Inflammation and prediction of death in type 2 diabetes. Evidence of an intertwined link with tryptophan metabolism.

OBJECTIVE: To study whether inflammation is associated with and helps predict mortality risk in patients with type 2 diabetes. To explore the intertwined link between inflammation and tryptophan metabolism on death risk. DESIGN: Two prospective cohorts: the aggregate Gargano Mortality Study (1,731 individuals; 872 all-cause deaths) as discovery sample, the Foggia Mortality Study (490 individuals; 256 deaths) as validation sample. Twenty-seven inflammatory markers were measured. Causal mediation analysis and in vitro studies were carried out to explore the link between inflammatory markers and the kynurenine-to-tryptophan ratio (KTR) in shaping mortality risk. RESULTS: Using multivariable stepwise Cox regression analysis, IL-4, IL-6, IL-8, IL-13, RANTES and IP-10, were independently associated with death. An inflammation score (I-score) comprising these six molecules is strongly associated with death in both the discovery and the validation cohorts HR (95%CI) = 2.13 (1.91-2.37) and 2.20 (1.79-2.72), respectively. The I-score improved discrimination and reclassification measures (all P<0.01) of two mortality prediction models based on clinical variables. The causal mediation analysis showed that 28% of the KTR effect on mortality was mediated by IP-10. Studies in cultured endothelial cells showed that 5-Methoxy-tryptophan, an anti-inflammatory metabolite derived from tryptophan, reduces the expression of IP-10, thus providing a functional basis for the observed causal mediation. CONCLUSIONS: Adding the I-score to clinical prediction models may help identify individuals who are at greater risk of death. Deeply addressing the intertwined relationship between low-grade inflammation and imbalanced tryptophan metabolism in shaping mortality risk may help discover new therapies targeting patients characterized by these abnormalities.

GFR decline predicts total mortality and mediates the effect of tryptophan metabolism on death risk in type 2 diabetes.

CONTEXT: The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed. OBJECTIVE: The objective of the study was twofold: i) to investigate the association between all-cause mortality and eGFR changes over time; ii) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk. DESIGN: Prospective study with an average follow-up of 14.8 years. SETTING: Research Hospital. PATIENTS: The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least three eGFR recordings and at least 1.5 years of follow-up. INTERVENTIONS: This was an observational study, with no intervention. MAIN OUTCOME MEASURES: Rate of all-cause mortality. RESULTS: Age and sex adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 ml/min per 1.73 m2 per year (range -3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine-to-tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline. CONCLUSIONS: In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death.

Severe Hypertriglyceridemia in Patients with Type 2 Diabetes Mellitus Participating in the AMD Annals Initiative.

Background: Familial chylomicronemia syndrome (FCS) is a rare inherited condition due to lipoprotein lipase deficiency, characterized by hyperchylomicronemia and severe hypertriglyceridemia. Diagnosis is often delayed, thus increasing the risk of acute pancreatitis and hospitalization. Hypertriglyceridemia is a common finding in patients with type 2 diabetes (T2D), who may harbor FCS among the most severe forms. Aim of the Study: We investigated the prevalence and clinical characteristics associated with severe hypertriglyceridemia in a range indicative of FCS, in a large population of subjects with T2D. Methods: Within the large population of the AMD Annals Initiative, patients with T2D with a lipid profile suggestive of FCS [triglycerides >880 mg/dL and/or high-density lipoprotein (HDL)-cholesterol <22 mg/dL or non-HDL-cholesterol ≤70 mg/dL] and their clinical features have been identified. Results: Overall, 8592 patients had triglyceride values >880 mg/dL in a single examination, 613 in two examinations, and 34 in three or more measurements. Patients with high triglyceride levels were mostly male (80%), with a relatively young age (54 years), short duration of diabetes (6.3 years), and elevated hemoglobin A1c (HbA1c) levels (9.4%). By stratifying this group of patients according to the severity of hypertriglyceridemia, more severe hypertriglyceridemia (triglyceride levels ≥2000 mg/dL) was associated with an even younger age (52 vs. 54 years), even higher mean HbA1c values (10.0% vs. 9.4%), and significantly higher HDL-cholesterol levels (37.9 vs. 32.4 mg/dL; P < 0.0001). Patients with persistently elevated triglyceride levels (n = 34), on three measurements, had a younger age; lower body mass index, HbA1c, and HDL-cholesterol levels; more frequent use of fibrates and insulin; and a higher prevalence of major cardiovascular events. Conclusions: Severe hypertriglyceridemia is a frequent condition in outpatients with T2D participating in the AMD Annals Initiative, and it is associated with male sex, young age, short disease duration, and a worse glycemic profile. Among patients with persistent severe hypertriglyceridemia, hidden FCS may be present.

