Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Screening HIV Patients at Risk for NAFLD Using MRI-PDFF and Transient Elastography: A European Multicenter Prospective Study.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a growing concern in the aging population with human immunodeficiency virus (HIV). Screening for NAFLD is recommended in patients with metabolic risk factors or unexplained transaminitis. This study aimed to prospectively assess the prevalence and associated factors of liver steatosis and advanced fibrosis (AF) in HIV-monoinfected patients at risk of NAFLD. METHODS: We conducted a multicenter study in HIV-monoinfected patients, nonexcessive drinkers with metabolic syndrome, and/or persistently elevated liver enzymes, and/or clinical lipodystrophy. All participants had magnetic resonance imaging proton density fat fraction (MRI-PDFF), Fibroscan/controlled attenuation parameter (CAP), and cytokine and genetic analysis. RESULTS: From March 2014 to November 2015, we enrolled 442 participants and analyzed 402: male (85%); median age, 55 years (interquartile range [IQR], 50-61 years); body mass index, 27.0 kg/m2 (IQR, 23.6-28.7 kg/m2); metabolic syndrome (67%); and CD4 cell count, 630/mm3 (IQR, 510-832/mm3). Overall 257 of 402 (64%) had NAFLD (MRI-PDFF ≥5%). Among them, 11.3% had a liver stiffness ≥9.6 kPa, suggestive of AF. Multivariable analysis identified 7 factors of steatosis: high CD4-cell count (odds ratio [OR], 4.04; 95% confidence interval [CI], 1.92-8.51), high leptin level (OR, 2.12; 95% CI, 1.14-3.93), non-CC PNPLA3s738409 genetic polymorphism (OR, 1.92; 95% CI, 1.11-3.33), low high-density lipoprotein (OR, 1.83; 95% CI, 1.03-3.27), high triglycerides (OR, 1.48; 95% CI, 1.18-1.84), elevated alanine transaminase (OR, 1.23; 95% CI, 1.16-1.31), and hyper ferritinemia (OR, 1.05; 95% CI, 1.03-1.07). Two factors were associated with AF: high body mass index (OR, 1.23 ; 95% CI, 1.07-1.42 ; P = .005, and elevated aspartate aminotransferase (OR, 1.03; 95% CI, 1.01-1.05; P = .001). Using MRI-PDFF as a reference, CAP (best cutoff, 280 dB/m) had good accuracy (area under the receiver operating characteristic curve = 0.86; 95% CI, 0.82-0.90) for the diagnosis of moderate to severe steatosis. CONCLUSIONS: In a large cohort of HIV-moninfected patients at risk of NAFLD, steatosis is present in two-thirds of cases, and around 10% have AF. The CAP technique is accurate for screening steatosis in this population.

Plasma total adiponectin and changes in renal function in a cohort from the community: the prospective Data from an Epidemiological Study on the Insulin Resistance Syndrome study.

BACKGROUND: High adiponectin levels are associated with diabetic nephropathy. Nevertheless, it is not known whether plasma adiponectin is associated with renal function decline in the general population. We evaluated whether adiponectin concentrations were associated with changes in renal function in a community cohort, the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. METHODS: Plasma adiponectin concentrations were measured in a random sample of 3284 people from the DESIR study, a 9-year prospective cohort from the general population. Data were analysed for three endpoints during follow-up: incidence of Stage 3 chronic kidney disease (CKD); the Kidney Disease: Improving Global Outcomes (KDIGO) criterion 'certain drop in eGFR' and rapid kidney function decline [estimated glomerular filtration rate (eGFR) slope steeper than -3 mL/min/1.73 m2/year]. RESULTS: After exclusion of participants with an eGFR <60 mL/min/1.73 m2 at baseline and those with type 2 diabetes or impaired fasting glycaemia at any time during follow-up (remaining n = 2174), there was a 113% higher risk for a rapid decline in kidney function in participants with adiponectin above the third tertile (T3) versus below the first tertile (T1) (Ptrend = 0.004) and a 53% higher risk for kidney function decline as defined by the KDIGO criterion (Ptrend = 0.04). In a cross-sectional analysis, adiponectin was positively associated with urinary albumin:creatinine ratio at baseline (P = 0.009). CONCLUSIONS: In a healthy cohort from the general population, higher levels of plasma adiponectin were associated with decreased renal function at baseline and at follow-up. This result is similar to what is observed in people with diabetic nephropathy, in contrast with animal models of nephropathy.

