bluuebunny/crossref_metadata_2025 huggingface dataset:
The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children
Authors: Bienczak Andrzej , Cook Adrian , Wiesner Lubbe , Olagunju Adeniyi , Mulenga Veronica , Kityo Cissy , Kekitiinwa Addy , Owen Andrew , Walker A. Sarah , Gibb Diana M. , McIlleron Helen , Burger David , Denti Paolo
Published: March 2016

Aims

Using a model‐based approach, the efavirenz steady‐state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population.

Methods

We modelled the steady‐state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed‐effects modelling. Individual mid‐dose efavirenz concentrations were derived and simulations explored genotype‐based dose optimization strategies.

Results

A two‐compartment model with absorption through transit compartments well described 2086 concentration‐time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC. The corresponding estimated clearance rates were 6.94, 4.90, 3.93, 1.92, 1.36, and 0.74 l h−1 for a 15.4 kg child and median (95% CI) observed mid‐dose concentrations 1.55 (0.51–2.94), 2.20 (0.97–4.40), 2.03 (1.19–4.53), 7.55 (2.40–14.74), 7.79 (3.66–24.59) and 18.22 (11.84–22.76) mg l−1, respectively. Simulations showed that wild‐type individuals had exposures at the bottom of therapeutic range, while slower metabolizers were overexposed.

Conclusions

Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C.
Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug‐induced liver injury case–control study in Italy
Authors: Donati Monia , Conforti Anita , Lenti Maria Carmela , Capuano Annalisa , Bortolami Oscar , Motola Domenico , Moretti Ugo , Vannacci Alfredo , Rafaniello Concetta , Vaccheri Alberto , Arzenton Elena , Bonaiuti Roberto , Sportiello Liberata , Leone Roberto ,   on behalf of DILI-IT Study Group
Published: March 2016

Aim

Drug‐induced liver injury is one of the most serious adverse drug reactions and the most frequent reason for restriction of indications or withdrawal of drugs. Some nonsteroidal anti‐inflammatory drugs (NSAIDs) were withdrawn from the market because of serious hepatotoxicity. We estimated the risk of acute and serious liver injury associated with the use of nimesulide and other NSAIDs, with a prevalence of use greater than or equal to 5%.

Methods

This is a multicentre case–control study carried out in nine Italian hospitals from October 2010 to January 2014. Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders not related to chronic conditions, not involving the liver. Adjusted odds ratio (ORs) with 95% confidence interval (CI) were calculated initially with a bivariate and then multivariate analysis.

Results

We included 179 cases matched to 1770 controls. Adjusted OR for acute serious liver injury associated with all NSAIDs was 1.69, 95% CI 1.21–2.37. Thirty cases were exposed to nimesulide (adjusted OR 2.10, 95% CI 1.28–3.47); the risk increased according to the length of exposure (OR > 30 days: 12.55, 95% CI 1.73–90.88) and to higher doses (OR 10.69, 95% CI 4.02–28.44). Risk of hepatotoxicity was increased also for ibuprofen, used both at recommended dosages (OR 1.92, 95% CI 1.13–3.26) and at higher doses (OR 3.73, 95% CI 1.11–12.46) and for ketoprofen ≥ 150 mg (OR 4.65, 95% CI 1.33–10.00).

Conclusion

Among all NSAIDs, nimesulide is associated with the higher risk, ibuprofen and high doses of ketoprofen are also associated with a modestly increased risk of hepatotoxicity.
Impact of patient characteristics on the pharmacokinetics of corifollitropin alfa during controlled ovarian stimulation
Authors: Zandvliet Anthe S. , Prohn Marita , de Greef Rik , van Aarle Frank , McCrary Sisk Christine , Stegmann Barbara J.
Published: March 2016

Aim

The aim of the present study was to characterize the pharmacokinetic profile of corifollitropin alfa and examine the relationships between dose, intrinsic factors [body weight, body mass index (BMI), age and race] and corifollitropin alfa pharmacokinetics.

Methods

Data from five phase II and III clinical trials of corifollitropin alfa were evaluated. All subjects included in the analysis received 60 – 180 μg corifollitropin alfa for controlled ovarian stimulation in a gonadotrophin‐releasing hormone antagonist protocol followed by daily recombinant follicle stimulating hormone (rFSH) from day 8 onwards. Serum corifollitropin alfa levels (across the entire range of treatment) and total follicle stimulating hormone immunoreactivity levels (up to the start of rFSH treatment) were indicators of drug exposure. The analyses were performed using a nonlinear mixed‐effects modelling approach.

Results

A total of 2630 subjects were treated with corifollitropin alfa, and 2557 subjects were evaluable for analysis. Body weight, BMI and race (Asian and Black vs. Caucasian) were significant determinants of corifollitropin alfa exposure. Dose‐normalized corifollitropin alfa exposure was ~89% higher in women with a body weight of 50 kg vs. 90 kg (in subjects with a similar BMI of 24 kg m−2); 14% higher in women with a BMI of 18 kg m−2 vs. 32 kg m−2 (provided they were of similar body weight); and ~15.7% lower in Asian subjects and 13% higher in Black subjects vs. Caucasian subjects.

