Cardiac adipose tissue volume and IL-6 level at admission are complementary predictors of severity and short-term mortality in COVID-19 diabetic patients.

BACKGROUND: COVID-19 diabetic adults are at increased risk of severe forms irrespective of obesity. In patients with type-II diabetes, fat distribution is characterized by visceral and ectopic adipose tissues expansion, resulting in systemic inflammation, which may play a role in driving the COVID-19 cytokine storm. Our aim was to determine if cardiac adipose tissue, combined to interleukin-6 levels, could predict adverse short-term outcomes, death and ICU requirement, in COVID-19 diabetic patients during the 21 days after admission. METHODS: Eighty one consecutive patients with type-II diabetes admitted for COVID-19 were included. Interleukin-6 measurement and chest computed tomography with total cardiac adipose tissue index (CATi) measurement were performed at admission. The primary outcome was death during the 21 days following admission while intensive care requirement with or without early death (ICU-R) defined the secondary endpoint. Associations of CATi and IL-6 and threshold values to predict the primary and secondary endpoints were determined. RESULTS: Of the enrolled patients (median age 66 years [IQR: 59-74]), 73% male, median body mass index (BMI) 27 kg/m2 [IQR: 24-31]) 20 patients had died from COVID-19, 20 required intensive care and 41 were in conventional care at day 21 after admission. Increased CATi and IL-6 levels were both significantly related to increased early mortality (respectively OR = 6.15, p = 0.002; OR = 18.2, p < 0.0001) and ICU-R (respectively OR = 3.27, p = 0.01; OR = 4.86, p = 0.002). These associations remained significant independently of age, sex, BMI as well as troponin-T level and pulmonary lesion extension in CT. We combined CATi and IL-6 levels as a multiplicative interaction score (CATi*IL-6). The cut-point for this score was ≥ 6386 with a sensitivity of 0.90 and a specificity of 0.87 (AUC = 0.88) and an OR of 59.6 for early mortality (p < 0.0001). CONCLUSIONS: Cardiac adipose tissue index and IL-6 determination at admission could help physicians to better identify diabetic patients with a potentially severe and lethal short term course irrespective of obesity. Diabetic patients with high CATi at admission, a fortiori associated with high IL-6 levels could be a relevant target population to promptly initiate anti-inflammatory therapies.

Mitochondrial dysfunction caused by novel ATAD3A mutations.

Mitochondrial respiratory chain integrity depends on a number of proteins encoded by nuclear and mitochondrial genomes. Mutations of such factors can result in isolated or combined respiratory chain deficits, some of which can induce abnormal morphology of the mitochondrial network or accumulation of intermediary metabolites. Consequently, affected patients are clinically heterogeneous, presenting with central nervous system, muscular, or neurodegenerative disorders. ATAD3A is a nuclear-encoded ATPase protein of the AAA+ family and has been localized to the inner mitochondrial membrane. Recently reported mutations or large deletions in the ATDA3A gene in patients have been shown to induce altered mitochondrial structure and function and abnormal cholesterol metabolism in a recessive or dominant manner. Here, we report two siblings presenting axonal sensory-motor neuropathy associated with neonatal cataract. Genetic analyses identified two novel mutations in ATAD3A; a point mutation and an intronic 15 bp deletion affecting splicing and leading to exon skipping. Biochemical analysis in patient cells and tissues showed abnormal function of the mitochondrial respiratory chain in muscle and abnormal mitochondrial cristae structure. These new cases underline the large spectrum of biochemical and clinical presentations of ATAD3A deficiency and the different modes of inheritance, making it an atypical mitochondrial disorder.

Effect of Stool Sampling on a Routine Clinical Method for the Quantification of Six Short Chain Fatty Acids in Stool Using Gas Chromatography-Mass Spectrometry.

