Time‐to‐event continual reassessment method incorporating treatment cycle information with application to an oncology phase I trial

Delayed dose limiting toxicities (i.e. beyond first cycle of treatment) is a challenge for phase I trials. The time‐to‐event continual reassessment method (TITE‐CRM) is a Bayesian dose‐finding design to address the issue of long observation time and early patient drop‐out. It uses a weighted binomial likelihood with weights assigned to observations by the unknown time‐to‐toxicity distribution, and is open to accrual continually. To avoid dosing at overly toxic levels while retaining accuracy and efficiency for DLT evaluation that involves multiple cycles, we propose an adaptive weight function by incorporating cyclical data of the experimental treatment with parameters updated continually. This provides a reasonable estimate for the time‐to‐toxicity distribution by accounting for inter‐cycle variability and maintains the statistical properties of consistency and coherence. A case study of a First‐in‐Human trial in cancer for an experimental biologic is presented using the proposed design. Design calibrations for the clinical and statistical parameters are conducted to ensure good operating characteristics. Simulation results show that the proposed TITE‐CRM design with adaptive weight function yields significantly shorter trial duration, does not expose patients to additional risk, is competitive against the existing weighting methods, and possesses some desirable properties.     

Identifying unusual mortality events in bats: a baseline for bat hibernation monitoring and white‐nose syndrome research

Bat population trends are particularly affected by adult mortality, especially when large numbers of individuals die, as evidenced by white‐nose syndrome in North America. We obtained baseline mortality data from 318 European hibernacula. Mortality was low and negatively associated with elevation but not with fungal infestation. Mortality events involving more than seven bats at a hibernaculum should be considered unusual, and above this threshold, pathological or microbiological analysis should be carried out. To increase understanding of mortality in bats, there is an urgent need to develop and co‐ordinate national and international programs for monitoring and investigating mortality and diseases.     

Semiparametric modelling and estimation of covariate-adjusted dependence between bivariate recurrent events

A time-dependent measure, termed the rate ratio, was proposed to assess the local dependence between two types of recurrent event processes in one-sample settings. However, the one-sample work does not consider modeling the dependence by covariates such as subject characteristics and treatments received. The focus of this paper is to understand how and in what magnitude the covariates influence the dependence strength for bivariate recurrent events. We propose the covariate-adjusted rate ratio, a measure of covariate-adjusted dependence. We propose a semiparametric regression model for jointly modeling the frequency and dependence of bivariate recurrent events: the first level is a proportional rates model for the marginal rates and the second level is a proportional rate ratio model for the dependence structure. We develop a pseudo-partial likelihood to estimate the parameters in the proportional rate ratio model. We establish the asymptotic properties of the estimators and evaluate the finite sample performance via simulation studies. We illustrate the proposed models and methods using a soft tissue sarcoma study that examines the effects of initial treatments on the marginal frequencies of local/distant sarcoma recurrence and the dependence structure between the two types of cancer recurrence.     

Multiple factors have shaped the phylogeography of Chinese spiny loach Cobitis sinensis in Taiwan as inferred from mitochondrial DNA variation

Mitochondrial DNA cytochrome b sequences (1140 bp) in 61 specimens of Chinese spiny loach Cobitis sinensis from 12 drainages in Taiwan were identified as two major clades, exhibiting a southern and a northern distribution, north of TzengWen and south of TzengWen (including TzengWen), respectively. The divergence time between these two phylogroups was estimated at 7·34–9·06 million years before present (b.p. ), but these two phylogroups were formed c. 3·41–4·23 and 2·22–2·75 M b.p. , respectively. Moreover, geological events have been recalculated that Taiwan Island emerged above sea level at an estimate of c. 4–5 M b.p. , and quickly became its present shape at c. 2 M b.p. through mountain building. These results suggest that these two major clades of C. sinensis in Taiwan might originate from two different continental populations, since the island's initial isolation in the Pliocene. Within southern Taiwan, the initial colonization was hypothesized to be in KaoPing River, followed by its northward dispersal. The high divergence between KaoPing and TzengWen was influenced by glaciations and landforms. Within north Taiwan, the colonization was from the Miaoli Plateau through western Taiwan to north‐eastern and northern Taiwan. This dispersal pattern is concordant with the previously proposed hypothesis. Apparently, both geological and phylogeographic evidence suggested that river capture of the upper Takia River by the LanYang River promoted range expansion in freshwater fishes and also indicated that the Central Range within Taiwan did not act as a barrier to the dispersal of C. sinensis.     

近40年中国干旱特征及其对植被变化的影响

全球变暖影响下，中国干旱事件发生愈加频繁。过去半个世纪里，中国半干旱和半湿润地区的分界线总体南移，干旱面积呈增加趋势，因此了解中国干旱变化趋势对区域生态环境保护具有重要意义。基于GLASS数据产品、ERA5-Land数据，采用游程理论和多元线性回归等方法，探究1982—2018年间多尺度干旱事件基本特征(干旱持续时间、干旱严重度、干旱强度等),并分析植被生产力变化趋势，揭示干旱对植被变化的累积影响。结果表明：(1)新疆、青藏高原以及东南地区干旱较为严峻，而华中、华东大部分区域处于轻旱或无旱状态；(2)1982—2018年间，中国植被生产力整体呈改善态势，显著改善区集中在中国中部，而退化区集中在东南部、内蒙古和西藏南部；(3)中国大部分区域干旱与植被呈正相关，且干旱对植被多为累积影响，在干旱区和半干旱区尤为明显；(4)随着植被覆盖度的增加，植被与近短期尺度干旱的相关性也逐渐增加，由干旱区到湿润区，近短尺度干旱对植被变化的影响逐步增大。其中，SPEI-6(标准化降水蒸散发指数—中期尺度)对植被轻微变化累积影响最显著，而SPEI-12(标准化降水蒸散发指数—长期尺度)对植被显著变化累积影响更...     