Conclusions

Body weight was the major determinant of corifollitropin alfa exposure; BMI and race (Asian and Black) were also determinants but to a lesser extent and without associated effects on clinical outcomes. Corifollitropin alfa dose adjustment is indicated, based on body weight but not for BMI or race. These recommendations are consistent with the product label.
Potential Future Pharmacological Treatment of Bladder Dysfunction
Authors: Andersson Karl‐Erik
Published: March 2016

In the last decades, a number of new antimuscarinic drugs have been introduced for treatment of the overactive bladder (OAB), defined symptomatically (OAB syndrome) or urodynamically (detrusor overactivity). Recently, three new drug principles have been approved for clinical use, the β3‐adrenoceptor agonist, mirabegron, the phosphodiesterase‐5 inhibitor, tadalafil and the blocker of afferent and efferent nerves, botulinum toxin. However, new alternatives are continuously being explored. OAB is a filling disorder, and ATP is involved in the generation of afferent impulses. One way of blocking the ATP afferent pathway is through the use of P2X3 receptor antagonists. In animal models, this strategy appears to work very well, but whether it translates effectively to man remains to be established. Evidence suggests that components of the endocannabinoid system are involved in regulation of bladder function. Clinical studies of cannabinoid extracts on LUTS are scarce and essentially restricted to patients with MS, and the results have so far not been convincing. Amplification of endocannabinoid activity by inhibiting their degradation via fatty acid amide hydrolase inhibitors may be an attractive approach, but no clinical experiences in OAB have been reported. Studies of the lower urinary tract have indicated that several transient receptor potential (TRP) channels, including TRPV1, TRPV2, TRPV4, TRPM8 and TRPA1, are expressed in the bladder and may act as sensors of stretch and/or chemical irritation. Animal studies have shown that inhibition of these pathways can be effective for the reduction in bladder activity. However, the roles of these channels for normal function and in pathological states have not been established, and so far adverse effects (hyperthermia) have hampered development of antagonists.
Health Security and Risk Aversion
Authors: Herington Jonathan
Published: March 2016

Health security has become a popular way of justifying efforts to control catastrophic threats to public health. Unfortunately, there has been little analysis of the concept of health security, nor the relationship between health security and other potential aims of public health policy. In this paper I develop an account of health security as an aversion to risky policy options. I explore three reasons for thinking risk avoidance is a distinctly worthwhile aim of public health policy: (i) that security is intrinsically valuable, (ii) that it is necessary for social planning and (iii) that it is an appropriate response to decision‐making in contexts of very limited information. Striking the right balance between securing and maximizing population health thus requires a substantive, and hitherto unrecognized, value judgment. Finally, I critically evaluate the current health security agenda in light of this new account of the concept and its relationship to the other aims of public health policy.
Propensity Score Matching and Subclassification in Observational Studies with Multi-Level Treatments
Authors: Yang Shu , Imbens Guido W. , Cui Zhanglin , Faries Douglas E. , Kadziola Zbigniew
Published: March 2016

In this article, we develop new methods for estimating average treatment effects in observational studies, in settings with more than two treatment levels, assuming unconfoundedness given pretreatment variables. We emphasize propensity score subclassification and matching methods which have been among the most popular methods in the binary treatment literature. Whereas the literature has suggested that these particular propensity-based methods do not naturally extend to the multi-level treatment case, we show, using the concept of weak unconfoundedness and the notion of the generalized propensity score, that adjusting for a scalar function of the pretreatment variables removes all biases associated with observed pretreatment variables. We apply the proposed methods to an analysis of the effect of treatments for fibromyalgia. We also carry out a simulation study to assess the finite sample performance of the methods relative to previously proposed methods.
Amount, Source, and Quality of Support as Predictors of Women's Birth Evaluations
Authors: Simon Richard M. , Johnson Katherine M. , Liddell Jessica
Published: March 2016

Background

This paper examines the separate effects of the perceived amount, source, and quality of support during labor and delivery on women's positive and negative evaluations of their birth experiences.

Methods

Data come from the Listening to Mothers I and II (LTM) surveys (n = 2,765). Women's perception of support was regressed separately onto indices of positive and negative words that women associated with their labor and delivery.

Results

The total number of support sources, type of support person, and quality of support all impacted women's birth evaluations across different regression models, controlling for demographics, birth interventions, and other birth characteristics. Support overall had a greater effect on increasing women's positive evaluations, but was not as protective against negative evaluations. Support from medical and birth professionals (doctors, nurses, doulas) had the greatest effect on women's positive evaluations. Good partner support was complexly related: it was associated with less positive evaluations but also appeared to have a protective effect against negative birth evaluations.

Discussion

Support in childbirth is a complex concept with multiple dimensions that matter for women's birth evaluations. Support from nursing staff, doctors, and doulas is important for enabling positive evaluations while support from partners is more complexly related to women's evaluations. Research on support for laboring women should more extensively address the division of labor between different sources of support.
Trends and Characteristics of United States Out‐of‐Hospital Births 2004–2014: New Information on Risk Status and Access to Care
Authors: MacDorman Marian F. , Declercq Eugene
Published: March 2016

Background

Out‐of‐hospital births are increasing in the United States. Our purpose was to examine trends in out‐of‐hospital births from 2004 to 2014, and to analyze newly available data on risk status and access to care.

