Management of vascular access in Europe. Part 1 ‐ A study of centre based policies

The EDTNA/ERCA survey of the management of vascular access was the first project organised through the Collaborative Research Programme. This paper reports in the first part, on the current policies for management of vascular access which were studied using centre‐based data collected with a computer based questionnaire. The survey included 103 European centres treating a total of 13,800 chronic haemodialysis patients. 75% of patients in the participating centres were dialysed using a native arteriovenous fistula, 10% had a synthetic graft and 15% had a catheter. In most centres, well‐established hygienic precautions were used. When handling catheters, hygiene was even better. We observed that many aspects of access management varied significantly from region to region as well as between centres. The second part of this paper will relate the large differences observed in centre policies of vascular access management to individual patients' outcome parameters.     

Efficacy and duration of benazepril plus amlodipine or hydrochlorothiazide on 24-hour ambulatory systolic blood pressure control

The combination of benazepril plus amlodipine was shown to be more effective than benazepril plus hydrochlorothiazide in reducing cardiovascular events in the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial. There was a small difference in clinic systolic blood pressure between the treatment arms favoring benazepril plus amlodipine. Ambulatory blood pressure monitoring provides a more rigorous estimate of blood pressure effects. A subset of 573 subjects underwent ambulatory blood pressure monitoring during year 2. Readings were obtained every 20 minutes during a 24-hour period. Between-treatment differences (benazepril plus amlodipine versus benazepril plus hydrochlorothiazide) in mean values were analyzed using ANOVA. Treatment comparisons with respect to categorical variables were made using Pearson's χ2. At year 2, the treatment groups did not differ significantly in 24-hour mean daytime or nighttime blood pressures (values of 123.9, 125.9, and 118.1 mm Hg for benazepril plus amlodipine group versus 122.3, 124.1, and 116.9 for the benazepril plus hydrochlorothiazide group), with mean between-group differences of 1.6, 1.8, and 1.2 mm Hg, respectively. Blood pressure control rates (24-hour mean systolic blood pressure <130 mm Hg on ambulatory blood pressure monitoring) were greater than 80% in both groups. Nighttime systolic blood pressure provided additional risk prediction after adjusting for the effects of drugs. The 24-hour blood pressure control was similar in both treatment arms, supporting the interpretation that the difference in cardiovascular outcomes favoring a renin angiotensin system blocker combined with amlodipine rather than hydrochlorothiazide shown in the ACCOMPLISH trial was not caused by differences in blood pressure, but instead intrinsic properties (metabolic or hemodynamic) of the combination therapies.     

日本血吸虫病流行区人群吡喹酮治疗前后细胞因子水平的研究

观察日本血吸虫病流行区人群的细胞免疫应答状态及吡喹酮治疗对其影响。 [方法 ]采集日本血吸虫病流行区 12 9人 (粪检阳性者 6 4例 ,粪检阴性者 6 5例 ) ,吡喹酮治疗前及治疗后 45d的静脉血 ,以血吸虫成虫和虫卵抗原分别刺激诱生细胞因子 ,检测培养上清中的细胞因子IL 5、IL 10和IFN γ水平。 [结果 ]12 9例中 ,对血吸虫抗原刺激诱生的细胞因子水平粪检阴性组明显高于粪检阳性组 ;治疗后 ,细胞因子诱生水平较治疗前显著升高 ,特别是IL 5和IFN γ。 [结论 ]流行区人群的细胞免疫应答显示总体下调趋势 ;吡喹酮治疗后出现细胞因子水平的明显升高。     

Single and multiple dose pharmacokinetics of rifapentine in man: part II.

OBJECTIVE: To characterize the pharmacokinetics of rifapentine following single, multiple, and intermittent doses. DESIGN: Twenty-three healthy male volunteers were randomized in a two-period, incomplete block, crossover design to receive two of four possible treatments: single daily oral rifapentine doses of 150, 300, or 600 mg given on day 1 and again on days 4-10, or a single oral 600 mg dose given on days 1, 4, 7, and 10. RESULTS: Maximum rifapentine plasma concentrations were observed in 4-5 hours. Mean rifapentine t(1/2) ranged from 13.2-14.1 hours and was similar across the 150-600 mg dose range. The changes in rifapentine Cmax (R = 0.86) and AUC(0-->infinity) (R + 0.90) were dose linear. The active 25-desacetyl metabolite appeared slowly in plasma, with mean Tmax of 14.4-17.8 hours. Mean t(1/2) for 25-desacetyl-rifapentine ranged from 13.3-24.3 hours. Disproportionate, dose-dependent increases in rifapentine and 25-desacetyl-rifapentine AUC were observed as single doses of rifapentine increased from 150 to 600 mg. At steady state, however, the magnitude of dose dependency was much less. CONCLUSION: Maximum plasma rifapentine concentrations were well above minimum inhibitory concentrations for Mycobacterium tuberculosis and M. avium following single 600 mg doses. In addition, the extended t(1/2) of rifapentine and its active metabolite support clinical investigation of once or twice-weekly rifapentine dosage regimens of rifapentine for the management of tuberculosis.     

