A methodological review of the high-dimensional propensity score in comparative-effectiveness and safety-of-interventions research finds incomplete reporting relative to algorithm development and robustness.

OBJECTIVES: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research. STUDY DESIGN AND SETTING: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. RESULTS: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias. CONCLUSION: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS.

Inadequate daily intakes of n-3 polyunsaturated fatty acids (PUFA) in the general French population of children (3-10 years) and adolescents (11-17 years): the INCA2 survey.

PURPOSE: This paper deals with the dietary daily intakes of main polyunsaturated fatty acids (PUFA) in French children and adolescents. METHODS: Dietary intakes of main PUFA were determined from a general French population of 1500 children (3-10 years) and adolescents (11-17 years) by using the most recent set of national robust data on food (National Survey INCA 2 performed in 2006 and 2007). RESULTS: Main results showed that mean daily intakes of total fat and n-6 PUFA linoleic acid (LA, 18:2n-6) were close to current recommended values for children and adolescent populations. However, 80% (children) to 90% (adolescents) of our French populations not only ingested low quantities of n-3 long-chain PUFA (docosahexaenoic (22:6n-3) and eicosapentaenoic (20:5n-3) acids) but also very low quantities of alpha-linolenic acid (ALA, 18:3n-3) at the origin of a non-balanced n-6/n-3 ratio. Inadequate consumption of EPA + DHA was also observed in subgroups of infants and adolescent who consumed more than two servings/week of fish. CONCLUSIONS: Such disequilibrium in PUFA dietary intakes in favor of n-6 PUFA could have adverse impact on cell membrane incorporation of long-chain n-3 PUFA and deleterious impacts on the health of children and adolescents. Promoting the consumption of both vegetable oils and margarines rich in ALA, and oily fish rich in long-chain n-3 PUFA might improve such PUFA disequilibrium.

Very low inadequate dietary intakes of essential n-3 polyunsaturated fatty acids (PUFA) in pregnant and lactating French women: The INCA2 survey.

BACKGROUND: The French National survey INCA2 pointed out that the majority of the French population (children, adolescents, adults and elderly) ingest low quantities of n-3 polyunsaturated fatty acid (PUFA) in the form of both precursor (alpha-linolenic acid, ALA) and long-chain (mainly docosahexaenoic acid, DHA). However, we don't know whether such inadequate n-3 PUFA consumption is also found again in pregnant and lactating women. METHODS: Dietary lipid and PUFA intakes were determined from 28 pregnant and 21 lactating French women by using the most recent set of national robust data on food (National Survey INCA2 performed in 2006 and 2007), and compared with that of 742 women of childbearing age. RESULTS: Main results showed that mean daily intakes of n-3 PUFA were very low in this French woman population because no pregnant and lactating women met recommended dietary intakes (RDIs). Moreover, some of them ingested quantities 4 times (ALA) to 10 times (DHA) lower than RDIs. Very similar dietary intakes were observed in women of childbearing age. CONCLUSION: French pregnant and lactating women did not change their dietary habits to favor ALA and n-3 long-chain PUFA consumption via rich-ALA vegetable oils and fish and oily fish consumption, and have low n-3 PUFA dietary consumption typical of French women of childbearing age. Such PUFA intakes could have adverse impact on long-chain n-3 PUFA incorporation in brain membranes of fetus and infants, but also on cognitive and visual development of infants during the first years of life.

Hospital Diet Enriched With Rapeseed or Sunflower Oils Is Associated With a Decrease in Plasma 16:1n-7 and Some Metabolic Disorders in the Elderly.

