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Background Males experience higher rates of coronary heart disease (CHD) than females, but the circulating traits underpinning this difference are poorly understood. We examined sex differences in systemic metabolites measured at four life stages, spanning childhood to middle adulthood. Methods Data were from the Avon Longitudinal Study of Parents and Children (7727 offspring, 49% male; and 6500 parents, 29% male). Proton nuclear magnetic resonance (1H-NMR) spectroscopy from a targeted metabolomics platform was performed on EDTA-plasma or serum samples to quantify 229 systemic metabolites (including lipoprotein-subclass-specific lipids, pre-glycaemic factors, and inflammatory glycoprotein acetyls). Metabolites were measured in the same offspring once in childhood (mean age 8 years), twice in adolescence (16 years and 18 years) and once in early adulthood (25 years), and in their parents once in middle adulthood (50 years). Linear regression models estimated differences in metabolites for males versus females on each occasion (serial cross-sectional associations). Results At 8 years, total lipids in very-low-density lipoproteins (VLDL) were lower in males; levels were higher in males at 16 years and higher still by 18 years and 50 years (among parents) for medium-or-larger subclasses. Larger sex differences at older ages were most pronounced for VLDL triglycerides—males had 0.19 standard deviations (SD) (95% CI = 0.12, 0.26) higher at 18 years, 0.50 SD (95% CI = 0.42, 0.57) higher at 25 years, and 0.62 SD (95% CI = 0.55, 0.68) higher at 50 years. Low-density lipoprotein (LDL) cholesterol, apolipoprotein-B, and glycoprotein acetyls were generally lower in males across ages. The direction and magnitude of effects were largely unchanged when adjusting for body mass index measured at the time of metabolite assessment on each occasion. Conclusions Our results suggest that males begin to have higher VLDL triglyceride levels in adolescence, with larger sex differences at older ages. Sex differences in other CHD-relevant metabolites, including LDL cholesterol, show the opposite pattern with age, with higher levels among females. Such life course trends may inform causal analyses with clinical endpoints in specifying traits which underpin higher age-adjusted CHD rates commonly seen among males.

BackgroundSupporting health care sector decisions using time-dependent endpoints (TDEs) such as time to progression (TTP), progression-free survival (PFS), and event-free survival (EFS) remains controversial. This study estimated the quantitative relationship between median TDE and median overall survival (OS) in multiple myeloma (MM) patients.MethodsStudies (excluding allogeneic transplantation) published from 1970 to 2011 were systematically searched (PubMed). The nonparametric Spearman’s rank correlation coefficient measured the association between median TDE and OS. The quantitative relationship between TDEs and OS was estimated with a two-step approach to a simultaneous Tobit model.ResultsWe identified 153 studies: 230 treatment arms, 22,696 patients and mean study duration of 3.8 years. Mean of median TDEs was 22.5 months and median OS was 39.1 months. Correlation coefficients of median TTP, PFS, and EFS with median OS were 0.51 (P = 0.003), 0.75 (P < 0.0001), and 0.84 (P < 0.0001), respectively. We estimate a 2.5 month (95% confidence interval, 1.7–3.2) increase in median OS for each additional month reported for median TDEs. There was no evidence that this relationship differed by type of surrogate.ConclusionTDEs predict OS in MM patients; this relationship may be valuable in clinical trial design, drug comparisons, and economic evaluation.

Sirs, Varicella is typically a benign childhood disease caused by varicella zoster virus (VZV), though serious complications can arise [1,2]. Varicella has been commonly associated with stroke in children [3], but exceptional reports have described afflicted immunocompetent adults, repeatedly relating vasculitis with this condition [4][5][6][7][8].A 39-year-old right-handed male, smoker (10 cigarettes/day), developed varicella 2 weeks after his 4-year-old daughter showed the characteristic rash. Acute pain and pallor of the left lower limb and absent ipsilateral foot pulses suddenly emerged 1 week later, as well as left hemiplegia, left homonymous hemianopia and hemineglect. Emergent lower limb angiography ( Fig. 1a and b) showed one occlusive (left femoral artery) and two sub-occlusive thrombi (left common iliac and right femoral arteries); thromboembolectomy was carried out. Intravenous non-fractionated heparin, acyclovir and methylprednisolone (5-day course, followed by oral prednisone and tapering) were prescribed. Acyclovir and corticosteroids were employed because of suspected VZV-related vasculitis. Central retinal artery occlusion of the right eye, probably the first event according to the patient, was later perceived. Laboratory examinations revealed: increased leucocytes (16.87 · 10 9 /l), C-reactive protein (19.3 mg/l) and erythrocyte sedimentation rate (49 mm/h), low protein S (0.18 U/ml, normal range 0.60-1.40), positive anticardiolipin IgM and antibeta2-glycoprotein-I IgM (25.3 MPL and 45.5 SMU, respectively; normal <15), positive VZV-specific IgM and positive VDRL at 1:8 dilutions (TPHA negative). Other blood tests were normal, including folic acid, vitamin B12, homocysteine, thyroid function tests; microbial cultures; screening for HIV, HBV and HCV; immunological screening; other basic coagulation tests and inherited prothrombotic disorders screening. Cerebrospinal fluid examination disclosed 9 cells/ mm 3 , normal protein and glucose levels;negative VZV DNA, anti-VZV antibodies (IgM, IgG), VDRL, TPHA and cultures. Transesophageal echocardiography and ECG were normal. Carotid and transcranial ultrasound showed eccentric luminal stenosis (40%) of the proximal right internal carotid artery with hypoechoic material; on serial testing, gradual shrinkage (to 20% 20 days later) and distal progression were demonstratedfindings that cannot be attributed to an atherosclerotic plaque. Brain MRI (1.5 T) was conducted 1 week after admission, showing the lesions observed in Fig. 1c. On discharge the patient presented right eye blindness, left hemiparesis and hemianopia; 3 months later he walked autonomously using one crutch. All abnormal laboratory findings returned to normal and so remained. Warfarin was stopped 6 months later; his current medication consists of antiplatelet drug and statin.We believe that these data strongly suggest that the vascular events sustained by this patient were associated with VZV, and occurred in the setting of a transitory prothrombotic condition, which also finds support in the ...