The Dynamics of a Meandering River

We present a statistical model of a meandering river on an alluvial plane which is motivated by the physical non-linear dynamics of the river channel migration and by describing heterogeneity of the terrain by noise. We study the dynamics analytically and numerically. The motion of the river channel is unstable and we show that by inclusion of the formation of ox-bow lakes, the system may be stabilised. We then calculate the steady state and show that it is in agreement with simulations and measurements of field data.Comment: Revtex, 12 pages, 2 postscript figure

A multistate model of health transitions in older people: a secondary analysis of ASPREE clinical trial data

Background: Understanding the nature of transitions from a healthy state to chronic diseases and death is important for planning health-care system requirements and interventions. We aimed to quantify the trajectories of disease and disability in a population of healthy older people. Methods: We conducted a secondary analysis of data from the ASPREE trial, which was done in 50 sites in Australia and the USA and recruited community-dwelling, healthy individuals who were aged 70 years or older (≥65 years for Black and Hispanic people in the USA) between March 10, 2010, and Dec 24, 2014. Participants were followed up with annual face-to-face visits, biennial assessments of cognitive function, and biannual visits for physical function until death or June 12, 2017, whichever occurred first. We used multistate models to examine transitions from a healthy state to first intermediate disease events (ie, cancer events, stroke events, cardiac events, and physical disability or dementia) and, ultimately, to death. We also examined the effects of age and sex on transition rates using Cox proportional hazards regression models. Findings: 19 114 participants with a median age of 74·0 years (IQR 71·6–77·7) were included in our analyses. During a median follow-up of 4·7 years (IQR 3·6–5·7), 1933 (10·1%) of 19 114 participants had an incident cancer event, 487 (2·5%) had an incident cardiac event, 398 (2·1%) had an incident stroke event, 924 (4·8%) developed persistent physical disability or dementia, and 1052 (5·5%) died. 15 398 (80·6%) individuals did not have any of these events during follow-up. The highest proportion of deaths followed incident cancer (501 [47·6%] of 1052) and 129 (12·3%) participants transitioned from disability or dementia to death. Among 12 postulated transitions, transitions from the intermediate states to death had much higher rates than transitions from a healthy state to death. The progression rates to death were 158 events per 1000 person-years (95% CI 144–172) from cancer, 112 events per 1000 person-years (86–145) from stroke, 88 events per 1000 person-years (68–111) from cardiac disease, 69 events per 1000 person-years (58–82) from disability or dementia, and four events per 1000 person-years (4–5) from a healthy state. Age was significantly associated with an accelerated rate for most transitions. Male sex (vs female sex) was significantly associated with an accelerate rate for five of 12 transitions. Interpretation: We describe a multistate model in a healthy older population in whom the most common transition was from a healthy state to cancer. Our findings provide unique insights into the frequency of events, their transition rates, and the impact of age and sex. These results have implications for preventive health interventions and planning for appropriate levels of residential care in healthy ageing populations. Funding: The National Institutes of Health

Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis

Background More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+)to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.Methods In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.Findings We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+.After 5\u20138 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0\ub717, 95% CI 0\ub711\u20130\ub725) among girls aged 13\u201319 years, and decreased significantly by 66% (RR 0\ub734, 95% CI 0\ub723\u20130\ub749) among women aged 20\u201324 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0\ub746, 95% CI 0\ub733\u20130\ub766) among girls aged 13\u201319 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0\ub733, 95% CI 0\ub724\u20130\ub746) among girls aged 15\u201319 years, decreased significantly by 54% (RR 0\ub746, 95% CI 0.36\u20130.60) among women aged 20\u201324 years, and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub753\u20130\ub789) among women aged 25\u201329 years. Among boys aged 15\u201319 years anogenital wart diagnoses decreased significantly by 48% (RR 0\ub752, 95% CI 0\ub737\u20130\ub775) and among men aged 20\u201324 years they decreased significantly by 32% (RR 0\ub768, 95% CI 0\ub747\u20130\ub798). After 5\u20139 years of vaccination, CIN2+ decreased significantly by 51% (RR 0\ub749, 95% CI 0\ub742\u20130\ub758) among screened girls aged 15\u201319 years and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub757\u20130\ub784) among women aged 20\u201324 years.Interpretation This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects

The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks’ gestation

Background: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term respiratory and neurological morbidity in very preterm infants. While survival rates of very preterm infants have increased over the past two decades there has been no decrease in the rate of BPD in surviving infants. Evidence from animal and human studies has suggested potential benefits of docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, in the prevention of chronic lung disease. This randomised controlled trial aims to determine the effectiveness of supplementary DHA in reducing the rate of BPD in infants less than 29 weeks’ gestation. Methods/design: This is a multicentre, parallel group, randomised, blinded and controlled trial. Infants born less than 29 weeks’ gestation, within 3 days of first enteral feed and with parent informed consent are eligible to participate. Infants will be randomised to receive an enteral emulsion containing DHA or a control emulsion without DHA. The DHA emulsion will provide 60 mg/kg/day of DHA. The study emulsions will continue to 36 weeks’ postmenstrual age (PMA). The primary outcome is BPD as assessed by the requirement for supplemental oxygen and/or assisted ventilation at 36 weeks’ PMA. Secondary outcomes include the composite of death or BPD; duration of respiratory support and hospitalisation, major neonatal morbidities. The target sample size is 1244 infants (622 per group), which will provide 90 % power to detect a clinically meaningful absolute reduction of 10 % in the incidence of BPD between the DHA and control emulsion (two tailed α =0.05). Discussion: DHA supplementation has the potential to reduce respiratory morbidity in very preterm infants. This multicentre trial will provide evidence on whether an enteral DHA supplement reduces BPD in very preterm infants

Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome

<p>Abstract</p> <p>Background</p> <p>Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m²) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m²IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.</p> <p>Results</p> <p>54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.</p> <p>Conclusion</p> <p>Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov: NCT00035867</p

Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development

Phase 2 study of dovitinib in patients with relapsed or refractory multiple myeloma with or without t(4;14) translocation

Objectives: Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with r