Prevalence of tubulopathy and association with renal function loss in HIV-infected patients.

BACKGROUND: The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the prevalence and determinants of proximal tubular dysfunction (PTD) in HIV-infected individuals, and assessed the impact of the tubulopathy on the estimated glomerular filtration rate (eGFR) outcome. METHODS: A cohort study was performed on 694 outpatients followed in a French centre to analyse the prevalence of PTD, the diagnosis performance of screening tools and the associated factors. eGFR was prospectively evaluated to analyse the predictive value of the tubulopathy on eGFR decrease. RESULTS: At inclusion, 14% of the patients presented with PTD and 5% with CKD. No individual tubular marker, including non-glomerular proteinuria, glycosuria dipstick or hypophosphataemia, registered sufficient performance to identify PTD. We found a significant interaction between tenofovir disoproxil fumarate exposure and ethnicity (P = 0.03) for tubulopathy risk. Tenofovir disoproxil fumarate exposure was associated with PTD in non-Africans [adjusted odds ratio (aOR) = 4.71, P < 10-3], but not in patients of sub-Saharan African origin (aOR = 1.17, P = 0.73). Among the 601 patients followed during a median of 4.3 years, 13% experienced an accelerated eGFR decline. Unlike microalbuminuria and glomerular proteinuria, tubulopathy was not associated with accelerated eGFR decline. CONCLUSION: PTD is not rare in HIV-infected individuals but is less frequent in sub-Saharan African patients and is associated with tenofovir disoproxil fumarate exposure only in non-Africans. Its diagnosis requires multiple biochemical testing and it is not associated with an accelerated eGFR decline.

Specific changes in faecal microbiota are associated with familial Mediterranean fever.

OBJECTIVES: Familial Mediterranean fever (FMF) can be complicated by AA amyloidosis (AAA), though it remains unclear why only some patients develop amyloidosis. We examined the gut microbiota composition and inflammatory markers in patients with FMF complicated or not by AAA. METHODS: We analysed the gut microbiota of 34 patients with FMF without AAA, 7 patients with FMF with AAA, 19 patients with AAA of another origin, and 26 controls using 16S ribosomal RNA gene sequencing with the Illumina MiSeq platform. Associations between bacterial taxa and clinical phenotypes were evaluated using multivariate association with linear models statistical method. Blood levels of interleukin (IL)-1ß, IL-6, tumour necrosis factor-α and adipokines were assessed by ELISA; indoleamine 2,3-dioxygenase (IDO) activity was determined by high-performance liquid chromatography. RESULTS: Compared with healthy subjects, specific changes in faecal microbiota were observed in FMF and AAA groups. Several operational taxonomic units (OTUs) were associated with FMF. Moreover, two OTUs were over-represented in FMF-related AAA compared with FMF without AAA. Additionally, higher adiponectin levels and IDO activity were observed in FMF-related AAA compared with FMF without AAA (p<0.05). CONCLUSION: The presence of specific changes in faecal microbiota in FMF and in FMF-related AAA suggests that intestinal microorganisms may play a role in the pathogenesis of these diseases. These findings may offer an opportunity to use techniques for gut microbiota manipulation.

Intravenous catheters induce a local inflammatory response.