Prevalence and clinical determinants of rapid eGFR decline among patients with newly diagnosed type 2 diabetes.

BACKGROUND: Diabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in the western world. Rapid estimated glomerular filtration rate (eGFR) decline is an independent predictor of ESKD and death in the general population and in subjects with type 2 diabetes mellitus (T2D). AIM: We investigated in a large sample of subjects with newly diagnosed T2D the prevalence and clinical determinants of fast eGFR decline, taking advantage from the dataset of the Associazione Medici Diabetologi (AMD) Annals initiative. METHODS: The eGFR trajectories were evaluated by applying a linear mixed model for repeated measures (LMMRM) and rapid eGFR decline defined as an eGFR decline greater than 5 mL/min/1.73 m2 per year at 3 years. RESULTS: Among 105,163 (57.7% M) subjects with newly diagnosed T2D, 13,587 (12.9 %) subjects showed a rapid eGFR loss. The independent significant predictors were age, female gender, HbA1c, smoking, high baseline eGFR, albuminuria and retinopathy. CONCLUSION: Our study demonstrates that a significant percentage of newly diagnosed T2D subjects have a rapid eGFR decline. Given the association between dynamic changes in eGFR and the risk of ESKD or death, we suggest to include this variable in the definition of CKD.

Low Diagnostic Accuracy of Transthoracic Ultrasound for the Assessment of Spontaneous Pneumothorax in the Emergency Setting: A Multicentric Study.

Background: Pneumothorax (PNX) represents a common clinical condition in emergency departments (EDs), requiring prompt recognition and treatment. The role of transthoracic ultrasounds (TUSs) in the diagnosis of PNX is still debated. We aimed to prospectively evaluate the accuracy of TUSs in the detection of spontaneous PNX in EDs. Methods: A total of 637 consecutive adult patients who presented to the EDs of four Italian hospitals complaining of acutely onset chest pain and dyspnoea were included in the study. Exclusion criteria were previous traumatic events, cardiogenic causes of pain/dyspnoea and suspected tension PNX. The absence of "lung sliding" (B-mode) and the "bar-code" sign (M-mode) were considered indicative of PNX in a TUS. Accuracy, sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) were calculated using a chest CT scan as reference. Results: Spontaneous PNX occurred in 93 patients: of those, 83 (89.2%) were correctly identified by TUSs. However, 306 patients with suspected PNX at TUS were not confirmed by chest CTs. The diagnostic accuracy of both the absence of "lung sliding" and "bar-code" sign during TUS was 50.4% (95% CI: 46.4-54.3), sensitivity was 89.2% (95% CI: 81.1-94.7), specificity was 43.8% (95% CI: 39.5-48.0), the PPV was 21.3% (95% CI: 19.7-23.1) and the NPV was 96.0% (95% CI: 92.9-97.7). Conclusions: TUS showed high sensitivity but low specificity in the identification of PNX in EDs. Relying exclusively on TUSs results for patients' management in ED settings is neither suitable nor recommendable. TUS examination can be useful to strengthen the clinical suspicion of PNX, but its results should be confirmed by a chest X-ray or CT scan.

Association between R2CHA2DS2-VASc score and three-vessel coronary artery disease in a large population at high cardiovascular risk.