Short chain fatty acids (SCFAs) are primarily produced in the caecum and proximal colon via the bacterial fermentation of undigested carbohydrates that have avoided digestion in the small intestine. Increasing evidence supports the critical role that SCFAs play in health and homeostasis. Microbial SCFAs, namely butyric acid, serve as a principal energy source for colonocytes, and their production is essential for gut integrity. A direct link between SCFAs and some human pathological conditions, such as inflammatory bowel disease, irritable bowel syndrome, diarrhea, and cancer, has been proposed. The direct measurement of SCFAs in feces provides a non-invasive approach to demonstrating connections between SCFAs, microbiota, and metabolic diseases to estimate their potential applicability as meaningful biomarkers of intestinal health. This study aimed to adapt a robust analytical method (liquid-liquid extraction, followed by isobutyl chloroformate derivatization and GC-MS analysis), with comparable performances to methods from the literature, and to use this tool to tackle the question of pre-analytical conditions, namely stool processing. We focused on the methodology of managing stool samples before the analysis (fresh stool or dilution in either ethanol/methanol, lyophilized stool, or RNAlater®), as this is a significant issue to consider for standardizing results between clinical laboratories. The objective was to standardize methods for future applications as diagnostic tools. In this paper, we propose a validated GC-MS method for SCFA quantification in stool samples, including pre- and post-analytical comparison studies that could be easily used for clinical laboratory purposes. Our results show that using lyophilization as a stool-processing method would be the best method to achieve this goal.

Ovarian reserve in patients with FMR1 gene premutation and the role of fertility preservation.

INTRODUCTION: Women with premutation (PM) of the FMR1 gene may suffer from reduced ovarian reserve or even premature ovarian insufficiency (POI). We studied hormonal and ultrasound ovarian reserve, fertility and fertility preservation outcomes in these patients. PATIENTS AND METHOD: Retrospective cohort study of 63 female FMR1 premutation carriers. RESULTS: Sixty-three female patients bearing an FMR1 premutation were included. Median age was 30 years [26.5-35]. Median number of CGG triplets was 83 [77.2-92]. Before diagnosis of PM, 19 women (30%) had had in all 35 pregnancies, resulting in 20 births, including 7 affected children. After diagnosis of PM, 17 women (26.1%) had in all 23 pregnancies, at a median age of 34.5 years [32.2-36.0]: 2 after pre-implantation genetic diagnosis, 3 after oocyte donation, 18 spontaneously, and 5 ending in medical termination for fragile X syndrome. Thirty-three patients (52.4%) had POI diagnosis (median age, 30 years [27-34]) with median FSH level 84 IU/L [50.5-110] and median AMH level 0.08ng/mL [0.01-0.19]. After POI diagnosis, 8 women had in all 9 pregnancies: 3 following oocyte donation, and 6 spontaneous in 5 women (15.1%). Eight of the 9 pregnancies resulted in a live birth (including 2 affected children) and 1 in medical termination for trisomy 13. The median age of the 30 patients without POI was 31 years [25.2-35.0]. Thirteen women (20.6%) underwent fertility preservation, at a median age of 29 years [24-33]: FSH 7.7 IU/L [6.8-9.9], AMH 1.1ng/mL [0.95-2.1], antral follicle count 9.5 [7.7-14.7]. A median 15 oocytes [10-26] were cryopreserved in a median 2 cycles [1-3]. At the time of writing, no oocytes had yet been thawed for in-vitro fertilization. CONCLUSIONS: This study shows the importance of early fertility preservation after diagnosis of FMR1 premutation in women, due to early deterioration of ovarian reserve. Genetic counseling is essential in these patients, as spontaneous pregnancies are not uncommon, even in cases of impaired ovarian reserve, and can lead to birth of affected children.

Circulating Apolipoprotein B-48 as a Biomarker of Parenteral Nutrition Dependence in Adult Patients with Short Bowel Syndrome.

Short bowel syndrome (SBS) is a rare but serious condition that may lead to chronic intestinal failure. Citrulline concentrations are currently used to reflect the residual intestinal mass in patients with SBS, although this method has several limitations. In a cohort of patients with SBS, we quantified apolipoprotein B-48 (ApoB-48), which is exclusively synthesized by enterocytes and secreted associated with dietary lipids and investigated the relationship between ApoB-48 and clinical and biological data as well as PN dependence. A total of 51 adult patients were included, 36 of whom were PN-dependent. We found a robust positive correlation between circulating ApoB-48 and residual small bowel length, which was also found in the subgroup of patients with jejunocolic anastomosis. Fasting ApoB-48 levels were significantly lower in PN-dependent patients than in PN-weaned patients and negatively correlated with parenteral nutrition dependence. Our results suggest that ApoB-48 could be proposed as a marker of intestinal absorptive function and could be an interesting follow-up marker in patients with SBS.