AIM: Chronic inflammation has been associated to the development of cardiometabolic dysfunctions. The use of an intravenous (IV) catheter is highly recommended for physiology testing. Yet, the presence of an IV catheter triggers local inflammation that does not reflect systemic inflammatory status. The aim of this study was to assess the effect of an IV catheter on serum concentrations of IL-6, IL-8 and hsCRP in a fasting state and after a high-fat meal known to trigger low-grade inflammation. METHODS: Twenty-two healthy subjects (7 men, 15 women) were included in this study. The trial included 2 visits. After an overnight fast, a venous catheter was inserted into an antecubital vein. A first blood sample was collected through this catheter at T = 0 min. On each visit, participants were requested either to drink only water for the whole duration of the test (WO test), or to consume a high-fat meal (HFM). Blood samples were collected through the catheter at T60, T120, T180 and T300 min. Additional venous punctures were performed on the contralateral arm at T180 and T300 min. Serum inflammatory mediators were measured at each time point of both interventions. RESULTS: When serum was collected by venous punctures, IL-6 concentrations remained unchanged during both WO and HFM tests (Ptime = 0.15 and Ptime = 0.23, respectively), whereas the concentrations increased progressively over time when serum was collected through the catheter (Ptime < 0.001). The high-fat meal had no additional effect on IL-6 levels (Pmeal = 0.27) neither in serum collected by venous puncture nor in serum collected through the catheter. Serum IL-8 and hsCRP concentrations did not vary over time, and were influenced neither by the meal type nor by the blood collection method. CONCLUSION: The insertion of an indwelling catheter is associated with a local inflammatory response possibly mediated by IL-6 but not IL-8. This inflammatory response was not enhanced by a pro-inflammatory high-fat meal.

T-cadherin gene variants are associated with nephropathy in subjects with type 1 diabetes.

BACKGROUND: High plasma adiponectin levels are associated with diabetic nephropathy (DN). T-cadherin gene (CDH13) variants have been shown to be associated with adiponectin levels. We investigated associations between allelic variations of CDH13 and DN in subjects with type 1 diabetes. METHODS: Two CDH13 polymorphisms were analysed in 1297 Caucasian subjects with type 1 diabetes from the 'Survival Genetic Nephropathy' (SURGENE) (n = 340, 10-year follow-up), 'Genesis France-Belgium' (GENESIS) (n = 501, 5-year follow-up for n = 462) and 'Génétique de la Néphropathie Diabétique' (GENEDIAB) (n = 456, 9-year follow-up for n = 283) cohorts. Adiponectin levels were measured in plasma samples from GENESIS and GENEDIAB cohorts. RESULTS: Pooled analysis of GENEDIAB and GENESIS studies showed that baseline plasma adiponectin levels were higher in subjects with established/advanced DN at inclusion (P < 0.0001) and in subjects who developed end-stage renal disease (ESRD) at follow-up (P < 0.0001). The minor allele of rs3865188 was associated with lower adiponectin levels (P = 0.006). rs11646213 [odds ratio (OR) 1.47; 95% confidence interval (CI) 1.18-1.85; P = 0.0009] and rs3865188 (OR 0.71; 95% CI 0.57-0.90; P = 0.004) were associated with baseline prevalence of established/advanced DN. These polymorphisms were also associated with the risk of ESRD (0.006 < P < 0.03). The association between rs11646213 (but not rs3865188) and renal function remained significant after adjustment for plasma adiponectin. In SURGENE, rs11646213 [hazard ratio (HR) 1.69; 95% CI 1.01-2.71; P = 0.04] and rs3865188 (HR 0.74; 95% CI 0.55-0.99; P = 0.04) were associated with risk of renal events (defined as progression to more severe DN stages). CONCLUSIONS: Plasma adiponectin levels are associated with the prevalence of DN and the incidence of ESRD in patients with type 1 diabetes. CDH13 polymorphisms are also associated with the prevalence and incidence of DN, and with the incidence of ESRD in these patients. The association between CDH13 and DN may be due to pleiotropic effects, both dependent and independent of plasma adiponectin levels.

Increased prevalence and severity of radiographic hand osteoarthritis in patients with HIV-1 infection associated with metabolic syndrome: data from the cross-sectional METAFIB-OA study.

