Cardio-renal-metabolic disease in primary care setting.

In the primary care setting providers have more tools available than ever before to impact positively obesity, diabetes, and their complications, such as renal and cardiac diseases. It is important to recognise what is available for treatment taking into account diabetes heterogeneity. For those who develop type 2 diabetes (T2DM), effective treatments are available that for the first time have shown a benefit in reducing mortality and macrovascular complications, in addition to the well-established benefits of glucose control in reducing microvascular complications. Some of the newer medications for treating hyperglycaemia have also a positive impact in reducing heart failure (HF). Technological advances have also contributed to improving the quality of care in patients with diabetes. The use of technology, such as continuous glucose monitoring systems (CGM), has improved significantly glucose and glycated haemoglobin A1c (HbA1c) values, while limiting the frequency of hypoglycaemia. Other technological support derives from the use of predictive algorithms that need to be refined to help predict those subjects who are at great risk of developing the disease and/or its complications, or who may require care by other specialists. In this review we also provide recommendations for the optimal use of the new medications; sodium-glucose co-transporter-2 inhibitors (SGLT2i) and Glucagon-like peptide-receptor agonists 1 (GLP1RA) in the primary care setting considering the relevance of these drugs for the management of T2DM also in its early stage.

Is Weight Loss-Induced Muscle Mass Loss Clinically Relevant?

This Viewpoint explores the effects of weight loss achieved through GLP-1­based antiobesity medications on weight regain, fat-free mass, and skeletal muscle mass in people with obesity.

Emotion expression salience and racially biased weapon identification: A diffusion modeling approach.

Racial stereotypes are commonly activated by informational cues that are detectable in people's faces. Here, we used a sequential priming task to examine whether and how the salience of emotion (angry/scowling vs. happy/smiling expressions) or apparent race (Black vs. White) information in male face primes shapes racially biased weapon identification (gun vs. tool) decisions. In two experiments (Ntotal = 546) using two different manipulations of facial information salience, racial bias in weapon identification was weaker when the salience of emotion expression versus race was heightened. Using diffusion decision modeling, we tested competing accounts of the cognitive mechanism by which the salience of facial information moderates this behavioral effect. Consistent support emerged for an initial bias account, whereby the decision process began closer to the "gun" response upon seeing faces of Black versus White men, and this racially biased shift in the starting position was weaker when emotion versus race information was salient. We discuss these results vis-à-vis prior empirical and theoretical work on how facial information salience moderates racial bias in decision-making.

Extinction and beyond: an expanded framework for exposure and response prevention for obsessive-compulsive disorder.

Exposure therapy is a first-line, empirically validated treatment for anxiety, obsessive-compulsive, and trauma-related disorders. Extinction learning is the predominant theoretical framework for exposure therapy, whereby repeated disconfirmation of a feared outcome yields fear reduction over time. Although this framework has strong empirical support and substantial translational utility, extinction learning is unlikely to be the sole process underlying the therapeutic effects of exposure therapy. In our clinic, we commonly treat obsessive-compulsive disorder (OCD) patients successfully with exposure therapy even when some or all of their feared outcomes are not amenable to disconfirmation and, by extension, to extinction learning. Herein, we present a generic clinical vignette illustrating a commonly encountered feared outcome in OCD that cannot be disconfirmed through exposure (damnation resulting from blasphemous thoughts). We describe two specific non-extinction-based strategies we commonly employ in such cases, and we associate these strategies with known change mechanisms that might account for their effectiveness: (1) non-associative habituation to aversive stimuli, and (2) fear-memory elicitation and subsequent reconsolidation. We discuss the limitations inherent in the reverse-translational approach taken and its opportunities for expanding the framework of exposure therapy.

Efficacy and Safety of Long-term Ketogenic Diet Therapy in a Patient With Type 1 Diabetes.

