Objectives The aim of this study was to evaluate the efficacy and safety of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Background Mipomersen is an apolipoprotein (apo) ...B synthesis inhibitor that has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in Phase 1 clinical trials in healthy volunteers. Methods A randomized, placebo-controlled, dose-escalation Phase 2 study was designed to evaluate the effects of mipomersen in hypercholesterolemic subjects taking stable statin therapy. Seventy-four subjects were enrolled sequentially into 1 of 6 dose cohorts at a 4:1 (active/placebo) ratio. Subjects received 7 doses of 30 to 400 mg over 5 weeks in the first 5 cohorts and 15 doses of 200 mg over 13 weeks in the sixth cohort. Pre-specified end points included percentage change from baseline in apo B and LDL cholesterol. Safety was assessed with laboratory test results and by the incidence and severity of adverse events. Results The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema 90%) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations ≥3× the upper limit of normal, 4 of which persisted on 2 consecutive occasions. Conclusions Mipomersen might hold promise for treatment of patients not reaching target LDL cholesterol levels on stable statin therapy. Further studies are needed to address the mechanisms and clinical relevance of transaminase changes after mipomersen administration. (Dose-Escalating Safety Study in Subjects on Stable Statin Therapy; NCT00231569 )
A randomized, double-blind, placebo-controlled, dose-escalation study was conducted to examine the efficacy and safety of mipomersen (ISIS 301012), an antisense inhibitor of apolipoprotein B, when ...added to conventional lipid-lowering therapy for patients with heterozygous familial hypercholesterolemia. A total of 44 patients were enrolled and were separated into 4 cohorts, with doses ranging from 50 to 300 mg (4:1 active treatment/placebo ratio). Patients received 8 doses subcutaneously during a 6-week treatment period. Patients assigned to the 300-mg dose continued for an additional 7 weeks with once-per-week dosing. The primary efficacy end point was the percentage of change from baseline to week 7 in low-density lipoprotein (LDL) cholesterol. Safety was assessed using the laboratory test results and according to the incidence, severity, and relation of adverse events to drug dose. Mipomersen produced significant reductions in LDL cholesterol and other atherogenic apolipoprotein B-containing lipoproteins. After 6 weeks of treatment, the LDL cholesterol level was reduced by 21% from baseline in the 200-mg/week dose group (p <0.05) and 34% from baseline in the 300-mg/week dose group (p <0.01), with a concomitant reduction in apolipoprotein B of 23% (p <0.05) and 33% (p <0.01), respectively. Injection site reactions were the most common adverse event. Elevations in liver transaminase levels (≥3 times the upper limit of normal) occurred in 4 (11%) of 36 patients assigned to active treatment; 3 of these patients were in the highest dose group. In conclusion, mipomersen has an incremental LDL cholesterol lowering effect when added to conventional lipid-lowering therapy.
Summary Background The prevalence of hepatitis E virus (HEV) genotype 3 infections in the English population (including blood donors) is unknown, but is probably widespread, and the virus has been ...detected in pooled plasma products. HEV-infected donors have been retrospectively identified through investigation of reported cases of possible transfusion-transmitted hepatitis E. The frequency of HEV transmission by transfusion and its outcome remains unknown. We report the prevalence of HEV RNA in blood donations, the transmission of the virus through a range of blood components, and describe the resulting morbidity in the recipients. Methods From Oct 8, 2012, to Sept 30, 2013, 225 000 blood donations that were collected in southeast England were screened retrospectively for HEV RNA. Donations containing HEV were characterised by use of serology and genomic phylogeny. Recipients, who received any blood components from these donations, were identified and the outcome of exposure was ascertained. Findings 79 donors were viraemic with genotype 3 HEV, giving an RNA prevalence of one in 2848. Most viraemic donors were seronegative at the time of donation. The 79 donations had been used to prepare 129 blood components, 62 of which had been transfused before identification of the infected donation. Follow-up of 43 recipients showed 18 (42%) had evidence of infection. Absence of detectable antibody and high viral load in the donation rendered infection more likely. Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia. Three recipients cleared longstanding infection after intervention with ribavirin or alteration in immunosuppressive therapy. Ten recipients developed prolonged or persistent infection. Transaminitis was common, but short-term morbidity was rare; only one recipient developed apparent but clinically mild post-transfusion hepatitis. Interpretation Our findings suggest that HEV genotype 3 infections are widespread in the English population and in blood donors. Transfusion-transmitted infections rarely caused acute morbidity, but in some immunosuppressed patients became persistent. Although at present blood donations are not screened, an agreed policy is needed for the identification of patients with persistent HEV infection, irrespective of origin, so that they can be offered antiviral therapy. Funding Public Health England and National Health Service Blood and Transplant.
