A long-period radio transient active for three decades.

Several long-period radio transients have recently been discovered, with strongly polarized coherent radio pulses appearing on timescales between tens to thousands of seconds1,2. In some cases, the radio pulses have been interpreted as coming from rotating neutron stars with extremely strong magnetic fields, known as magnetars; the origin of other, occasionally periodic and less-well-sampled radio transients is still debated3. Coherent periodic radio emission is usually explained by rotating dipolar magnetic fields and pair-production mechanisms, but such models do not easily predict radio emission from such slowly rotating neutron stars and maintain it for extended times. On the other hand, highly magnetic isolated white dwarfs would be expected to have long spin periodicities, but periodic coherent radio emission has not yet been directly detected from these sources. Here we report observations of a long-period (21 min) radio transient, which we have labelled GPM J1839-10. The pulses vary in brightness by two orders of magnitude, last between 30 and 300 s and have quasiperiodic substructure. The observations prompted a search of radio archives and we found that the source has been repeating since at least 1988. The archival data enabled constraint of the period derivative to <3.6 × 10-13 s s-1, which is at the very limit of any classical theoretical model that predicts dipolar radio emission from an isolated neutron star.

Are respiratory disorders risk factors for troublesome neck/shoulder pain? A study of a general population cohort in Sweden.

PURPOSE: The etiology of neck/shoulder pain is complex. Our purpose was to investigate if respiratory disorders are risk factors for troublesome neck/shoulder pain in people with no or occasional neck/shoulder pain. METHODS: This prospective cohort study was based on the Stockholm Public Health Cohorts (SPHC) 2006/2010 and the SPHC 2010/2014. We included adults who at baseline reported no or occasional neck/shoulder pain in the last six months, from the two subsamples (SPHC 06/10 n = 15 155: and SPHC 2010/14 n = 25 273). Exposures were self-reported asthma at baseline in SPHC 06/10 and Chronic Obstructive Pulmonary Disease (COPD) at baseline in SPHC 10/14. The outcome was having experienced at least one period of troublesome neck/shoulder pain which restricted work capacity or hindered daily activities to some or to a high degree during the past six months, asked for four years later. Binomial regression analyses were used to calculate risk ratios (RR) with 95% confidence intervals (95% CI). RESULTS: Adjusted results indicate that those reporting to suffer from asthma at baseline had a higher risk of troublesome neck/shoulder pain at follow-up four years later (RR 1.48, 95% CI 1.10-2.01) as did those reporting to suffer from COPD (RR 2.12 95%CI 1.54-2.93). CONCLUSION: Our findings indicate that those with no or occasional neck/shoulder pain and reporting to suffer from asthma or COPD increase the risk for troublesome neck/shoulder pain over time. This highlights the importance of taking a multi-morbidity perspective into consideration in health care. Future longitudinal studies are needed to confirm our findings.

The host galaxy of a fast radio burst.

In recent years, millisecond-duration radio signals originating in distant galaxies appear to have been discovered in the so-called fast radio bursts. These signals are dispersed according to a precise physical law and this dispersion is a key observable quantity, which, in tandem with a redshift measurement, can be used for fundamental physical investigations. Every fast radio burst has a dispersion measurement, but none before now have had a redshift measurement, because of the difficulty in pinpointing their celestial coordinates. Here we report the discovery of a fast radio burst and the identification of a fading radio transient lasting ~6 days after the event, which we use to identify the host galaxy; we measure the galaxy's redshift to be z = 0.492 ± 0.008. The dispersion measure and redshift, in combination, provide a direct measurement of the cosmic density of ionized baryons in the intergalactic medium of ΩIGM = 4.9 ± 1.3 per cent, in agreement with the expectation from the Wilkinson Microwave Anisotropy Probe, and including all of the so-called 'missing baryons'. The ~6-day radio transient is largely consistent with the radio afterglow of a short γ-ray burst, and its existence and timescale do not support progenitor models such as giant pulses from pulsars, and supernovae. This contrasts with the interpretation of another recently discovered fast radio burst, suggesting that there are at least two classes of bursts.

Diabetes care in remote Australia: the antenatal, postpartum and inter-pregnancy period.