Methods

Newly available data from the revised birth certificate for 47 states and Washington, DC, were used to examine out‐of‐hospital births by characteristics and to compare them with hospital births. Trends from 2004 to 2014 were also examined.

Results

Out‐of‐hospital births increased by 72 percent, from 0.87 percent of United States births in 2004 to 1.50 percent in 2014. Compared with mothers who had hospital births, those with out‐of‐hospital births had lower prepregnancy obesity (12.5% vs 25.0%) and smoking (2.8% vs 8.5%) rates, and higher college graduation (39.3% vs 30.0%) and breastfeeding initiation (94.3% vs 80.8%) rates. Among planned home births, 67.1 percent were self‐paid, compared with 31.9 percent of birth center and 3.4 percent of hospital births. Vaginal births after cesarean (VBACs) comprised 4.6 percent of planned home births and 1.6 percent of hospital and birth center births. Sociodemographic and medical risk status of out‐of‐hospital births improved substantially from 2004 to 2014.

Conclusions

Improvements in risk status of out‐of‐hospital births from 2004 to 2014 suggest that appropriate selection of low‐risk women is improving. High rates of self‐pay for the costs of out‐of‐hospital birth suggest serious gaps in insurance coverage, whereas higher‐than‐average rates of VBAC could reflect lack of access to hospital VBACs. Mandating private insurance and Medicaid coverage could substantially improve access to out‐of‐hospital births. Improving access to hospital VBACs might reduce the number of out‐of‐hospital VBACs.
Evaluating a Midwife‐Led Model of Antenatal Care for Women with a Previous Cesarean Section: A Retrospective, Comparative Cohort Study
Authors: White Helen K. , le May Andrée , Cluett Elizabeth R.
Published: March 2016

Background

Research is yet to identify effective and safe interventions to increase the vaginal birth after cesarean (VBAC) rate. This research aimed to compare intended and actual VBAC rates before and after implementation of midwife‐led antenatal care for women with one previous cesarean birth and no other risk factors in a large, tertiary maternity hospital in England.

Methods

This was a retrospective, comparative cohort study. Data were collected from the medical records of women with one previous lower segment cesarean delivery and no other obstetric, medical, or psychological complications who gave birth at the hospital before (2008) and after (2011) the implementation of midwife‐led antenatal care. Chi‐squared analysis was used to calculate the odds ratio, and logistic regression to account for confounders.

Results

Intended and actual VBAC rates were higher in 2011 compared with 2008: 90 percent vs. 77 percent, adjusted odds ratio (aOR) 2.69 (1.48–4.87); and 61 percent vs. 47 percent, aOR 1.79 (1.17–2.75), respectively. Mean rates of unscheduled antenatal care sought via the delivery suite and inpatient admissions were lower in 2011 than 2008. Postnatal maternal and neonatal safety outcomes were similar between the two groups, except mean postnatal length of stay, which was shorter in 2011 compared with 2008 (2.67 vs. 3.15 days).

Conclusions

Implementation of midwife‐led antenatal care for women with one previous cesarean offers a safe and effective alternative to traditional obstetrician‐led antenatal care, and is associated with increased rates of intended and actual VBAC.
Paid Maternity Leave and Breastfeeding Outcomes
Authors: Mirkovic Kelsey R. , Perrine Cria G. , Scanlon Kelley S.
Published: March 2016

Background

Despite the benefits of breastfeeding, rates in the United States are low. Shorter maternity leave is associated with lower initiation and shorter durations of breastfeeding; however, little is known about how paid maternity leave may influence breastfeeding rates.

Methods

We used data from the 2006–2010 U.S. National Survey of Family Growth on the most recent birth to employed women who delivered a child within the previous 5 years. Separate multivariable logistic regression models were used to describe the associations between paid leave duration (0, 1–5, 6–11, ≥ 12 weeks, maternity leave not taken) and three outcomes: 1) breastfeeding initiation, 2) 6‐month duration, and 3) 6‐month duration among initiators.

Results

Twenty‐eight percent of prenatally employed women received no paid leave. Women who received 12 or more weeks of paid leave were more likely to initiate breastfeeding compared to women with no paid leave (87.3% vs 66.7%, adjusted odds ratio [aOR] 2.83 [95% confidence interval {CI} 1.23–6.48]). Similarly, women with 12 or more weeks of paid leave were more likely to breastfeed at 6 months, compared to women with no paid leave (24.9% vs 50.1%, aOR 2.26 [95% CI 1.20–4.26]). Among women who initiated breastfeeding, having received 12 or more weeks' paid leave increased the odds of breastfeeding for 6 or more months; however, the association was not statistically significant in the adjusted model (aOR 1.81 [95% CI 0.93–3.52]).

Conclusions

Employed women who received 12 or more weeks of paid maternity leave were more likely to initiate breastfeeding and be breastfeeding their child at 6 months than those without paid leave.
Survey of Obstetric Care and Cesarean Delivery Rates in Shanghai, China
Authors: Hellerstein Susan , Feldman Sarah , Duan Tao
Published: March 2016

Background

China has one of the highest cesarean delivery rates in the world, with most cesareans done without indication.