Coronary artery disease (CAD), particularly three-vessel coronary disease (3VD), is the main cause of death in industrialized countries. Chronic kidney disease is an independent risk factor for CAD. The CHA2DS2-VASc score shows a good ability to predict CV events in high-risk population independently from atrial fibrillation. The aim of the present study was to evaluate the association between the R2CHA2DS2-VASc score and 3VD in a population of patients at high cardiovascular risk. Monocentric prospective study evaluated 1017 patients undergoing coronary angiography. The R2CHA2DS2-VASc score was obtained by adding 2 points to the CHA2DS2-VASc score in case of eGFR < 60 ml/min/1.73m2. Coronary lesions causing ≥ 50% reduction of a major epicardial vessel diameter were considered significant. Patients were grouped based on R2CHA2DS2-VASc tertiles and according to the severity of CAD: 3VD vs No-3VD. The 3VD group showed significantly higher R2CHA2DS2-VASc score than the No-3VD group (4.20 ± 2.18 vs 3.36 ± 2.06, p < 0.001). The risk of 3VD increased by 21% for every 1-point increase in the score (OR 1.21; 95% CI 1.13-1.28, p < 0.001). The prevalence of 3VD was higher among patients belonging to higher tertiles of R2CHA2DS2-VASc (17.2% vs 26.7% vs 33.6% for first, second, and third tertile respectively, p < 0.001) with a risk more than doubled for the third tertile compared to the first one (OR 2.45; 95% CI 1.71-3.49, p < 0.001). The R2CHA2DS2-VASc score is independently associated with 3VD in patients at high cardiovascular risk. The score could be considered a useful tool for clinicians to identify patients who are at high risk of 3VD.

The legacy effect of hyperglycemia and early use of SGLT-2 inhibitors: a cohort study with newly-diagnosed people with type 2 diabetes.

Background: A delay in reaching HbA1c targets in patients with newly-diagnosed type 2 diabetes (T2D) is associated with an increased long-term risk of developing cardiovascular diseases (CVD), a phenomenon referred to as legacy effect. Whether an early introduction of glucose-lowering drugs with proven benefit on CVD can attenuate this phenomenon is unknown. Methods: Using data derived from a large Italian clinical registry, i.e. the AMD Annals, we identified 251,339 subjects with newly-diagnosed T2D and without CVD at baseline. Through Cox regressions adjusted for multiple risk factors, we examined the association between having a mean HbA1c between 7.1 and 8% or >8%, compared with ≤7%, for various periods of early exposure (0-1, 0-2, 0-3 years) and the development of later (mean subsequent follow-up 4.6 ± 2.9 years) CVD, evaluated as a composite of myocardial infarction, stroke, coronary or peripheral revascularization, and coronary or peripheral bypass. We performed this analysis in the overall cohort and then splitting the population in two groups of patients: those that introduced sodium-glucose transport protein 2 inhibitors (SGLT-2i) during the exposure phase and those not treated with these drugs. Findings: Considering the whole cohort, subjects with both a mean HbA1c between 7.1 and 8% and >8%, compared with patients attaining a mean HbA1c ≤ 7%, showed an increased risk of developing the outcome in all the three early exposure periods assessed, with the highest risk observed in patients with mean HbA1c > 8% in the 3 years exposure period (hazard ratio [HR]1.33; 95% confidence interval [CI] 1.063-1.365). The introduction of SGLT-2i during the exposure periods of 0-1 and 0-2 years eliminated the association between poor glycemic control and the outcome (p for interaction 0.006 and 0.003, respectively, vs. patients with the same degree of glycemic control but not treated with these drugs). Interpretation: Among patients with newly diagnosed T2D and free of CVD at baseline, a poor glycemic control in the first three years after diagnosis is associated with an increased subsequent risk of CVD. This association is no longer evident when SGLT-2i are introduced in the first two years, suggesting that these drugs attenuate the phenomenon of legacy effect. An early treatment with these drugs might thus promote a long-lasting benefit in patients not attaining proper glycemic control after T2D diagnosis. Funding: This work was supported, in part, by the Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica.

Thoracic ultrasound combined with low-dose computed tomography may represent useful screening strategy in highly exposed population in the industrial city of Taranto (Italy).

