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Cardiovascular (CV) disease accounts for about half of all deaths in rheumatoid arthritis (RA). This excess risk is driven in part by inflammation but may be reduced by management of traditional risk factors. EULAR recommends a multiplier of 1.5, applied to a conventional CV risk assessment (SCORE or Framingham equation), for patients with RA with 2 of the following 3 criteria: disease duration >10 years, rheumatoid factor (RF) or ACPA positivity and presence of severe extra-articular manifestation. Crowson suggests multiplying when only one criterion is fulfilled. New targets for LDL-cholesterol have been defined with SCORE equation. A new FRS (Framingham global risk score) has been developed for a composite of all cerebrovascular events. Objective According to guidelines, the aim of our study was to determine in an early RA cohort during 4-year follow-up, the proportion of patients in whom the LDL-Cholesterol level was not reached. Methods and results We followed 186 patients with RA from the French ESPOIR cohort from 2003 to 2007. At inclusion, the mean age was 53.45, and 77.42% were women. Respectively 90 and 103 patients had RF and ACPA positivity and 11 had extra articular manifestations. Eight had diabetes mellitus and 90 were smokers. Statins were prescribed in 14 (7.5%) patients and 37 received antihypertensive drugs. The percentage of patients identified with dyslipidemia ranged significantly depending on the method (cf. table). The rate of patients who needed to be treated by statins varied from 7 to 25.8% at inclusion and from 22.7 to 32.8% at 4 years. By considering RA as an independent risk factor or applying a 1.5 multiplying factor, this rate varied from 18.8 to 26.9% at inclusion and from 22.7 to 43% at 4 years. Conclusion The application of a 1.5 multiplier identified more patients especially when only one factor was taken into account. Although rheumatologists are increasingly aware of the increase in cardiovascular risk, there was no improvement in management of lipid disorders over time. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatitis B virus (HBV) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Unlike other liver diseases, HBV can cause HCC in the absence of cirrhosis. We investigated whether features of HCC in patients with HBV infection without cirrhosis and survival times differ from those of patients who develop HCC after cirrhosis. Methods We performed a retrospective cohort study of 487 consecutive cases of HBV-related HCC who were seen from 2000 through 2014 at a tertiary care center. Laboratory values, imaging results, and treatment information were obtained from subjects’ medical records. Symptoms of HCC included weight loss, abdominal pain, or new hepatic decompensation. The primary outcome was overall survival, which was categorized as short-term survival (up to 3 years after the diagnosis of HCC) or long-term survival (3–10 years after diagnosis). Results The mean tumor size at diagnosis was significantly larger in patients without cirrhosis (6.4 ± 4.3 cm) than in patients with cirrhosis (5.0 ± 3.8 cm) ( P = .0009). A significantly larger proportion of patients without cirrhosis had symptoms at diagnosis (43.8% vs 35.4% in patients without cirrhosis, P = .09). A significantly higher proportion of patients without cirrhosis survived for the long-term ( P = .003), but there was no significant difference between groups in short-term survival ( P = .37). Notably, the same proportions of asymptomatic patients with and without cirrhosis survived for the short-term (64.3% vs 64.2%, P = .73), but a lower proportion of asymptomatic patients with cirrhosis survived for the long-term ( P = .015). In multivariate Cox regression analysis, cirrhosis was an independent predictor of death in 3–10 years (hazard ratio, 3.76; P = .003) but not in less than 3 years ( P = .48). Symptoms at diagnosis predicted death within 3 years (hazard ratio, 1.76; P =.006) but not in 3–10 years ( P = .15). Conclusions Patients with HBV infection and HCC without cirrhosis present with larger tumors, and a larger percentage have symptoms of cancer than patients with cirrhosis. This may indicate that HCC surveillance is less than optimal for patients with HBV infection without cirrhosis. Despite this suboptimal surveillance, patients without cirrhosis have higher long-term survival than those with cirrhosis, especially when asymptomatic at diagnosis. [ABSTRACT FROM AUTHOR]

During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ9-tetrahydrocannabinol (THC), might persistently alter microglia function. We administered THC (5 mg/kg, intraperitoneal) once daily to male and female mice from postnatal day (PND) 30 to PND44 and examined the transcriptome of purified microglia in adult animals (PND70 and PND120) under baseline conditions or following either of two interventions known to recruit microglia: lipopolysaccharide injection and repeated social defeat. We used high-dimensional mass cytometry by time-of-flight to map brain immune cell populations after lipopolysaccharide challenge. Adolescent THC exposure produced in mice of both sexes a state of microglial dyshomeostasis that persisted until young adulthood (PND70) but receded with further aging (PND120). Key features of this state included broad alterations in genes involved in microglia homeostasis and innate immunity along with marked impairments in the responses to lipopolysaccharide- and repeated social defeat–induced psychosocial stress. The endocannabinoid system was also dysfunctional. The effects of THC were prevented by coadministration of either a global CB 1 receptor inverse agonist or a peripheral CB 1 neutral antagonist and were not replicated when THC was administered in young adulthood (PND70–84). Daily low-intensity CB 1 receptor activation by THC during adolescence may disable critical functions served by microglia until young adulthood with potentially wide-ranging consequences for brain and mental health. [ABSTRACT FROM AUTHOR]

Although α-diazo-β-ketoesters are synthetically versatile intermediates, methodology for introducing this functionality into complex molecules is still limited, most frequently involving a carboxylic acid precursor, which is then activated and transformed into a β-ketoester, with the diazo group being subsequently added with a diazo transfer reagent. While introducing this highly functional moiety in a convergent one step process would be ideal, such an objective is limited by the relatively few studies which address functionalization of the α-diazo-β-ketoester at the γ-position. In the present investigation, we evaluate strategies, both new and established, for functionalizing α-diazo-β-ketoesters, particularly with regard to generating compounds prospectively useful in the synthesis of C1-substituted carbapenems. We report the first δ-aldehydo-α-diazo-β-ketoester as well as a method for its oxidation to the corresponding methyl ester, and the formation of a new substituted pyrazole under basic conditions. [ABSTRACT FROM AUTHOR]

A diastereoselective process for the formation of intermediates suitable for the preparation of C1 substituted carbapenems was developed. The process is readily scalable and does not involve organometallics or strong bases such as LDA. [ABSTRACT FROM AUTHOR]