Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

Determination of Second Lactate Threshold Using Near-infrared Spectroscopy in Elite Cyclists.

The use of near-infrared spectroscopy could be an interesting alternative to other invasive or expensive methods to estimate the second lactate threshold. Our objective was to compare the intensities of the muscle oxygen saturation breakpoint obtained with the Humon Hex and the second lactate threshold in elite cyclists. Ninety cyclists performed a maximal graded exercise test. Blood capillary lactate was obtained at the end of steps and muscle oxygenation was continuously monitored. There were no differences (p>0.05) between muscle oxygen oxygenation breakpoint and second lactate threshold neither in power nor in heart rate, nor when these values were relativized as a percentage of maximal aerobic power or maximum heart rate. There were also no differences when men and women were studied separately. Both methods showed a highly correlation in power (r=0.914), percentage of maximal aerobic power (r=0.752), heart rate (r=0.955), and percentage of maximum heart rate (r=0.903). Bland-Altman resulted in a mean difference of 0.05±0.27 W·kg-1, 0.91±4.93%, 0.63±3.25 bpm, and 0.32±1.69% for power, percentage of maximal aerobic power, heart rate and percentage of maximum heart rate respectively. These findings suggest that Humon may be a non-invasive and low-cost alternative to estimate the second lactate threshold intensity in elite cyclists.

Validity and Reliability of Two Near-infrared Spectroscopy Devices to Measure Resting Hemoglobin in Elite Cyclists.

A new method to monitor internal training load from muscle oxygen saturation using near-infrared spectroscopy could be of practical application for research and training purposes. This technology has been validated in different scientific fields, including sports science, and Humon Hex and Moxy are two leading brands. However, its relationship with hemoglobin has not been studied. Forty-eight professional cyclists, 19 men and 29 women, underwent a blood test to measure hemoglobin in the early morning. Immediately afterwards, hemoglobin and muscle oxygenation were monitored at rest by Moxy and Humon Hex on their right quadriceps (where the skinfold was measured). Venous blood hemoglobin was higher than the measurement for both devices (p<0.001). Both hemoglobin (p<0.001) and muscle oxygen saturation measurements (p<0.05) were higher in Humon Hex than for Moxy, and there was a reasonable reproducibility (ICC=0.35 for hemoglobin and 0.26 for muscle oxygen saturation). Skinfold had an inverse relationship with hemoglobin measurement (r=-0.85 p<0.001 for Humon Hex and r=-0.75 p<0.001 for Moxy). These findings suggest that resting hemoglobin data provided by these devices are not coincident with those of blood sample, and skinfold has an inverse relationship with blood hemoglobin measurement.

Transmission of human immunodeficiency virus Type-1 by fresh-frozen plasma treated with methylene blue and light.

BACKGROUND: The risk of transfusion-transmitted infection (TTI) has been minimized by introduction of nucleic acid testing (NAT) and pathogen inactivation (PI). This case report describes transmission of human immunodeficiency virus Type 1 (HIV-1) to two recipients despite these measures. STUDY DESIGN AND METHODS: In March 2009 a possible TTI of HIV-1 was identified in a patient that had received pooled buffy coat platelet concentrate (BC-PLT) in November 2005. The subsequent lookback study found two more patients who had received methylene blue (MB)-treated fresh-frozen plasma (FFP) and red blood cells (RBCs) from the same donation. In November 2005 the donor had tested negative for both HIV antibodies and HIV-1 RNA by 44 minipool (44 MP) NAT. Repository samples of this donation and samples from the recipients were used for viral load (VL) and sequence analysis. RESULTS: HIV-1 RNA was detectable by individual donation (ID)-NAT in the repository sample from the 2005 window period donation and a VL of 135 copies/mL was measured. HIV-1 infection was confirmed in both recipients of both BC-PLT (65 mL of plasma) and MB-FFP (261 mL of plasma), but not in the patient that had received 4-week-old RBCs (20 mL of plasma). The sequence analysis revealed a close phylogenetic relationship between the virus strains isolated from the donor and recipients, compatible with TTI. CONCLUSIONS: Approximately 17,600 and 4400 virions in the MB-FFP and BC-PLT were infectious, but 1350 virions in the RBCs were not. ID-NAT would have prevented this transmission, but the combination of MP-NAT and MB-PI did not.

Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia.

The effectiveness of rituximab maintenance therapy in the treatment of chronic lymphocytic leukemia has been investigated in a phase 2 clinical trial that included an initial treatment with rituximab 500 mg/m2 on day 1 (375 mg/m2 the first cycle), fludarabine 25 mg/m2 on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 on day 1 (R-FCM), for 6 cycles, followed by a maintenance phase with rituximab 375 mg/m2 every 3 months for 2 years. Sixty-seven patients having achieved complete response (CR) or partial response (PR) with R-FCM were given maintenance therapy. At the end of maintenance, 40.6% of patients were in CR with negative minimal residual disease (MRD), 40.6% were in CR MRD-positive, 4.8% remained in PR, and 14% were considered failures. Six of 29 patients (21%) who were in CR MRD-positive or in PR after R-FCM improved their response upon rituximab maintenance. The 4-year progression-free survival (PFS) and overall survival rates were 74.8% and 93.7%, respectively. MRD status after R-FCM induction was the strongest predictor of PFS. Maintenance with rituximab after R-FCM improved the quality of the response, particularly in patients MRD-positive after initial treatment, and obtained a prolonged PFS. This trial was registered at www.clinicaltrialsregister.eu as identifier #2005-001569-33.

Effect of CD8⁺ cell content on umbilical cord blood transplantation in adults with hematological malignancies.

Total nucleated (TNCs) and CD34(+) cells are considered major determinants of outcome after umbilical cord blood (UCB) transplantation but the effect of other cell subtypes present in the graft is unknown. This single-center cohort study included patients with hematological malignancies who received UCB transplantation after a myeloablative conditioning regimen. UCB units were primarily selected according to cell content, both TNCs and CD34(+) cells, and also according to the degree of HLA matching. Counts of several cell subtypes of the infused UCB unit, together with HLA disparities and other patient- and transplantation-related characteristics, were analyzed by multivariable methodology for their association with myeloid and platelet engraftment, graft-versus-host disease, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Two hundred patients (median age, 32 years) were included in the study. In multivariable analyses, a greater number of CD8(+) cells was significantly associated with better results for myeloid (P = .001) and platelet (P = .008) engraftment, NRM (P = .02), DFS (P = .007), and OS (P = .01). CD34(+) cell content was predictive of myeloid engraftment (P < .001). This study suggests that the outcome after UCB transplantation in adults with hematological malignancies could be better when UCB grafts had a greater CD8(+) cell content.

Type 1 diabetes-related distress: Current implications in care.

Type 1 diabetes (T1D) is a complex chronic disease associated with major health and economic consequences, also involving important issues in the psychosocial sphere. In this regard, T1D-related distress, defined as the emotional burden of living with T1D, has emerged as a specific entity related to the disease. Diabetes distress (DD) is an overlooked but prevalent condition in people living with T1D, and has significant implications in both glycemic control and mental health in this population. Although overlapping symptoms may be found between DD and mental health disorders, specific approaches should be performed for the diagnosis of this problem. In recent years, different DD-targeted interventions have been postulated, including behavioral and psychosocial strategies. Moreover, new technologies in this field may be helpful to address DD in people living with T1D. In this article, we summarize the current knowledge on T1D-related distress, and we also discuss the current approaches and future perspectives in its management.

Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study.

OBJECTIVE: To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS: We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS: A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION: The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.

Triglyceride to HDL Cholesterol Ratio for the Identification of MASLD in Obesity: A Liver Biopsy-Based Case-Control Study.