BACKGROUND: Aboriginal and Torres Strait Islander women experience high rates of diabetes in pregnancy (DIP), contributing to health risks for mother and infant, and the intergenerational cycle of diabetes. By enhancing diabetes management during pregnancy, postpartum and the interval between pregnancies, the DIP Partnership aims to improve health outcomes and reduce risks early in the life-course. We describe a mixed methods formative study of health professional's perspectives of antenatal and post-partum diabetes screening and management, including enablers and barriers to care. METHODS: Health professionals involved in providing diabetes care in pregnancy, from a range of health services across the Northern Territory, completed the survey (n = 82) and/or took part in interviews and/or focus groups (n = 62). RESULTS: Qualitative findings highlighted factors influencing the delivery of care as reported by health professionals, including: whose responsibility it is, access to care, the baby is the focus and pre-conception care. The main challenges were related to: disjointed systems and confusion around whose role it is to provide follow-up care beyond six weeks post-partum. Quantitative findings indicated that the majority of health professionals reported confidence in their own skills to manage women in the antenatal period (62%, 40/79) and slightly lower rates of confidence in the postpartum interval (57%, 33/58). CONCLUSION: These findings regarding whose role it is to provide postpartum care, along with opportunities to improve communication pathways and follow up care have informed the design of a complex health intervention to improve health systems and the provision of DIP related care.

Are respiratory disorders risk factors for troublesome low-back pain? A study of a general population cohort in Sweden.

PURPOSE: A multi-morbidity perspective of troublesome low back pain (LBP) has been highlighted for example in relation to respiratory disorders. Our purpose was to investigate whether respiratory disorders are risk factors for reporting troublesome LBP in people with no or occasional LBP at baseline. METHODS: This prospective cohort study was based on the Stockholm Public Health Cohort 2006/2010. We included adults reporting no or occasional LBP the last 6 months at baseline (n = 17,177). Exposures were self-reported asthma and/or Chronic Obstructive Pulmonary Disease (COPD). Outcome was troublesome LBP defined as reporting LBP a couple of days per week or more often that restricted work capacity or hindered daily activities to some or to a high degree, the last 6 months. Binomial regression models were used to calculate risk ratios (RR) with 95% confidence intervals (95% CI). RESULTS: Adjusted results indicate that those suffering from asthma had a risk of troublesome LBP at follow-up (RR 1.29, 95% CI 0.92-1.81) as do those suffering from COPD (RR 2.0, 95% CI 1.13-3.56). If suffering from asthma and concurrent COPD the RR was 3.55 (95% CI 1.58-7.98). CONCLUSION: Our findings indicate that suffering from asthma and/or COPD increases the risk of developing troublesome LBP, which highlights the importance to consider the overall health of people at risk of troublesome LBP and to take the multi-morbidity perspective into consideration. Future longitudinal studies are needed to confirm our findings. These slides can be retrieved under Electronic Supplementary Material.

Efficacy and safety of 12 weeks of elbasvir ± grazoprevir ± ribavirin in participants with hepatitis C virus genotype 2, 4, 5 or 6 infection: The C-SCAPE study.

People with hepatitis C virus (HCV) infection other than genotype 1 represent a heterogeneous group. The aim of the phase 2 C-SCAPE study was to evaluate elbasvir/grazoprevir (EBR/GZR), with or without ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infection. This was a part randomised, open-label, parallel-group study (NCT01932762; PN047-03) of treatment-naive, noncirrhotic participants. Participants with HCV genotype 2 infection received GZR 100 mg + RBV ± EBR 50 mg for 12 weeks and those with genotype 4, 5 or 6 infection were randomized to receive EBR/GZR ± RBV for 12 weeks. The primary endpoint was sustained virological response 12 weeks after completion of treatment (SVR12; HCV RNA <25 IU/mL). Among participants with genotype 2 infection, SVR12 was achieved by 80% (24/30) of those receiving EBR/GZR + RBV and 73% (19/26) of those receiving GZR + RBV. SVR rates were high in participants with HCV genotype 4 infection receiving EBR/GZR with and without RBV (100% [10/10] and 90% [9/10]; respectively). In contrast, the addition of RBV to EBR/GZR appeared to increase SVR12 in participants with genotype 5 infection (EBR/GZR, 25%; EBR/GZR + RBV 100% [4/4]). In participants with genotype 6 infection, SVR12 was 75% (3/4) in both those receiving EBR/GZR and those receiving EBR/GZR + RBV. The safety profile was similar across treatment arms, with adverse events tending to occur more frequently among participants receiving RBV. In conclusion, these data support the inclusion of participants with genotype 4 or 6 infection in the EBR/GZR phase 3 studies. EBR/GZR ± RBV was unsatisfactory for participants with genotype 2 or 5 infection.

