Spectral analysis of boundary layers in Rayleigh-Benard convection

A combined experimental and numerical study of the boundary layer in a 4:1 aspect-ratio Rayleigh-B\'{e}nard cell over a four-decade range of Rayleigh numbers has been undertaken aimed at gaining a better insight into the character of the boundary layers. The experiments involved the simultaneous Laser Doppler Anemometry (LDA) measurements of fluid velocity at two locations, i.e. in the boundary layer and far away from it in the bulk, for Rayleigh numbers varying between $1.6 \times 10^7$ and $2.4 \times 10^9$. In parallel, direct numerical simulations (DNS) have been performed for the same configuration for Rayleigh numbers between $7.0 \times 10^4$ and $7.7 \times 10^7$. The temperature and velocity probability density functions and the power spectra of the horizontal velocity fluctuations measured in the boundary layer and in the bulk flow are found to be practically identical. Except for the smallest Rayleigh numbers, the spectra in the boundary layer and in the bulk central region are continuous and have a wide range of active scales. This indicates that both the bulk and the boundary layers are turbulent in the $\textrm{Ra}$ number range considered. However, molecular effects can still be observed and the boundary layer does not behave like a classical shear-driven turbulent boundary layer.Comment: 10 pages, 6 figures, Accepted for publication in Phys. Rev.

Both resistance- and endurance-type exercise reduce the prevalence of hyperglycaemia in individuals with impaired glucose tolerance and in insulin-treated and non-insulin-treated type 2 diabetic patients

Aims/hypothesis The present study compares the impact of endurance- vs resistance-type exercise on subsequent 24 h blood glucose homeostasis in individuals with impaired glucose tolerance (IGT) and type 2 diabetes. Methods Fifteen individuals with IGT, 15 type 2 diabetic patients treated with exogenous insulin (INS), and 15 type 2 diabetic patients treated with oral glucose-lowering medication (OGLM) participated in a randomised crossover experiment. Participants were studied on three occasions for 3 days under strict dietary standardisation, but otherwise free-living conditions. Blood glucose homeostasis was assessed by ambulatory continuous glucose monitoring over the 24 h period following a 45 min session of resistance-type exercise (75% one repetition maximum), endurance-type exercise (50% maximum workload capacity) or no exercise at all. Results Average 24 h blood glucose concentrations were reduced from 7.4±0.2, 9.6±0.5 and 9.2±0.7 mmol/l during the control experiment to 6.9±0.2, 8.6±0.4 and 8.1±0.5 mmol/l (resistance-type exercise) and 6.8±0.2, 8.6±0.5 and 8.5±0.5 mmol/l (endurance-type exercise) over the 24 h period following a single bout of exercise in the IGT, OGLM and INS groups, respectively (p 10 mmol/l) was reduced by 35±7 and 33±11% over the 24 h period following a single session of resistanceand endurance-type exercise, respectively (p< 0.001 for both treatments). Conclusions/interpretation A single session of resistanceor endurance-type exercise substantially reduces the prevalence of hyperglycaemia during the subsequent 24 h period in individuals with IGT, and in insulin-treated and non-insulin-treated type 2 diabetic patients. Both resistance- and endurance-type exercise can be integrated in exercise intervention programmes designed to improve glycaemic control. Trial registration: Clinicaltrials.gov NCT00945165 Funding: The Netherlands Organization for Health Research and Development (ZonMw, the Netherlands). © 2011 The Author(s)

Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy.

BACKGROUND: Immunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described. METHODS: We used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells. RESULTS: Our study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth. CONCLUSIONS: Our results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy

Linked Pharmacometric-Pharmacoeconomic Modeling and Simulation in Clinical Drug Development

Market access and pricing of pharmaceuticals are increasingly contingent on the ability to demonstrate comparative effectiveness and cost-effectiveness. As such, it is widely recognized that predictions of the economic potential of drug candidates in development could inform decisions across the product life cycle. This may be challenging when safety and efficacy profiles in terms of the relevant clinical outcomes are unknown or highly uncertain early in product development. Linking pharmacometrics and pharmacoeconomics, such that outputs from pharmacometric models serve as inputs to pharmacoeconomic models, may provide a framework for extrapolating from early-phase studies to predict economic outcomes and characterize decision uncertainty. This article reviews the published studies that have implemented this methodology and used simulation to inform drug development decisions and/or to optimize the use of drug treatments. Some of the key practical issues involved in linking pharmacometrics and pharmacoeconomics, including the choice of final outcome measures, methods of incorporating evidence on comparator treatments, approaches to handling multiple intermediate end points, approaches to quantifying uncertainty, and issues of model validation are also discussed. Finally, we have considered the potential barriers that may have limited the adoption of this methodology and suggest that closer alignment between the disciplines of clinical pharmacology, pharmacometrics, and pharmacoeconomics, may help to realize the potential benefits associated with linked pharmacometric-pharmacoeconomic modeling and simulation

ESUR/ESUI consensus statements on multi-parametric MRI for the detection of clinically significant prostate cancer: quality requirements for image acquisition, interpretation and radiologists’ training

Objectives: This study aims to define consensus-based criteria for acquiring and reporting prostate MRI and establishing prerequisites for image quality. Methods: A total of 44 leading urologists and urogenital radiologists who are experts in prostate cancer imaging from the European Society of Urogenital Radiology (ESUR) and EAU Section of Urologic Imaging (ESUI) participated in a Delphi consensus process. Panellists completed two rounds of questionnaires with 55 items under three headings: image quality assessment, interpretation and reporting, and radiologists’ experience plus training centres. Of 55 questions, 31 were rated for agreement on a 9-point scale, and 24 were multiple-choice or open. For agreement items, there was consensus agreement with an agreement ≥ 70% (score 7–9) and disa

