19F-NMR-based determination of the absorption,metabolism and excretion of the oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor leniolisib (CDZ173) in healthy volunteers

1. Leniolisib is a novel oral phosphatidylinositol-3-kinase (PI3K) delta inhibitor, currently in clinical development for the treatment of inflammatory and autoimmune diseases.

2. We investigated the absorption, metabolism, and excretion of leniolisib in healthy subjects after a single oral 400?mg dose as part of a first-in-human clinical study. The parent drug and metabolites were quantified by ¹⁹F-NMR in plasma, urine and faeces after liquid chromatography separation, and structures were determined by liquid chromatography coupled to tandem mass spectrometry.

3. Drug-related material was mainly excreted as oxidative metabolites in urine and faeces, providing evidence that elimination occurs mainly by metabolism. No metabolites were abundant in plasma relative to the parent drug. An average mass balance of 66% was obtained, demonstrating that relatively extensive elimination/excretion data can be obtained by ¹⁹F-NMR in a first in human clinical study without the use of a radiolabeled drug.     

Association between serum trans-monounsaturated fatty acids and breast cancer risk in the E3N-EPIC Study

The authors assessed the association between serum phospholipid fatty acids as biomarkers of fatty acid intake and breast cancer risk among women in the E3N Study (1989-2002), the French component of the European Prospective Investigation into Cancer and Nutrition. During an average of 7 years of follow-up, 363 cases of incident invasive breast cancer were documented among 19,934 women who, at baseline (1995-1998), had completed a diet history questionnaire and provided serum samples. Controls were randomly matched to cases by age, menopausal status at blood collection, fasting status at blood collection, date, and collection center. Serum phospholipid fatty acid composition was assessed by gas chromatography. Adjusted odds ratios for risk of breast cancer with increasing levels of fatty acids were calculated using conditional logistic regression. An increased risk of breast cancer was associated with increasing levels of the trans-monounsaturated fatty acids palmitoleic acid and elaidic acid (highest quintile vs. lowest: odds ratio = 1.75, 95% confidence interval: 1.08, 2.83; p-trend = 0.018). cis-Monounsaturated fatty acids were unrelated to breast cancer risk. A high serum level of trans-monounsaturated fatty acids, presumably reflecting a high intake of industrially processed foods, is probably one factor contributing to increased risk of invasive breast cancer in women.     

Induction of antibody response against hepatitis E virus (HEV) with recombinant human papillomavirus pseudoviruses expressing truncated HEV capsid proteins in mice

A hepatitis E virus (HEV) vaccine would be valuable to reduce the morbidity and mortality associated with the infection in endemic areas. HEV pseudocapsids and epidermal delivery of HEV ORF2 DNA vaccine by gene-gun have been shown to confer protection against virus challenge in monkeys. Vectorization of a DNA vaccine by virus-like particles is a new immunization approach. We report here the successful immunization of mice with two ORF2 genes encapsidated into human papillomavirus type 31 virus-like particles. The HEV genes ORF2(112-660) and ORF2(112-608) were optimized for expression in mammalian cells and inserted in a baculovirus-derived vector for expression in insect cells. When expressed in Sf21 insect cells, ORF2(112-660) led to the production of irregular 15 nm particles that accumulated in the cytoplasm of the cells, whereas ORF2(112-608) induced the production of 18nm particles that were present in both the cell culture medium and the cell cytoplasm. Anti-HEV immune responses were higher for the 15 nm particles (HEV112-660) than that for to the 18 nm particles (HEV112-608). Delivery into mice of two HEV ORF2 genes via a papillomavirus VLP was very effective in the induction of anti-HEV antibodies. In addition, an effective immune response to human papillomavirus capsids occurred. These engineered pseudoviruses were thus demonstrated to induce immune responses to both hepatitis E virus and human papillomavirus when they were administered to mice intramuscularly.     

Eave Screening and Push-Pull Tactics to Reduce House Entry by Vectors of Malaria

Long-lasting insecticidal nets and indoor residual spraying have contributed to a decline in malaria over the last decade, but progress is threatened by the development of physiological and behavioral resistance of mosquitoes against insecticides. Acknowledging the need for alternative vector control tools, we quantified the effects of eave screening in combination with a push-pull system based on the simultaneous use of a repellent (push) and attractant-baited traps (pull). Field experiments in western Kenya showed that eave screening, whether used in combination with an attractant-baited trap or not, was highly effective in reducing house entry by malaria mosquitoes. The magnitude of the effect varied for different mosquito species and between two experiments, but the reduction in house entry was always considerable (between 61% and 99%). The use of outdoor, attractant-baited traps alone did not have a significant impact on mosquito house entry but the high number of mosquitoes trapped outdoors indicates that attractant-baited traps could be used for removal trapping, which would enhance outdoor as well as indoor protection against mosquito bites. As eave screening was effective by itself, addition of a repellent was of limited value. Nevertheless, repellents may play a role in reducing outdoor malaria transmission in the peridomestic area.     

A comparative population‐based analysis of the rate of partial vs radical nephrectomy for clinically localized renal cell carcinoma

Study Type – Prevalence (prospective cohort with good follow up)Level of Evidence 1a

OBJECTIVE

To examine contemporary (1989–2004) trends in partial nephrectomy (PN) within the Surveillance, Epidemiology and End Results (SEER) database, as among other considerations, a survival benefit due to avoidance of surgically induced renal insufficiency distinguishes PN from radical nephrectomy (RN).