Invasive squamous cell carcinoma: comparison of differentiation grade and tumour depth by anatomical site in 1666 tumours.

BACKGROUND: Invasive squamous cell carcinomas (SCCs) presents with different grades of differentiation and depths of invasion. AIM: To compare the grade of differentiation, tumour diameter and tumour depth by anatomical site in invasive SCC. METHODS: Retrospective clinical and histopathological data on consecutive cases of SCC came from a clinic in Sydney, Australia were assessed. A multinomial logistic regression model was applied to compare grades of differentiation by age, sex, anatomical sites, and histological tumour maximum diameter and depth. RESULTS: In total, 1666 SCCs were identified, including 82.1% (n = 1367) well-differentiated, 13.3% (n = 222), moderately differentiated and 4.6% (n = 77) poorly differentiated SCCs. Patients with poorly differentiated tumours were more likely to be older and male (both P < 0.001). The most common site for poor differentiation was the scalp in men (n = 12; 15.6%) and the cheek or chin in women (n = 7; 9.1%). In the multivariate model, compared with well-differentiated SCC, older age was significantly associated with poorly and moderately differentiated SCC (P < 0.01 and P = 0.02, respectively). Larger tumour diameters were related to poor differentiation (P = 0.03). Ear, forehead and chest sites had increased tumour depth and poor differentiation. CONCLUSIONS: This study found increased rates of poorly differentiated SCC on the forehead and cheek for both sexes, while men displayed increased rates of poorly differentiated SCC on the bald scalp and the ears. Tumour diameter and depth increased as tumours varied from well-differentiated to moderately differentiated and from moderately differentiated to poorly differentiated. An increase in depth and increased prevalence of poorly differentiated tumours were found on the ears for men and on various facial sites for both sexes.

Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naïve, noncirrhotic HCV genotype 3-infected patients.

Elbasvir (EBR; HCV NS5A inhibitor) and grazoprevir (GZR; HCV NS3/4A protease inhibitor) are approved as a fixed-dose combination to treat patients chronically infected with HCV genotypes 1 and 4. During the development programme and supported by in vitro potency, the efficacy of EBR+GZR was assessed in HCV GT3-infected patients. This study's aim was to determine the efficacy and tolerability of 12 or 18 weeks of EBR+GZR with ribavirin (RBV) in treatment-naïve, noncirrhotic HCV GT3-infected patients. Randomized patients received open-label EBR (50 mg once daily) + GZR (100 mg once daily) + RBV. The primary efficacy objective was to evaluate the sustained virologic response rates 12 weeks after the end of all study therapy (SVR12). SVR12 rates (95% confidence interval) were 45.0% (23.1, 68.5) and 57.1% (34.0, 78.2) after treatment with EBR+GZR+RBV for 12 weeks or 18 weeks, respectively. On-treatment virologic failure was observed in 41% (17 of 41) of patients. At virologic failure, resistance-associated substitutions (RASs) with a >five-fold shift in potency occurred in the NS3 region in six (35%) patients and in the NS5A region in 16 (94%) patients. The most common RAS at virologic failure was Y93H in NS5A which was identified in 13 of 17 (76%) patients. The efficacy of EBR+GZR+RBV was suboptimal in HCV GT3-infected patients due to a high rate of on-treatment virologic failure and treatment-emergent RASs which demonstrates an inadequate barrier to the development of GT3 resistance. However, rapid viral clearance demonstrated the antiviral activity of EBR+GZR+RBV in GT3-infected patients.clinicaltrials.gov: NCT01717326.