Associations between dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD) have been reported. Previous studies have shown that the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio may be a surrogate marker of MASLD, assessed by liver ultrasound. However, no studies have evaluated the utility of this ratio according to biopsy-proven MASLD and its stages. Therefore, our aim was to evaluate if the TG/HDL-C ratio allows for the identification of biopsy-proven MASLD in patients with obesity. We conducted a case-control study in 153 patients with obesity who underwent metabolic surgery and had a concomitant liver biopsy. Fifty-three patients were classified as no MASLD, 45 patients as metabolic dysfunction-associated steatotic liver-MASL, and 55 patients as metabolic dysfunction-associated steatohepatitis-MASH. A receiver operating characteristic (ROC) analysis was performed to assess the accuracy of the TG/HDL-C ratio to detect MASLD. We also compared the area under the curve (AUC) of the TG/HDL-C ratio, serum TG, and HDL-C. A higher TG/HDL-C ratio was observed among patients with MASLD, compared with patients without MASLD. No differences in the TG/HDL-C ratio were found between participants with MASL and MASH. The greatest AUC was observed for the TG/HDL-C ratio (AUC 0.747, p < 0.001) with a cut-off point of 3.7 for detecting MASLD (sensitivity = 70%; specificity = 74.5%). However, no statistically significant differences between the AUC of the TG/HDL-C ratio and TG or HDL-C were observed to detect MASLD. In conclusion, although an elevated TG/HDL-C ratio can be found in patients with MASLD, this marker did not improve the detection of MASLD in our study population, compared with either serum TG or HDL-C.

Lipidomic Analysis Reveals Alterations in Hepatic FA Profile Associated With MASLD Stage in Patients With Obesity.

CONTEXT: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the intracellular lipid accumulation in hepatocytes. Excess caloric intake and high-fat diets are considered to significantly contribute to MASLD development. OBJECTIVE: To evaluate the hepatic and serum fatty acid (FA) composition in patients with different stages of MASLD, and their relationship with FA dietary intake and MASLD-related risk factors. METHODS: This was a case-control study in patients with obesity undergoing bariatric surgery at a university hospital between January 2020 and December 2021. Participants were distributed in 3 groups: no MASLD (n = 26), steatotic liver disease (n = 33), and metabolic dysfunction-associated steatohepatitis (n = 32). Hepatic and serum FA levels were determined by gas chromatography-mass spectrometry. Nutritional status was evaluated using validated food frequency questionnaires. The hepatic expression of genes involved in FA metabolism was analyzed by reverse transcription quantitative polymerase chain reaction. RESULTS: The hepatic, but not serum, FA profiles were significantly altered in patients with MASLD compared with those without MASLD. No differences were observed in FA intake between the groups. Levels of C16:0, C18:1, and the C18:1/C18:0 ratio were higher, while C18:0 levels and C18:0/C16:0 ratio were lower in patients with MASLD, being significantly different between the 3 groups. Hepatic FA levels and ratios correlated with histopathological diagnosis and other MASLD-related parameters. The expression of genes involved in the FA metabolism was upregulated in patients with MASLD. CONCLUSION: Alterations in hepatic FA levels in MASLD patients were due to enhancement of de novo lipogenesis in the liver.

Effects of exercise timing on metabolic health.

The increasing prevalence of metabolic syndrome is associated with major health and socioeconomic consequences. Currently, physical exercise, together with dietary interventions, is the mainstay of the treatment of obesity and related metabolic complications. Although exercise training includes different modalities, with variable intensity, duration, volume, or frequency, which may have a distinct impact on several characteristics related to metabolic syndrome, the potential effects of exercise timing on metabolic health are yet to be fully elucidated. Remarkably, promising results with regard to this topic have been reported in the last few years. Similar to other time-based interventions, including nutritional therapy or drug administration, time-of-day-based exercise may become a useful approach for the management of metabolic disorders. In this article, we review the role of exercise timing in metabolic health and discuss the potential mechanisms that could drive the metabolic-related benefits of physical exercise performed in a time-dependent manner.

Management of thyroid dysfunction and thyroid nodules in the ageing patient.

Thyroid dysfunction is a common endocrine disorder in the general population, with a reported prevalence of 10-15%. However, this rate is even higher in older adults, with an estimated prevalence of ≈25% in some populations. Since elderly patients usually present more comorbidities than younger individuals, thyroid dysfunction may carry a synergistic negative health impact, mainly due to increased cardiovascular disease risk. Moreover, thyroid dysfunction in the elderly can be more difficult to diagnose due to its subtle or even asymptomatic clinical presentation, and the interpretation of thyroid function tests may be affected by drugs that interfere with thyroid function or by the coexistence of several diseases. On the other hand, thyroid nodules are also a prevalent condition in older adults, and its incidence increases with age. The assessment and management of thyroid nodules in the ageing patient should take into account several factors, as risk stratification, thyroid cancer biology, patient´s overall health, comorbidities, treatment preferences, and goals of care. In this review article, we summarize the current knowledge on the pathophysiology, diagnosis, and therapeutic management of thyroid dysfunction in elderly patients and we also review how to identify and manage thyroid nodules in this population.

Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case-control study.

OBJECTIVE: Alterations in the hepatic lipidome are a crucial factor involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the serum and hepatic profile of branched-chain fatty acids (BCFAs) in patients with different stages of NAFLD. METHODS: This was a case-control study performed in 27 patients without NAFLD, 49 patients with nonalcoholic fatty liver, and 17 patients with nonalcoholic steatohepatitis, defined by liver biopsies. Serum and hepatic levels of BCFAs were analyzed by gas chromatography-mass spectrometry. The hepatic expression of genes involved in the endogenous synthesis of BCFAs was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: A significant increase in hepatic BCFAs was found in subjects with NAFLD compared with those without NAFLD; no differences were observed in serum BCFAs between study groups. Trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs were increased in subjects with NAFLD (either nonalcoholic fatty liver or nonalcoholic steatohepatitis) compared with those without NAFLD. Correlation analysis showed a relationship between hepatic BCFAs and the histopathological diagnosis of NAFLD, as well as other histological and biochemical parameters related to this disease. Gene expression analysis in liver showed that the mRNA levels of BCAT1, BCAT2, and BCKDHA were upregulated in patients with NAFLD. CONCLUSIONS: These results suggest that the increased production of liver BCFAs might be related to NAFLD development and progression.

Hypertension and hypercholesterolemia are predictive factors associated with type 2 diabetes persistence after metabolic surgery: A prospective study.

BACKGROUND: Metabolic surgery is the most effective therapeutic strategy for the management of type 2 diabetes (T2DM). Several preoperative clinical factors have been associated with T2DM remission after metabolic surgery. However, other potential predictors remain unexplored. AIM: To assess the role of basal (pre-surgery) clinical and biochemical parameters in T2DM remission after metabolic surgery. METHODS: A prospective study including 98 patients with T2DM undergoing metabolic surgery was performed. Clinical, anthropometric, and biochemical data were collected at baseline and 1 year following metabolic surgery. RESULTS: Patients without T2DM remission 1 year after metabolic surgery presented a longer duration of diabetes and higher glycated hemoglobin (HbA1c) levels; a higher percentage of these subjects were using insulin therapy, antihypertensive drugs, and lipid-lowering therapies before metabolic surgery, compared to those patients with T2DM remission. A lower percentage of T2DM remission after metabolic surgery was observed among patients with hypertension/hypercholesterolemia before surgery, compared to those patients without hypertension/hypercholesterolemia (51.7 % vs 86.8 %, p < 0.001, and 38.5 % vs 75 %, p < 0.001, respectively), and among patients with longer duration of diabetes (≥5 years vs <5 years; 44.4 % vs 83 %, respectively; p < 0.001). In the logistic regression model, diabetes duration, basal HbA1c, and the presence of hypertension and hypercholesterolemia before surgery were inversely related to T2DM remission following metabolic surgery, after adjusting for sex, age, waist circumference, and type of surgery. CONCLUSIONS: In a cohort of patients with obesity and T2DM, preoperative hypertension and hypercholesterolemia, together with a longer diabetes duration and higher HbA1c concentrations, were independent predictors of T2DM persistence after metabolic surgery.

Role of the Gut Microbiome in Beta Cell and Adipose Tissue Crosstalk: A Review.

In the last decades, obesity has reached epidemic proportions worldwide. Obesity is a chronic disease associated with a wide range of comorbidities, including insulin resistance and type 2 diabetes mellitus (T2D), which results in significant burden of disease and major consequences on health care systems. Of note, intricate interactions, including different signaling pathways, are necessary for the establishment and progression of these two closely related conditions. Altered cell-to-cell communication among the different players implicated in this equation leads to the perpetuation of a vicious circle associated with an increased risk for the development of obesity-related complications, such as T2D, which in turn contributes to the development of cardiovascular disease. In this regard, the dialogue between the adipocyte and pancreatic beta cells has been extensively studied, although some connections are yet to be fully elucidated. In this review, we explore the potential pathological mechanisms linking adipocyte dysfunction and pancreatic beta cell impairment/insulin resistance. In addition, we evaluate the role of emerging actors, such as the gut microbiome, in this complex crosstalk.