Methods

Observation of how perinatal care is delivered in a range of Shanghai hospitals was done to gain insight into the 50 percent cesarean delivery rate. A mixed methods approach combined a descriptive structured survey of obstetric services with standardized interview with obstetricians and qualitative observation of obstetric services in six different Shanghai obstetric facilities.

Results

The volume was extremely high: physicians in public hospitals routinely saw up to 80–120 prenatal patients per day. Frequent prenatal testing substituted for time spent in patient–doctor interactions. Family members were not allowed in delivery wards where women labored alone. Obstetrics services had low levels of nursing support and anesthesia for labor. Physical space favored rapid surgical turnover over longer labor. Physicians reported practical incentives to perform cesarean sections.

Discussion

Cesarean delivery was an efficient way to move patients through the systems observed, given the staffing and physical limitations of the public facilities. Physicians reported that patients and families perceived cesarean delivery as safer. Physicians also reported fear of charges of malpractice, for which they might be found to be financially liable or in physical danger. Societal expectations are high, and in a “one child” society, perception that cesarean section was safer may also have driven cesarean rates. Given the end of the One Child Policy, the preference for cesarean delivery may change.
The change in perceived motor competence and motor task values during elementary school: A longitudinal cohort study
Authors: Noordstar Johannes J. , van der Net Janjaap , Jak Suzanne , Helders Paul J. M. , Jongmans Marian J.
Published: March 2016

Participation in motor activities is essential for social interaction and life satisfaction in children. Self‐perceptions and task values have a central position in why children do or do not participate in (motor) activities. Investigating developmental changes in motor self‐perceptions and motor task values in elementary school children would provide vital information about their participation in motor activities. We therefore examined the change in, and associations between, self‐perceptions and task values of fine motor competence, ball competence, and athletic competence in 292 children from kindergarten to grade 4. We also investigated differences between boys and girls, and between children with motor problems and typically developing children. Results indicated that self‐perceptions and task values are domain specific and differ between boys and girls, but not between children with motor problems and typically developing children. Self‐perceptions were not associated with task values. Educators should address specific self‐perceptions to enhance participation into the corresponding motor activities in children between kindergarten and grade 4, and differences in self‐perceptions and task values between boys and girls should be taken into account.
Children's understanding of the addition/subtraction complement principle
Authors: Torbeyns Joke , Peters Greet , De Smedt Bert , Ghesquière Pol , Verschaffel Lieven
Published: March 2016

Background

In the last decades, children's understanding of mathematical principles has become an important research topic. Different from the commutativity and inversion principles, only few studies have focused on children's understanding of the addition/subtraction complement principle (if a − b = c, then c + b = a), mainly relying on verbal techniques.

Aim

This contribution aimed at deepening our understanding of children's knowledge of the addition/subtraction complement principle, combining verbal and non‐verbal techniques.

Sample

Participants were 67 third and fourth graders (9‐ to 10‐year‐olds).

Methods

Children solved two tasks in which verbal reports as well as accuracy and speed data were collected. These two tasks differed only in the order of the problems and the instructions. In the looking‐back task, children were told that sometimes the preceding problem might help to answer the next problem. In the baseline task, no helpful preceding items were offered. The looking‐back task included 10 trigger–target problem pairs on the complement relation.

Results

Children verbally reported looking back on about 40% of all target problems in the looking‐back task; the target problems were also solved faster and more accurately than in the baseline task. These results suggest that children used their understanding of the complement principle. The verbal and non‐verbal data were highly correlated.

Discussion

This study complements previous work on children's understanding of mathematical principles by highlighting interindividual differences in 9‐ to 10‐year‐olds’ understanding of the complement principle and indicating the potential of combining verbal and non‐verbal techniques to investigate (the acquisition of) this understanding.
Learning English using children's stories in mobile devices
Authors: Cavus Nadire , Ibrahim Dogan
Published: March 2016

The topic of this paper is to describe the development of an interactive application that can be used in teaching English as a second language using children's stories in mobile devices. The aim of this experimental study has been to find out the potential of using the developed interactive mobile application in improving the learning skills such as vocabulary, pronunciation, listening and comprehension of the learners of the English language without the help of a teacher. The novelty of the research in this paper has been the use of a speech recognition engine on the mobile phone to identify spoken words of the learner in an attempt to teach correct pronunciation of words. The learning is interactive and it takes place entirely on a mobile phone. In this experimental study 37 voluntary students have participated. A Pre‐Test and a Post‐Test have been performed to find out the learning abilities of students. The results of the experimental study clearly indicated that English learning skills of young students had higher statistically significant improvements as a result of using the developed application in the experimental group. It can be concluded that the developed mobile application can be used as an educational tool in teaching English as a second language. Young students who may be interested in improving their listening, vocabulary, comprehension and pronunciation skills while learning English as a second language should find this mobile application enjoyable and useful.
Collaborative learning across physical and virtual worlds: Factors supporting and constraining learners in a blended reality environment
Authors: Bower Matt , Lee Mark J. W. , Dalgarno Barney
Published: March 2016