Associations of mortality and cardiovascular disease risks with diabetes and albuminuria in urban Indigenous Australians: the DRUID follow-up study.

AIM: To assess the relationships of diabetes and albuminuria with all-cause mortality and cardiovascular disease outcomes in a population without prior cardiovascular disease using data from the Darwin Region Urban Indigenous Diabetes (DRUID) study. METHODS: We conducted a prospective cohort study of 706 participants (aged 15-81 years, 68% women) without prior cardiovascular disease who underwent a 75-g oral glucose tolerance test. Deaths and fatal or non-fatal cardiovascular disease were determined over 7 years, and hazard ratios with 95% CIs and population attributable risks were estimated for baseline glycaemia and albuminuria. RESULTS: Compared with normoglycaemia and after adjustment for age, sex, hypertension, dyslipidaemia and smoking, known diabetes was associated with an adjusted hazard ratio of 4.8 (95% CI 1.5-14.7) for all-cause mortality and 5.6 (95% CI 2.1-15.2) for cardiovascular disease. Compared with normoalbuminuria, the respective adjusted risks for macroalbuminuria were 10.9 (95% CI 3.7-32.1) and 3.9 (95% CI 1.4-10.8). The Adjusted all-cause mortality and cardiovascular disease estimated population attributable risks for diabetes were 27% and 32%, and for albuminuria they were 32% and 21%, respectively. CONCLUSIONS: In our study population, the burden of mortality and cardiovascular disease was largely driven by diabetes and albuminuria. This finding on the influence of diabetes and albuminuria is consistent with reports in other high-risk Indigenous populations and should be better reflected in risk scores and intervention programmes.

Serum osteoprotegrin (OPG) in subclinical atherosclerosis in systemic lupus erythematosus.

Introduction Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family. It has recently been demonstrated that OPG is produced by a variety of tissues, including the cardiovascular system (heart, arteries, veins), lung, kidney, immune tissues, and bone. The OPG-RANKL signaling pathway is strongly related to vascular calcification. We determined the association of this biomarker with subclinical atherosclerosis in systemic lupus erythematous (SLE). Methods We measured OPG and markers of subclinical atherosclerosis (coronary artery calcium (CAC), carotid intima-media thickness (cIMT) carotid plaque) in 166 SLE patients (91% female, 64% Caucasian, 31% African American, 5% others, mean age 45 years). Subgroups of patients with different levels of OPG level were compared with respect to average levels of CAC, cIMT, and with respect to presence of carotid plaque. Age was adjusted for using multiple regression. Results OPG was highly correlated with age ( p < 0.0001). Individuals with higher levels of OPG tended to have higher measures of CAC, cIMT, and more carotid plaque. However, after adjustment for age, these associations, while still positive, were no longer statistically significant. Conclusion In our study much of the association observed was due to confounding by age, and after adjusting for age, our findings do not rule out the possibility of a null association.

Acantholytic invasive squamous cell carcinoma: tumor diameter, invasion depth, grade of differentiation, surgical margins, perineural invasion, recurrence and death rate.

BACKGROUND: Squamous cell carcinoma (SCC) may present with or without the feature of acantholysis. METHODS: Investigate invasive acantholytic SCC by microscopic maximum tumor surface diameter, depth of invasion, grade of differentiation, perineural invasion (PNI) and percentage of acantholysis. Assess recurrence following excision. RESULTS: A total of 1658 consecutive invasive SCC cases were examined, comprising 4.9% acantholytic SCC. Median tumor microscopic maximum diameter was 8 mm for acantholytic SCC and 7.3 mm for non-acantholytic SCC. Median tumor invasion depth was 1.0 mm for acantholytic SCC and 1.5 mm for non-acantholytic SCC. Well, moderate and poor differentiation were not significantly different between acantholytic SCC and non-acantholytic SCC. One PNI case was found in 82 acantholytic SCC cases. A total of 77 acantholytic SCC cases were followed up over a median 25 months finding histologic proven recurrence at three acantholytic SCC excision sites. CONCLUSIONS: Acantholytic SCC were more likely to be located on head sites with less median depth than non-acantholytic SCC. Increasing percentage of acantholysis within acantholytic SCC was not associated with a shift towards poor differentiation. Histologic margins of 1.2 mm may adequately excise small acantholytic SCC. No recorded deaths, low PNI and low recurrence rates suggests acantholytic SCC is low-risk.