We recently demonstrated that the prevalence of dysglycemia was high among hospitalized elderly people who were fed a low fat diet (27.7% of energy) and was positively associated with plasma 16:1n-7, an indicator of de novo lipogenesis (DNL). Fatty acids in the DNL pathway have been shown to be associated with a higher risk of metabolic syndrome (MetS). The purpose of this study was to investigate the potential beneficial effects of fat enrichment (up to 34.1%en) of the hospital diet in 111 patients (30 men and 81 women, 84 ± 7 years) during 6 weeks. Based on gender, they were randomly given a diet supplemented either with rapeseed oil (RO) or with sunflower oil (SO). Fatty acids of cholesteryl esters and erythrocyte phospholipids and markers of metabolic disorders were evaluated before and after dietary intervention. Both enriched diets significantly, and to a similar extent, decreased (1) the overall prevalence of dysglycemia (by 25-33%) and MetS (by 31-43%) and (2) plasma 16:1n-7 mol% in men and women. Dysglycemia prevalence adjusted by the diets was reduced in men versus baseline; no change was found in women. Enrichment of the diet with RO or SO resulted in a difference in fatty acid compositions, that is, EPA (mol%) and the omega-3 index increased with RO, while proportions of 18:1n-7, 18:1n-9, and EPA decreased with SO. These findings highlight the need for adequate fat intake in the elderly. For supplementation of the hospital diet, RO, which led to a higher proportion of circulating n-3 polyunsaturated fatty acids (PUFA) and is known to be beneficial, may be preferred to SO.

Fatty acid dietary intake in the general French population: are the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) national recommendations met?

Quantity and quality of fatty acids (FA) in diet influence CVD risk. Consequently, health authorities promote recommended dietary intakes for FA, looking for optimal intakes in a primary prevention of CVD perspective. In parallel, a few data are available detailing intakes in national populations. The objective of the present study was to perform a large analysis combining the data of the French National Survey INCA 2 on food consumption performed in 2006 and 2007, and the nutritional content of food consumed in France updated in 2013 by the French Information Centre on Food Quality, to explore in details the FA intakes in French adults using the most recent available data. To compare the discrepancies in the observed intake levels with the French recommended levels, a weighted fat adherence score was built combining intakes of the different FA. Individual scores were computed in relation to official recommendations, and potential explanatory factors were identified. These data show that SFA intakes are persistently higher than national recommendations, combined with low intakes of MUFA and PUFA, particularly long-chain n-3 FA. Only 14·6 % of the French population met DHA intake recommendation, 7·8 % for EPA and 21·6 % for SFA. This situation remains unfavourable in terms of primary prevention of CVD. Consuming fish and other sources of n-3 FA, living in the south of France, being female, having a higher education level, and low alcohol consumption were associated with a healthier fat adherence score.

n-3 Fatty acids preserve muscle mass and insulin sensitivity in a rat model of energy restriction.

In obese subjects, the loss of fat mass during energy restriction is often accompanied by a loss of muscle mass. The hypothesis that n-3 PUFA, which modulate protein homoeostasis via effects on insulin sensitivity, could contribute to maintain muscle mass during energy restriction was tested in rats fed a high-fat diet (4 weeks) rich in 18 : 1 n-9 (oleic acid, OLE-R), 18 : 3 n-3 (α-linolenic acid, ALA-R) or n-3 long-chain (LC-R) fatty acid and then energy restricted (8 weeks). A control group (OLE-ad libitum (AL)) was maintained with AL diet throughout the study. Rats were killed 10 min after an i.v. insulin injection. All energy-restricted rats lost weight and fat mass, but only the OLE-R group showed a significant muscle loss. The Gastrocnemius muscle was enriched with ALA in the ALA-R group and with LC-PUFA in the ALA-R and LC-R groups. The proteolytic ubiquitin-proteasome system was differentially affected by energy restriction, with MAFbx and muscle ring finger-1 mRNA levels being decreased in the LC-R group (-30 and -20 %, respectively). RAC-α serine/threonine-protein kinase and insulin receptor substrate 1 phosphorylation levels increased in the LC-R group (+70 %), together with insulin receptor mRNA (+50 %). The ALA-R group showed the same overall activation pattern as the LC-R group, although to a lesser extent. In conclusion, dietary n-3 PUFA prevent the loss of muscle mass associated with energy restriction, probably by an improvement in the insulin-signalling pathway activation, in relation to enrichment of plasma membranes in n-3 LC-PUFA.

Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis.

Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

Ex vivo analysis of renal proximal tubular cells.

BACKGROUND: Experimental models are inevitably a compromise between accurately reproducing a pathological situation and schematically simplifying it, which is intended to provide both relevance and conclusiveness. In-vivo models are very relevant, but multiple cell-types undergoing various changes may hinder the observation of individual molecular events. RESULTS: Here, we describe a method for analyzing and isolating specific cell types from the kidney and studying the phenotype they have acquired in vivo. Using flow cytometry, immunofluorescence, and RT-PCR, we show that our method is suitable for studying and isolating proximal tubular cells with an anti Prominin-1 antibody. Kidneys are subjected to mechanical dissociation followed by flow-cytometry analysis. Hundreds of thousands of proximal tubular cells are then isolated by magnetic separation followed by direct analysis or primary cell culture. Using our method, we detect phenotypic changes in the proximal tubular cells after renal ischemia reperfusion, and we isolate the proximal tubular cells, with a purity over 80%. CONCLUSIONS: This method is efficient, quick, simple, and cheap, and should be useful for studying cell-type specific parameters after in vivo experimental studies. It is also a simple method to obtain a specific primary cell culture from any animal strain.

Modulation of the insulin anabolic signalling cascade in growing chickens by n-3 PUFA.

n-3 PUFA are crucial for health and development. Their effects as regulators of lipid and glucose metabolism are well documented. They also appear to affect protein metabolism, especially by acting on insulin sensitivity. The aim of the present study was to investigate the role of n-3 PUFA, i.e. the precursor α-linolenic acid (ALA) 18:3n-3 or long-chain PUFA (LC-PUFA), in chickens, by focusing on their potential function as co-regulators of the insulin anabolic signalling cascade. Ross male broilers were divided into six dietary treatment groups. Diets were isoproteic (22 % crude protein) and isoenergetic (12·54 MJ metabolisable energy/kg) and contained similar lipid levels (6 %) provided by different proportions of various lipid sources: oleic sunflower oil rich in 18:1n-9 as control; fish oil rich in LC-PUFA; rapeseed and linseed oils providing ALA. The provision of diets enriched with n-3 PUFA, i.e. rich in LC-PUFA or in the precursor ALA, for 3 weeks improved the growth performance of chickens, whereas that of only the ALA diet enhanced the development of the pectoralis major muscle. At 23 d of age, we studied the insulin sensitivity of the pectoralis major muscle and liver of chickens after an intravenous injection of insulin or saline. The present results indicate that the activation patterns of n-3 PUFA are different in the liver and muscles. An ALA-enriched diet may improve insulin sensitivity in muscles, with greater activation of the insulin-induced 70 kDa ribosomal protein S6 kinase/ribosomal protein S6 pathway involved in the translation of mRNA into proteins, thereby potentially increasing muscle protein synthesis and growth. Our findings provide a basis on which to optimise dietary fatty acid provision in growing animals.

Glomerular filtration rate as a determinant of free light chains in renal transplantation.

BACKGROUND: Transplant patients have an increased incidence of lymphoproliferative disorders. The development of a sensitive immunoassay for serum free light chain (sFLC) determination has improved the diagnosis of monoclonal gammapathy. However, metabolism of FLC largely depends on renal function which could lead to misinterpretation of results. The aim of this study was to assess polyclonal FLC in kidney transplant recipients in relation to markers of renal function. MATERIALS AND METHODS: 97 renal transplant patients (median transplantation follow-up of 2.2 years) were included in this study. Kappa FLC, lambda FLC and cystatin C were measured by particle-enhanced turbidimetric immunoassay (PETIA) using kits from a Binding Site (Birmingham, UK) SPAPLUS(®) analyzer. Glomerular filtration rate was measured using urinary clearance of (99m)Tc-DTPA and estimated using CKD-EPI creatinine 2009, CKD-EPI cystatin C 2012 and CKD-EPI creatinine-cystatin C 2012. RESULTS: Serum kappa FLC was 22.38 [6.39-68.91] mg/L and serum lambda FLC was 15.66 [7.29-50.81] mg/L. Both levels of kappa and lambda were correlated with renal function. Median κ/λ ratio was 1.34 [0.57 to 2.67] leaving 19.6% of renal transplant patients outside the normal reference range [0.26-1.65]. However, using a reference interval normalized by renal function [0.37-3.1], none of our patients was classified as abnormal. CONCLUSION: κ/λ ratio should be cautiously analyzed in renal transplantation and renal function, estimated by creatinine/cystatin C equations should be taken into account.