This article presents the outcomes of a pilot study investigating factors that supported and constrained collaborative learning in a blended reality environment. Pre‐service teachers at an Australian university took part in a hybrid tutorial lesson involving a mixture of students who were co‐located in the same face‐to‐face (F2F) classroom along with others who were participating remotely via their avatars in a three‐dimensional virtual world. Video and sound recording equipment captured activity in the classroom, which was streamed live into the virtual world so the remote participants could see and hear their instructor and F2F peers; the in‐world activity was also simultaneously displayed on a projector screen, with the audio broadcast via speakers, for the benefit of the F2F participants. While technical issues constrained communication and learning in some instances, the majority of remote and F2F participants felt the blended reality environment supported effective communication, collaboration and co‐presence. Qualitative analysis of participant evaluations revealed a number of pedagogical, technological and logistical factors that supported and constrained learning. The article concludes with a detailed discussion of present and future implications of blended reality collaborative environments for learning and teaching as well as recommendations for educators looking to design and deliver their own blended reality lessons.
Morbidity and mortality of sickle cell disease patients starting intermittent haemodialysis: a comparative cohort study with non‐ Sickle dialysis patients
Authors: Nielsen Louise , Canouï‐Poitrine Florence , Jais Jean‐Philippe , Dahmane Djamal , Bartolucci Pablo , Bentaarit Bouteina , Gellen‐Dautremer Justine , Remy Philippe , Kofman Tomek , Matignon Marie , Suberbielle Caroline , Jacquelinet Christian , Wagner‐Ballon Orianne , Sahali Dil , Lang Philippe , Damy Thibaud , Galactéros Frédéric , Grimbert Philippe , Habibi Anoosha , Audard Vincent
Published: March 2016

We performed a retrospective study to assess the changes in clinical, biological and heart echocardiographic parameters in 32 sickle cell disease (SCD) patients beginning haemodialysis. Acute SCD‐related complications were similar at 6 months before and 6 months after the initiation of haemodialysis. Median haemoglobin level did not change significantly, but the need for blood transfusions increased (P < 0·001). The 5‐year incidence of death was higher in SCD patients (P < 0·0001). The 5‐year likelihood of receiving a renal graft was lower in SCD patients (P = 0·022). Our findings suggest that SCD patients have poorer survival and a lower likelihood of receiving a renal graft.
Polymer‐delivered subcutaneous leuprolide acetate formulations achieve and maintain castrate concentrations of testosterone in four open‐label studies in patients with advanced prostate cancer
Authors: Shore Neal D. , Chu Franklin , Moul Judd , Saltzstein Daniel , Concepcion Raoul , McLane John A. , Atkinson Stuart , Yang Alex , Crawford E. David
Published: March 2016

Objective

To determine whether luteinising hormone‐releasing hormone (LHRH) agonist, ATRIGEL® polymer‐delivered, subcutaneous, leuprolide acetate (ADSC‐LA), formulations suppressed serum testosterone to concentrations of ≤20 ng/dL.

Patients and Methods

Data from four open‐label, fixed‐dose studies were evaluated. Male patients aged 40–86 years with advanced prostatic adenocarcinoma, whom had not undergone prior androgen‐deprivation therapy (ADT), were treated with a depot formulation of ADSC‐LA: 7.5 mg (1‐month, 120 patients), 22.5 mg (3‐month, 117 patients), 30 mg (4‐month, 90 patients), or 45 mg (6‐month, 111 patients). Serum testosterone was sampled at screening, baseline, 2, 4, 8 h after dosing, 1, 2, 3, and 7 days, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (24 weeks for 1‐ and 3‐month formulations, 32 weeks for 4‐month, and 48 weeks for the 6‐month). The primary analyses were mean serum testosterone concentrations and proportion of patients who achieved concentrations of ≤20 ng/dL.

Results

The mean (SE) serum testosterone concentrations at the end of study were consistently ≤20 ng/dL in each study, at 6.1 (0.4), 10.1 (0.7), 12.4 (0.8), and 12.6 (2.1) ng/dL for the 1‐, 3‐, 4‐, and 6‐month formulations, respectively. A high proportion of patients (94%, 90%, 92%, 96% for the 1‐, 3‐, 4‐, and 6‐month formulations, respectively) achieved testosterone concentrations of ≤20 ng/dL within 6 weeks, and 90–97% of patients in all studies maintained concentrations of ≤20 ng/dL from weeks 6–24.

Conclusions

Recent studies have shown improved outcomes in patients with prostate cancer who consistently attained a more rigorous level of testosterone suppression (≤20 ng/dL) with ADT than the historical standard (≤50 ng/dL). All doses of ADSC‐LA rapidly achieved and maintained mean serum testosterone to the more rigorous target concentration of ≤20 ng/dL. These data suggest that ADSC‐LA delivers equivalent testosterone suppression as achieved by surgical castration.
Co‐introduction of a steroid with docetaxel chemotherapy for metastatic castration‐resistant prostate cancer affects PSA flare
Authors: Shiota Masaki , Yokomizo Akira , Takeuchi Ario , Kiyoshima Keijiro , Inokuchi Junichi , Tatsugami Katsunori , Shiga Ken‐ichiro , Koga Hirofumi , Yamaguchi Akito , Naito Seiji , Eto Masatoshi
Published: March 2016

Objective

To investigate the potential relationship of steroid usage with prostate‐specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10–20% of patients with metastatic castration‐resistant prostate cancer during docetaxel chemotherapy.