Do physical activity level and body mass index predict recovery from persistent neck pain in men and women of working age? A population-based cohort study.

PURPOSE: The study sought to examine the gender-specific effects of physical activity level and body mass index on recovery from persistent neck pain (PNP) among citizens of working age in Stockholm, Sweden. METHODS: A population-based cohort of 1,730 subjects (18-65) with PNP answered surveys in 2002 and 2007. Prognostic factors were self-reported body mass index (BMI) and physical activity level (PAL) at baseline. Analyses were performed with odds ratios (OR) with corresponding 95 % confidence intervals (95 % CI). RESULTS: Women reporting higher physical activity level had higher odds of recovering from PNP than women with sedentary leisure time (OR of 1.5, 95 % CI 1.0-2.4), but no associations were found in men. No associations were found between BMI and recovery from PNP in any analyses. CONCLUSION: Physical activity seems to be associated with recovery from PNP in women and should therefore be encouraged. Future studies should continue investigating physical activity and lifestyle factors in relation to recovery from persistent neck pain, since these modifiable factors may be considered in interventions.

Neutron star mass estimates from gamma-ray eclipses in spider millisecond pulsar binaries.

Reliable neutron star mass measurements are key to determining the equation of state of cold nuclear matter, but such measurements are rare. Black widows and redbacks are compact binaries consisting of millisecond pulsars and semi-degenerate companion stars. Spectroscopy of the optically bright companions can determine their radial velocities, providing inclination-dependent pulsar mass estimates. Although inclinations can be inferred from subtle features in optical light curves, such estimates may be systematically biased due to incomplete heating models and poorly understood variability. Using data from the Fermi Large Area Telescope, we have searched for gamma-ray eclipses from 49 spider systems, discovering significant eclipses in 7 systems, including the prototypical black widow PSR B1957+20. Gamma-ray eclipses require direct occultation of the pulsar by the companion, and so the detection, or significant exclusion, of a gamma-ray eclipse strictly limits the binary inclination angle, providing new robust, model-independent pulsar mass constraints. For PSR B1957+20, the eclipse implies a much lighter pulsar (1.81 ± 0.07 solar masses) than inferred from optical light curve modelling.

Effect of pregnancy on emtricitabine pharmacokinetics.

OBJECTIVES: The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum. METHODS: The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6-12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography-mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC(0-24) ), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects. RESULTS: Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1-8.9) vs. 9.7 (8.6-10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6-28.3) vs. 20.6 (18.4-23.2) L/h (P = 0.025); 24 hour post dose concentration (C(24) ): 0.058 (0.037-0.063) vs. 0.085 (0.070-0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0-1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects. CONCLUSIONS: While we found higher emtricitabine CL/F and lower C(24) and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.

Associations between epigenetic aging and childhood peer victimization, depression, and suicidal ideation in adolescence and adulthood: A study of two population-based samples.

