Cardiovascular Safety of Testosterone-Replacement Therapy.

BACKGROUND: The cardiovascular safety of testosterone-replacement therapy in middle-aged and older men with hypogonadism has not been determined. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, noninferiority trial, we enrolled 5246 men 45 to 80 years of age who had preexisting or a high risk of cardiovascular disease and who reported symptoms of hypogonadism and had two fasting testosterone levels of less than 300 ng per deciliter. Patients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. The primary cardiovascular safety end point was the first occurrence of any component of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-event analysis. A secondary cardiovascular end point was the first occurrence of any component of the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization, assessed in a time-to-event analysis. Noninferiority required an upper limit of less than 1.5 for the 95% confidence interval of the hazard ratio among patients receiving at least one dose of testosterone or placebo. RESULTS: The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. CONCLUSIONS: In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, NCT03518034.).

Discordance Analysis of VLDL-C and ApoB in UK Biobank and Framingham Study: A Prospective Observational Study.

BACKGROUND: Recent observational and Mendelian randomization analyses have reported significant effects of VLDL-C (very-low density lipoprotein cholesterol) on risk that is independent of ApoB (apolipoprotein B). We aim to determine the independent association of VLDL-C and ApoB with the risk of new onset cardiovascular events in the UK Biobank and Framingham Heart Study cohorts. METHODS: We included 294 289 UK Biobank participants with a median age of 56 years, 42% men, and 2865 Framingham Heart Study participants (median age, 53 years; 47% men). The residual resulting from regressing VLDL-C on ApoB expresses the portion of VLDL-C not explained by ApoB, while the residual from regressing ApoB on VLDL-C expresses the portion of ApoB not explained by VLDL-C. Cox proportional hazards models for atherosclerotic cardiovascular disease incidence were created for residual VLDL-C and residual ApoB. Models were analyzed with and without high-density lipoprotein cholesterol (HDL-C). Furthermore, we investigated the independent effects of VLDL-C after accounting for ApoB and HDL-C and of HDL-C after accounting for ApoB and VLDL-C. RESULTS: In the UK Biobank, ApoB was highly correlated with VLDL-C (r=0.70; P<0.001) but weakly negatively correlated with HDL-C (r=-0.11; P<0.001). The ApoB residual and the VLDL-C residual were significantly associated with new-onset atherosclerotic cardiovascular disease (hazard ratio [HR], 1.08 and 1.05, respectively; P<0.001). After adjusting for HDL-C, the ApoB residual remained similar in magnitude (HR, 1.10; P<0.001), whereas the effect size of the VLDL-C residual was reduced (HR, 1.02; P=0.029). The independent effect of HDL-C (after accounting for ApoB and VLDL-C) remained robust (HR, 0.86; P<0.0001), while the independent effect of VLDL-C (after accounting for ApoB and HDL-C) was modest (HR, 1.02; P=0.029). All results were consistent in the Framingham cohort. CONCLUSIONS: When adjusted for HDL-C, the association of VLDL-C with cardiovascular risk was no longer clinically meaningful. Our residual discordance analysis suggests that adjustment for HDL-C cannot be ignored.

Discordance among apoB, non-high-density lipoprotein cholesterol, and triglycerides: implications for cardiovascular prevention.