Hyperphagia is prominent in adult patients with short bowel syndrome: A role for the colon?

RATIONALE: Short Bowel Syndrome (SBS) is the major cause of chronic intestinal failure (IF) and requires parenteral nutrition (PN). After bowel resection, some patients develop spontaneous intestinal adaptations and hyperphagia. Since promoting oral energy intake contributes to PN weaning, this study aims to characterize hyperphagia in patients with SBS and identify its determinants. METHODS: This observational retrospective study included adult patients with SBS who were followed at an expert PN center between 2006 and 2019, with at least 2 separate nutritional assessments. Exclusion criteria were: active neoplasia, alternative treatment for IF or appetite-affecting medication. Resting energy expenditure (REE) was calculated for each patient using the Harris-Benedict equation. Food Intake Ratio (FIR) was calculated by dividing the highest caloric oral intake by REE and hyperphagia was defined as FIR >1.5. RESULTS: Among the 59 patients with SBS included in this study, 82.6% had a FIR >1.5, including 15.5% with a FIR >3. Protein supplied approximately 16% of total energy intake while fat and carbohydrates provided 36% and 48%, respectively. The FIR was independent of gender and whether patients received oral nutrition alone (n = 28) or combined with PN (n = 31). The FIR was also not associated with residual small bowel length, nor the proportion of preserved colon. However, it was negatively correlated with the body mass index (BMI) of these patients (r = -0.533, p < 0.001), whether they had PN support or not. Patients with either a jejuno-colonic (n = 31) or a jejuno-ileal anastomosis (n = 9), had a significantly higher FIR compared to those with an end-jejunostomy (n = 18) (p < 0.05). However, no difference was found in the proportion of calories provided by protein, fat and carbohydrate between the 3 patients groups divided according to the SBS anatomical type. CONCLUSION: A large majority of patients with SBS exhibited a hyperphagia regardless of PN dependence or bowel length, which was inversely correlated with BMI. The presence of the colon in continuity, thus in contact with the nutritional flow, seems to favor a higher oral intake which is beneficial for the nutritional autonomy of patients. This raises the question of a role of colonic microbiota and hormones in this behavior. Finally, this study also revealed an unexpected discrepancy between recommended energy intakes from protein, fat and carbohydrate and the actual intake of patients with SBS.

Could the chylomicron marker apoB48 be of value in the diagnosis of chylous effusions?

BACKGROUND: Chylous effusions such as chylothorax, chylopericardium and chylous ascites are marked by the abnormal presence of chylomicrons in serous membranes. These relatively rare situations are associated with high morbidity and mortality rates. Given that a macroscopic assessment of the fluid is insufficient, the current gold standard method for chylous effusion is the electrophoretic separation of lipoproteins. Serous effusions are most frequently assayed for triglycerides, with a diagnostic threshold varying between studies. The present study is the first to assess the value of the apolipoprotein B48, specific of the chylomicron, in the diagnosis of chylous effusions. METHODS: A chemiluminescent sandwich enzyme immunoassay was used to measure levels of apoB48 in remnant samples of effusion fluid sent to our laboratory for chylomicron detection and lipid assays. The diagnostic values of apoB48 and triglyceride assays were compared with that of the gold standard method. RESULTS: The triglyceride and apoB48 levels and the triglyceride/cholesterol ratio in the effusion fluid were significantly higher in patients with chylous effusion. The threshold values for apoB48 were respectively 2.45, 0.25 and 19.00 µg/mL for a maximal Youden index, a sensitivity > 95 %, and a specificity > 95 %. The apoB48 assay's diagnostic value might be at least as high as that of a triglyceride assay (area under the receiver operating characteristic curve [95 % confidence interval]: 0.84 [0.72, 0.96]) and 0.80 [0.67, 0.94], respectively). CONCLUSION: ApoB48 appears to be a promising marker for the diagnosis of chylous effusions; the putative diagnostic improvement must be confirmed in larger studies.