OBJECTIVE: To determine radiographic hand osteoarthritis (HOA) prevalence in patients with HIV-1 infection in comparison with the general population and to address whether metabolic syndrome (MetS) may increase the risk of HOA during HIV-1 infection. PATIENTS: Patients with HIV-1 infection and MetS (International Diabetes Federation, IDF criteria) aged 45-65 years were matched by age and gender to HIV-1-infected subjects without MetS and underwent hand radiographs. Framingham OA cohort was used as general population cohort. METHODS: Radiographic HOA was defined as Kellgren-Lawrence (KL) score ≥2 on more than one joint. Radiographic severity was assessed by global KL score and number of OA joints. HOA prevalence was compared with that found in the Framingham study, stratified by age and sex. Logistic and linear regression models were used to determine the risk factors of HOA in patients with HIV-1 infection. RESULTS: 301 patients (88% male, mean age 53.4±5.0 years) were included, 152 with MetS and 149 without it. Overall, HOA prevalence was 55.5% and was higher for those with MetS than those without it (64.5% vs 46.3%, p=0.002). When considering men within each age group, HOA frequency was greater in patients with HIV-1 infection than the general population (all ages: 55.8% vs 38.7%; p<0.0001), due to the subgroup with MetS (64.9%; p<0.0001), as well as the subgroup without MetS, although not significant (46.6%; p=0.09). Risk of HOA was increased with MetS (OR 2.23, 95% 95% CI 1.26% to 3.96%) and age (OR 1.18, 95% CI 1.12 to 1.25). HOA severity was greater for patients with MetS than those without. HOA was not associated with previous or current exposure to protease inhibitors or HIV infection-related markers. CONCLUSIONS: HOA frequency is greater in patients with HIV-1 infection, especially those with MetS, than the general population. TRIAL REGISTRATION NUMBER: NCT02353767.

Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity.

OBJECTIVES: The objective of this study was to analyse the respective roles of personal factors and HIV infection markers on the systemic immune activation/inflammatory profile of long-term antiretroviral treatment-controlled patients. PATIENTS AND METHODS: A panel of soluble immune activation/inflammatory biomarkers was measured in 352 HIV-infected treatment-controlled patients from the APROCO-COPILOTE cohort, all of whom were started on a PI in 1997-99 and had a final evaluation 11 years later, and in 59 healthy controls. RESULTS: A total of 81.5% of the patients were male, with the following characteristics: median age 49 years; 620 CD4 cells/mm(3); 756 CD8 cells/mm(3); CD4/CD8 ratio 0.81; BMI 23.0 kg/m(2); waist-to-hip ratio 0.95. Markers of inflammation-high-sensitivity (hs) IL-6 (median and IQR) (1.3 pg/L, 0.7-2.6), hs C-reactive protein (CRP) (2.1 mg/L, 0.9-4.5) and D-dimer (252 ng/mL, 177-374)-were elevated compared with healthy controls (P < 0.001) and strongly related to each other, as were markers of immune activation [soluble (s) CD14 (1356 ng/mL, 1027-1818), ß2-microglobulin (2.4 mg/L, 2.0-3.1) and cystatin-C (0.93 mg/L, 0.82-1.1)]. Inflammatory and immune activation markers were also associated with each other. In HIV-infected patients: age was related to D-dimer, ß2-microglobulin and cystatin-C levels; being a smoker was related to increased IL-6 and cystatin-C; and BMI and waist-to-hip ratio were related to CRP. Conversely, markers of HIV infection, current CD4 or CD8 values, CD4 nadir, CD4/CD8 ratio, AIDS stage at initiation of PIs, current viral load and duration of ART were not associated with immune activation/inflammation markers. CONCLUSIONS: In these long-term treatment-controlled HIV-infected patients, all systemic markers of inflammation and immune activation were increased compared with healthy controls. This was related to demographic and behavioural factors, but not to markers of severity of the HIV infection. Intervention to decrease low-grade inflammation must thus prioritize modifiable personal factors.

Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons.

BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers. METHODS: Prospective 1-1 case-control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n = 50 matched pairs), non-AIDS-defining (n = 63) events and death (n = 41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers. RESULTS: In sum, 250 patients were included. Median time between first and last sample and last sample and event was 44.6(interquartile range [IQR]: 22.7-72.3) and 3.1(IQR: 1.4-6.4) months. Odds of death decreased by 46.0%(95% confidence interval [CI], 2.0-70.0, P = .04) for a 2-fold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P > .05). In patients with current 25(OH)D <10 ng/mL, hsIL-6 concentration increased by 4.7%(95% CI, .2,9.4, P = .04) annually after adjustment for immunological/inflammatory markers, and no change in hsCRP rate was observed (P = .76). CONCLUSIONS: Low Vitamin D predicts short term mortality in HIV-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated.