Background The neurobiology of suicide is largely unknown. Studies of white matter tracts in patients with a history of suicidal behaviour have shown alteration in the left anterior limb of the ...internal capsule (ALIC). Our aim was to determine whether particular target fields of fibre projections through the ALIC are affected in depressed patients who recently attempted suicide. Methods We studied patients with major depressive disorder (MDD) with and without a history of suicide attempts and healthy controls using diffusion tensor imaging (DTI) and deterministic tractography to generate fibre tract maps for each participant. Tract voxels were coded as being unique to the left ALIC. We compared the mean percentage of fibres projecting to relevant brain regions in the 3 groups using analysis of covariance. Results We included 63 patients with MDD (23 with and 40 without a history of suicide attempts) and 46 controls in our study. Both groups of depressed patients had reduced fibre projections through the ALIC to the left medial frontal cortex, orbitofrontal cortex and thalamus. Those with a history of suicide attempts had greater abnormalities than those without suicide attempts in the left orbitofrontal cortex and thalamus. Limitations Diffusion tensor imaging deterministic tracking is unable to distinguish between afferent and efferent pathways, limiting our ability to distinguish the directionality of altered fibre tracts. Conclusion Frontothalamic loops passing through the ALIC are abnormal in patients with depression and significantly more abnormal in depressed patients with a history of suicide attempts than in those without a history of suicide attempts. Abnormal projections to the orbitofrontal cortex and thalamus may disrupt affective and cognitive functions to confer a heightened vulnerability for suicidal behaviour.
Purpose: The Collaborative Ocular Tuberculosis Study (COTS) Group sought to address the diagnostic uncertainty through retrospective cohort analysis of treatment regimens and therapeutic outcomes for ...patients with tubercular Anterior Uveitis (TAU) across international centers.
Methods: Multicentre retrospective analysis of patients diagnosed with TAU between January 2004 to December 2014 that had a minimum follow-up of 1 year.
Results: One hundred and sixty-five patients were included. One hundred and seven subjects received antitubercular therapy (ATT) (n = 107/165; 64.9%) with all the patients receiving topical steroid therapy. Treatment failure was noted in 17 patients (n = 17/165; 10.3%), more frequently described in patients that received ATT (n = 13/107, 12.2%), than those that did not receive ATT (n = 4/58, 6.9%).
Conclusion: In this retrospective study, addition of ATT did not have any statistically significant impact on outcome in patients with TAU.
Objective: Aim of the study was to examine extent, natural history, and clinical features associated with visual impairment (VI) in patients diagnosed with ocular tuberculosis (OTB) by the ...Collaborative Ocular Tuberculosis Study (COTS)-1.
Methods: Multi-center retrospective cohort study. Main outcomes were VI.
Results: A total of 302 patients were included in the study, including 175 patients whose data related to BCVA were available throughout the 2 years of follow up. Mean BCVA grossly improved at 12, 18, and 24 months of follow-up (p < .001). Mean BCVA was worse at 12-18th month follow-up for patients treated with ATT versus patients who were not treated with ATT, but patients treated with ATT had a statistically significant improvement in BCVA at the 24-month endpoint.
Conclusions: OTB is associated with significant visual morbidity, future well-designed prospective studies are warranted to establish the causal association between OTB and visual loss.