Background: Prior studies indicate that peer victimization (including bullying) is associated with higher risk for depression and suicidal ideation across the life course. However, molecular mechanisms underlying these associations remain unclear. This two-cohort study proposes to test whether epigenetic aging and pace of aging, as well as a DNA methylation marker of responsive to glucocorticoids, are associated to childhood peer victimization and later depressive symptoms, or suicidal ideation. Methods: Cohort 1: Epigenome-wide DNA methylation (EPIC array) was measured in saliva collected when participants were 10.47 years (standard deviation = 0.35) in a subsample of the Quebec Longitudinal Study of Child Development (QLSCD, n = 149 participants), with self-reported peer victimization at 6-8 years, depressive symptoms (mean symptoms, and dichotomized top 30% symptoms) and suicidal ideation at 15-17 years. Cohort 2: Epigenome-wide DNA methylation (EPIC array) was measured in blood collected from participants aged 45.13 years (standard deviation = 0.37) in a subsample of the 1958 British Birth cohort (1958BBC, n = 238 participants) with information on mother-reported peer victimization at 7-11 years, self-reported depressive symptoms at 50 years, and suicidal ideation at 45 years. Five epigenetic indices were derived: three indicators of epigenetic aging [Horvath's pan-tissue (Horvath1), Horvath's Skin-and-Blood (Horvath2), Pediatric-Buccal-Epigenetic age (PedBE)], pace of aging (DunedinPACE), and stress response reactivity (Epistress). Results: Peer victimization was not associated with the epigenetic indices in either cohort. In the QLSCD, higher PedBE epigenetic aging and a slower pace of aging as measured by DunedinPACE predicted higher depressive symptoms scores. In contrast, neither the Horvath1, or Horvath2 epigenetic age estimates, nor the Epistress score were associated with depressive symptoms in either cohort, and none of the epigenetic indices predicted suicidal ideation. Conclusion: The findings are consistent with epigenome-wide and candidate gene studies suggesting that these epigenetic indices did not relate to peer victimization, challenging the hypothesis that cumulative epigenetic aging indices could translate vulnerability to depressive symptoms and suicidal ideation following peer victimization. Since some indices of epigenetic aging and pace of aging signaled higher risk for depressive symptoms, future studies should pursue this investigation to further evaluate the robustness and generalization of these preliminary findings.

Television viewing time and mortality: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab).

BACKGROUND: Television viewing time, the predominant leisure-time sedentary behavior, is associated with biomarkers of cardiometabolic risk, but its relationship with mortality has not been studied. We examined the associations of prolonged television viewing time with all-cause, cardiovascular disease (CVD), cancer, and non-CVD/noncancer mortality in Australian adults. METHODS AND RESULTS: Television viewing time in relation to subsequent all-cause, CVD, and cancer mortality (median follow-up, 6.6 years) was examined among 8800 adults > or =25 years of age in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). During 58 087 person-years of follow-up, there were 284 deaths (87 CVD deaths, 125 cancer deaths). After adjustment for age, sex, waist circumference, and exercise, the hazard ratios for each 1-hour increment in television viewing time per day were 1.11 (95% confidence interval [CI], 1.03 to 1.20) for all-cause mortality, 1.18 (95% CI, 1.03 to 1.35) for CVD mortality, and 1.09 (95% CI, 0.96 to 1.23) for cancer mortality. Compared with a television viewing time of <2 h/d, the fully adjusted hazard ratios for all-cause mortality were 1.13 (95% CI, 0.87 to 1.36) for > or =2 to <4 h/d and 1.46 (95% CI, 1.04 to 2.05) for > or =4 h/d. For CVD mortality, corresponding hazard ratios were 1.19 (95% CI, 0.72 to 1.99) and 1.80 (95% CI, 1.00 to 3.25). The associations with both cancer mortality and non-CVD/noncancer mortality were not significant. CONCLUSIONS: Television viewing time was associated with increased risk of all-cause and CVD mortality. In addition to the promotion of exercise, chronic disease prevention strategies could focus on reducing sitting time, particularly prolonged television viewing.

Maternal medium-chain acyl-CoA dehydrogenase deficiency identified by newborn screening.

Prior to the advent of expanded newborn screening, sudden and unexplained death was often the first and only symptom of medium-chain acyl-CoA dehydrogenase deficiency (MCADD). With the use of tandem mass spectrometry, infants can now be identified and treated before a life threatening metabolic decompensation occurs. Newborn screening has also been shown to detect previously undiagnosed maternal inborn errors of metabolism. We have now diagnosed two women with MCADD following the identification of low free carnitine in their newborns. While one of the women reported prior symptoms of fasting intolerance, neither had a history of metabolic decompensation or other symptoms consistent with a fatty acid oxidation disorder. These cases illustrate the importance of including urine organic acid analysis and an acylcarnitine profile as part of the confirmatory testing algorithm for mothers when low free carnitine is identified in their infants.

HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study.