Objectives: We validated a screening protocol in which thoracic ultrasound (TUS) acts as a first-line complementary imaging technique in selecting patients which may deserve a second-line low-dose high resolution computed tomography (HRCT) scan among a population of asymptomatic high-risk subjects for interstitial lung abnormalities (ILA) and lung cancer. Due to heavy environmental pollution burden, the district Tamburi of Taranto has been chosen as "case study" for this purpose. Methods: From July 2018 to October 2020, 677 patients aged between 45 and 65 year and who had been living in the Tamburi district of Taranto for at least 10 years were included in the study. After demographic, clinical and risk factor exposition data were collected, each participant underwent a complete TUS examination. These subjects were then asked to know if they agreed to perform a second-level examination by low-dose HRCT scan. Results: On a total of 167 subjects (24.7%) who agreed to undergo a second-level HRCT, 85 patients (50.9%) actually showed pleuro-pulmonary abnormalities. Interstitial abnormalities were detected in a total of 36 patients on HRCT scan. In particular, 34 participants presented subpleural ILAs, that were classified in the fibrotic subtype in 7 cases. The remaining 2 patients showed non-subpleural interstitial abnormalities. Subpleural nodules were observed in 46 patients. TUS showed an overall diagnostic accuracy of 88.6% in detecting pleuro-pulmonary abnormalities in comparison with HRCT scan, with a sensitivity of 95.3%, a specificity of 81.7%, a positive predictive value of 84.4% and a negative predictive value of 94.4%. The matched evaluation of specific pulmonary abnormalities on HRTC scan (i.e., interstitial abnormalities or pulmonary nodules) with determinate sonographic findings revealed a reduction in both TUS sensibility and specificity. Focusing TUS evaluation on the assessment of interstitial abnormalities, a thickened pleural line showed a sensitivity of 63.9% and a specificity of 69.5%, hypoechoic striae showed a sensitivity of 38.9% and a specificity of 90.1% and subpleural nodules showed a sensitivity of 58.3% and a specificity of 77.1%. Regarding to the assessment of subpleural nodules, TUS showed a sensitivity of 60.9% and a specificity of 81.0%. However, the combined employment of TUS examination and HRCT scans allowed to identify 34 patients with early subpleural ILA and to detect three suspicious pulmonary nodules (of which two were intraparenchymal and one was a large subpleural mass), which revealed to be lung cancers on further investigations. Conclusion: A first-line TUS examination might aid the identification of subjects highly exposed to environmental pollution, who could benefit of a second-line low-dose HRCT scan to find early interstitial lung diseases as well as lung cancer. Protocol registration code: PLEURO-SCREENING-V1.0_15 Feb, 17.

Albuminuria improves R2CHA2DS2-VASc score in predicting mortality in high cardiovascular risk population.

BACKGROUND AND AIMS: The CHA2DS2-VASc score estimates the risk of cardioembolism in patients with atrial fibrillation (AF). It also predicts vascular events and death in different clinical settings, even in the absence of AF. The R2CHA2DS2-VASc score, obtained by adding the glomerular filtration rate to CHA2DS2-VASc, shows a higher prediction ability for new events and all-cause mortality. The present study aims to assess whether the addition of albuminuria to R2CHA2DS2-VASc score further improves its discrimination ability in predicting all-cause mortality in a sample of high cardiovascular risk population. METHODS AND RESULTS: Prospective, monocentric, observational study, evaluating a subset of 737 subjects consecutively undergoing to coronary angiography at Coronary Unit of Scientific Institute "Casa Sollievo della Sofferenza" from June 2016 to December 2018. The presence of albuminuria was significantly associated with all-cause mortality (p < 0.0001). Any one-point increase of Alb-R2CHA2DS2-VASc score increased mortality of about 1.5-fold (adjusted HR 1.49; 95%CI: 1.37-1.63; p < 0.0001). Considering tertiles of Alb-R2CHA2DS2-VASc, the third tertile showed a 9.5-fold increased risk of mortality (HR 9.52; 95% CI: 5.15-17.60, p < 0.001). Comparing the two scores, the Alb-R2CHA2DS2-VASc score (C-statistic = 0.751; 95%CI: 0.69-0.81) outperformed the R2-CHA2DS2-VASc score (C-statistic = 0.736; 95%CI: 0.68-0.961) in predicting mortality (delta C-statistic = 0.015; 95%CI: 0.001-0.029). The better prediction ability of the Alb-R2CHA2DS2-VASc score was also proven by an IDI of 0.024 (p < 0.0001) and a relative IDI of 24.11% (p < 0.0001), with an NRI = 0.608 (p < 0.00001). CONCLUSIONS: The addition of albuminuria to R2CHA2DS2-VASc significantly and independently predicts the risk of all-cause mortality in a sample of high CV risk patients. Moreover, Alb-R2CHA2DS2-VASc outperforms R2CHA2DS2-VASc.

Identifying Predictors Associated with Risk of Death or Admission to Intensive Care Unit in Internal Medicine Patients with Sepsis: A Comparison of Statistical Models and Machine Learning Algorithms.

