Point estimation of the 100p percent lethal dose using a novel penalised likelihood approach.

Estimation of the 100p percent lethal dose (LD100p) is of great interest to pharmacologists for assessing the toxicity of certain compounds. However, most existing literature focuses on the interval estimation of LD100p and little attention has been paid to its point estimation. Currently, the most commonly used method for estimating the LD100p is the maximum likelihood estimator (MLE), which can be represented as a ratio estimator, with the denominator being the slope estimated from the logistic regression model. However, the MLE can be seriously biased when the sample size is small, a common nature in such studies, or when the dose-response curve is relatively flat (i.e. the slope approaches zero). In this study, we address these issues by developing a novel penalised maximum likelihood estimator (PMLE) that can prevent the denominator of the ratio from being close to zero. Similar to the MLE, the PMLE is computationally simple and thus can be conveniently used in practice. Moreover, with a suitable penalty parameter, we show that the PMLE can (a) reduce the bias to the second order with respect to the sample size and (b) avoid extreme estimates. Through simulation studies and real data applications, we show that the PMLE generally outperforms the existing methods in terms of bias and root mean square error.

Double-edged sword: effects of human sperm reactive oxygen species on embryo development in IVF cycles.

BACKGROUND: The exact role of sperm reactive oxygen species (ROS) in early embryo development has yet to be fully identified, and most of existing research did not differentiate female infertility factors, ignoring the importance of oocyte quality in embryo development and the large differences in oocyte quality in women with infertility of different etiologies. And there has been no relevant report on whether different types of sperm ROS have distinct effects on embryo development. This study aimed to study the impact of selected sperm ROS, namely, sperm mitochondrial ROS (mROS) and hydrogen peroxide, on human embryo development after conventional in vitro fertilization (IVF) cycles in patients with normo-ovulatory infertility vs. anovulatory infertility. METHODS: This was a prospective investigation including 393 couples underwent IVF cycles, among whom 90 patients had anovulatory infertility and 303 patients had normo-ovulatory infertility in a public university-affiliated in vitro fertilization center. Sperm mROS and hydrogen peroxide testing were performed by flow cytometry and analyzed for their relationship with embryo development indices on days 1-6 after IVF. Multivariate logistic regression analysis was used to control for female potential confounders. The nonlinear effects of sperm ROS on embryo development were analyzed by the Restricted cubic spline (RCS) method. RESULTS: 1. Multivariate linear logistic regression analysis showed that high proportion of mROS positive sperm improved the 2PN rate (OR = 1.325, 95% CI: 1.103-1.595), day 3 embryo utilization rate (OR = 1.362, 95% CI: 1.151-1.614) and good-quality day 3 embryo rate (OR = 1.391, 95% CI: 1.089-1.783) in patients with anovulatory infertility. High percentage of sperm mROS and hydrogen peroxide had adverse effects on cleavage-stage embryo and blastocyst development in patients with normo-ovulatory infertility. 2. For patients with polycystic ovarian syndrome (PCOS) anovulatory infertility, there were significant distinct effects on embryo development indices between sperm mROS and hydrogen peroxide, and the increased rate of sperm mROS improved the good-quality day 3 embryo rate (OR = 1.435, 95% CI: 1.045-1.981); however, high percentage of sperm hydrogen peroxide reduced the blastocyst utilization rate (OR = 0.555, 95% CI: 0.353-0.864) and the good-quality blastocyst rate (OR = 0.461, 95% CI: 0.292-0.718). 3. Multivariate RCS analysis revealed that sperm ROS had a nonlinear (such as a parabolic curve) effect on embryo development in patients with anovulatory infertility (P < 0.05), and either greatly increased or greatly decreased affected cleavage-stage embryo and blastocyst development. The effects of sperm ROS in patients with normo-ovulatory infertility were both linear and nonlinear. CONCLUSIONS: These findings indicate that contrary effects of sperm mROS on embryo development depending on whether patients treated with IVF cycles had normal ovulation. Regardless of whether the patients ovulated normally, increased sperm hydrogen peroxide rate damaged blastocyst development. It is necessary to evaluate male sperm ROS levels and the female ovulatory state to determine an individualized intervention plan before starting cycles, as this may be beneficial for infertile couples.

Increased emergency cases for out-of-hospital cardiac arrest due to cold spells in Shenzhen, China.