PATIENTS AND METHODS

Diagnostic, stage and surgical codes of patients with T1‐2N0M0 renal cell carcinoma treated with either PN or RN were assessed. Proportions, trends and multivariable logistic regression models tested the predictors of the use of PN.

RESULTS

Of 19 733 assessable patients, 2614 (13.2%) and 17 119 (86.8%), respectively, had PN or RN. The use of PN decreased with increasing tumour size, was more frequent in younger patients and increased with more contemporary years of surgery (all P < 0.001). Intriguingly, there was important geographical variability (P < 0.001), e.g. in the San Francisco‐Oakland Metropolitan Area the absolute PN rate was 16.4%, vs 7.6% in New Mexico (P < 0.001). In multivariable analyses, tumour size, age, year of surgery, gender and SEER registries were independent predictors of PN use.

CONCLUSION

Although as expected the rate of PN use increased over time, unexplained variability remained. For example, gender and SEER registries affected the likelihood of PN. These variables warrant further analyses to reduce unnecessary variability and to maximize PN use and its benefit.     

Assessment of typical SpA lesions on MRI of the spine: do local readers and central readers agree in the DESIR-cohort at baseline?

Comparing local reading (LocR) with central reading (CentR) of typical spondyloarhritis lesions including bone marrow edema (BME) and structural lesions on magnetic resonance imaging of the spine (MRI-spine), in patients with inflammatory back pain (IBP; ≥3 months, <3 years). Baseline data of 667 patients, age 18–50 years, from the Devenir des Spondylarthopathies Indifferenciees Recentes (DESIR)-cohort were used. Two trained central readers scored anterior and posterior corner BME, fatty lesions, erosions and syndesmophytes on MRI-spine. Presences of lesions, based on average scores, were used for CentR. A local radiologist and/or rheumatologist scored MRI-spine on presence/doubt/absence of ‘inflammation’ and ‘structural lesions’. 相似文献   

On the prevalence of constipation and fecal incontinence,and their co-occurrence,in the Netherlands

Purpose

Numerous studies have investigated the prevalence of constipation and fecal incontinence (FI) in the general population and, even though these disorders are known to co-occur, they were studied independently of each other. Our aim was to investigate the prevalence of constipation and FI, and their co-occurrence, in the general population in the Netherlands.

Methods

We studied a cross-section of the Dutch population (N = 1259). All respondents completed the Groningen Defecation & Fecal Continence checklist. We defined constipation and FI in accordance with the Rome III criteria.

Results

We found that 24.5% (95% CI, 22.1–26.8) suffered from constipation, 7.9% (95% CI, 6.4–9.4) suffered from FI, and 3.5% (95% CI, 2.5–4.5) suffered from both disorders. Constipated respondents were 2.7 times more likely to suffer from FI than non-constipated respondents (95% CI, 1.8–4.0). Moreover, 48.7% of the respondents with constipation, 35.0% with FI, and 38.6% in whom the disorders co-occurred qualified their bowel habits as either “good” or “very good”. We found that 49.4% of the respondents with constipation and 48.0% with FI had not discussed their complaints with anyone.

Conclusions

Constipation and FI, isolated or co-occurring, are common disorders in the general population, even in young and healthy respondents. Since constipation and FI often co-occur, we recommend that patients who seek medical attention for either disorder should be examined for both. Moreover, constipation and/or FI are not always identified appropriately by patients. Therefore, physicians should take the initiative to diagnose and treat these disorders.

     

Circulating concentration of infliximab and response to treatment in ankylosing spondylitis: Results from a randomized control study

Objective

A minority of patients with ankylosing spondylitis (AS) fail to respond to infliximab treatment. This study compared the circulating infliximab concentration and the presence of clinical symptoms in patients continuously treated with infliximab or after treatment interruption.

Methods

Patients with active AS were randomly assigned at week 0 to receive infliximab either at weeks 4, 6, 10, and then every 6 weeks (continuous treatment), or at weeks 4, 6, and 10 and then upon symptom recurrence (on‐demand treatment). The circulating concentration of infliximab was determined early during treatment and at weeks 46 and 52 for the continuous treatment group or upon relapse for the on‐demand group. Response in the continuous treatment group was defined at week 58 using the ASsessment in AS International Working Group Criteria for 20% improvement.

Results

Among the 93 patients in the continuous treatment group, treatment failure was not associated with a low circulating concentration of infliximab, either during early treatment or at 1 year. Eleven (39.2%) of the 28 nonresponders had an infliximab concentration of >10 μg/ml at week 52, whereas 9 (13.8%) of the 65 responders had an infliximab concentration of <1 μg/ml. In the on‐demand group, the infliximab concentration at relapse closely correlated with the time to relapse. However, 24 (36.9%) of 65 patients had a resurgence of clinical symptoms at an infliximab concentration of >10 μg/ml, whereas 25 patients (38.4%) had a relapse at an infliximab concentration of <0.5 μg/ml.

Conclusion

Responsiveness to infliximab treatment is highly heterogeneous among individuals with AS, and this parameter overcomes the circulating infliximab concentration to explain treatment success or failure.