Origin and evolution of the Micronesian biota: Insights from molecular phylogenies and biogeography reveal long-distance dispersal scenarios and founder-event speciation

Micronesian islands taxa show high endemism rates, but very little is known about their biogeographical histories. The lack of systematic biogeography is mainly due to insufficient phylogenetic research in Micronesia. With the recent increase in published molecular biogeographic data, we were able to, for the first time, answer fundamental biogeography questions by reviewing and analyzing numerous geological, ecological, and evolutionary studies. This review, in addition to providing an overview of Micronesian geological history, confirmed the importance of long-distance dispersal mechanisms and founder-event speciation, and morphological and physiological adaptations of plant propagules to cross vast stretches of ocean by wind, ocean currents, bird, or bat dispersal. These adaptations to habitat and geological features, including reef types, determined colonization success as well as inland dispersal and speciation mechanisms. We further identified the source areas of the Micronesian biota and reconstructed historical dispersal scenarios: a dominant Austro-Melanesian dispersal scenario, an Indo-Malaysian connecting to the Austro-Melanesian dispersal scenario, and a Neotropical American and an African dispersal scenario toward Micronesia. Most generic origins were estimated between the Eocene and the Miocene and dispersed to Micronesia between the Miocene and the Pleistocene.     

Adverse childhood experiences: a meta-analysis of prevalence and moderators among half a million adults in 206 studies

Exposure to adverse childhood experiences (ACEs), including maltreatment and family dysfunction, is a major contributor to the global burden of disease and disability. With a large body of international literature on ACEs having emerged over the past 25 years, it is timely to now synthetize the available evidence to estimate the global prevalence of ACEs and, through a series of moderator analyses, determine which populations are at higher risk. We searched studies published between January 1, 1998 and August 5, 2021 in Medline, PsycINFO and Embase. Study inclusion criteria were using the 8- or 10-item ACE Questionnaire (±2 items), reporting the prevalence of ACEs in population samples of adults, and being published in English. The review protocol was registered with PROSPERO (CRD42022348429). In total, 206 studies (208 sample estimates) from 22 countries, with 546,458 adult participants, were included. The pooled prevalence of the five levels of ACEs was: 39.9% (95% CI: 29.8-49.2) for no ACE; 22.4% (95% CI: 14.1-30.6) for one ACE; 13.0% (95% CI: 6.5-19.8) for two ACEs; 8.7% (95% CI: 3.4-14.5) for three ACEs, and 16.1% (95% CI: 8.9-23.5) for four or more ACEs. In subsequent moderation analyses, there was strong evidence that the prevalence of 4+ ACEs was higher in populations with a history of a mental health condition (47.5%; 95% CI: 34.4-60.7) and with substance abuse or addiction (55.2%; 95% CI: 45.5-64.8), as well as in individuals from low-income households (40.5%; 95% CI: 32.9-48.4) and unhoused individuals (59.7%; 95% CI: 56.8-62.4). There was also good evidence that the prevalence of 4+ ACEs was larger in minoritized racial/ethnic groups, particularly when comparing study estimates in populations identifying as Indigenous/Native American (40.8%; 95% CI: 23.1-59.8) to those identifying as White (12.1%; 95% CI: 10.2-14.2) and Asian (5.6%; 95% CI: 2.4-10.2). Thus, ACEs are common in the general population, but there are disparities in their prevalence. They are among the principal antecedent threats to individual well-being and, as such, constitute a pressing social issue globally. Both prevention strategies and downstream interventions are needed to reduce the prevalence and mitigate the severity of the effects of ACEs and thereby reduce their deleterious health consequences on future generations.     

Apatinib for heavily treated patients with non-small cell lung cancer: Report of a case series and literature review

Although many strategies have been developed for non-small cell lung cancer (NSCLC), more secondary and further treatments are needed due to drug resistance or tumor recurrence. Apatinib is a novel oral antiangiogenic agent and in this study, we aim to investigate the clinical value of apatinib in heavily pretreated NSCLC. Here, we reported the characteristics, efficacy and adverse events of three patients treated with apatinib (500?mg/day). We also summarized the currently available evidence and ongoing clinical trials regarding the use of apatinib in NSCLC. Two cases of adenocarcinoma and one case of squamous cell carcinoma were treated with apatinib due to disease progression after previous treatments of chemotherapy and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). All patients responded to apatinib rapidly and underwent drug resistance shortly afterwards. The patient with squamous cell carcinoma died of hemoptysis. Other adverse events were acceptable. All previous relevant studies were compared and showed similar results but a longer progression-free survival. Additionally, ongoing clinical trials were systematically searched and listed. In conclusion, apatinib shows some efficacy in heavily treated NSCLC and generally tolerable toxicity in non-squamous NSCLC. More solid evidence will be accessible in near future.