Biological markers of adipose tissue: Adipokines.

We currently have a large sum of clinical and experimental data documenting the involvement of numerous adipokines in the maintenance of energy homeostasis in healthy individuals and their dysregulation in diseases such as obesity, metabolic syndrome or type 2 diabetes. Despite the impressive discoveries made in this field over many years, much remains to be done before understanding all the physiological and pathological implications, and hoping for the development of other effective and safe therapeutic strategies. Two original adipokines will be taken as examples to illustrate these remarks, chemerin and neuregulin 4.

C-reactive protein is more suitable than Serum Amyloid A to monitor crises and attack-free periods in Systemic Auto-Inflammatory Diseases.

BACKGROUND: With their broad presentations and no global biomarker to discriminate crises and attack-free periods, Systemic Auto-Inflammatory Diseases (SAID) are difficult to manage. This study assessed Serum Amyloid A (SAA), C-reactive protein (CRP) and serum calprotectin as potential biomarkers to monitor patients with SAID. METHOD: SAA (already studied in Familial Mediterranean Fever (FMF)), CRP and serum calprotectin were measured on SAID adult patients from Juvenile Inflammatory Rheumatism (JIR) cohort during their follow-up visits between 2020 and 2022. Crises and attack-free periods were clinically determined. RESULTS: 96 measures, mainly from FMF (43 %) and Unclassified SAID (USAID) (37 %) patients were included. Using ROC curves, a threshold with sensitivity and specificity of/over 75 % was determined for SAA (9 mg/L) and CRP (9 mg/L) but not for serum calprotectin, not investigated further. With this threshold, the results were similar in FMF and USAID patients' subgroups. SAA and CRP showed a positive correlation with crises and attack-free periods in SAID patients (r = 0.4796, p < 0.001 and r = 0.5525, p < 0.001, respectively) as in FMF and USAID patients, with no significant difference between both markers in diagnosis value and ROC curves Area Under Curve (AUC) (p = 0.32). Only the CRP results were not influenced by obesity. CONCLUSION: SAA and CRP can discriminate crisis and attack-free periods in our cohort of SAID patients mainly composed of FMF and USAID patients. However, only CRP can be used regardless of body mass index. It is the first report of common biomarkers for all SAID, including USAID patients, with CRP widely accessible in routine worldwide.

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs.

BACKGROUND: Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. METHODS: In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. RESULTS: Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80-82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. CONCLUSION: High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

AIMS: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. METHODS AND RESULTS: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 µmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 µmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. CONCLUSIONS: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Adipokine profile in glucocorticoid-treated patients: baseline plasma leptin level predicts occurrence of lipodystrophy.

CONTEXT: Glucocorticoid therapy may result in adipose tissue redistribution of unknown pathophysiology. OBJECTIVES: To evaluate the effects of glucocorticoids on adipokine levels and adipose tissue inflammation. To compare the results in patients with or without glucocorticoid-induced lipodystrophy (GIL) after 3 months of therapy. DESIGN AND SETTING: Prospective monocentric study. PATIENTS: Adult patients initiating systemic, high-dose prednisone therapy for at least 3 months. Blood samples and subcutaneous abdominal adipose tissue biopsies were collected at baseline and month 3. The presence of GIL after 3 months of therapy was assessed using standardized photography. RESULTS: Thirty-two patients were enrolled. Blood samples and subcutaneous abdominal adipose tissue were available at baseline and month 3 for 30 patients [median age: 61 (38-79) years, 77% women]. Among those 30 patients, 15 were classified as GIL+ and 15 were GIL- at month 3. Between baseline and month 3, adiponectin and leptin levels increased in the overall population while the level of resistin remained unchanged. At baseline, leptin level was higher [19.3 (8.3-31.1) vs 4.5 (2.4-11.3) µg/l, P = 0.006] and resistin level lower [7.1 (6.3-12.4) vs 10.4 (8.0-21.7) µg/l, P = 0.05] in GIL+ than in GIL- patients. Baseline leptin level was predictive of GIL occurrence. Receiver operating characteristic curve analysis demonstrated that the best diagnostic accuracy was obtained with a baseline leptin cut-off of 5.9 µg/l (sensitivity: 93%, specificity: 60%). At month 3, leptin and adiponectin levels increased more in the GIL+ than in the GIL- group, as did the number of anti-inflammatory M2 macrophages in subcutaneous abdominal fat. CONCLUSION: Glucocorticoid-induced lipodystrophy is associated with a different adipokine profile both before and after glucocorticoid therapy. Serum leptin level prior to glucocorticoid therapy is highly predictive of GIL occurrence.