BACKGROUND AND AIMS: Despite growing evidence that apolipoprotein B (apoB) is the most accurate marker of atherosclerotic cardiovascular disease (ASCVD) risk, its adoption in clinical practice has been low. This investigation sought to determine whether low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), and triglycerides are sufficient for routine cardiovascular care. METHODS: A sample of 293 876 UK Biobank adults (age: 40-73 years, 42% men), free of cardiovascular disease, with a median follow-up for new-onset ASCVD of 11 years was included. Distribution of apoB at pre-specified levels of LDL-C, non-HDL-C, and triglycerides was examined graphically, and 10-year ASCVD event rates were compared for high vs. low apoB. Residuals of apoB were constructed after regressing apoB on LDL-C, non-HDL-C, and log-transformed triglycerides and used as predictors in a proportional hazards regression model for new-onset ASCVD adjusted for standard risk factors, including HDL-C. RESULTS: ApoB was highly correlated with LDL-C and non-HDL-C (Pearson's r = .96, P < .001 for both) but less so with log triglycerides (r = .42, P < .001). However, apoB ranges necessary to capture 95% of all observations at pre-specified levels of LDL-C, non-HDL-C, or triglycerides were wide, spanning 85.8-108.8 md/dL when LDL-C 130 mg/dL, 88.3-112.4 mg/dL when non-HDL-C 160 mg/dL, and 67.8-147.4 md/dL when triglycerides 115 mg/dL. At these levels (±10 mg/dL), 10-year ASCVD rates for apoB above mean + 1 SD vs. below mean - 1 SD were 7.3 vs. 4.0 for LDL-C, 6.4 vs. 4.6 for non-HDL-C, and 7.0 vs. 4.6 for triglycerides (all P < .001). With 19 982 new-onset ASCVD events on follow-up, in the adjusted model, residual apoB remained statistically significant after accounting for LDL-C and HDL-C (hazard ratio 1.06, 95% confidence interval 1.0-1.07), after accounting for non-HDL-C and HDL-C (hazard ratio 1.04, 95% confidence interval 1.03-1.06), and after accounting for triglycerides and HDL-C (hazard ratio 1.13, 95% confidence interval 1.12-1.15). None of the residuals of LDL-C, non-HDL-C, or of log triglycerides remained significant when apoB was included in the model. CONCLUSIONS: High variability of apoB at individual levels of LDL-C, non-HDL-C, and triglycerides coupled with meaningful differences in 10-year ASCVD rates and significant residual information contained in apoB for prediction of new-onset ASCVD events demonstrate that LDL-C, non-HDL-C, and triglycerides are not adequate proxies for apoB in clinical care.

Discovery of a novel transcriptional regulator of sugar catabolism in archaea.

The haloarchaeon Haloferax volcanii degrades D-glucose via the semiphosphorylative Entner-Doudoroff pathway and D-fructose via a modified Embden-Meyerhof pathway. Here, we report the identification of GfcR, a novel type of transcriptional regulator that functions as an activator of both D-glucose and D-fructose catabolism. We find that in the presence of D-glucose, GfcR activates gluconate dehydratase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase and also acts as activator of the phosphotransferase system and of fructose-1,6-bisphosphate aldolase, which are involved in uptake and degradation of D-fructose. In addition, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase are activated by GfcR in the presence of D-fructose and also during growth on D-galactose and glycerol. Electrophoretic mobility shift assays indicate that GfcR binds directly to promoters of regulated genes. Specific intermediates of the degradation pathways of the three hexoses and of glycerol were identified as inducer molecules of GfcR. GfcR is composed of a phosphoribosyltransferase (PRT) domain with an N-terminal helix-turn-helix motif and thus shows homology to PurR of Gram-positive bacteria that is involved in the transcriptional regulation of nucleotide biosynthesis. We propose that GfcR of H. volcanii evolved from a PRT-like enzyme to attain a function as a transcriptional regulator of central sugar catabolic pathways in archaea.

Exploring current and emerging therapies for porphyrias.

Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.

cclib 2.0: An updated architecture for interoperable computational chemistry.

Interoperability in computational chemistry is elusive, impeded by the independent development of software packages and idiosyncratic nature of their output files. The cclib library was introduced in 2006 as an attempt to improve this situation by providing a consistent interface to the results of various quantum chemistry programs. The shared API across programs enabled by cclib has allowed users to focus on results as opposed to output and to combine data from multiple programs or develop generic downstream tools. Initial development, however, did not anticipate the rapid progress of computational capabilities, novel methods, and new programs; nor did it foresee the growing need for customizability. Here, we recount this history and present cclib 2, focused on extensibility and modularity. We also introduce recent design pivots-the formalization of cclib's intermediate data representation as a tree-based structure, a new combinator-based parser organization, and parsed chemical properties as extensible objects.

Interplay of Atherogenic Particle Number and Particle Size and the Risk of Coronary Heart Disease.