Non-alcoholic fatty liver disease-related fibrosis and sarcopenia: An altered liver-muscle crosstalk leading to increased mortality risk.

In the last few decades, the loss of skeletal muscle mass and function, known as sarcopenia, has significantly increased in prevalence, becoming a major global public health concern. On the other hand, the prevalence of non-alcoholic fatty liver disease (NAFLD) has also reached pandemic proportions, constituting the leading cause of hepatic fibrosis worldwide. Remarkably, while sarcopenia and NAFLD-related fibrosis are independently associated with all-cause mortality, the combination of both conditions entails a greater risk for all-cause and cardiac-specific mortality. Interestingly, both sarcopenia and NAFLD-related fibrosis share common pathophysiological pathways, including insulin resistance, chronic inflammation, hyperammonemia, alterations in the regulation of myokines, sex hormones and growth hormone/insulin-like growth factor-1 signaling, which may explain reciprocal connections between these two disorders. Additional contributing factors, such as the gut microbiome, may also play a role in this relationship. In skeletal muscle, phosphatidylinositol 3-kinase/Akt and myostatin signaling are the central anabolic and catabolic pathways, respectively, and the imbalance between them can lead to muscle wasting in patients with NAFLD-related fibrosis. In this review, we summarize the bidirectional influence between NAFLD-related fibrosis and sarcopenia, highlighting the main potential mechanisms involved in this complex crosstalk, and we discuss the synergistic effects of both conditions in overall and cardiovascular mortality.

Evaluation of Quality and Bone Microstructure Alterations in Patients with Type 2 Diabetes: A Narrative Review.

Bone fragility is a common complication in subjects with type 2 diabetes mellitus (T2DM). However, traditional techniques for the evaluation of bone fragility, such as dual-energy X-ray absorptiometry (DXA), do not perform well in this population. Moreover, the Fracture Risk Assessment Tool (FRAX) usually underestimates fracture risk in T2DM. Importantly, novel technologies for the assessment of one microarchitecture in patients with T2DM, such as the trabecular bone score (TBS), high-resolution peripheral quantitative computed tomography (HR-pQCT), and microindentation, are emerging. Furthermore, different serum and urine bone biomarkers may also be useful for the evaluation of bone quality in T2DM. Hence, in this article, we summarize the limitations of conventional tools for the evaluation of bone fragility and review the current evidence on novel approaches for the assessment of quality and bone microstructure alterations in patients with T2DM.

Obesity-related glomerulopathy: Current approaches and future perspectives.

Obesity-related glomerulopathy (ORG) is a silent comorbidity which is increasing in incidence as the obesity epidemic escalates. ORG is associated with serious health consequences including chronic kidney disease, end-stage renal disease (ESRD), and increased mortality. Although the pathogenic mechanisms involved in the development of ORG are not fully understood, glomerular hemodynamic changes, renin-angiotensin-aldosterone system (RAAS) overactivation, insulin-resistance, inflammation and ectopic lipid accumulation seem to play a major role. Despite albuminuria being commonly used for the non-invasive evaluation of ORG, promising biomarkers of early kidney injury that are emerging, as well as new approaches with proteomics and metabolomics, might permit an earlier diagnosis of this disease. In addition, the assessment of ectopic kidney fat by renal imaging could be a useful tool to detect and evaluate the progression of ORG. Weight loss interventions appear to be effective in ORG, although large-scale trials are needed. RAAS blockade has a renoprotective effect in patients with ORG, but even so, a significant proportion of patients with ORG will eventually progress to ESRD despite therapeutic efforts. It is noteworthy that certain antidiabetic agents such as sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) could be useful in the treatment of ORG through different pleiotropic effects. In this article, we review current approaches and future perspectives in the care and treatment of ORG.