Fecal microbiota transplantation in a rodent model of short bowel syndrome: A therapeutic approach?

Extensive intestinal resection leads to Short Bowel Syndrome (SBS), the main cause of chronic intestinal failure. Colon preservation is crucial for spontaneous adaptation, to improve absorption and reduce parenteral nutrition dependence. Fecal microbiota transplantation (FMT), a promising approach in pathologies with dysbiosis as the one observed in SBS patients, was assessed in SBS rats with jejuno-colonic anastomosis. The evolution of weight and food intake, the lenght of intestinal villi and crypts and the composition of fecal microbiota of Sham and SBS rats, transplanted or not with high fat diet rat microbiota, were analyzed. All SBS rats lost weight, increased their food intake and exhibited jejunal and colonic hyperplasia. Microbiota composition of SBS rats, transplanted or not, was largely enriched with Lactobacillaceae, and α- and ß-diversity were significantly different from Sham. The FMT altered microbiota composition and α- and ß-diversity in Sham but not SBS rats. FMT from high fat diet rats was successfully engrafted in Sham, but failed to take hold in SBS rats, probably because of the specific luminal environment in colon of SBS subjects favoring aero-tolerant over anaerobic bacteria. Finally, the level of food intake in SBS rats was positively correlated with their Lactobacillaceae abundance. Microbiota transfer must be optimized and adapted to this specific SBS environment.

[Short bowel syndrome: From intestinal insufficiency to intestinal adaptation]. / Le syndrome de grêle court chez l'adulte - De l'insuffisance intestinale à l'adaptation intestinale.

The short bowel syndrome results from an extensive intestinal resection. When intestinal function is below the minimum necessary for the absorption of macronutrients, water and electrolytes, short small bowel syndrome is responsible for chronic intestinal failure. The management is then parenteral nutrition. The evolution of the short bowel syndrome is schematically divided into three successive periods: (a) Immediate postoperative period lasting 3 to 6 weeks; (b) adaptive period lasting about 2 years and (c) stabilization period. However, the development of hyperphagia, spontaneous intestinal adaptation allowing an increase in the absorption surface area and in secretion of enterohormones and a modification of the microbiota occur spontaneously, improving intestinal absorption and decreasing dependence on parenteral nutrition. This review summarizes the main positive and negative pathophysiological consequences of extensive intestinal resection and the nutritional and drug management of short bowel syndrome in adults.

TITLE: Le syndrome de grêle court chez l'adulte - De l'insuffisance intestinale à l'adaptation intestinale. ABSTRACT: Le syndrome de grêle court, conséquence d'une résection étendue de l'intestin, est la principale cause d'insuffisance intestinale, définie comme la réduction de la fonction intestinale en dessous du minimum nécessaire à l'absorption des macronutriments, de l'eau et des électrolytes. La prise en charge nécessite alors la nutrition parentérale. L'évolution du syndrome de grêle court est schématiquement scindée en trois périodes successives : 1) la période post-opératoire, d'une durée de 3 à 6 semaines ; 2) la période adaptative, d'une durée de 2 ans environ ; et 3) la période de stabilisation, dite séquellaire. Le développement d'une hyperphagie, d'une adaptation intestinale permettant l'augmentation de la surface d'absorption et de la sécrétion d'entérohormones, ainsi qu'une modification du microbiote, se produisent spontanément, améliorant l'absorption intestinale et diminuant la dépendance à la nutrition parentérale. Cet article résume les principales conséquences physiopathologiques (bénéfiques ou délétères) d'une résection étendue de l'intestin grêle et la prise en charge nutritionnelle et médicamenteuse du syndrome de grêle court chez l'adulte.

IgA dominates the early neutralizing antibody response to SARS-CoV-2.

Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and composed of IgG, IgA, and IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva, and bronchoalveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM, and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably 1 month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post-symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against reinfection and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.