BACKGROUND: We examined the interplay of apolipoprotein B (apoB) and LDL particle size, approximated by the LDL-cholesterol (LDL-C)/apoB ratio, on the risk of new-onset coronary heart disease (CHD). METHODS: Participants without cardiovascular disease from the UK Biobank (UKB; n = 308 182), the Women's Health Study (WHS; n = 26 204), and the Framingham Heart Study (FHS; n = 2839) were included. Multivariable Cox models were used to assess the relationship between apoB and LDL-C/apoB ratio and incidence of CHD (14 994 events). Our analyses were adjusted for age, sex (except WHS), HDL-cholesterol (HDL-C), systolic blood pressure, antihypertensive treatment, diabetes, and smoking. RESULTS: In all 3 studies, there was a strong positive correlation between apoB and LDL-C (correlation coefficients r = 0.80 or higher) and a weak inverse correlation of apoB with LDL-C/apoB ratio (-0.28 ≤ r ≤ -0.14). For all 3 cohorts, CHD risk was higher for higher levels of apoB. Upon multivariable adjustment, the association between apoB and new-onset CHD remained robust and statistically significant in all 3 cohorts with hazard ratios per 1 SD (95% CI): 1.24 (1.22-1.27), 1.33 (1.20-1.47), and 1.24 (1.09-1.42) for UKB, WHS, and FHS, respectively. However, the association between LDL-C/apoB and CHD was statistically significant only in the FHS cohort: 0.78 (0.64-0.94). CONCLUSIONS: Our analysis confirms that apoB is a strong risk factor for CHD. However, given the null association in 2 of the 3 studies, we cannot confirm that cholesterol-depleted LDL particles are substantially more atherogenic than cholesterol-replete particles. These results lend further support to routine measurement of apoB in clinical care.

Nutritional Interventions with Bacillus coagulans Improved Glucose Metabolism and Hyperinsulinemia in Mice with Acute Intermittent Porphyria.

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.

Brain ventricular enlargement in human and murine acute intermittent porphyria.

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Effects of long-term testosterone treatment on cardiovascular outcomes in men with hypogonadism: Rationale and design of the TRAVERSE study.

BACKGROUND: Testosterone exerts some effects on the cardiovascular system that could be considered beneficial; some other effects may potentially increase the risk of cardiovascular (CV) events. Neither the long-term efficacy nor safety of testosterone treatment has been studied in an adequately-powered randomized trial. METHODS: The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study is a randomized, double-blind, placebo-controlled, parallel group, non-inferiority, multicenter study. Eligible participants are men, 45 to 80 years, with serum testosterone concentration <300 ng/dL and hypogonadal symptoms, who have evidence pre-existing CV disease or increased risk of CV disease. Approximately 6,000 subjects will be randomized to either 1.62% transdermal testosterone gel or a matching placebo gel daily for an anticipated duration of up to 5 years. The primary outcome is CV safety defined by the major adverse CV event composite of nonfatal myocardial infarction, nonfatal stroke, or death due to CV causes. The trial will continue until at least 256 adjudicated major adverse CV event endpoints have occurred to assess whether the 95% (2-sided) upper confidence limit for a hazard ratio of 1.5 can be ruled out. Secondary endpoints include prostate safety defined as the incidence of adjudicated high grade prostate cancer and efficacy in domains of sexual function, bone fractures, depression, anemia, and diabetes. RESULTS: As of July 1, 2021, 5,076 subjects had been randomized. CONCLUSIONS: The TRAVERSE study will determine the CV safety and long-term efficacy of testosterone treatment in middle-aged and older men with hypogonadism with or at increased risk of CV disease.

Oncolytic Foamy Virus - generation and properties of a nonpathogenic replicating retroviral vector system that targets chronically proliferating cancer cells.

Nonpathogenic retroviruses of the Spumaretrovirinae subfamily can persist long-term in the cytoplasm of infected cells, completing their lifecycle only after the nuclear membrane dissolves at the time of cell division. Since the targeting of slowly dividing cancer cells remains an unmet need in oncolytic virotherapy we constructed a replication competent Foamy Virus vector (oFV) from the genomes of two chimpanzee Simian Foamy Viruses (PAN1 and PAN2) and inserted a GFP transgene in place of the bel-2 open reading frame. oFV-GFP infected and propagated with slow kinetics in multiple human tumor cell lines, inducing a syncytial cytopathic effect. Infection of growth arrested MRC5 cells was not productive, but oFV genomes persisted in the cytoplasm and the productive viral lifecycle resumed when cell division was later restored. In vivo, the virus propagated extensively in intraperitoneal ovarian cancer xenografts, slowing tumor growth, significantly prolonging survival of the treated mice and sustaining GFP transgene expression for at least 45 days. Our data indicate that oFV is a promising new replication-competent viral and gene delivery platform for efficient targeting of the most fundamental trait of cancer cells, their ability to sustain chronic proliferation.Significance:The infectivity of certain retroviruses is limited to dividing cells, which makes them attractive tools for targeting cancer cell proliferation. Previously developed replication-competent gammaretroviral vectors spread efficiently in rapidly dividing cancer cells, but not in cancer cells that divide more slowly. In contrast to rapidly proliferating transplantable mouse tumors, slow proliferation is a hallmark of human cancers and may have contributed to the clinical failure of the preclinically promising Murine Leukemia Virus vector Toca511 which failed to show efficacy in a phase 3 clinical trial in patients with glioblastoma. The studies presented in our manuscript show that oncolytic Foamy Virus (oFV) vectors are capable of persisting unintegrated in quiescent cells and resuming their life cycle once the cells start dividing again. This property of oFVs, together with their lack of pathogenicity and their ability to catalyze the fusion of infected cancer cells, makes them an attractive platform for further investigation.

