Effect of Heterogeneous Mixing and Vaccination on the Dynamics of Anthelmintic Resistance: A Nested Model

Anthelmintic resistance is a major threat to current measures for helminth control in humans and animals. The introduction of anthelmintic vaccines, as a complement to or replacement for drug treatments, has been advocated as a preventive measure. Here, a computer-based simulation, tracking the dynamics of hosts, parasites and parasite-genes, shows that, depending on the degree of host-population mixing, the frequency of totally recessive autosomes associated with anthelmintic resistance can follow either a fast dynamical regime with a low equilibrium point or a slow dynamical regime with a high equilibrium point. For fully dominant autosomes, only one regime is predicted. The effectiveness of anthelminthic vaccines against resistance is shown to be strongly influenced by the underlying dynamics of resistant autosomes. Vaccines targeting adult parasites, by decreasing helminth fecundity or lifespan, are predicted to be more effective than vaccines targeting parasite larvae, by decreasing host susceptibility to infection, in reducing the spread of resistance. These results may inform new strategies to prevent, monitor and control the spread of anthelmintic resistance, including the development of viable anthelmintic vaccines

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections

Impact of resolving the diurnal cycle in an ocean-atmosphere GCM. Part 1: A diurnally forced OGCM

The diurnal cycle is a fundamental time scale in the climate system, at which the upper ocean and atmosphere are routinely observed to vary. Current climate models, however, are not configured to resolve the diurnal cycle in the upper ocean or the interaction of the ocean and atmosphere on these time scales. This study examines the diurnal cycle of the tropical upper ocean and its climate impacts. In the present paper, the first of two, a high vertical resolution ocean general circulation model (OGCM), with modified physics, is developed which is able to resolve the diurnal cycle of sea surface temperature (SST) and current variability in the upper ocean. It is then validated against a satellite derived parameterization of diurnal SST variability and in-situ current observations. The model is then used to assess rectification of the intraseasonal SST response to the Madden–Julian oscillation (MJO) by the diurnal cycle of SST. Across the equatorial Indo-Pacific it is found that the diurnal cycle increases the intraseasonal SST response to the MJO by around 20%. In the Pacific, the diurnal cycle also modifies the exchange of momentum between equatorially divergent Ekman currents and the meridionally convergent geostrophic currents beneath, resulting in a 10% increase in the strength of the Ekman cells and equatorial upwelling. How the thermodynamic and dynamical impacts of the diurnal cycle effect the mean state, and variability, of the climate system cannot be fully investigated in the constrained design of ocean-only experiments presented here. The second part of this study, published separately, addresses the climate impacts of the diurnal cycle in the coupled system by coupling the OGCM developed here to an atmosphere general circulation model