Background: Sepsis is a time-dependent disease: the early recognition of patients at risk for poor outcome is mandatory. Aim: To identify prognostic predictors of the risk of death or admission to intensive care units in a consecutive sample of septic patients, comparing different statistical models and machine learning algorithms. Methods: Retrospective study including 148 patients discharged from an Italian internal medicine unit with a diagnosis of sepsis/septic shock and microbiological identification. Results: Of the total, 37 (25.0%) patients reached the composite outcome. The sequential organ failure assessment (SOFA) score at admission (odds ratio (OR): 1.83; 95% confidence interval (CI): 1.41-2.39; p < 0.001), delta SOFA (OR: 1.64; 95% CI: 1.28-2.10; p < 0.001), and the alert, verbal, pain, unresponsive (AVPU) status (OR: 5.96; 95% CI: 2.13-16.67; p < 0.001) were identified through the multivariable logistic model as independent predictors of the composite outcome. The area under the receiver operating characteristic curve (AUC) was 0.894; 95% CI: 0.840-0.948. In addition, different statistical models and machine learning algorithms identified further predictive variables: delta quick-SOFA, delta-procalcitonin, mortality in emergency department sepsis, mean arterial pressure, and the Glasgow Coma Scale. The cross-validated multivariable logistic model with the least absolute shrinkage and selection operator (LASSO) penalty identified 5 predictors; and recursive partitioning and regression tree (RPART) identified 4 predictors with higher AUC (0.915 and 0.917, respectively); the random forest (RF) approach, including all evaluated variables, obtained the highest AUC (0.978). All models' results were well calibrated. Conclusions: Although structurally different, each model identified similar predictive covariates. The classical multivariable logistic regression model was the most parsimonious and calibrated one, while RPART was the easiest to interpret clinically. Finally, LASSO and RF were the costliest in terms of number of variables identified.

Abdominal Lymphadenopathies: Lymphoma, Brucellosis or Tuberculosis? Multidisciplinary Approach-Case Report and Review of the Literature.

Abdominal pain represents a frequent symptom for referral to emergency departments and/or internal medicine outpatient setting. Similarly, fever, fatigue and weight loss are non-specific manifestations of disease. The present case describes the diagnostic process in a patient with abdominal pain and a palpable abdominal mass. Abdominal ultrasonography confirmed the presence of a mass in the mesogastrium. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans oriented toward calcific lymphadenopathies with increased metabolism in the positron emission tomography-computed tomography (PET-CT) scan. Laboratory examinations were inconclusive, although serology for Brucella and the Quantiferon test were positive. After multidisciplinary discussion, the patient underwent surgical excision of the abdominal mass. Histological examination excluded malignancies and oriented toward brucellosis in a patient with latent tuberculosis. The patient was treated with rifampin 600 mg qd and doxycycline 100 mg bid for 6 weeks with resolution of the symptoms. In addition, rifampin was continued for a total of 6 months in order to treat latent tuberculosis. This case underlines the need for a multidisciplinary approach in the diagnostic approach to abdominal lymphadenopathies.

Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway.

Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5'-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.

CHA2DS2-VASc and R2CHA2DS2-VASc scores predict mortality in high cardiovascular risk population.

BACKGROUND: The CHA2 DS2 -VASc score, widely used to estimate cardioembolic risk in patients with atrial fibrillation (AF), appears to be useful also in predicting vascular adverse events and death in different sets of patients without AF. The R2 CHA2 DS2 -VASc score, which includes renal impairment, allows a better prediction of death and thromboembolism in patients without AF. The aims of our study were to assess, in a large sample of patients at high cardiovascular (CV) risk, (i) the correlation between CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc with all-cause mortality, and (ii) to compare the performances of CHA2 DS2 -VASc and R2 CHA2 DS2 -VASc in predicting all-cause mortality. METHODS: In this single-centre prospective observational study, conducted at the Research Hospital 'Casa Sollievo della Sofferenza' between June 2016 and December 2018, 1017 CV patients at high risk of undergoing coronary angiography were enrolled. RESULTS: CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores significantly associated with all-cause mortality. For each one-point increase in CHA2 DS2 -VASc or R2 CHA2 DS2 -VASc scores, mortality increased by almost 1.5-fold. The R2 CHA2 DS2 -VASc score (C-statistic = 0.71; 95% CI = 0.65-76) outperformed the CHA2 DS2 -VASc score (C-statistic = 0.66; 95% CI = 0.61-0.71) in predicting 4-year mortality (delta C-statistic = 0.05; 95% CI = 0.02-0.07). The better predictive ability of the R-CHA2 DS2 -VASc score was also demonstrated by an IDI = 0.027 (95% CI = 0.021-0.034, p < .00001) and a relative IDI = 62.8% (95% CI = 47.9%-81.3%, p < .00001). The R2 CHA2 DS2 -VASc score correctly reclassified the patients with a NRI = 0.715 (95% = 0.544-0.940, p < .00001). CONCLUSIONS: The CHA2DS2-VASc and R2 CHA2 DS2 -VASc scores are useful predictors of all-cause mortality in subjects at high CV risk, with the R2 CHA2 DS2 -VASc score being the best performer.