Goal-directed haemodynamic therapy during general anaesthesia for noncardiac surgery: a systematic review and meta-analysis.

BACKGROUND: During general anaesthesia for noncardiac surgery, there remain knowledge gaps regarding the effect of goal-directed haemodynamic therapy on patient-centred outcomes. METHODS: Included clinical trials investigated goal-directed haemodynamic therapy during general anaesthesia in adults undergoing noncardiac surgery and reported at least one patient-centred postoperative outcome. PubMed and Embase were searched for relevant articles on March 8, 2021. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. The primary outcomes were mortality and hospital length of stay, whereas 15 postoperative complications were included based on availability. From a main pool of comparable trials, meta-analyses were performed on trials with homogenous outcome definitions. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). RESULTS: The main pool consisted of 76 trials with intermediate risk of bias for most outcomes. Overall, goal-directed haemodynamic therapy might reduce mortality (odds ratio=0.84; 95% confidence interval [CI], 0.64 to 1.09) and shorten length of stay (mean difference=-0.72 days; 95% CI, -1.10 to -0.35) but with low certainty in the evidence. For both outcomes, larger effects favouring goal-directed haemodynamic therapy were seen in abdominal surgery, very high-risk surgery, and using targets based on preload variation by the respiratory cycle. However, formal tests for subgroup differences were not statistically significant. Goal-directed haemodynamic therapy decreased risk of several postoperative outcomes, but only infectious outcomes and anastomotic leakage reached moderate certainty of evidence. CONCLUSIONS: Goal-directed haemodynamic therapy during general anaesthesia might decrease mortality, hospital length of stay, and several postoperative complications. Only infectious postoperative complications and anastomotic leakage reached moderate certainty in the evidence.

Ventilation Strategies During General Anesthesia for Noncardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: The optimal ventilation strategy during general anesthesia is unclear. This systematic review investigated the relationship between ventilation targets or strategies (eg, positive end-expiratory pressure [PEEP], tidal volume, and recruitment maneuvers) and postoperative outcomes. METHODS: PubMed and Embase were searched on March 8, 2021, for randomized trials investigating the effect of different respiratory targets or strategies on adults undergoing noncardiac surgery. Two investigators reviewed trials for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and several subgroup analyses were conducted. The certainty of evidence was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: This review included 63 trials with 65 comparisons. Risk of bias was intermediate for all trials. In the meta-analyses, lung-protective ventilation (ie, low tidal volume with PEEP) reduced the risk of combined pulmonary complications (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.28-0.49; 9 trials; 1106 patients), atelectasis (OR, 0.39; 95% CI, 0.25-0.60; 8 trials; 895 patients), and need for postoperative mechanical ventilation (OR, 0.36; 95% CI, 0.13-1.00; 5 trials; 636 patients). Recruitment maneuvers reduced the risk of atelectasis (OR, 0.44; 95% CI, 0.21-0.92; 5 trials; 328 patients). We found no clear effect of tidal volume, higher versus lower PEEP, or recruitment maneuvers on postoperative pulmonary complications when evaluated individually. For all comparisons across targets, no effect was found on mortality or hospital length of stay. No effect measure modifiers were found in subgroup analyses. The certainty of evidence was rated as very low, low, or moderate depending on the intervention and outcome. CONCLUSIONS: Although lung-protective ventilation results in a decrease in pulmonary complications, randomized clinical trials provide only limited evidence to guide specific ventilation strategies during general anesthesia for adults undergoing noncardiac surgery.

