Serum metabolomics profiling by proton nuclear magnetic resonance spectrometry of the response to single oral macronutrient challenges in women with polycystic ovary syndrome (PCOS) compared with male and female controls.

BACKGROUND: The polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiometabolic comorbidities. We here challenged the hypothesis, using state-of-the-art proton nuclear magnetic resonance spectrometry (1H-NMRS) metabolomics profiling, that androgen excess in women induces a certain masculinization of postprandial metabolism that is modulated by obesity. MATERIALS AND METHODS: Participants were 53 Caucasian young adults, including 17 women with classic PCOS consisting of hyperandrogenism and ovulatory dysfunction, 17 non-hyperandrogenic women presenting with regular menses, and 19 healthy men, selected to be similar in terms of age and body mass index (BMI). Half of the subjects had obesity. Patients were submitted to isocaloric separate glucose, lipid and protein oral challenges in alternate days and fasting and postprandial serum samples were submitted to 1H-NMRS metabolomics profiling for quantification of 36 low-molecular-weight polar metabolites. RESULTS: The largest postprandial changes were observed after glucose and protein intake, with lipid ingestion inducing smaller differences. Changes after glucose intake consisted of a marked increase in carbohydrates and byproducts of glycolysis, and an overall decrease in byproducts of proteolysis, lipolysis and ketogenesis. After the protein load, most amino acids and derivatives increased markedly, in parallel to an increase in pyruvate and a decrease in 3-hydroxybutyric acid and glycerol. Obesity increased ß- and D-glucose and pyruvate levels, with this effect being observed mostly after glucose ingestion in women with PCOS. Regardless of the type of macronutrient, men presented increased lysine and decreased 3-hydroxybutyric acid. In addition, non-obese men showed increased postprandial ß-glucose and decreased pyroglutamic acid, compared with non-obese control women. We observed a common pattern of postprandial changes in branched-chain and aromatic amino acids, where men showed greater amino acids increases after protein intake than control women and patients with PCOS but only within the non-obese participants. Conversely, this increase was blunted in obese men but not in obese women, who even presented a larger increase in some amino acids compared with their non-obese counterparts. Interestingly, regardless of the type of macronutrient, only obese women with PCOS showed increased leucine, lysine, phenylalanine and tryptophan levels compared with non-obese patients. CONCLUSIONS: Serum 1H-NMRS metabolomics profiling indicated sexual dimorphism in the responses to oral macronutrient challenges, which were apparently driven by the central role of postprandial insulin effects with obesity, and to a lesser extent PCOS, exerting modifying roles derived from insulin resistance. Hence, obesity impaired metabolic flexibility in young adults, yet sex and sex hormones also influenced the regulation of postprandial metabolism.

The polycystic ovary syndrome (PCOS) is a common endocrine disorder in women. PCOS is associated with diabetes, obesity and cardiometabolic disease. Mild excess of androgens (male hormones) characterize PCOS, and facilitate that body fat accumulates in the visceral abdominal area. Visceral fat promotes insulin resistance increasing the risk for diabetes and cardiometabolic disease, and further androgen excess. We here explored intermediate metabolism after the separate administration of either carbohydrates, fats or proteins, in young adult women with or without PCOS and in men, using state-of-the-art proton nuclear magnetic resonance metabolomics profiling. Results suggest that postprandial metabolomics profiles reflect mostly insulin actions, with changes derived from insulin resistance being more important with obesity but also being influenced by male sex and PCOS in women.

Association between Clinical Frailty Scale (CFS) and clinical presentation and outcomes in older inpatients with COVID-19.

