The Mean Drift: Tailoring the Mean Field Theory of Markov Processes for Real-World Applications

The statement of the mean field approximation theorem in the mean field theory of Markov processes particularly targets the behaviour of population processes with an unbounded number of agents. However, in most real-world engineering applications one faces the problem of analysing middle-sized systems in which the number of agents is bounded. In this paper we build on previous work in this area and introduce the mean drift. We present the concept of population processes and the conditions under which the approximation theorems apply, and then show how the mean drift is derived through a systematic application of the propagation of chaos. We then use the mean drift to construct a new set of ordinary differential equations which address the analysis of population processes with an arbitrary size

Recruitment of low-income pregnant women into a dietary and dental care intervention: lessons from a feasibility trial

Background: There are difficulties in carrying out research in low-income urban communities, but the methodological challenges and suggestions on how to deal with them are often undocumented. The aims of this study are to describe the challenges of recruiting and enrolling low-income pregnant women with periodontitis to a clinical trial on vitamin D/calcium milk fortification and periodontal therapy and also to describe the patient-, study protocol- and setting-related factors related to women’s ineligibility and refusal to participate in the study. Methods: A mixed-method sequential exploratory design was applied. Qualitative and quantitative data on recruitment to a 2 × 2 factorial feasibility clinical trial were used. Eighteen women attending the health centre in a low-income area in Duque de Caxias (Rio de Janeiro, Brazil) took part in focus group discussions, and the data were thematically analysed. Quantitative data were analysed using appropriate descriptive statistics, including absolute and relative frequencies. Results: Of all referrals (767), 548 (78.5%) did not meet the initial eligibility criteria. The main reason for exclusion (58%) was advanced gestational age (> 20 weeks) at first prenatal appointment. In the periodontal examination (dental screen), the main reason for exclusion was the presence of extensive caries (64 out of 127 exclusions). Non-participation of those eligible after the periodontal examination was approximately 24% (22 out 92 eligible women) and predominantly associated with patient-related barriers (e.g. transportation barriers, family obligations, patients being unresponsive to phone calls and disconnected telephones). The study recruited 70 women with periodontitis in 53 weeks and did not reach the benchmark of 120 women in 36 weeks (58.3% of the original target). Recruitment was severely hindered by health centre closures due to general strikes. The recruitment yields were 9.1% (70/767) of all women contacted at first prenatal visit and 76.1% (70/92) of those screened eligible and enrolled in the trial. Women did not report concerns regarding random allocation and considered fortified milk as a healthful and safe food for pregnant women. Some women reported that financial constraints (e.g. transportation costs) could hinder participation in the study. Conclusion: Engagement between the research team and health centre staff (e.g. nurses) facilitated referral and recruitment, yet some pregnant women failed to participate in the study largely due to significant patient-related sociodemographic barriers and setting-related factors. Our data illustrate the complexity of overcoming recruitment and enrolment challenges for clinical trials in resource-limited settings. Trial registration: ClinicalTrials.gov, NCT03148483. Registered on 11 May 2017

Activity of the antiarrhythmic drug amiodarone against Leishmania (L.) infantum: an in vitro and in vivo approach

<div><p>Abstract Background: Considering the high toxicity and limited therapies available for treating visceral leishmaniasis (VL), the drug repositioning approach represents a faster way to deliver new therapies to the market. Methods: In this study, we described for the first time the activity of a potent antiarrhythmic, amiodarone (AMD), against L. (L.)infantum and its in vitro and in vivo activity. Results: The evaluation against promastigotes has shown that amiodarone presents leishmanicidal effect against the extracellular form, with an IC50 value of 10 μM. The activity was even greater against amastigotes in comparison with promastigotes with an IC50 value of 0.5 μM. The selectivity index in relation to the intracellular form demonstrated that the antiparasitic activity was approximately 56 times higher than its toxicity to mammalian cells. Investigation of the in vivo AMD activity in the L. infantum-infected hamster model showed that 51 days after the initial infection, amiodarone was unable to reduce the parasite burden in the spleen and liver when treated for 10 consecutive days, intraperitoneally, at 50 mg/kg/day, as determined by qPCR. Although not statistically significant, AMD was able to reduce the parasite burden by 20% in the liver when treated for 10 consecutive days, orally, at 100 mg/kg/day; no reduction in the spleen was found by qPCR. Conclusions: Our findings may help further drug design studies seeking new AMD derivatives that may provide new candidates with an in vitro selectivity close to or even greater than that observed in the prototype delivering effectiveness in the experimental model of VL.</p></div

Dietary patterns and their association with adiponectin and leptin concentrations throughout pregnancy:a prospective cohort