[Impact of voxelotor on hemoglobin electrophoretic and chromatographic profiles]. / Conséquences du traitement par voxelotor sur les profils électrophorétiques et chromatographiques de l'hémoglobine.

Voxelotor (GBT440, OXBRYTA®) appeared recently as one of the possible treatments for sickle cell disease. This molecule, by binding the alpha globin of hemoglobin, causes hyperaffinity of the latter for oxygen and reduces its polymerization properties. Several therapeutic trials have been able to show its effectiveness on certain aspects of sickle cell disease; thus, the french HAS (High Authority of Health) college issued an early access authorization and, since 2021, this treatment can be offered to patients under a temporary authorization for use. Consequently, the laboratories that carry out the biological monitoring of sickle cell patients will be confronted with new profiles characteristic of the presence of hemoglobin combined with GBT440. This work presents a collection of images obtained by different techniques: HPLC, capillary electrophoresis, isoelectrofocusing, alkaline gel and acid agar gel electrophoresis in transfused or non-transfused sickle cell disease patients. The ability to observe the presence of GBT440 by these analyzes could be useful in order to characterize the therapeutic follow-up of patients.

Serum Versus Fecal Calprotectin Levels in Patients with Severe Obesity Before and 6 Months After Roux-Y-Gastric Bypass: Report of the Prospective Leaky-Gut Study.

INTRODUCTION: Obesity is associated with low-grade inflammation, including intestinal inflammation based on fecal or serum calprotectin (FC-SC) measurement. Roux-en-Y gastric bypass (RYGB) improves obesity-related parameters. However, the association between FC-SC levels and postoperative course and the link with metabolic and inflammatory phenotypes before and after RYGB remains unclear. METHODS: We determined SC levels in 48 patients before (T0) and 6 months after (T6M) RYGB. We then analyzed postoperative changes in FC-SC levels and the relationship with inflammation and metabolic status. RESULTS: Twenty-three patients (48%) had elevated SC levels (˃2.9 µg/mL) at T0 and T6M. Six of 29 patients (20.7%) had elevated FC concentrations (>50 µg/g) at T0 vs. 16 of 17 patients (94.1%) at T6M (p=0.006). At T0, FC levels correlated with BMI (Rho=0.63; p=0.001) and systemic inflammation (CRP: Rho=0.66, p=0.0006; IL-6: Rho=0.48, p=0.03; haptoglobin: Rho=0.75; p= 0.0006). SC tended to be positively associated with triglyceride levels (Rho=0.34; p=0.08), BMI (Rho=0.34; p=0.08), and inflammatory markers (CRP: Rho=0.33; p=0.09; IL-6: Rho=0.36; p=0.06). FC levels were associated with increased jejunal IL-17+CD8+ T-cell densities (Rho:0.90; p=0.0002). FC and SC were correlated together at T0 (Rho=0.83; p<0.001) but not at T6M. At T6M, SC decreased by 53.6%, whereas FC increased by 79.7%. SC and FC were not associated with any of the variables studied at T6M. CONCLUSION: FC is a surrogate marker of systemic and intestinal inflammation and adiposity, whereas SC only tends to correlate with systemic inflammation. At 6 months after RYGB, SC-based systemic inflammation decreased, whereas FC-based intestinal inflammation increased. FC and SC levels follow different trajectories and are unrelated to improvements following bariatric surgery.