Contribution of rare variants in monogenic diabetes-genes to early-onset type 2 diabetes.

AIM: This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D). METHODS: A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested. RESULTS: When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02). CONCLUSION: Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.

Echocardiographic markers of early alcoholic cardiomyopathy: Six-month longitudinal study in heavy drinking patients.

BACKGROUND: The development of alcoholic cardiomyopathy (ACM) is related to chronic excessive alcohol use. However, features of early-stage ACM are still unclear. We assessed echocardiographic characteristics of patients with alcohol dependence (DSM-IV criteria) during a six-month treatment period. METHODS: Active drinking patients, heavy alcohol users, without heart disease, referred to our Alcohol Addiction Unit were enrolled in the study. After signing informed consent, patients started outpatient treatment program. Echocardiography was performed at enrollment, then three and six months afterwards, by cardiologists blinded to drinking status. RESULTS: Forty-three patients (36 males, 7 females) were enrolled. At six months, 20 patients (46.5%) reduced alcohol consumption below heavy drinking levels. Although within normal range, baseline mean IVS thickness and mean LVDD were significantly higher (p < 0.001) and mean EF significantly reduced (p = 0.009), as compared to age-matched mean references. Mean E/A ratio, DcT and LA diameter were significantly different (p < 0.001) from mean references, but within normal range. Baseline mean E/e' ratio was significantly higher than the mean reference (p < 0.001) and out of the normal range. A significant correlation between the number of drinks per drinking days in the 7 days before baseline assessment and E/e' ratio was observed (p = 0.028). After six months, a trend-level reduction of mean E/e' ratio (p = 0.051) was found in the whole sample; this reduction was statistically significant (p = 0.041) among patients reducing drinking, compared to baseline. CONCLUSIONS: Altered E/e' ratio may characterize early-ACM before the occurrence of relevant echocardiographic alterations. The reduction of alcohol consumption could restore this alteration after six months.

Circulating Metabolites Associate With and Improve the Prediction of All-Cause Mortality in Type 2 Diabetes.

Death rate is increased in type 2 diabetes. Unraveling biomarkers of novel pathogenic pathways capable to identify high-risk patients is instrumental to tackle this burden. We investigated the association between serum metabolites and all-cause mortality in type 2 diabetes and then whether the associated metabolites mediate the effect of inflammation on mortality risk and improve ENFORCE (EstimatioN oF mORtality risk in type2 diabetic patiEnts) and RECODe (Risk Equation for Complications Of type 2 Diabetes), two well-established all-cause mortality prediction models in diabetes. Two cohorts comprising 856 individuals (279 all-cause deaths) were analyzed. Serum metabolites (n = 188) and pro- and anti-inflammatory cytokines (n = 7) were measured. In the pooled analysis, hexanoylcarnitine, kynurenine, and tryptophan were significantly and independently associated with mortality (hazard ratio [HR] 1.60 [95% CI 1.43-1.80]; 1.53 [1.37-1.71]; and 0.71 [0.62-0.80] per 1 SD). The kynurenine-to-tryptophan ratio (KTR), a proxy of indoleamine-2,3-dioxygenase, which degrades tryptophan to kynurenine and contributes to a proinflammatory status, mediated 42% of the significant association between the antiatherogenic interleukin (IL) 13 and mortality. Adding the three metabolites improved discrimination and reclassification (all P < 0.01) of both mortality prediction models. In type 2 diabetes, hexanoylcarnitine, tryptophan, and kynurenine are associated to and improve the prediction of all-cause mortality. Further studies are needed to investigate whether interventions aimed at reducing KTR also reduce the risk of death, especially in patients with low IL-13.