Fraction of inspired oxygen during general anesthesia for non-cardiac surgery: Systematic review and meta-analysis.

BACKGROUND: Controversy exists regarding the effects of a high versus a low intraoperative fraction of inspired oxygen (FiO2 ) in adults undergoing general anesthesia. This systematic review and meta-analysis investigated the effect of a high versus a low FiO2 on postoperative outcomes. METHODS: PubMed and Embase were searched on March 22, 2022 for randomized clinical trials investigating the effect of different FiO2 levels in adults undergoing general anesthesia for non-cardiac surgery. Two investigators independently reviewed studies for relevance, extracted data, and assessed risk of bias. Meta-analyses were performed for relevant outcomes, and potential effect measure modification was assessed in subgroup analyses and meta-regression. The evidence certainty was evaluated using GRADE. RESULTS: This review included 25 original trials investigating the effect of a high (mostly 80%) versus a low (mostly 30%) FiO2 . Risk of bias was intermediate for all trials. A high FiO2 did not result in a significant reduction in surgical site infections (OR: 0.91, 95% CI 0.81-1.02 [p = .10]). No effect was found for all other included outcomes, including mortality (OR = 1.27, 95% CI: 0.90-1.79 [p = .18]) and hospital length of stay (mean difference = 0.03 days, 95% CI -0.25 to 0.30 [p = .84). Results from subgroup analyses and meta-regression did not identify any clear effect modifiers across outcomes. The certainty of evidence (GRADE) was rated as low for most outcomes. CONCLUSIONS: In adults undergoing general anesthesia for non-cardiac surgery, a high FiO2 did not improve outcomes including surgical site infections, length of stay, or mortality. However, the certainty of the evidence was assessed as low.

Understanding Carbohydrate Metabolism and Insulin Resistance in Acute Intermittent Porphyria.

Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.

The Expected 30-Year Benefits of Early Versus Delayed Primary Prevention of Cardiovascular Disease by Lipid Lowering.

BACKGROUND: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid lowering in younger adults as a function of expected 30-year benefit. METHODS: Data from 3148 National Health and Nutrition Examination Survey (2009-2016) participants, age 30 to 59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analyzed. We estimated the absolute and relative impact of lipid lowering as a function of age, age at initiation, and non-high-density lipoprotein cholesterol (HDL-C) level on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorter-term effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B). RESULTS: In both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater with older age and higher non-HDL-C level. Immediate initiation of lipid lowering (ie, treatment for 30 years) in 40- to 49-year-old patients with non-HDL-C ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction [ARR], 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6% (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved ARR as a function of delay in treatment was also higher with older age and higher non-HDL-C level. CONCLUSIONS: Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid lowering in individuals in their 40s and 50s with non-HDL-C ≥160 mg/dL. For many, the question of when to start lipid lowering might be more relevant than whether to start lipid lowering.

Ambulatory blood pressure using 60 rather than 20-min intervals may better reflect the resting blood pressure.

PURPOSE: Twenty-four hours of ambulatory blood pressure monitoring (ABPM) is recommended in several guidelines as the best method for diagnosing hypertension. In general, the prognostic value of ABPM is superior to single office blood pressure (BP) measurements. Unfortunately, some patients experience considerable discomfort during frequently repeated forceful cuff inflations. MATERIALS AND METHODS: In this study we investigated the difference in mean daytime systolic BP (SBP) between low-frequency ABPM (LF-ABPM), measuring once every hour, and high-frequency ABPM (HF-ABPM), measuring three times an hour during daytime, and two times an hour during night-time. RESULTS: Seventy-one patients were included in the analysis. All included patients had an HF-ABPM performed first and within a few weeks they underwent an LF-ABPM. The average day time difference in SBP between the two frequencies was 3.8 mmHg (p-value = 0.07) for mild, 8.2 mmHg (p-value < 0.01) for moderate and 15 mmHg (p-value < 0.001) for severe hypertension. A similar pattern was seen for night-time SBP. This study suggests that mean BP is similar between the two measuring frequencies for normotensive and mild hypertensive patients, while HF-ABPM results in a higher 24-h mean BP for moderate- and severe hypertensive patients. CONCLUSION: LF-ABPM may more correctly reflect the resting blood pressure in patients with moderate and severe hypertension.