Doctors' alertness, contentedness and calmness before and after night shifts: a latent profile analysis

Background While night shifts are crucial for patient care, they threaten doctors’ well-being and performance. Knowledge of how the impact of night shifts differs for doctors is needed to attenuate the adverse effects of night shifts. This study aimed to obtain more precise insight into doctors’ feelings surrounding night shift by: identifying profiles based on doctors’ alertness, contentedness and calmness scores before and after night shifts (research question (RQ) 1); assessing how doctors’ pre- and post-shift profiles change (RQ2); and determining associations of doctors’ demographics and shift circumstances with alertness, contentedness and calmness change (RQ3). Methods Latent Profile Analysis using doctors’ pre- and post-shift self-rated alertness, contentedness and calmness scores was employed to identify pre- and post-shift profiles (RQ1). A cross-tabulation revealed pre- and post-shift profile changes (RQ2). Multiple regressions determined associations of demographics (i.e. age, sex, specialty) and night shift circumstances (i.e. hours worked pre-call, hours awake pre-call, shift duration, number of consecutive shifts, total hours of sleep) with alertness, contentedness and calmness change (RQ3). Results In total, 211 doctors participated with a mean age of 39.8 ± 10 years; 47.4% was male. The participants included consultants (46.4%) and trainees (53.6%) of the specialties surgery (64.5%) and obstetrics/gynaecology (35.5%). Three pre-shift (Indifferent, Ready, Engaged) and four post-shift profiles (Lethargic, Tired but satisfied, Excited, Mindful) were found. Most doctors changed from Ready to Tired but satisfied, with alertness reducing most. Age, specialty, sleep, shift duration and the number of consecutive shifts associated with alertness, contentedness and calmness changes. Conclusions The results provided nuanced insight into doctors’ feelings before and after night shifts. Future research may assess whether specific subgroups benefit from tailored interventions

PIN71 QUALITY OF LIFE (QOL) AND OTHER ENDPOINTS COMPARISON IN THE TREATMENT OF FACIAL LIPOATROPHY WITH INJECTION OF POLY-L-LACTIC ACID

Context: Longitudinal data on bone mineral density(BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMAD(LS)) in children with PWS. Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort. Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. Intervention: The children received GH treatment, 1 mg/m(2)/day (congruent to 0.035 mg/kg/d). Main Outcome Measures: BMDTB, BMDLS, and BMAD(LS) was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMAD(LS)SDS remained stable. During adolescence, BMDTBSDS and BMAD(LS)SDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lowerBMAD(LS)SDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMAD(LS) remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty

Occupational stress in health professionals: a study with Portuguese Nurses

Este trabalho analisa o estresse ocupacional em 286 enfermeiros de hospitais e centros de saúde portugueses. Avaliaram-se as fontes de estresse, o burnout, os problemas de saúde física, a satisfação e a realização profissional. Os resultados apontaram 30% de enfermeiros com experiências significativas de estresse e 15% com problemas de exaustão emocional. As análises de regressão múltipla apontaram maior capacidade preditiva das dimensões de estresse na exaustão emocional, na saúde física, na satisfação e na realização profissional. As análises comparativas evidenciaram maiores problemas de stresse e reacções mais negativas ao trabalho nas mulheres, nos enfermeiros mais novos e com menor experiência, nos trabalhadores com contratos a prazo, nos profissionais que realizam trabalho por turnos e nos que trabalham mais horas.This work analyses occupational stress in 286 nurses from hospitals and health care centres in Portugal. The following dimensions were evaluated: stress, burnout, physical health problems, satisfaction and professional fulfilment. Results revealed significant stress experiences in 30% of the professionals, and emotional exhaustion problems in 15%. Multiple regression analysis pointed out stress as an important predictor of emotional exhaustion, physical health, satisfaction and professional fulfilment. Comparative analysis suggested more occupational stress and professional negative experiences in the following groups: female nurses, younger and less experienced nurses, those with short-term working contracts, nurses working on a shift-basis system, and nurses working during long hours.(undefined

Notch 1 Receptor, Delta 1 Ligand and HES 1 Transcription Factor are Expressed in the Lining Epithelium of Periapical Cysts (Preliminary Study)

Periapical cyst is a chronic inflammatory disorder of periradicular tissues. The precise pathological mechanisms involved in periapical cyst enlargement remain unclear. Notch signaling is an evolutionarily conserved pathway with a regulatory role in cell fate decisions during development and in carcinogenesis. To date, there are no published data available on the expression of Notch signaling components in periapical cysts or any other jaw cyst. In this immunohistochemical study we have examined the expression of the receptor Notch 1, the ligand Delta 1 and the transcription factor HES 1 in the epithelium of well defined periapical cysts. Immunostaining reaction of Notch 1, Delta 1 and HES 1 was observed in the cytoplasm and/or the cytoplasmic membrane and occasionally in the nucleus in the majority of epithelial cells of all periapical cysts. The present observations indicate that Notch pathway is active in the epithelium of periapical cysts. It can be speculated that activation of epithelial cells of periapical cysts is associated with activation of Notch pathway and imply involvement of this pathway in periapical cyst growth and expansion