Motoneuron membrane potentials follow a time inhomogeneous jump diffusion process

Stochastic leaky integrate-and-fire models are popular due to their simplicity and statistical tractability. They have been widely applied to gain understanding of the underlying mechanisms for spike timing in neurons, and have served as building blocks for more elaborate models. Especially the Ornstein–Uhlenbeck process is popular to describe the stochastic fluctuations in the membrane potential of a neuron, but also other models like the square-root model or models with a non-linear drift are sometimes applied. Data that can be described by such models have to be stationary and thus, the simple models can only be applied over short time windows. However, experimental data show varying time constants, state dependent noise, a graded firing threshold and time-inhomogeneous input. In the present study we build a jump diffusion model that incorporates these features, and introduce a firing mechanism with a state dependent intensity. In addition, we suggest statistical methods to estimate all unknown quantities and apply these to analyze turtle motoneuron membrane potentials. Finally, simulated and real data are compared and discussed. We find that a square-root diffusion describes the data much better than an Ornstein–Uhlenbeck process with constant diffusion coefficient. Further, the membrane time constant decreases with increasing depolarization, as expected from the increase in synaptic conductance. The network activity, which the neuron is exposed to, can be reasonably estimated to be a threshold version of the nerve output from the network. Moreover, the spiking characteristics are well described by a Poisson spike train with an intensity depending exponentially on the membrane potential

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Kriging modelization in predicting metal sheet elongation

Modern industries are increasingly replacing real experiments with nonstochastic simulation models due to their restrained costs and growing reliability. The non‐stochastic simulator used in this paper is the Finite Element simulation code (FEM), a widely used numerical technique for the engineering problems modeled by a system of partial differential equations defined on a time‐space domain. In such a context, it is common practice to provide a metamodel, a global approximation of the FEM experiment response on the design space to capture local minima/maxima. We use the most popular metamodel, the Kriging model, applied to an industrial instance: prediction of bend deduction. Metal sheet bending is a manufacturing process in which there is a plastic deformation of the workpieces over an axis. This is a metal forming process, similar to other processes where bending changes the shape of the workpieces. The work focuses on the construction of an optimal initial design in order to achieve a good accuracy of the metamodel at an acceptable computational cost, the theoretical study of this model, and the understanding of how it could be conformed to the bend deduction prediction. The correlation structure, mandatory in a Kriging model, was evaluated by means of the variogram, allowing to refine the correlation specification naturally improving the Kriging predictions. The empirical variograms for each input variable brought to light unusual behaviors. This suggested that the bending angle could be related to the bend deduction according to 2 different models. It is clear that there is a discontinuity in the relationship between the models, but its exact location is not known. The accuracy achieved was then evaluated using different indicators of robustness and the uncertainty of the “leave‐one‐out” methods

Single:channel properties of cloned cGMP-activated channels from retinal rods

Single-channel properties of a cloned channel activated by cyclic GMP have been analysed. The mRNA encoding for the channel was injected into oocytes of Xenopus laevis and the current flowing through a single ionic channel activated by cGMP was studied in excised patches under voltage-clamp conditions. The ionic channel activated by cGMP had a single-channel conductance of 32 +/- 2 pS at +120 mV and 25 +/- 4 pS at -120 mV, and its conductance was not significantly affected by increasing the cGMP concentration from 20 microM to 200 microM. The single-channel currents in the presence of NH+4, Na+, K+, Li+ and Rb+ in the medium bathing the cytoplasmic side of the membrane at +140 mV were 5.3, 4.7, 3.8, 1.3 and 0.8 pA, respectively. The single-channel current in the presence of Cs+ was less than 0.5 pA. Ca2+ and Mg2+ (both 0.5 mM) in the presence of 100 microM cGMP did not appreciably affect the channel activity at membrane potentials more negative than -80 mV, whereas at +100 mV they reduced the single-channel conductance by about threefold. The ionic selectivity and the blockage by divalent cations of the native channel found in amphibian rods and in the cloned channel from bovine rods are quite similar. However, the cloned channel has well-resolved openings, especially at positive membrane voltages, whereas the native channel is characterized by a continuous flickering between the open and closed state

Efficacy of combined intravenous immunoglobulins and steroids in children with primary immune thrombocytopenia and persistent bleeding symptoms.

Background. The aim of this study was to investigate the effect of the combined administration of intravenous immunoglobulins and steroids as a second-line therapy in 34 children with primary immune thrombocytopenia and persistent, symptomatic bleeding. Materials and methods. Combined therapy (intravenous immunoglobulins 0.4 g/kg daily on days 1 and 2, and methylprednisolone 20 mg/kg daily on days 1-3) was administered to 12 patients with newly diagnosed ITP who did not respond to the administration of a single therapy (either intravenous immunoglobulins or steroids) and to 22 children with persistent and chronic disease who required frequent administrations (i.e. more frequently than every 30 days) of either immunoglobulins or steroids (at the same standard dosages) in order to control active bleeding. Results. A response (i.e. platelet count >50×109/L and remission of active bleeding) was observed in 8/12 (67%) patients with newly diagnosed ITP. The clinical presentation of responders and non-responders did not differ apparently. Patients in the chronic/persistent phase of disease had a significantly longer median period of remission from symptoms compared with the previous longest period of remission (p=0.016). The treatment was well tolerated. Discussion. Our data suggest that the combined approach described is a well-tolerated therapeutic option for children with primary immune thrombocytopenia and persistent bleeding symptoms that can be used in both emergency and/or maintenance settings

The Association between Educational Level and Cardiovascular and Cerebrovascular Diseases within the EPICOR Study: New Evidence for an Old Inequality Problem

A consistent association has been reported between low socioeconomic status (SES) and cardiovascular events (CE), whereas the association between SES and cerebrovascular events (CBVD) is less clear. The aim of this study was to investigate the association between SES (measured using education) and CE/CBVD in a cohort study, as well as to investigate lifestyle and clinical risk factors, to help to clarify the mechanisms by which SES influences CE/CBVD.We searched for diagnoses of CE and CBVD in the clinical records of 47,749 members of the EPICOR cohort (average follow-up time: 11 years). SES was determined by the relative index of inequality (RII).A total of 1,156 CE and 468 CBVD were found in the clinical records. An increased risk of CE was observed in the crude Cox model for the third tertile of RII compared to the first tertile (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.21–1.61). The increased risk persisted after adjustment for lifestyle risk factors (HR = 1.19; 95%CI 1.02–1.38), clinical risk factors (HR = 1.35; 95%CI 1.17–1.56), and after full adjustment (HR = 1.17; 95%CI 1.01–1.37). Structural equation model showed that lifestyle rather than clinical risk factors are involved in the mechanisms by which education influences CE. No significant association was found between education and CBVD. A strong relationship was observed between education and diabetes at baseline.The most important burden of inequality in CE incidence in Italy is due to lifestyle risk factors