BACKGROUND: Frailty is a physiological condition characterized by a decreased reserve to stressors. In patients with COVID-19, frailty is a risk factor for in-hospital mortality. The aim of this study was to assess the relationship between clinical presentation, analytical and radiological parameters at admission, and clinical outcomes according to frailty, as defined by the Clinical Frailty Scale (CFS), in old people hospitalized with COVID-19. MATERIALS AND METHODS: This retrospective cohort study included people aged 65 years and older and admitted with community-acquired COVID-19 from 3 March 2020 to 31 April 2021. Patients were categorized using the CFS. Primary outcomes were symptoms of COVID-19 prior to admission, mortality, readmission, admission in intensive care unit (ICU), and need for invasive mechanical ventilation. Analysis of clinical symptoms, clinical outcomes, and CFS was performed using multivariable logistic regression, and results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of the 785 included patients, 326 (41.5%, 95% CI 38.1%-45.0%) were defined as frail (CFS ≥ 5 points): 208 (26.5%, 95% CI 23.5%-29.7%) presented mild-moderate frailty (CFS 5-6 points) and 118 (15.0%, 95% CI 12.7%-17.7%), severe frailty (7-9 points). After adjusting for epidemiological variables (age, gender, residence in a nursing home, and Charlson comorbidity index), frail patients were significantly less likely to present dry cough (OR 0.58, 95% CI 0.40-0.83), myalgia-arthralgia (OR 0.46, 95% CI 0.29-0.75), and anosmia-dysgeusia (OR 0.46, 95% CI 0.23-0.94). Confusion was more common in severely frail patients (OR 3.14; 95% CI 1.64-5.97). After adjusting for epidemiological variables, the risk of in-hospital mortality was higher in frail patients (OR 2.79, 95% CI 1.79-4.25), including both those with mild-moderate frailty (OR 1.98, 95% CI 1.23-3.19) and severe frailty (OR 5.44, 95% CI 3.14-9.42). Readmission was higher in frail patients (OR 2.11, 95% CI 1.07-4.16), but only in mild-moderate frailty (OR 2.35, 95% CI 1.17-4.75).. CONCLUSION: Frail patients presented atypical symptoms (less dry cough, myalgia-arthralgia, and anosmia-dysgeusia, and more confusion). Frailty was an independent predictor for death, regardless of severity, and mild-moderate frailty was associated with readmission.

Early carbohydrate antigen 125 as a mortality predictor in hospitalized patients with coronavirus disease 2019.

Background: Carbohydrate antigen 125 (CA125) is an indicator of inflammation, immune response, and impaired cardiac function. The aim was to investigate whether CA125 behaves as a biomarker of severity and poor clinical outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: Serum CA125 [Elecsys CA125 II assay-(Roche Diagnostics GmbH)] was measured in stored biobank samples from COVID-19 hospitalized patients between 01 March 2020 and 17 October 2021. Multiple logistic regression models were built to explore the association between CA125 and clinical outcomes [in-hospital all-cause mortality, need for invasive mechanical ventilation (IMV), or non-invasive respiratory support (non-IRS)], estimating odds ratios (ORs; 95% CI). The gradient of risk of CA125 was evaluated by fractional polynomials. Results: A total of 691 patients were included, median age of 63 years (50-76), men (57.2%), with high comorbidity. At admission, 85.8% had pneumonia. Median CA125 was 10.33 U/ml (7.48-15.50). The in-hospital mortality rate was 7.2%. After adjusting for confounding factors, CA125 ≥ 15.5 U/ml (75th percentile) showed an increased risk of death [OR 2.85(1.21-6.71)], as age ≥ 65 years, diabetes, and immunosuppression. Furthermore, CA125 as a continuous variable was positive and significantly associated with the risk of death after multivariate adjustment. The mean hospital stay of the patients with CA125 ≥ 15.5 U/ml was longer than the rest of the study population. Conclusion: CA125 in the first 72 h of hospital admission seems a useful biomarker of mortality in hospitalized patients with moderate-severe COVID-19. If our findings are confirmed, the wide availability of this biomarker would make easy its widespread implementation in clinical practice.

Effect of Iron Depletion by Bloodletting vs. Observation on Oxidative Stress Biomarkers of Women with Functional Hyperandrogenism Taking a Combined Oral Contraceptive: A Randomized Clinical Trial.