AbstractThe aim of this study was to evaluate the association of dietary patterns (DP) with maternal adiposity indicators, leptin, adiponectin and insulin concentrations during pregnancy. A prospective cohort of pregnant women followed up at the 5th–13th, 20th –26th and 30th–36th gestational weeks and 30–40 d postpartum was conducted in Rio de Janeiro. A FFQ was administered in the third trimester (30th–36th gestational weeks). The reduced rank regression procedure was used to identify DP that explain response variables (dietary fibre and total fat) related to indicators of maternal adiposity (postpartum weight retention and gestational weight gain (GWG) adequacy), and plasma leptin, adiponectin and insulin concentrations. The associations between tertiles of DP and the outcomes were determined using logistic regression or longitudinal linear mixed-effect regression models. The mean daily energy intake during pregnancy was 10 104 (sd 3234) kJ (2415 (sd 773) kcal), and GWG was 11·9 (sd 4·2) kg. In all, 40 % of women presented pre-gestational overweight/obesity. Excessive GWG occurred in 34·7 % of pregnant women and 56·6 % were overweight/obese at postpartum. The ‘common-Brazilian’ DP (characterised by higher intake of beans, rice and lower intake of fast food/snacks, candies/table sugar and processed meats/bacon) was positively associated with adiponectin (β=1·07; 95 % CI 0·17, 1·98). The ‘Western’ DP (characterised by higher intake of fast food/snacks and processed meat/bacon and lower intake of noodles/pasta/roots/tubers and sodas) was negatively associated with adiponectin (β=−1·11; 95 % CI −2·00, −0·22) and positively associated with leptin concentrations (β=64·9; 95 % CI 22·8, 107·0) throughout pregnancy. It may be suggested that the ‘common-Brazilian’ is a healthy DP and beneficial for serum concentrations of adiponectin and leptin.</jats:p

Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia

Purpose Amplification or over-expression of the mitotic Aurora A kinase (AAK) has been reported in several heme-lymphatic malignancies. MLN8237 (alisertib) is a novel inhibitor of AAK that is being developed for the treatment of advanced malignancies. The objectives of this phase I study were to establish the safety, tolerability, and pharmacokinetic profiles of escalating doses of MLN8237 in patients with relapsed or refractory heme-lymphatic malignancies. Methods Sequential cohorts of patients received MLN8237 orally as either a powder-in-capsule (PIC) or enteric-coated tablet (ECT) formulation. Patients received MLN8237 PIC 25–90 mg for 14 or 21 consecutive days plus 14 or 7 days’ rest, respectively, or MLN8237 ECT, at a starting dose of 40 mg/day once-daily (QD) for 14 days plus 14 days’ rest, all in 28-day cycles. Subsequent cohorts received MLN8237 ECT 30–50 mg twice-daily (BID) for 7 days plus 14 days’ rest in 21-day cycles. Results Fifty-eight patients were enrolled (PIC n = 28, ECT n = 30). The most frequent grade ≥3 drug-related toxicities were neutropenia (45 %), thrombocytopenia (28 %), anemia (19 %), and leukopenia (19 %). The maximum tolerated dose on the ECT 7-day schedule was 50 mg BID. The terminal half-life of MLN8237 was approximately 19 h. Six (13 %) patients achieved partial responses and 13 (28 %) stable disease. Conclusion The recommended phase II dose of MLN8237 ECT is 50 mg BID for 7 days in 21-day cycles, which is currently being evaluated as a single agent in phase II/III trials in patients with peripheral T-cell lymphoma. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10637-013-0050-9) contains supplementary material, which is available to authorized users

Transcultural adaptation and validation of a French version of the Prosthetic Limb Users Survey of Mobility 12-item Short-Form (PLUS-M/FC-12) in active amputees.

The PLUS-M 12-item Short-Form is a self-questionnaire that assesses the perceived capacity of lower limb amputees (LLAs) to perform a number of daily-life activities. Its psychometric properties are excellent (intraclass correlation coefficient [ICC]&gt;0.9, fast administration and scoring, normative data available), and it can be used in clinical practice or for research purposes. We aimed to develop a French version of this questionnaire and to assess its psychometric properties. We followed international recommendations for translation and cross-cultural validation of questionnaires. In total, 52 LLAs (age 53±16, 40 males, 28/12/12 transtibial/Gritti-Stokes/transfemoral, 20/28/4 ischemic/traumatic/other) participated. Criterion and construct validities were assessed with the Pearson correlation coefficient (PCC) between the PLUS-M 12-item Short-Form and other constructs (Prosthetic-Profile-of-the-Amputee-Locomotor Capabilities Index, Activities-specific Balance Confidence scale, 2-min walking test and Timed Up and Go test), internal consistency with the Cronbach α and reliability with the ICC in 46 individuals who completed the questionnaire twice in a 7-day interval. The mean (SD) PLUS-M 12-item Short-Form T-score was 56.1 (7.8; range 40.3 to 71.4). Construct and criterion validity, internal consistency and reliability ranged from low to excellent (r=0.43 to 0.84, P&lt;10 &lt;sup&gt;-2&lt;/sup&gt; to 0.002; Cronbach α=0.90, ICC=0.89 [0.81-0.94]). We found no floor or ceiling effect. The French version of the PLUS-M 12-item Short-Form has good to excellent psychometric properties, comparable to those of the original version. Its use could definitely be proposed for both clinical and research purposes, once its validation is completed by assessing other psychometric qualities, especially sensitivity to change