did not significantly reduce recurrent VTE or VTE-related death (OR, 0.96; 95% CI, 0.82 to 1.11) but significantly reduced bleeding events (0.76, 0.68 to 0.90) compared with warfarin. In the extended treatment of VTE, DOACs produced significant benefits in recurrent VTE or VTE-related death (0.23, 0.16 to 0.29), but significantly increased bleeding events (1.86, 1.04 to 3.33) compared with placebo/aspirin. There were no significant differences in efficacy and safety of DOACs among the three CrCl stratified subgroups in acute and extended treatment of VTE (p for subgroup heterogeneity >0.1). Bayesian network meta-analysis suggested that apixaban 2.5 mg and 5 mg two times per day were associated with a lower risk of bleeding than dabigatran, rivaroxaban, warfarin and aspirin in the subgroup with CrCl >80 mL/min. CONCLUSIONS: For the treatment of acute VTE, DOACs are similar to warfarin in reducing recurrent VTE and VTE-related death but are significantly superior to warfarin in reducing the risk of bleeding. For the efficacy and safety of DOACs across different CrCl stratifications (30-50, 50-80 and more than 80 mL/min), no significant difference was found. In light of minimal evidence, apixaban might be associated with a lower risk of bleeding in patients with VTE and CrCl >80 mL/min. PROSPERO REGISTRATION NUMBER: CRD42018090896.

Effects of higher protein formula with improved fat blend on growth, feeding tolerance and nutritional biomarkers in preterm infants: A double-blind, randomized, controlled clinical trial.

BACKGROUND: Preterm formulas containing greater protein:energy ratio are beneficial for non-breastfed infants, since protein is critical for promoting catch-up growth and synthesis of lean body mass. Additionally, formulas containing enriched sn-2 palmitate (sn-2) and reduced medium chain triglycerides (MCTs) may support better feeding tolerance and nutrient utilization. METHODS: The objective of this randomized, controlled, double-blinded clinical trial is to evaluate growth, feeding tolerance and nutritional biomarkers of preterm infants with birth weight ≤2000g and gestational age ≤33wks from one neonatal unit in Vietnam receiving experimental formula (EF, n = 80) containing higher protein level of 3.4 g/100 kcal and improved fat blend with enriched sn-2 and modified level of MCTs or isocaloric control formula (CF, n = 80) containing protein level of 2.9 g/100 kcal and standard fat blend. The differences in weight gain (g/d; primary endpoint) from day 1 (D1) of full enteral feeding (FEF) until D21 between groups was evaluated for non-inferiority (margin = -2.5  g/d) and superiority (margin = 0  g/d). RESULTS: Mean weight gain was 3.09  g/d greater in EF than CF; the lower limit of 95% CI (0.31  g/d) exceeded both non-inferiority and superiority margins. There was no significant difference in length-for-age and head circumference-for-age z-score. By D79, the mean change in weight-for-age z-scores from D1 in EF group (+0.76 SDs) surpassed the criteria for catch-up growth (+0.67 SDs). Infants in the EF group (vs. CF) tended to have softer stools (EF = 3.2 ± 0.59 vs. CF = 3.4 ± 0.58; P = 0.07) based on 5-point scale (1 = watery, 5 = hard). Difference in blood urea nitrogen and biomarkers for bone mineral status (i.e., plasma phosphorus, alkaline phosphatase and urinary calcium/phosphorus ratio) between EF and CF on FEF Day 21 reached statistical significance (P < 0.05) but all mean values stayed within normal clinical ranges for both groups. CONCLUSION: Preterm formula with greater protein:energy ratio and new fat blend is safe, nutritionally suitable, well-tolerated, and improves catch-up weight gain of preterm infants. Clinical trial registry identifier is NCT03055052 (ClinicalTrials.gov).

Use of a Liquid Supplement Containing 2 Human Milk Oligosaccharides: The First Double-Blind, Randomized, Controlled Trial in Pre-term Infants.

