Potential Benefits of Sequential Inhibitor-Mutagen Treatments of RNA Virus Infections

Lethal mutagenesis is an antiviral strategy consisting of virus extinction associated with enhanced mutagenesis. The use of non-mutagenic antiviral inhibitors has faced the problem of selection of inhibitor-resistant virus mutants. Quasispecies dynamics predicts, and clinical results have confirmed, that combination therapy has an advantage over monotherapy to delay or prevent selection of inhibitor-escape mutants. Using ribavirin-mediated mutagenesis of foot-and-mouth disease virus (FMDV), here we show that, contrary to expectations, sequential administration of the antiviral inhibitor guanidine (GU) first, followed by ribavirin, is more effective than combination therapy with the two drugs, or than either drug used individually. Coelectroporation experiments suggest that limited inhibition of replication of interfering mutants by GU may contribute to the benefits of the sequential treatment. In lethal mutagenesis, a sequential inhibitor-mutagen treatment can be more effective than the corresponding combination treatment to drive a virus towards extinction. Such an advantage is also supported by a theoretical model for the evolution of a viral population under the action of increased mutagenesis in the presence of an inhibitor of viral replication. The model suggests that benefits of the sequential treatment are due to the involvement of a mutagenic agent, and to competition for susceptible cells exerted by the mutant spectrum. The results may impact lethal mutagenesis-based protocols, as well as current antiviral therapies involving ribavirin

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

A Mathematical Model of Thyroid Disease Response to Radiotherapy

We present a mechanistic biomathematical model of molecular radiotherapy of thyroid disease. The general model consists of a set of differential equations describing the dynamics of different populations of thyroid cells with varying degrees of damage caused by radiotherapy (undamaged cells, sub-lethally damaged cells, doomed cells, and dead cells), as well as the dynamics of thyroglobulin and antithyroglobulin autoantibodies, which are important surrogates of treatment response. The model is presented in two flavours: on the one hand, as a deterministic continuous model, which is useful to fit populational data, and on the other hand, as a stochastic Markov model, which is particularly useful to investigate tumor control probabilities and treatment individualization. The model was used to fit the response dynamics (tumor/thyroid volumes, thyroglobulin and antithyroglobulin autoantibodies) observed in experimental studies of thyroid cancer and Graves' disease treated with I-131-radiotherapy. A qualitative adequate fitting of the model to the experimental data was achieved. We also used the model to investigate treatment individualization strategies for differentiated thyroid cancer, aiming to improve the tumor control probability. We found that simple individualization strategies based on the absorbed dose in the tumor and tumor radiosensitivity (which are both magnitudes that can potentially be individually determined for every patient) can lead to an important raise of tumor control probabilities

Abordaje de la analgesia postoperatoria en cirugía de cadera: comparativa de 3 técnicas