Cold spells have been associated with specific diseases. However, there is insufficient scientific evidence on the effects of cold spells on out-of-hospital cardiac arrest (OHCA). Data on OHCA cases and on meteorological factors and air pollutants were collected between 2013 and 2020. We adopted a quasi-Poisson generalized additive model with a distributed lag nonlinear model (DLNM) to estimate the effect of cold spells on daily OHCA incidence. Backward attributable risk within the DLNM framework was calculated to quantify the disease burden. We compared the effects and OHCA burden of cold spells using nine definitions. The risks of different cold spells on OHCA increased at higher intensities and longer durations. Based on Akaike's information criterion for the quasi-Poisson regression model and the attributable risk, the optimal cold spell was defined as a period in the cold month when the daily mean temperature was below the 10th percentile of the temperature distribution in the study period for at least 2 days. The single-day effect of the optimal cold spell on OHCA occurred immediately and lasted for approximately 1 week. The maximum single-day effect was 1.052 (95% CI: 1.018-1.087) at lag0, while the maximum cumulative effect was 1.433 (95% CI:1.148-1.788) after a 14-day lag. Men were more susceptible to cold spells. Young and middle-aged people were affected by cold spells similar to the elderly. Cold spells can increase the risk of OHCA with an approximately 1-week lag effect. Health regulators should take more targeted measures to protect susceptible populations during cold weather.

Evaluating the predictive ability of temperature-related indices on the stroke morbidity in Shenzhen, China: Under cross-validation methods framework.

BACKGROUND: Composite temperature-related indices have been utilized to comprehensively reflect the impact of multiple meteorological factors on health. We aimed to evaluate the predictive ability of temperature-related indices, choose the best predictor of stroke morbidity, and explore the association between them. METHODS: We built distributed lag nonlinear models to estimate the associations between temperature-related indices and stroke morbidity and then applied two types of cross-validation (CV) methods to choose the best predictor. The effects of this index on overall stroke, intracerebral hemorrhage (ICH), and ischemic stroke (IS) morbidity were explored and we explained how this index worked using heatmaps. Stratified analyses were conducted to identify vulnerable populations. RESULTS: Among 12 temperature-related indices, the alternative temperature-humidity index (THIa) had the best overall performance in terms of root mean square error when combining the results from two CVs. With the median value of THIa (25.70 °C) as the reference, the relative risks (RRs) of low THIa (10th percentile) reached a maximum at lag 0-10, with RRs of 1.20 (95%CI:1.10-1.31), 1.49 (95%CI:1.29-1.73) and 1.12 (95%CI:1.03-1.23) for total stroke, ICH and IS, respectively. According to the THIa formula, we matched the effects of THIa on stroke under various combinations of temperature and relative humidity. We found that, although the low temperature (<20 °C) had the greatest adverse effect, the modification effect of humidity on it was not evident. In contrast, lower humidity could reverse the protective effect of temperature into a harmful effect at the moderate-high temperature (24 °C-27 °C). Stratification analyses showed that the female was more vulnerable to low THIa in IS. CONCLUSIONS: THIa is the best temperature-related predictor of stroke morbidity. In addition to the most dangerous cold weather, the government should pay more attention to days with moderate-high temperature and low humidity, which have been overlooked in the past.

XCMAX4: A Robust X Chromosomal Genetic Association Test Accounting for Covariates.

Although the X chromosome accounts for about 5% of the human genes, it is routinely excluded from genome-wide association studies probably due to its unique structure and complex biological patterns. While some statistical methods have been proposed for testing the association between X chromosomal markers and diseases, very a few of them can adjust for covariates. Unfortunately, those methods that can incorporate covariates either need to specify an X chromosome inactivation model or require the permutation procedure to compute the p value. In this article, we proposed a novel analytic approach based on logistic regression that allows for covariates and does not need to specify the underlying X chromosome inactivation pattern. Simulation studies showed that our proposed method controls the size well and has robust performance in power across various practical scenarios. We applied the proposed method to analyze Graves' disease data to show its usefulness in practice.

Dynamic control of the mode-locked fiber laser using a GO/PS modulator.

This Letter proposes a novel, to the best of our knowledge, transistor-like optical fiber modulator composed of graphene oxide (GO) and polystyrene (PS) microspheres. Unlike previously proposed schemes based on waveguides or cavity enhancement, the proposed method can directly enhance the photoelectric interaction with the PS microspheres to form a light local field. The designed modulator exhibits a distinct optical transmission change (62.8%), with a power consumption of <10 nW. Such low power consumption enables electrically controllable fiber lasers to be switched in various operational regimes, including continuous wave (CW), Q switched mode-locked (QML), and mode-locked (ML). With this all-fiber modulator, the pulse width of the mode-locked signal can be compressed to 12.9 ps, and the corresponding repetition rate is 21.4 MHz.