Background Obesity and being overweight are becoming epidemic, and indeed, the proportion of such women of reproductive age has increased in recent times. Being overweight or obese prior to pregnancy ...is a risk factor for gestational diabetes mellitus, and increases the risk of adverse pregnancy outcome for both mothers and their offspring. Furthermore, the combination of gestational diabetes mellitus with obesity/overweight status may increase the risk of adverse pregnancy outcome attributable to either factor alone. Regular exercise has the potential to reduce the risk of developing gestational diabetes mellitus and can be used during pregnancy; however, its efficacy remain controversial. At present, most exercise training interventions are implemented on Caucasian women and in the second trimester, and there is a paucity of studies focusing on overweight/obese pregnant women. Objective We sought to test the efficacy of regular exercise in early pregnancy to prevent gestational diabetes mellitus in Chinese overweight/obese pregnant women. Study Design This was a prospective randomized clinical trial in which nonsmoking women age >18 years with a singleton pregnancy who met the criteria for overweight/obese status (body mass index <28/≥28 kg/m2 ) and had an uncomplicated pregnancy at <12+6 weeks of gestation were randomly allocated to either exercise or a control group. Patients did not have contraindications to physical activity. Patients allocated to the exercise group were assigned to exercise 3 times per week (at least 30 min/session with a rating of perceived exertion between 12-14) via a cycling program begun within 3 days of randomization until 37 weeks of gestation. Those in the control group continued their usual daily activities. Both groups received standard prenatal care, albeit without special dietary recommendations. The primary outcome was incidence of gestational diabetes mellitus. Results From December 2014 through July 2016, 300 singleton women at 10 weeks’ gestational age and with a mean prepregnancy body mass index of 26.78 ± 2.75 kg/m2 were recruited. They were randomized into an exercise group (n = 150) or a control group (n = 150). In all, 39 (26.0%) and 38 (25.3%) participants were obese in each group, respectively. Women randomized to the exercise group had a significantly lower incidence of gestational diabetes mellitus (22.0% vs 40.6%; P < .001). These women also had significantly less gestational weight gain by 25 gestational weeks (4.08 ± 3.02 vs 5.92 ± 2.58 kg; P < .001) and at the end of pregnancy (8.38 ± 3.65 vs 10.47 ± 3.33 kg; P < .001), and reduced insulin resistance levels (2.92 ± 1.27 vs 3.38 ± 2.00; P = .033) at 25 gestational weeks. Other secondary outcomes, including gestational weight gain between 25-36 gestational weeks (4.55 ± 2.06 vs 4.59 ± 2.31 kg; P = .9), insulin resistance levels at 36 gestational weeks (3.56 ± 1.89 vs 4.07 ± 2.33; P = .1), hypertensive disorders of pregnancy (17.0% vs 19.3%; odds ratio, 0.854; 95% confidence interval, 0.434–2.683; P = .6), cesarean delivery (except for scar uterus) (29.5% vs 32.5%; odds ratio, 0.869; 95% confidence interval, 0.494–1.529; P = .6), mean gestational age at birth (39.02 ± 1.29 vs 38.89 ± 37 weeks’ gestation; P = .5); preterm birth (2.7% vs 4.4%, odds ratio, 0.600; 95% confidence interval, 0.140–2.573; P = .5), macrosomia (defined as birthweight >4000 g) (6.3% vs 9.6%; odds ratio, 0.624; 95% confidence interval, 0.233–1.673; P = .3), and large-for-gestational-age infants (14.3% vs 22.8%; odds ratio, 0.564; 95% confidence interval, 0.284–1.121; P = .1) were also lower in the exercise group compared to the control group, but without significant difference. However, infants born to women following the exercise intervention had a significantly lower birthweight compared with those born to women allocated to the control group (3345.27 ± 397.07 vs 3457.46 ± 446.00; P = .049). Conclusion Cycling exercise initiated early in pregnancy and performed at least 30 minutes, 3 times per week, is associated with a significant reduction in the frequency of gestational diabetes mellitus in overweight/obese pregnant women. And the decrease of gestational diabetes mellitus is very relevant to the less gestational weight gain before the mid-second trimester. Furthermore, there was no evidence that the exercise prescribed in this study increased the risk of preterm birth or reduced the mean gestational age at birth.
Background Stress responses have been studied extensively in animal models, but effects of major life stress on the human brain remain poorly understood. The aim of this study was to determine ...whether survivors of a major earthquake, who were presumed to have experienced extreme emotional stress during the disaster, demonstrate differences in brain anatomy relative to individuals who have not experienced such stressors. Methods Healthy survivors living in an area devastated by a major earthquake and matched healthy controls underwent 3-dimentional high-resolution magnetic resonance imaging (MRI). Survivors were scanned 13–25 days after the earthquake; controls had undergone MRI for other studies not long before the earthquake. We used optimized voxel-based morphometry analysis to identify regional differences of grey matter volume between the survivors and controls. Results We included 44 survivors (17 female, mean age 37 standard deviation (SD) 10.6 yr) and 38 controls (14 female, mean age 35.3 SD 11.2 yr) in our analysis. Compared with controls, the survivors showed significantly lower grey matter volume in the bilateral insula, hippocampus, left caudate and putamen, and greater grey matter volume in the bilateral orbitofrontal cortex and the parietal lobe (all p < 0.05, corrected for multiple comparison). Limitations Differences in the variance of survivor and control data could impact study findings. Conclusion Acute anatomic alterations could be observed in earthquake survivors in brain regions where functional alterations after stress have been described. Anatomic changes in the present study were observed earlier than previously reported and were seen in prefrontal–limbic, parietal and striatal brain systems. Together with the results of previous functional imaging studies, our observations suggest a complex pattern of human brain response to major life stress affecting brain systems that modulate and respond to heightened affective arousal.
Capsule summary APDS is a newly described and prevalent primary immunodeficiency disease, and we now expand the list of mutation sites to include E81K and G124D of p110δ and uncover an intramolecular ...mechanism of activation that is inhibited by clinically relevant targeting of p110δ.
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