Women with functional hyperandrogenism show both increased markers of oxidative stress and a mild iron overload. Combined oral contraceptives (COC) may worsen redox status in the general population. Since iron depletion ameliorates oxidative stress in other iron overload states, we aimed to address the changes in the redox status of these women as a consequence of COC therapy and of bloodletting, conducting a randomized, controlled, parallel, open-label clinical trial in 33 adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. After three months of treatment with a COC, participants were randomized (1:1) to three scheduled bloodlettings or observation for another nine months. After taking a COC, participants showed a mild decrease in their plasma electrochemical antioxidant capacity, considering fast-acting antioxidants [MD: −1.51 (−2.43 to −0.60) µC, p = 0.002], and slow-acting antioxidants [MD: −1.90 (−2.66 to −1.14) µC, p < 0.001]. Women submitted to bloodletting showed a decrease in their non-enzymatic antioxidant capacity levels (NEAC) throughout the trial, whereas those individuals in the control arm showed a mild increase in these levels at the end of the study (Wilks' λ: 0.802, F: 3.572, p = 0.041). Decreasing ferritin and plasma hemoglobin during the trial were associated with worse NEAC levels. COC may impair redox status in women with functional hyperandrogenism. Decreasing iron stores by scheduled bloodletting does not override this impairment.

Mosaic attenuation in non-fibrotic areas as a predictor of non-usual interstitial pneumonia pathologic diagnosis.

The new radiological diagnostic criteria for diagnosing idiopathic pulmonary fibrosis (IPF) seek to optimize the indications for surgical lung biopsy (SLB). We applied the new criteria to a retrospective series of patients with interstitial lung disease (ILD) who underwent SLB in order to analyse the correlation between the radiological findings suggestive of another diagnosis (especially mosaic attenuation and its location with respect to fibrotic areas) and the usual interstitial pneumonia (UIP) pathologic diagnosis. Two thoracic radiologists reviewed the HRCT images of 83 patients with ILD and SLB, describing the radiological findings and patterns based on the new criteria. The association of each radiological finding with radiological patterns and histology was analysed. Mosaic attenuation is highly prevalent in both the UIP and non-UIP pathologic diagnosis and with similar frequency (80.0% vs. 78.6%). However, the presence of significant mosaic attenuation (≥ 3 lobes) only in non-fibrotic areas was observed in 60.7% of non-UIP pathologic diagnosis compared to 20.0% in UIP. This finding was associated with other diagnoses different from IPF, mostly connective tissue disease-associated interstitial lung disease (CTD-ILD) and hypersensitivity pneumonitis (HP). In our series of pathologically confirmed ILD, mosaic attenuation in non-fibrotic areas was a predictor of non-UIP pathologic diagnosis, and was associated with other diagnoses different from UIP, mostly CTD-ILD and HP. If confirmed in larger series, this finding could constitute a valuable tool for improving the interpretation of radiological.

Hospitalized patients with breakthrough COVID-19: Clinical features and poor outcome predictors.

OBJECTIVES: To describe breakthrough COVID-19 infection in patients who needed hospitalization and the factors associated with poor outcomes. METHODS: We conducted a retrospective study on patients hospitalized with COVID-19 between December 27, 2020, and October 17, 2021, with either a complete vaccination (CV) scheme (diagnosed 2 weeks after the second dose of the Pfizer/Moderna/AstraZeneca or first dose of the Janssen vaccine was administered) or a partial vaccination (PV) scheme. The main outcomes were all-cause mortality and the need for invasive mechanical ventilation (IMV). The baseline factors associated with the outcomes were analyzed by multiple logistic regression to estimate the odds ratios (odds ratio [OR]; 95% confidence interval [CI]). RESULTS: A total of 145 (101 CV) patients were included. The CV subgroup was mainly composed of older males with high comorbidity (Charlson Index ≥3, 72%; immunosuppression, 20%) and with bilateral pneumonia in 63.4%. Limited therapeutic effort (LTE) was agreed upon for 28% of the patients. In the CV subgroup, endotracheal intubation was required in 10.9% of patients, reaching 15.3% when excluding LTE patients; the global mortality was 22.8%, reaching 41.4% in the subgroup with LTE. Although the patients with PV were younger and had fewer comorbidities, the main outcomes did not differ significantly between the CV and PV groups. The predictors of poor outcomes were age ≥ 65 years, confusion, ferritin > 500 mg/L, extensive lung infiltrates, and a Charlson Index ≥ 3. CONCLUSIONS: Patients with CV hospitalized because of breakthrough COVID-19 infection tend to be older persons, with comorbidities, and have a high mortality.