There is growing evidence supporting the benefit of human milk oligosaccharides (HMOs) on reducing risk of illnesses and improving immune function in newborn infants, but evidence in pre-term infants is lacking. This randomized, double-blind, placebo-controlled trial (NCT03607942) of pre-term infants evaluated the effects of HMO supplementation on feeding tolerance, growth, and safety in 7 neonatal units in France. Pre-term infants (27-33 weeks' gestation, birth weight <1,700 g) were randomized early after birth to receive HMO supplement (n = 43) [2'-fucosyllactose (2'FL) and lacto-N-neotetraose (LNnT) in a 10:1 ratio (0.374 g/kg body weight/day)] or an isocaloric placebo (n = 43) consisting of only glucose (0.140 g/kg/day) until discharge from the neonatal unit. Anthropometric z-scores were calculated using Fenton growth standards. Primary outcome was feeding tolerance, measured by non-inferiority (NI) in days to reach full enteral feeding (FEF) from birth in HMO vs. placebo group (NI margin = 4+ days). Mean number of days on intervention prior to FEF was 8.9 and 10.3 days in HMO and placebo, respectively. Non-inferiority in time to reach FEF in HMO (vs. placebo) was achieved [LS mean difference (95% CI) = -2.16 (-5.33, 1.00); upper bound of 95% CI < NI margin] in full analysis set and similar for per protocol. Adjusted mean time to reach FEF from birth was 2 days shorter in HMO (12.2) vs. placebo (14.3), although not statistically significant (p = 0.177). There was no difference in weight-for-age z-scores between groups throughout the FEF period until discharge. Length-for-age z-scores were higher in HMO at FEF day 14 [0.29 (0.02, 0.56), p = 0.037] and 21 [0.31 (0.02, 0.61), p = 0.037]. Head circumference-for-age z-score was higher in HMO vs. placebo at discharge [0.42 (0.12, 0.71), p = 0.007]. Occurrence of adverse events (AEs) was similar in both groups and relatively common in this population, whereas 2.3 and 14.3%, respectively, experienced investigator-confirmed, related AEs. HMO supplementation is safe and well-tolerated in pre-term infants. After 9 days of supplementation, the HMO group reached FEF 2 days earlier vs. placebo, although the difference was not statistically significant. In addition, HMO supplementation supports early postnatal growth, which may have a positive impact on long-term growth and developmental outcomes.

Human milk oligosaccharides in breast milk and 2-year outcome in preterm infants: An exploratory analysis.

BACKGROUND & AIMS: The health benefit of human milk (HM) for preterm infant development is known but the role of human milk oligosaccharides (HMOs) contained in HM remains underexplored. We explored the relationship between exposure to HMOs contained in mother's milk and growth and neurodevelopment at 2-years corrected age in preterm infants. METHODS: Exclusively breastfed preterm infants born between 27 and 34 weeks of gestation were enrolled in a monocentric prospective observational study, LACTACOL. Samples of breast milk were collected once a week for 7 weeks after birth. HMOs and sialic acid were measured by liquid chromatography. Age and Stages questionnaire (ASQ) version 2 was used to assess 2-year neurodevelopmental outcome. We analyzed the relationship between HMO content and (i) infant neurodevelopment at 2-years, and (ii) growth outcome at discharge and at 2 years. A secondary analysis was performed among Secretor(+) Lewis(+) mothers. Only associations with a false discovery rate of 10% or less according to the Benjamini-Hochberg procedure were considered significant. RESULTS: 137 preterm infants (mean gestational age of 31.3 ± 1.7 weeks, mean birth weight of 1494 g ± 336 g) born to 117 mothers (mean age of 30.8 ± 5.0 years) were enrolled. Total HMOs and most individual HMOs and sialic acid concentrations decreased with advancing postnatal age, except for lacto-N-fucopentaose-III and 3-fucosyllactose, which increased. Total HMOs were positively correlated with neonatal length growth (adjusted p = 0.012). Neither total HMOs nor any individual HMO correlated with ASQ score in the overall cohort. However, lacto-N-fucopentaose-III (LNFP-III) was significantly associated with total ASQ score (adjusted p ≤ 0.015) among the 104 infants born to Secretor(+) Lewis(+) mothers. CONCLUSIONS: In this exploratory study in very preterm infants, total HMOs and most individual HMOs, except LNFP-III, decreased with advancing postnatal age. Neither the concentration of total HMOs nor that of any individual HMO were associated with ASQ score at 2 years, except for LNFP-III in Secretor(+) Lewis(+) mothers.

Colorimetric detection of Fe3+ ions using pyrophosphate functionalized gold nanoparticles.

A sensitive, selective colorimetric Fe(3+) detection method has been developed by using pyrophosphate functionalized gold nanoparticles (P(2)O(7)(4-)-AuNPs). Gold nanoparticles were prepared by reducing HAuCl(4) with sodium borohydride, in the presence of Na(4)P(2)O(7). IR spectra suggested that pyrophosphates were capped on the surface of the gold nanoparticles. Aggregation of P(2)O(7)(4-)-AuNPs was induced immediately in the presence of Fe(3+) ions, yielding a color change from pink to violet. This Fe(3+)-induced aggregation of P(2)O(7)(4-)-AuNPs was monitored using first the naked eye and then UV-vis spectroscopy with a detection limit of 5.6 µM. The P(2)O(7)(4-)-AuNPs bound by Fe(3+) showed excellent selectivity compared to other metal ions (Ca(2+), Cd(2+), Co(2+), Fe(2+), Hg(2+), K(+), Mg(2+), Mn(2+), Na(+), Ni(2+), Pb(2+), and Zn(2+)). The best detection of Fe(3+) was achieved in a pH range from 3 to 9. In addition, the P(2)O(7)(4-)-AuNPs were also used to detect Fe(3+) in lake water samples, with low interference.