Increased prevalence of methylenetetrahydrofolate reductase C677T variant in patients with inflammatory bowel disease, and its clinical implications

BACKGROUND: Inflammatory bowel disease (IBD) is associated with an increased incidence of thromboembolic disease. Hyperhomocysteinaemia (hyper-tHcy), a condition associated with the C677T variant of 5, 10-methylenetetrahydrofolate reductase (MTHFR), is linked with an increased incidence of thromboembolic disease. Hyper-tHcy has been reported in patients with IBD. AIMS: To assess the prevalence of the C677T MTHFR genotype and the contribution of this genotype to hyper-tHcy in patients with IBD. METHODS: Patients with established IBD (n=174) and healthy controls (n=273) were studied. DNA samples were genotyped for the MTHFR (C677T) mutation. Subjects were categorised as homozygous for the thermolabile variant (TT), heterozygous for wild type and variant (CT), or homozygous for the wild type (CC). RESULTS: Plasma homocysteine concentrations were significantly higher in patients with IBD than in healthy controls. A total of 17.5% of ulcerative colitis and 16.8% of Crohn's disease patients were homozygous for the C677T variant compared with 7.3% of controls. Homozygosity (TT) for the variant was associated with higher plasma tHcy levels in patients with IBD and in healthy controls. When all subjects who were TT for the variant were excluded, median plasma tHcy was still significantly higher in IBD than controls. Plasma vitamin B(12) levels were lower in patients with IBD irrespective of MTHFR genotype. CONCLUSIONS: There is an association between the thermolabile MTHFR C677T variant and IBD. This accounts in part for the raised plasma tHcy found in patients with IBD and may contribute to the increased incidence of thromboembolic complications. All patients with IBD should receive low dose folic acid and vitamin B(12) therapy to protect against the thromboembolic complications of raised tHcy.     

From Coitus to Concurrency: Sexual Partnership Characteristics and Risk Behaviors of 15–19 Year Old Men Recruited from Urban Venues in Tanzania

Understanding the uptake and patterns of sexual partnerships of adolescent males reveals their risky behaviors that could persist into adulthood. Using venue-based sampling, we surveyed 671 male youth ages 15–19 from an urban Tanzanian neighborhood about their sexual partnerships during the past 6 months. The proportion of males who had ever had sex increased with age (21 % at age 15; 70 % at age 17; 94 % at age 19), as did the proportion who engaged in concurrency (5 % at age 15; 28 % at age 17; 44 % at age 19). Attendance at ≥2 social venues per day and meeting a sexual partner at a venue was associated with concurrency. Concurrency was associated with alcohol consumption before sex among 18–19 year olds and with not being in school among 15–17 year olds. We find that concurrency becomes normative over male adolescence. Venue-based sampling may reach youth vulnerable to developing risky sexual partnership patterns.     

Standardisation of inactivated influenza vaccines—Learning from history

The single radial immunodiffusion assay has been the accepted method for determining the potency of inactivated influenza vaccines since 1978. The worldwide adoption of this assay for vaccine standardisation was facilitated through collaborative studies that demonstrated a high level of reproducibility and its applicability to the different types of influenza vaccine being produced at that time. Clinical evidence indicated the relevance of SRID as a potency assay. Unique features of the SRID assay are likely responsible for its longevity even as newer technologies for vaccine characterisation have been developed and refined. Nevertheless, there are significant limitations to the SRID assay that indicate the need for improvement, and there has been a substantial amount of work undertaken in recent years to develop and evaluate alternative potency assays, including collaborative studies involving research laboratories, regulatory agencies and vaccine manufacturers. Here, we provide an overview of the history of inactivated influenza vaccine potency testing, the current state of alternative assay development and the some of the major challenges to be overcome before implementation of new assays for potency determination.     

A novel approach for preparation of the antisera reagent for potency determination of inactivated H7N9 influenza vaccines

Background

The potency of inactivated influenza vaccines is determined using a single‐radial immunodiffusion (SRID) assay and requires standardized reagents consisting of a Reference Antigen and an influenza strain‐specific antiserum. Timely availability of reagents is a critical step in influenza vaccine production, and the need for backup approaches for reagent preparation is an important component of pandemic preparedness.

Objectives

When novel H7N9 viruses emerged in China in 2013, candidate inactivated H7N9 influenza vaccines were developed for evaluation in clinical trials, and reagents were needed to measure vaccine potency.