Fewer than 1% of patients with type 1 diabetes achieve normal glycemic control (glycated hemoglobin [HbA1c] < 5.7%/ < 39 mmol/mol). Additionally, exogenous insulin administration often causes "iatrogenic hyperinsulinemia," leading to whole-body insulin resistance and increased risk of cardiovascular complications. We present data on the clinical efficacy and safety of a long-term (10-year) ketogenic diet (≤50 g carbohydrates/day) therapy in a patient with type 1 diabetes. The use of a ketogenic diet resulted in successful glycemic control, assessed by HbA1c (5.5%; 36.6 mmol/mol), continuous glucose monitoring median glucose (98 mg/dL; 5.4 mmol/L), and glucose time-in-range of 70 to 180 mg/dL (90%) without acute glycemic complications. In conjunction, there was a 43% decrease in daily insulin requirements. Low-density lipoprotein cholesterol increased, whereas small-dense low-density lipoprotein was in the normal range (<90 nmol/L). No adverse effects were observed on thyroid function, kidney function, or bone mineral density. This case report demonstrates that a long-term ketogenic diet in a person with type 1 diabetes has considerable therapeutic benefits.

The Pressure Reactivity Index as a Measure for Cerebrovascular Autoregulation: Validation in a Porcine Cranial Window Model.

BACKGROUND AND OBJECTIVES: Pressure reactivity index (PRx) has been proposed as a metric associated with cerebrovascular autoregulatory (CA) function and has been thoroughly investigated in clinical research. In this study, PRx is validated in a porcine cranial window model, developed to visualize pial arteriolar autoregulation and its limits. METHODS: We measured arterial blood pressure, intracranial pressure, pial arteriolar diameter, and red blood cell (RBC) velocity in a closed cranial window piglet model during gradual balloon catheter-induced arterial hypotension (n = 10) or hypertension (n = 10). CA limits were derived through piecewise linear regression of calculated RBC flux vs cerebral perfusion pressure (CPP), leading for each arteriole to 1 lower limit of autoregulation (LLA) and 2 upper limits of autoregulation (ULA1 and ULA2). Autoregulation limits were compared with PRx thresholds, and receiver operating curve analysis was performed with and without CPP binning. A linear mixed effects model of PRx was performed. RESULTS: Receiver operating curve analysis indicated an area under the curve (AUC) for LLA prediction by a PRx of 0.65 (95% CI: 0.64-0.67) and 0.77 (95% CI: 0.69-0.86) without and with CPP binning, respectively. The AUC for ULA1 prediction by PRx was 0.69 (95% CI: 0.68-0.69) without and 0.75 (95% CI: 0.68-0.82) with binning. The AUC for ULA2 prediction was 0.55 (95% CI: 0.55-0.58) without and 0.63 (95% CI 0.53-0.72) with binning. The sensitivity and specificity of binned PRx were 65%/90% for LLA, 69%/71% for ULA1, and 59%/74% for ULA2, showing wide interindividual variability. In the linear mixed effects model, pial arteriolar diameter changes were significantly associated with PRx changes (P = .002), whereas RBC velocity (P = .28) and RBC flux (P = .24) were not. CONCLUSION: We conclude that PRx is predominantly determined by pial arteriolar diameter changes and moderately predicts CA limits. Performance to detect the CA limits varied highly on an individual level. Active therapeutic strategies based on PRx and the associated correlation metrics should incorporate these limitations.

Altered Use of Context During Visual Perception in Psychotic Psychopathology: A Neurophysiological Investigation of Tuned and Untuned Suppression During Contrast Perception.

BACKGROUND AND HYPOTHESIS: The human visual system streamlines visual processing by suppressing responses to textures that are similar to their surrounding context. Surround suppression is weaker in individuals with schizophrenia (ISZ); this altered use of visuospatial context may relate to the characteristic visual distortions they experience. STUDY DESIGN: To understand atypical surround suppression in psychotic psychopathology, we investigated neurophysiological responses in ISZ, healthy controls (HC), individuals with bipolar disorder (IBP), and first-degree relatives (ISZR/IBPR). Participants performed a contrast judgment task on a circular target with annular surrounds, with concurrent electroencephalography. Orientation-independent (untuned) suppression was estimated from responses to central targets with orthogonal surrounds; the orientation-dependence of suppression was estimated by fitting an exponential function to the increase in suppression as surrounds became more aligned with the center. RESULTS: ISZ exhibited weakened untuned suppression coupled with enhanced orientation-dependence of suppression. The N1 visual evoked potential was associated with the orientation-dependence of suppression, with ISZ and ISZR (but not IBP or IBPR) showing enhanced orientation-dependence of the N1. Collapsed across orientation conditions, the N1 for ISZ lacked asymmetry toward the right hemisphere; this reduction in N1 asymmetry was associated with reduced untuned suppression, real-world perceptual anomalies, and psychotic psychopathology. The overall amplitude of the N1 was reduced in ISZ and IBP. CONCLUSIONS: Key measures of symptomatology for ISZ are associated with reductions in untuned suppression. Increased sensitivity for ISZ to the relative orientation of suppressive surrounds is reflected in the N1 VEP, which is commonly associated with higher-level visual functions such as allocation of spatial attention or scene segmentation.