Patients and Methods

This study included 71 patients with metastatic castration‐resistant prostate cancer treated by docetaxel chemotherapy with co‐introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease.

Results

PSA flare was recognized in 7.0–23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression‐free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure.

Conclusions

Our results suggest that de novo steroid co‐introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure.
New aspects of p66Shc in ischaemia reperfusion injury and other cardiovascular diseases
Authors: Di Lisa Fabio , Giorgio Marco , Ferdinandy Peter , Schulz Rainer
Published: March 2016

Although reactive oxygen species (ROS) act as crucial factors in the onset and progression of a wide array of diseases, they are also involved in numerous signalling pathways related to cell metabolism, growth and survival. ROS are produced at various cellular sites, and it is generally agreed that mitochondria generate the largest amount, especially those in cardiomyocytes. However, the identification of the most relevant sites within mitochondria, the interaction among the various sources, and the events responsible for the increase in ROS formation under pathological conditions are still highly debated, and far from being clarified. Here, we review the information linking the adaptor protein p66Shc with cardiac injury induced by ischaemia and reperfusion (I/R), including the contribution of risk factors, such as metabolic syndrome and ageing. In response to several stimuli, p66Shc migrates into mitochondria where it catalyses electron transfer from cytochrome c to oxygen resulting in hydrogen peroxide formation. Deletion of p66Shc has been shown to reduce I/R injury as well as vascular abnormalities associated with diabetes and ageing. However, p66Shc‐induced ROS formation is also involved in insulin signalling and might contribute to self‐endogenous defenses against mild I/R injury. In addition to its role in physiological and pathological conditions, we discuss compounds and conditions that can modulate the expression and activity of p66Shc.

Linked Articles

This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc
Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats
Authors: Youcef G , Olivier A , Nicot N , Muller A , Deng C , Labat C , Fay R , Rodriguez‐Guéant R‐M , Leroy C , Jaisser F , Zannad F , Lacolley P , Vallar L , Pizard A
Published: March 2016

Background and Purpose

Mineralocorticoid receptor (MR) activation contributes to heart failure (HF) progression. Its overactivity in obesity is thought to accelerate cardiac remodelling and HF development. Given that MR antagonists (MRA) are beneficial in chronic HF patients, we hypothesized that early MRA treatment may target obesity‐related disorders and consequently delay the development of HF.

Experimental Approach

Twenty spontaneously hypertensive HF dyslipidaemic obese SHHFcp/cp rats and 18 non‐dyslipidaemic lean SHHF+/+ controls underwent regular monitoring for their metabolic and cardiovascular phenotypes with or without MRA treatment [eplerenone (eple), 100 mg∙kg−1∙day−1] from 1.5 to 12.5 months of age.

Key Results

Eleven months of eple treatment in obese rats (SHHFcp/cpeple) reduced the obesity‐related metabolic disorders observed in untreated SHHFcp/cp rats by reducing weight gain, triglycerides and total cholesterol levels and by preserving adiponectinaemia. The MRA treatment predominantly preserved diastolic and systolic functions in obese rats by alleviating the eccentric cardiac hypertrophy observed in untreated SHHFcp/cp animals and preserving ejection fraction (70 ± 1 vs. 59 ± 1%). The MRA also improved survival independently of these pressure effects.

Conclusion and Implications

Early chronic eple treatment resulted in a delay in cardiac remodelling and HF onset in both SHHF+/+ and SHHFcp/cp rats, whereas SHHFcp/cp rats further benefited from the MRA treatment through a reduction in their obesity and dyslipidaemia. These findings suggest that preventive MRA therapy may provide greater benefits in obese patients with additional risk factors of developing cardiovascular complications.
When is bigger better? The effects of group size on the evolution of helping behaviours
Authors: Powers Simon T. , Lehmann Laurent
Published: March 2016

Understanding the evolution of sociality in humans and other species requires understanding how selection on social behaviour varies with group size. However, the effects of group size are frequently obscured in the theoretical literature, which often makes assumptions that are at odds with empirical findings. In particular, mechanisms are suggested as supporting large‐scale cooperation when they would in fact rapidly become ineffective with increasing group size. Here we review the literature on the evolution of helping behaviours (cooperation and altruism), and frame it using a simple synthetic model that allows us to delineate how the three main components of the selection pressure on helping must vary with increasing group size. The first component is the marginal benefit of helping to group members, which determines both direct fitness benefits to the actor and indirect fitness benefits to recipients. While this is often assumed to be independent of group size, marginal benefits are in practice likely to be maximal at intermediate group sizes for many types of collective action problems, and will eventually become very small in large groups due to the law of decreasing marginal returns. The second component is the response of social partners on the past play of an actor, which underlies conditional behaviour under repeated social interactions. We argue that under realistic conditions on the transmission of information in a population, this response on past play decreases rapidly with increasing group size so that reciprocity alone (whether direct, indirect, or generalised) cannot sustain cooperation in very large groups. The final component is the relatedness between actor and recipient, which, according to the rules of inheritance, again decreases rapidly with increasing group size. These results explain why helping behaviours in very large social groups are limited to cases where the number of reproducing individuals is small, as in social insects, or where there are social institutions that can promote (possibly through sanctioning) large‐scale cooperation, as in human societies. Finally, we discuss how individually devised institutions can foster the transition from small‐scale to large‐scale cooperative groups in human evolution.
Social structure and indirect genetic effects: genetics of social behaviour
Authors: Schneider Jonathan , Atallah Jade , Levine Joel D.
Published: March 2016