Methods

We previously described an alternative approach for generating strain‐specific potency antisera, utilizing modified vaccinia virus Ankara vectors to produce influenza hemagglutinin (HA)‐containing virus‐like particles (VLPs) for immunization. Vector‐produced HA antigen is not dependent upon the success of the traditional bromelain‐digestion and HA purification.

Results

Antiserum for H7N9 vaccines, produced after immunization of sheep with preparations of bromelain‐HA (br‐HA), was not optimal for the SRID assay, and the supply of antiserum was limited. However, antiserum obtained from sheep boosted with VLPs containing H7 HA greatly improved the ring quality in the SRID assay. Importantly, this antiserum worked well with both egg‐ and cell‐derived antigen and was distributed to vaccine manufacturers.

Conclusions

Utilizing a previously developed approach for preparing vaccine potency antiserum, we have addressed a major bottleneck encountered in preparation of H7N9 vaccine reagents. The combination of br‐HA and mammalian VLPs for sequential immunization represents the first use of an alternative approach for producing an influenza vaccine potency antiserum.     

An overview of the regulation of influenza vaccines in the United States

Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines.     

Cardiovascular Outcomes According to Systolic Blood Pressure in Patients With and Without Diabetes: An ACCOMPLISH Substudy

To evaluate the effects of achieved systolic blood pressure (SBP) during treatment on cardiovascular (CV) outcomes, the authors measured event rates of a composite primary endpoint (CV death or nonfatal myocardial infarction or stroke) at on‐treatment SBPs of ≥140 mm Hg and the 10 mm Hg intervals of <140 mm Hg, <130 mm Hg, and <120 mm Hg in 6459 patients with diabetes (mean age, 67) and 4246 patients without diabetes (mean age, 69) from the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. In the diabetic cohort, the primary endpoint was 49% lower (P<.001) at <140 mm Hg than at ≥140 mm Hg, and the separate components of this endpoint were also significantly reduced. Further SBP reductions did not improve outcomes, and at <120 mm Hg they were no longer different (except for stroke) from ≥140 mm Hg. In contrast, in the nondiabetic cohort, the primary endpoint event rate fell steadily (although not significantly) through the decreasing SBP categories until it was reduced by 45% (P=.0413) at <120 mm Hg. Total stroke rates for both the diabetic (−56%, P=.0120) and nondiabetic (−68%, P=.0067) cohorts were lowest at <120 mm Hg, and adverse renal events (serum creatinine increase ≥50%) were significantly lowest in the range of 130 mm Hg to 139 mm Hg for both cohorts. Diabetic patients (<140 mm Hg or <130 mm Hg) and nondiabetic patients (<120 mm Hg) may require different SBP targets for optimal CV protection, although stroke and renal considerations should also influence the selection of blood pressure targets.

There has been uncertainty regarding optimal blood pressure (BP) targets in patients with hypertension. For several years, guideline publications have recommended a systolic BP (SBP) of below 140 mm Hg for most patients,¹, ², ³ although one recent report asserted—for patients aged 60 years or older—that the available clinical trial evidence best supported a goal of below 150 mm Hg.⁴ Most information on BP targets has come from retrospective analyses of major clinical trials that were not originally designed to prospectively compare the effects of differing achieved SPB on cardiovascular (CV) outcomes. Still, these trials have been reasonably consistent in demonstrating that SBP values <140 mm Hg are associated with lower event rates than values ≥140 mm Hg.⁵, ⁶, ⁷, ⁸ Although interpretation of other hypertension trials⁹, ¹⁰ was thought to justify the less rigorous goal of <150 mm Hg in older people,⁴ this recommendation has been disputed.¹¹, ¹² Recently, two prospective trials have explored a more intensive target in predominantly older high‐risk hypertensive patients, comparing CV event rates in patients randomized to SBP targets of <140 mm Hg or <120 mm Hg. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial¹³ found that there was no greater overall CV benefit at <120 mm Hg than at <140 mm Hg, although stroke rates were significantly lower at the more intensive target.¹² However, the Systolic Prevention Intervention Trial (SPRINT),¹⁴ conducted in high‐risk patients without diabetes, did show lower overall fatal and nonfatal CV event rates in patients treated to <120 mm Hg.The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial¹⁵ was a major outcomes study designed to compare the effects on CV outcomes of differing classes of drugs in both diabetic and nondiabetic hypertensive patients at high CV risk.¹⁴ Using the ACCOMPLISH database, we have previously analyzed the effects of achieving differing levels of SBPs in the full cohort of patients.⁸ We found that, compared with ≥140 mm Hg, achieving <140 mm Hg produced clear CV outcomes benefits, but that there was no further benefit at lower SBP levels, including <120 mm Hg.In the present study, we have further analyzed CV outcomes according to achieved SBP categories, but studied patients with and without diabetes separately to enable a comparison of optimal treatment targets in these two patient groups.