A case report of varicella-zoster virus infection associated glomerulonephritis and encephalitis.

15-year-old boy was admitted with nephritic and nephrotic syndrome, renal dysfunction and decreased serum C3, who suffered from varicella for two months. His renal histopathology revealed endocapillary proliferative glomerulonephritis with podocytes proliferation and severe tubular injury by light microscopy. Direct immunofluorescence showed global granular deposition of IgG, IgA, IgM, C3, C1q and fibrinogen in mesangium and along glomerular capillary wall. Electron microscopic examination showed electron-dense deposits in multiple sites of glomeruli. Furthermore, specific serum IgM antibodies against varicella-zoster virus (VZV) were detected. VZV antigen and mRNA were demonstrated in glomerular and tubular epithelial cells by immunohistochemical staining and in-situ hybridization. Virus particles and virus inclusions were identified by electron microscopy and special staining (Methylene Blue and Eosion staining or Mann staining). The patient also experienced epileptic episodes and his brain MRI and electroencephalogram indicated herpes encephalitis with secondary epilepsy. Therefore, the diagnosis of VZV-associated glomerulonephritis and encephalitis was established. This is the first case of VZV-associated glomerulonephritis with renal histopathological evidence using in situ hybridization technique.

Microbiota and Human Milk Oligosaccharides in Premature Infants.

Gut microbiota plays an important role in infants' health. The prevalence of bifidobacteria in the gastrointestinal tract of term breastfed infants has been associated with reduced infection rates compared with formula-fed infants. However, few studies evaluated microbiota in premature infants. In an observational study of 577 preterm newborns born below 32 weeks gestation, gut microbiota was not driven by bifidobacteria but could be classified into six different clusters with regard to the most abundant bacteria present. Clusters were related to infants' maturity, perinatal determinants, and were associated with short- and long-term outcome. In another study, the effects of caesarean birth on infant gut microbiota could be alleviated by human milk oligosaccharides (HMOs) in mothers' milk. In addition, 58 infants fed with a formula enriched with 2 HMOs had microbiota closer to breastfed infants than 63 infants receiving the same formula without HMOs. The question then arose of the benefit of HMO supplementation for microbiota in premature infants. Thus, a multicenter randomized controlled intervention study of the effect of a liquid supplement containing 2 HMOs was set up. Ongoing data analysis will evaluate gastrointestinal tolerance parameters, intake of HMOs from human milk, long-term growth outcomes, fecal microbiota, and fecal biomarkers of gut maturation and immunity.

The Effects of a Partially Hydrolyzed Formula with Low Lactose and Probiotics on Mild Gastrointestinal Disorders of Infants: A Single-Armed Clinical Trial.

Partially hydrolyzed formula (pHF) containing low lactose and probiotics may benefit the gastrointestinal health of infants. We aimed to assess the effects of pHF on mild gastrointestinal disorders (MGDs) of infants. In this single-armed trial, 80 full-term infants with MGDs were enrolled and fed a pHF for 14 consecutive days. The primary outcome resulted from the scores of gastrointestinal symptoms reported by parents using a validated Infant Gastrointestinal Symptom Questionnaire (IGSQ) at Day 0 (baseline), Day 7, and Day 14. The total IGSQ scores ranged from 13 to 65. Higher scores indicated worse gastrointestinal symptoms. The IGSQ scores (mean ± SD) decreased from Day 0 (36.0 ± 5.7) to Day 7 (28.7 ± 7.4) and Day 14 (26.5 ± 8.1 (p < 0.001), with corresponding digestive distress prevalence (IGSQ score > 30) decreasing from 87.5% to 35.0% and 28.8% (p < 0.001). In the first three days, vomiting and flatulence scores decreased at Day 1 versus Day 0, and the crying score decreased at Day 2, but no significant changes were observed for fussy and stool characteristics. All growth parameters increased and no parents reported adverse events. In conclusion, feeding with a pHF containing low lactose and probiotics may comfort infants with MGDs, and the comforting effect likely manifests early in the first three days of the feeding interventions. Trial registration: ClinicalTrials.gov NCT04112056.