The social environment modulates gene expression, physiology, behaviour and patterns of inheritance. For more than 50 years, this concept has been investigated using approaches that include partitioning the social component out of behavioural heritability estimates, studying maternal effects on offspring, and analysing dominance hierarchies. Recent advances have formalized this ‘social environment effect’ by providing a more nuanced approach to the study of social influences on behaviour while recognizing evolutionary implications. Yet, in most of these formulations, the dynamics of social interactions are not accounted for. Also, the reciprocity between individual behaviour and group‐level interactions has been largely ignored. Consistent with evolutionary theory, the principles of social interaction are conserved across a broad range of taxa. While noting parallels in diverse organisms, this review uses Drosophila melanogaster as a case study to revisit what is known about social interaction paradigms. We highlight the benefits of integrating the history and pattern of interactions among individuals for dissecting molecular mechanisms that underlie social modulation of behaviour.
When Project Management Meets Design Theory: Revisiting the Manhattan and Polaris Projects to Characterize ‘Radical Innovation’ and its Managerial Implications
Authors: Lenfle Sylvain , Le Masson Pascal , Weil Benoit
Published: March 2016

In this paper we propose to revisit two emblematic projects, Manhattan and Polaris, with the models developed by design theory. In particular we demonstrate, relying on C/K theory, how these major projects, traditionally presented as radical innovations, are in fact quite different. In particular we show that the structure of the knowledge base (splitting or non‐splitting) has major consequences. This explains the different managerial strategies of this two cases : whereas Polaris focuses on the control of the design process, Manhattan exhibit a very original strategy, characterized by the simultaneous exploration of different solutions, to manage unforeseeable uncertainties. We discuss the implications of this result for design theory and project management.
Design Contribution to the Competitive Performance of SMEs: The Role of Design Innovation Capabilities
Authors: Landoni Paolo , Dell'Era Claudio , Ferraloro Gregorio , Peradotto Mattia , Karlsson Helena , Verganti Roberto
Published: March 2016

The strategic role of design‐driven innovation is being increasingly recognized. Many studies show that investments in design positively influence the innovative capacity of firms and consequently their competitive performance. However, few researchers have explored how this relationship comes about. The studies that over the years have contributed to the understanding of design have identified two main barriers: the lack of a common language on design, and poor analysis of the dynamics that characterize the relationship between investment in design and competitive performance. In this paper, we investigate six small and medium‐sized enterprises (SMEs) located in the Lombardy region of Italy that have received funding from a policy aimed to develop design innovation capabilities. We identify and discuss five different design innovation capabilities and we analyse their role in mediating the relationship between investment in design and competitive performance.
Prognostic significance of CD169‐positive lymph node sinus macrophages in patients with endometrial carcinoma
Authors: Ohnishi Koji , Yamaguchi Munekage , Erdenebaatar Chimeddulam , Saito Fumitaka , Tashiro Hironori , Katabuchi Hidetaka , Takeya Motohiro , Komohara Yoshihiro
Published: March 2016

Lymph node (LN) macrophages play critical roles in anti‐tumor immunity, which develops via the activation of cytotoxic T cells (CTL) and NK cells. The present study aims to determine the prognostic significance of CD169+ LN macrophages in patients with endometrial carcinoma (EC). The number of CD169+ cells or the CD169+‐to‐CD68+ macrophage ratio in regional LN (RLN), and the number of CD8+ CTL or CD57+ NK cells in tumor tissues were investigated by immunohistochemistry in paraffin‐embedded tissue samples from 79 patients with EC. A high density of CD169+ cells in the RLN of patients with EC was correlated with an early clinical stage or no LN metastasis. A high number of CD169+ cells and a high CD169+‐to‐CD68+ macrophage ratio were significantly associated with longer overall survival in EC. We also found that the density of CD169+ macrophages was positively correlated with the number of CD8+ CTL and CD57+ NK cells that infiltrated into tumor tissues. A high density of CD57+ cells in EC tissues was associated with a better prognosis, while a high density of CD8+ cells was not linked to an altered prognosis. The present study showed that the density of CD169+ macrophages in RLN was associated with an improved prognosis in EC patients. CD169+ macrophages in RLN might represent a useful marker for assessing clinical prognoses and monitoring anti‐tumor immunity in patients with EC.
Phase I study of palbociclib, a cyclin‐dependent kinase 4/6 inhibitor, in Japanese patients
Authors: Tamura Kenji , Mukai Hirofumi , Naito Yoichi , Yonemori Kan , Kodaira Makoto , Tanabe Yuko , Yamamoto Noboru , Osera Shozo , Sasaki Masaoki , Mori Yuko , Hashigaki Satoshi , Nagasawa Takashi , Umeyama Yoshiko , Yoshino Takayuki
Published: March 2016