Radiation therapy and immunotherapy: implications for a combined cancer treatment.

Ionizing radiation (IR) is used as primary treatment for numerous localized cancers. Although it is usually described as an immunosuppressive modality, there are new preclinical evidences suggesting that IR could have also generated substantial changes in the tumor microenvironment, including triggering an inflammatory process. This finding implies that radiotherapy could both modulate tumor immunity and have out-of-field activity by recruiting biological effectors. There are numerous uncertainties regarding the true biological impact of radiation on tumor immunogenicity, but some preclinical studies established the proof of concept that combining IR with strategies modifying immunology could enhance antitumor effects. From these findings, clinical trials are now analyzing how immunotherapy and radiation work while given together, with promising preliminary results. This review aims at summarizing the recent developments regarding the impact of IR on tumor immunity, with focus on potential therapeutic targets.

Accuracy of GFR predictive equations using ID-MS traceable creatinine: compensated Jaffe and enzymatic.

BACKGROUND: New ID-MS traceable creatinine kits including enzymatic creatinine (e-creat) and compensated Jaffe (j-creat) has been developed by Olympus. METHODS: Analytical performances of these reagents were tested on an AU 640 analyzer. A comparison study was performed against the method used in our laboratory (Randox creatinine enzymatic). Values of the glomerular filtration rate estimated (eGFR) from ID-MS traceable equation were compared to the GFR measured (mGFR) by a reference isotope method in a kidney transplant cohort. RESULTS: Total intra- and inter-assay variation coefficients were below 4%. Creatinine values were correlated with the Randox enzymatic method (e-creat = 0.98 Randox - 0.48 and j-creat = 0.99 Randox - 1.44, r2 = 0.98). Values of eGFR obtained with both e-creat and j-creat were well correlated to mGFR in our population of renal transplants. CONCLUSIONS: The new ID-MS traceable methods improved estimation of GFR by predictive equations. However, the limitation of the Jaffe method in specific populations such as paediatric and elderly patients needs further investigations.

Cystatin C is a reliable marker for estimation of glomerular filtration rate in renal transplantation: validation of a new turbidimetric assay using monospecific sheep antibodies.

BACKGROUND: The potential use of cystatin C was recently assessed in kidney transplantation. A new particle-enhanced turbidimetric immunoassay (PETIA) that uses sheep antibodies (Binding Site human cystatin C immunoassay) has been developed. Analytical performance of this new assay was evaluated. Clinical relevance was determined by comparison with a reference method in a cohort of kidney transplant patients. METHODS: First, the analytical performance of the Binding Site cystatin C kit was tested on SPA(PLUS)® and Hitachi® analyzers. Second, a comparison study was performed using SPA(PLUS)® analyzer against two other cystatin C methods (the Siemens-PENIA method on BNII® and the Dako-PETIA application on Olympus AU640®). Third, the glomerular filtration rate (GFR) was estimated using several predictive cystatin C- and creatinine-based equations and compared to GFR measured by an isotopic method (99(m)Tc-DTPA). These predictive algorithms were analyzed with respect to bias, precision and accuracy. RESULTS: Total intra-assay and inter-assay coefficients of variation were below 5%. Values obtained with the SPA(PLUS)® correlated with the Siemens-PENIA and the Dako-PETIA methods. The creatinine and cystatin C-based equation allowed reliable assessment of GFR in our population of renal transplantation. CONCLUSIONS: The use of algorithms based on cystatin C and creatinine could provide a reliable estimate of GFR in kidney transplantation.