Impaired plasma glucose clearance is a key determinant of fasting hyperglycemia in people with obesity.

OBJECTIVE: The objective of this study was to evaluate the relative importance of the basal rate of glucose appearance (Ra) in the circulation and the basal rate of plasma glucose clearance in determining fasting plasma glucose concentration in people with obesity and different fasting glycemic statuses. METHODS: The authors evaluated basal glucose kinetics in 33 lean people with normal fasting glucose (<100 mg/dL; Lean < 100 group) and 206 people with obesity and normal fasting glucose (Ob < 100 group, n = 118), impaired fasting glucose (100-125 mg/dL; Ob 100-125 group, n = 66), or fasting glucose diagnostic of diabetes (≥126 mg/dL; Ob ≥ 126 group, n = 22). RESULTS: Although there was a large (up to three-fold) range in glucose Ra within each group, the ranges in glucose concentration in the Lean < 100, Ob < 100, and Ob 100-125 groups were small because of a close relationship between glucose Ra and clearance rate. However, the glucose clearance rate at any Ra value was lower in the hyperglycemic than the normoglycemic groups. In the Ob ≥ 126 group, plasma glucose concentration was primarily determined by glucose Ra, because glucose clearance was markedly attenuated. CONCLUSIONS: Fasting hyperglycemia in people with obesity represents a disruption of the precisely regulated integration of glucose production and clearance rates.

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Successful Treatment with Dabrafenib/Trametinib of a Malignantly Transformed and Metastasized BRAF V600E Mutant Pleiomorphic Xanthoastrocytoma: A Case Report and Review of the Literature.

Introduction: Pleiomorphic xanthoastrocytoma (PXA) is considered a low-grade glioma with a favorable prognosis following surgical resection. We present a case report of a BRAFV600E mutant malignantly transformed and disseminated PXA that was successfully treated with BRAF-/MEK-targeted therapy (dabrafenib/trametinib). Case Presentation: At the age of 16 years, our patient underwent an initial subtotal resection of a right occipital PXA. Six months later, a reintervention for an asymptomatic tumor recurrence was performed and complete resection was achieved. The patient has been followed up by MRI for 14 years without arguments for recurrence but was lost to follow-up thereafter. At 38 years of age, he presented with a symptomatic local recurrence with extra-cerebral soft tissue extension, for which a third surgical resection was performed. Anatomopathological examination reported a grade 3 anaplastic PXA (aPXA); molecular analysis detected a BRAFV600E mutation. Three months later, before the initiation of radiotherapy, a local tumor recurrence was diagnosed, for which he underwent a fourth surgical resection. Radiotherapy was performed following the surgical debulking. One month after completion of radiotherapy, disease progression was documented including multiple sites of extracranial metastases (skeletal, lung, cervical lymph node, and subcutaneous metastases). Systemic treatment with a combination of BRAF-/MEK-inhibitors (dabrafenib/trametinib) was initiated and resulted in a rapid and deep tumor response (partial response according to RECISTv1.1) and absence of BRAFV600E mutant ctDNA in plasma at 6 weeks after treatment initiation. A near-complete metabolic remission was documented on [18F]FDG-PET/CT 3 months after starting systemic therapy. Conclusion: We present a rare case of malignant transformation and systemic dissemination of a BRAFV600E mutant PXA, occurring 20 years after the initial diagnosis. This case highlights the importance of long-term follow-up of patients diagnosed with these rare central nervous system tumors that initially are considered benign and also illustrates that BRAF/MEK inhibition can be an effective therapy for BRAFV600E mutated PXA, underscoring the importance of performing molecular genetic profiling of these tumors.