High serum copeptin may be a marker of an increased carotid intima-media thickness in asymptomatic patients with type 1 diabetes.

We aimed to study the association of copeptin with carotid intima-media thickness in 60 patients with type 1 diabetes (T1DM-patients). Our results suggest that copeptin might improve the stratification of cardiovascular risk in T1DM-patients. Further research is needed to determine the value in identifying carotid disease of this biochemical marker.

Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes.

CONTEXT: Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. OBJECTIVES: (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. DESIGN: Randomized, parallel, open-label, clinical trial. SETTING: Academic hospital. PATIENTS: Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. INTERVENTION: After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. MAIN OUTCOME MEASURES: Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. RESULTS: From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. CONCLUSIONS: Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.

Fasting serum copeptin and asymptomatic peripheral artery disease: No association in patients with type 1 diabetes mellitus.

OBJECTIVE: As copeptin is associated with lower-extremity amputation in patients with type 1 diabetes mellitus (T1DM), our study aimed to address the putative association between copeptin and asymptomatic peripheral artery disease (aPAD) in those patients. DESIGN AND METHODS: This observational cross-sectional study included 112 patients with T1DM from a larger cohort (ClinicalTrials.gov: NCT02910271), selected (1:2) as per the presence of aPAD (n = 37) or not (n = 75). aPAD was evaluated by ankle-brachial index (ABI), toe-brachial index (TBI), and peripheral Doppler ultrasound. The two groups of patients were matched by age, gender distribution and duration of T1DM. Fasting serum copeptin was measured by high-sensitivity ELISA, and its relationships with clinical and biochemical variables as well as aPAD were evaluated too. RESULTS: The study population was aged 42 ± 8 years, duration of T1DM was 27 ± 7 years, and mean HbA1c was 7.7 ± 1.1%. No significant differences in copeptin concentrations were found between patients with or without aPAD (16.9 ± 10.8 vs 17.3 ± 14.7 pmol/L, respectively; P = 0.462). Considering all patients as a whole, copeptin correlated with systolic blood pressure (SBP; ρ = -0.209, P = 0.027), eGFR ρ = -0.271, P = 0.004), and serum sodium (ρ = -0.208, P = 0.027), but not with ABI (ρ = -0.068, P = 0.476). Stepwise multiple linear regression analysis (R2: 0.059; P = 0.035) retained SBP (ß: -0.219, 95% CI: -1.391; -0.089) as the only significant predictor of copeptin concentration. CONCLUSION: As serum copeptin does not appear to be associated with aPAD in patients with T1DM, further studies are now needed to elucidate whether it has any other potential role to play in the subclinical vascular disease of this patient population.

Plasma thiobarbituric acid reactive substances (TBARS) in young adults: Obesity increases fasting levels only in men whereas glucose ingestion, and not protein or lipid intake, increases postprandial concentrations regardless of sex and obesity.

SCOPE: Oxidative stress and damage participate in the pathophysiology of obesity and its metabolic complications. We studied the influence of sex, obesity, and ingestion of different macronutrients on fasting and postprandial thiobarbituric acid reactive substances (TBARS), which can be considered as an index of lipid peroxidation and oxidative damage. METHODS AND RESULTS: We studied 19 men and 17 women, out of whom nine men and eight women had obesity. We collected blood samples in the fasting state and, on alternate days, following the ingestion of 300 kcal in the form of glucose, lipids, or proteins. Fasting TBARS concentrations correlated with waist circumference and were increased in obese men compared with nonobese men. This increase was not, however, observed in women. TBARS concentrations showed a marked increase following the ingestion of glucose in parallel to the increase in plasma glucose when considering all subjects as a whole, but did not increase after the oral intake of lipids and proteins. CONCLUSION: Plasma TBARS concentrations are increased in the fasting state only in obese men in association with abdominal adiposity, and increases markedly after the ingestion of glucose, but not after oral intake of lipids and proteins, regardless of sex and obesity.