Crystal structure of Maternal Embryonic Leucine Zipper Kinase (MELK) in complex with dorsomorphin (Compound C).

Maternal Embryonic Leucine Zipper Kinase (MELK) is overexpressed in various tumors which has been convincingly linked to tumor cell survival. As such, MELK became an interesting target for pharmacological intervention. In this study we present the crystal structure of MELK in complex with dorsomorphin, an inhibitor of VEGFR and AMPK. By defining the mechanistic details of ligand recognition we identify a key residue (Cys89) at the hinge region of MELK responsible for positioning of the ligand at the catalytic pocket. This conclusion is supported by kinetic characterization of Cys89 mutants which show decreased affinity towards both ATP and dorsomorphin. The detailed binding mode of dorsomorphin characterized in this study defines a minimal requirement for MELK ligands, a valuable information for future rational design of inhibitors based on entirely new scaffolds.

Relationship of mildly increased albuminuria and coronary artery revascularization outcomes in patients with diabetes.

BACKGROUND: The aim of this study was to examine the relationship of albuminuria to cardiovascular disease outcomes in diabetic patients undergoing treatment for stable coronary artery disease. METHODS AND RESULTS: We analyzed data from 2176 participants of the Bypass Angioplasty Revascularization Investigation in type-2 diabetes (BARI-2D) trial, a randomized clinical trial comparing Percutaneous coronary intervention/Coronary artery bypass grafting (PCI/CABG) to medical therapy for people with diabetes. The population was stratified by baseline spot urine albumin-creatinine ratio (uACR) into normal (uACR <10 mg/g), mildly (uACR ≥10 mg/g < 30 mg/g), moderately (uACR ≥30 mg/g < 300 mg/g) and severely increased (uACR ≥300 mg/g) groups, and outcomes compared between groups. Death, myocardial infarction (MI) and/or stroke were experienced by 489 patients at a mean follow-up of 4.3 ± 1.5 years. Compared with normal uACR, mildly increased uACR was associated with a 1.4 times (P = 0.042) increase in all-cause mortality. Additionally, nonwhites with type-II diabetes and stable coronary artery disease who had mildly increased albuminuria had a Hazard ratio (HR) of 3.3 times (P = 0.028) for cardiovascular death, 3.1 times for (P = 0.002) all-cause mortality, and two times for (P = 0.015) MI during follow-up. CONCLUSIONS: Mildly increased albuminuria is a significant predictor of all-cause mortality in those with type-II diabetes mellitus and stable coronary artery disease, as well as for cardiovascular events those who are nonwhites.

Atypical Skeletal Muscle Profiles in Human Immunodeficiency Virus-Infected Asymptomatic Middle-Aged Adults.

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of age-associated functional impairment, even with effective antiretroviral therapy (ART). A concurrent characterization of skeletal muscle, physical function, and immune phenotype in aviremic middle-aged HIV-infected adults represents a knowledge gap in prognostic biomarker discovery. Methods: We undertook a prospective observational study of 170 middle-aged, HIV-infected ambulatory men and women with CD4+ T-cell counts of at least 350/µL and undetectable plasma viremia while on effective ART, and uninfected control participants. We measured biomarkers for inflammation and immune activation, fatigue, the Veterans Aging Cohort Study mortality index, and physical function. A subset also received a skeletal muscle biopsy and computed tomography scan. Results: Compared to the uninfected participants, HIV-infected participants displayed increased immune activation (P < .001), inflammation (P = .001), and fatigue (P = .010), and in a regression model adjusting for age and sex displayed deficits in stair-climb power (P < .001), gait speed (P = .036), and predicted metabolic equivalents (P = .019). Skeletal muscle displayed reduced nuclear peroxisome proliferator-activated receptor-γ coactivator 1α-positive myonuclei (P = .006), and increased internalized myonuclei (P < .001) that correlated with immune activation (P = .003) and leukocyte infiltration (P < .001). Internalized myonuclei improved a model for HIV discrimination, increasing the C-statistic from 0.84 to 0.90. Conclusions: Asymptomatic HIV-infected middle-aged adults display atypical skeletal muscle profiles, subclinical deficits in physical function, and persistent inflammation and immune activation. Identifying biomarker profiles for muscle dysregulation and risk for future functional decline in the HIV-infected population will be key to developing and monitoring preventive interventions. Clinical Trials Registration: NCT03011957.