AIMS/HYPOTHESIS: We assessed whether the relationships between insulin sensitivity and all-cause mortality as well as fatal or non-fatal cardiovascular disease (CVD) events are independent of elevated blood glucose, high blood pressure, dyslipidaemia and body composition in individuals without diagnosed diabetes. METHODS: Between 1999 and 2000, baseline fasting insulin, glucose and lipids, 2 h plasma glucose, HbA(1c), anthropometrics, blood pressure, medication use, smoking and history of CVD were collected from 8,533 adults aged >35 years from the population-based Australian Diabetes, Obesity and Lifestyle study. Insulin sensitivity was estimated by HOMA of insulin sensitivity (HOMA-%S). Deaths and fatal or non-fatal CVD events were ascertained through linkage to the National Death Index and medical records adjudication. RESULTS: After a median of 5.0 years there were 277 deaths and 225 CVD events. HOMA-%S was not associated with all-cause mortality. Compared with the most insulin-sensitive quintile, the combined fatal or non-fatal CVD HR (95% CI) for quintiles of decreasing HOMA-%S were 1.1 (0.6-1.9), 1.4 (0.9-2.3), 1.6 (1.0-2.5) and 2.0 (1.3-3.1), adjusting for age and sex. Smoking, CVD history, hypertension, lipid-lowering medication, total cholesterol and waist-to-hip ratio moderately attenuated this relationship. However, the association was rendered non-significant by adding HDL. Fasting plasma glucose, but not HOMA-%S significantly improved the prediction of CVD, beyond that seen with other risk factors. CONCLUSIONS/INTERPRETATION: In this cohort, HOMA-%S showed no association with all-cause mortality and only a modest association with CVD events, largely explained by its association with HDL. Fasting plasma glucose was a better predictor of CVD than HOMA-%S.

Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study.

AIMS/HYPOTHESIS: Hyperglycaemia is a risk factor for cardiovascular disease (CVD) and all-cause mortality in individuals without diabetes. We investigated: (1) whether the risk of all-cause and CVD mortality extended continuously throughout the range of fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and HbA(1c) values; and (2) the ability of these measures to improve risk prediction for mortality. METHODS: Data on 10,026 people aged >or=25 years without diagnosed diabetes were obtained from the population-based Australian Diabetes, Obesity and Lifestyle study. Between 1999 and 2000, FPG, 2hPG and HbA(1c) were assessed and all-cause (332 deaths) and CVD (88 deaths) mortality were obtained after 7 years. RESULTS: Both 2hPG and HbA(1c) exhibited linear relationships with all-cause and CVD mortality, whereas FPG showed J-shaped relationships. The adjusted HR (95% CI) for all-cause mortality per SD increase was 1.2 (1.1-1.3) for 2hPG and 1.1 (1.0-1.2) for HbA(1c). The HR for FPG <5.1 mmol/l (per SD decrease) was 2.0 (1.3-3.0); for FPG >or=5.1 mmol/l (per SD increase) the HR was 1.1 (1.0-1.2). Corresponding HRs for CVD mortality were 1.2 (1.0-1.4), 1.2 (1.0-1.3), 4.0 (2.1-7.6) and 1.3 (1.1-1.4). The discriminative ability of each measure was similar; no measure substantially improved individual risk identification over traditional risk factors. CONCLUSIONS/INTERPRETATION: In individuals without diagnosed diabetes, 2hPG and FPG, but not HbA(1c) were significant predictors of all-cause mortality, whereas all measures were significant predictors of CVD mortality. However, these glucose measures did not substantially improve individual risk identification.

Systemic delivery of recombinant proteins by genetically modified myoblasts.

The ability to stably deliver recombinant proteins to the systemic circulation would facilitate the treatment of a variety of acquired and inherited diseases. To explore the feasibility of the use of genetically engineered myoblasts as a recombinant protein delivery system, stable transfectants of the murine C2C12 myoblast cell line were produced that synthesize and secrete high levels of human growth hormone (hGH) in vitro. Mice injected with hGH-transfected myoblasts had significant levels of hGH in both muscle and serum that were stable for at least 3 weeks after injection. Histological examination of muscles injected with beta-galactosidase-expressing C2C12 myoblasts demonstrated that many of the injected cells had fused to form multinucleated myotubes. Thus, genetically engineered myoblasts can be used for the stable delivery of recombinant proteins into the circulation.