Introduction: The treatment of postoperative pain after hip surgery is essential for an early start of rehabilitation and for reducing morbidity and mortality. Given that patients are elderly and have multiple medical conditions, local-regional analgesia can be an effective approach. Objectives: Our aim was to compare the efficacy of the fascia iliaca compartment block, the obturator and femoral cutaneous nerve blocks and total intravenous analgesia in terms of level of patient satisfaction, complications, start of rehabilitation and cost in each group. Patients and methods: Prospective study of 90 patients undergoing hip surgery. Patients were randomised to receive intravenous analgesia only, fascia iliaca compartment block or blockade of the obturator and femoral cutaneous nerves. In each group, we recorded visual analogue scale (VAS) pain scores, satisfaction with postoperative analgesia, time elapsed until start of rehabilitation, need for postoperative analgesics, side effects, and the cost of drugs. Results: Analgesia and level of patient satisfaction were significantly more effective in patients with nerve blocks than in those who received intravenous analgesia only (mean [SD] VAS scores, 2.14 [1.24], mean [SD] satisfaction scores 3.75 [0.8] and mean [SD] VAS scores, 5.57[0.64], mean [SD] satisfaction scores 2.83[0.7], respectively) (p<0.001). Patients with nerve blocks also had a pain-free period of more than 24h (p<0.01), needed fewer doses of supplementary analgesics or other drugs, had fewer side effects (p<0.01), started rehabilitation earlier (31.2 [5.01]h vs 44.62 [7.9]h) (p<0.001), generated less expenditure (€13.26 [€6.34]/patient vs €30.26 [€1.88]/patient), with no complications in the blockade techniques. No significant differences were found between the efficacy of both blockades, VAS scores, level of satisfaction, or the cost between the patients who received a blockade. Conclusions: The nerve blocks were effective, easy to perform, and safe. They afforded numerous advantages: extended period of postoperative analgesia, fast recovery, lower costs, and no complications.Introducción: Resulta indispensable tratar el dolor postoperatorio de cirugía de cadera para iniciar una rehabilitación precoz y para disminuir la morbimortalidad. Dada la pluripatología y edad de los pacientes, la analgesia locorregional se revela como el arma más eficaz para tratarlo. Objetivos: Valorar la eficacia del bloqueo iliofascial y del bloqueo de los nervios obturador y femorocutáneo frente a analgesia intravenosa, así como registrar el grado de satisfacción, las complicaciones, inicio de rehabilitación y costes económicos en cada grupo. Pacientes y método: Estudio prospectivo con 90 pacientes sometidos a cirugía de cadera. Se dividieron en 3 grupos aleatorios: A: solo analgesia intravenosa, B: bloqueo iliofascial y C: bloqueo de los nervios obturador y femorocutáneo lateral. Se investigó el grado de dolor y satisfacción analgésica, tiempo transcurrido hasta el inicio de la sedestación, necesidad de analgésicos postoperatorios, efectos secundarios y los costes económicos farmacéuticos en cada grupo. Resultados: La eficacia analgésica y el grado de satisfacción fueron significativamente mayores en los pacientes con bloqueos nerviosos (EVA medio 2,14±1,24, satisfacción 3,75±0,8) que en los que solo recibieron analgesia intravenosa (EVA medio 5,57±0,64, satisfacción 2,83±0,7) (p<0,001), con una duración superior a las 24h (p<0,01) y un menor consumo de analgésicos suplementarios y otros fármacos que en el grupo A, por lo que tuvieron menos reacciones adversas (p<0,01), iniciaron la rehabilitación más precozmente (31,2±5,01h vs 44,62±7,9h) (p<0,001) y supusieron un menor coste económico farmacéutico (13,26±6,34€/paciente vs 30,26±1,88€/paciente) no encontrándose complicaciones en la realización de los bloqueos. No se encontraron diferencias significativas entre la eficacia de ambos bloqueos, evolución de los EVAs medio, grado de satisfacción ni gasto económico entre los pacientes que recibieron algún tipo de bloqueo. Conclusiones: Los bloqueos realizados son una técnica efectiva, fácil y segura que proporciona numerosas ventajas: analgesia postoperatoria prolongada, recuperación más rápida, menor coste y escasas complicaciones

A model of indirect cell death caused by tumor vascular damage after high-dose radiotherapy

There is increasing evidence that high doses of radiotherapy, like those delivered in stereotactic body radiotherapy (SBRT), trigger indirect mechanisms of cell death. Such effect seems to be two-fold. High doses may trigger an immune response and may cause vascular damage, leading to cell starvation and death. Development of mathematical response models, including indirect death, may help clinicians to design SBRT optimal schedules. Despite increasing experimental literature on indirect tumor cell death caused by vascular damage, efforts on modeling this effect have been limited. In this work, we present a biomathematical model of this effect. In our model, tumor oxygenation is obtained by solving the reaction-diffusion equation; radiotherapy kills tumor cells according to the linear-quadratic model, and also endothelial cells (EC), which can trigger loss of functionality of capillaries. Capillary death will affect tumor oxygenation, driving nearby tumor cells into severe hypoxia. Capillaries can recover functionality due to EC proliferation. Tumor cells entering a predetermined severe hypoxia status die according to a hypoxia-death model. This model fits recently published experimental data showing the effect of vascular damage on surviving fractions. It fits surviving fraction curves and qualitatively reproduces experimental values of percentages of functional capillaries 48 hours postirradiation, and hypoxic cells pre- and 48 hours postirradiation. This model is useful for exploring aspects of tumor and EC response to radiotherapy and constitutes a stepping stone toward modeling indirect tumor cell death caused by vascular damage and accounting for this effect during SBRT planning. SIGNIFICANCE: A novel biomathematical model of indirect tumor cell death caused by vascular radiation damage could potentially help clinicians interpret experimental data and design better radiotherapy schedules

Peptides Mimicking the β7/β8 loop of HIV-1 Reverse Transcriptase p51 as “Hotspot-Targeted” Dimerization Inhibitors

A conformationally constrained short peptide designed to target a protein-protein interaction hotspot in HIV-1 reverse transcriptase (RT) disrupts p66-p51 interactions and paves the way to the development of novel RT dimerization inhibitor