This phase I study in Japanese patients evaluated the safety, pharmacokinetics, and preliminary efficacy of palbociclib, a highly selective and reversible oral cyclin‐dependent kinase 4/6 inhibitor, as monotherapy for solid tumors (part 1) and combined with letrozole as first‐line treatment of postmenopausal patients with estrogen receptor‐positive, human epidermal growth factor receptor 2‐negative advanced breast cancer (part 2). Part 1 evaluated palbociclib 100 and 125 mg once daily (3 weeks on/1 week off; n = 6 each group) to determine the maximum tolerated dose. Part 2 evaluated palbociclib maximum tolerated dose (125 mg) plus letrozole 2.5 mg (n = 6). The most common treatment‐related adverse event was neutropenia (all grades/grade 3/4): 100 mg, 83%/67%; 125 mg, 67%/33%; and palbociclib plus letrozole, 100%/83%. Heavier pretreatment with chemotherapy may have resulted in higher neutropenia rates observed with the 100‐mg dose. Palbociclib exposure was higher with 125 vs 100 mg (mean area under the plasma concentration–time curve over dosing interval [τ]: 1322 vs 547.5 ng·h/mL [single dose], 2838 vs 1276 ng·h/mL [multiple dose]; mean maximum plasma concentration: 104.1 vs 41.4 ng/mL [single dose], 185.5 vs 77.4 ng/mL [multiple dose]). Half‐life was 23–26 h. No drug–drug interactions between palbociclib and letrozole occurred. Four patients had stable disease (≥24 weeks in one patient with rectal cancer [100 mg] and one with esophageal cancer [125 mg]) in part 1; two patients had partial response and two had stable disease (both ≥24 weeks) in part 2. Palbociclib at the 125‐mg dose (schedule 3/1) was tolerated and is the recommended dose for monotherapy and letrozole combination therapy in Japanese patients. The trials are registered with www.ClinicalTrials.gov: A5481010 and NCT01684215.
Bioassay‐Guided Isolation and Structural Modification of the Anti‐TB Resorcinols from Ardisia gigantifolia
Authors: Guan Yi‐Fu , Song Xun , Qiu Ming‐Hua , Luo Shi‐Hong , Wang Bao‐Jie , Van Hung Nguyen , Cuong Nguyen M. , Soejarto Djaja Doel , Fong Harry H.S. , Franzblau Scott G. , Li Sheng‐Hong , He Zhen‐Dan , Zhang Hong‐Jie
Published: March 2016

Tuberculosis (TB) is a highly contagious disease mainly caused by Mycobacterium tuberculosis H37RV. Antitubercular (anti‐TB) bioassay‐guided isolation of the CHCl3 extract of the leaves and stems of the medicinal plant Ardisia gigantifolia led to the isolation of two anti‐TB 5‐alkylresorcinols, 5‐(8Z‐heptadecenyl) resorcinol (1) and 5‐(8Z‐pentadecenyl) resorcinol (2). We further synthesized 15 derivatives based on these two natural products. These compounds (natural and synthetic) were evaluated for their anti‐TB activity against Mycobacterium tuberculosis H37RV. Resorcinols 1 and 2 exhibited anti‐TB activity with MIC values at 34.4 and 79.2 μm in MABA assay, respectively, and 91.7 and 168.3 μm in LORA assay, respectively. Among these derivatives, compound 8 was found to show improved anti‐TB activity than its synthetic precursor (2) with MIC values at 42.0 μm in MABA assay and 100.2 μm in LORA assay. The active compounds should be regarded as new hits for further study as a novel class of anti‐TB agents. The distinct structure–activity correlations of the parent compound were elucidated based on these derivatives.
Neonatal respiratory syncytial virus infection has an effect on lung inflammation and the CD4+CD25+ T cell subpopulation during ovalbumin sensitization in adult mice
Authors: Comas-García A , López-Pacheco C P , García-Zepeda E A , Soldevila G , Ramos-Martínez P , Ramos-Castañeda J
Published: March 2016

In BALB/c adult mice, respiratory syncytial virus (RSV) infection enhances the degree of lung inflammation before and/or after ovalbumin (OVA) respiratory sensitization. However, it is unclear whether RSV infection in newborn mice has an effect on the immune response to OVA respiratory sensitization in adult mice. The aim of this study was to determine if RSV neonatal infection alters T CD4+ population and lung inflammation during OVA respiratory sensitization in adult mice. BALB/c mice were infected with RSV on the fourth day of life and challenged by OVA 4 weeks later. We found that in adult mice, RSV neonatal infection prior to OVA sensitization reduces the CD4+CD25+ and CD4+CD25+ forkhead protein 3 (FoxP3)+ cell populations in the lungs and bronchoalveolar lavage. Furthermore, it also attenuates the inflammatory infiltrate and cytokine/chemokine expression levels in the mouse airways. In conclusion, the magnitude of the immune response to a non-viral respiratory perturbation in adult mice is not enhanced by a neonatal RSV infection.