The role of brown adipose tissue in branched-chain amino acid clearance in people.

Brown adipose tissue (BAT) in rodents appears to be an important tissue for the clearance of plasma branched-chain amino acids (BCAAs) contributing to improved metabolic health. However, the role of human BAT in plasma BCAA clearance is poorly understood. Here, we evaluate patients with prostate cancer who underwent positron emission tomography-computed tomography imaging after an injection of 18F-fluciclovine (L-leucine analog). Supraclavicular adipose tissue (AT; primary location of human BAT) has a higher net uptake rate for 18F-fluciclovine compared to subcutaneous abdominal and upper chest AT. Supraclavicular AT 18F-fluciclovine net uptake rate is lower in patients with obesity and type 2 diabetes. Finally, the expression of genes involved in BCAA catabolism is higher in the supraclavicular AT of healthy people with high BAT volume compared to those with low BAT volume. These findings support the notion that BAT can potentially function as a metabolic sink for plasma BCAA clearance in people.

Short-term cold exposure induces persistent epigenomic memory in brown fat.

Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPß was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPß in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPß-dependent and HDAC3-independent cold-adaptive epigenomic memory.

Non-invasive biomarkers for detecting progression toward hypovolemic cardiovascular instability in a lower body negative pressure model.

Occult hemorrhages after trauma can be present insidiously, and if not detected early enough can result in patient death. This study evaluated a hemorrhage model on 18 human subjects, comparing the performance of traditional vital signs to multiple off-the-shelf non-invasive biomarkers. A validated lower body negative pressure (LBNP) model was used to induce progression towards hypovolemic cardiovascular instability. Traditional vital signs included mean arterial pressure (MAP), electrocardiography (ECG), plethysmography (Pleth), and the test systems utilized electrical impedance via commercial electrical impedance tomography (EIT) and multifrequency electrical impedance spectroscopy (EIS) devices. Absolute and relative metrics were used to evaluate the performance in addition to machine learning-based modeling. Relative EIT-based metrics measured on the thorax outperformed vital sign metrics (MAP, ECG, and Pleth) achieving an area-under-the-curve (AUC) of 0.99 (CI 0.95-1.00, 100% sensitivity, 87.5% specificity) at the smallest LBNP change (0-15 mmHg). The best vital sign metric (MAP) at this LBNP change yielded an AUC of 0.6 (CI 0.38-0.79, 100% sensitivity, 25% specificity). Out-of-sample predictive performance from machine learning models were strong, especially when combining signals from multiple technologies simultaneously. EIT, alone or in machine learning-based combination, appears promising as a technology for early detection of progression toward hemodynamic instability.

N-acetylaspartate from fat cells regulates postprandial body temperature.

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.

Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Informe especial: avances en nutrición y gastroenterología

El taller de Investigación de ASPEN de 1.997 se llevó a cabo durante su reunión anual en San Francisco, el 26 de enero de 1997. El taller se centró en los avances de la investigación clínica y básica en relación con la interfase entre gastroenterología de nutrientes y luminal. Métodos: Líderes en este campo realizarón presentaciones sobre la regulación genética del desarrollo gastrointestinal; la biología molecular de la adaptación del intestino delgado; el efecto del soporte nutricional en la masa mucosa del intestino; la relación entre nutrición y motilidad gastrointestinal, absorción de nutrientes y metabolismo de substrato del tracto gastrointestinal. Resultados: Los investigadores presentaron un análisis muy amplio de cada tópico aportando información de sus propios laboratorios y de la literatura publicada. Conclusiones: Este taller puso de relieve las interacciones importantes entre nutrición y gastroenterología luminal a nivel de ciencias básicas, metabolismo/fisiología y clínica. La integración de presentaciones de diferentes disciplinas contituyó una ocación única de interacción de información e ideas para acrecentar nuestra comprensión sobre nutrición y tracto gastrointestinal.