I. II. III. IV. V. VI. References SUMMARY: Mycorrhizal fungi can form common mycelial networks (CMNs) that interconnect plants. Here, we provide an insight into recent findings demonstrating that ...CMNs can be conduits for interplant signalling, influencing defence against insect herbivores and foliar necrotrophic fungi. A likely mechanism is direct transfer of signalling molecules within hyphae. However, electrical signals, which can be induced by wounding, may also enable signalling over relatively long distances, because the biophysical constraints imposed by liquid transport in hyphae and interaction with soil are relieved. We do not yet understand the ecological, evolutionary and agronomic implications of interplant signalling via CMNs. Identifying the mechanism of interplant signalling will help to address these gaps.
Ticks exist on all continents and carry more zoonotic pathogens than any other type of vector. Ticks spend most of their lives in the external environment away from the host and are thus expected to ...be affected by changes in climate. Most empirical and theoretical studies demonstrate or predict range shifts or increases in ticks and tick-borne diseases, but there can be a lot of heterogeneity in such predictions. Tick-borne disease systems are complex, and determining whether changes are due to climate change or other drivers can be difficult. Modeling studies can help tease apart and understand the roles of different drivers of change. Predictive models can also be invaluable in projecting changes according to different climate change scenarios. However, validating these models remains challenging, and estimating uncertainty in predictions is essential. Another focus for future research should be assessing the resilience of ticks and tick-borne pathogens to climate change.
Purpose To evaluate the associations among mathematical modeling with the use of magnetic resonance (MR) imaging-based texture features and deep myometrial invasion (DMI), lymphovascular space ...invasion (LVSI), and histologic high-grade endometrial carcinoma. Materials and Methods Institutional review board approval was obtained for this retrospective study. This study included 137 women with endometrial carcinomas measuring greater than 1 cm in maximal diameter who underwent 1.5-T MR imaging before hysterectomy between January 2011 and December 2015. Texture analysis was performed with commercial research software with manual delineation of a region of interest around the tumor on MR images (T2-weighted, diffusion-weighted, and dynamic contrast material-enhanced images and apparent diffusion coefficient maps). Areas under the receiver operating characteristic curve and diagnostic performance of random forest models determined by using a subset of the most relevant texture features were estimated and compared with those of independent and blinded visual assessments by three subspecialty radiologists. Results A total of 180 texture features were extracted and ultimately limited to 11 features for DMI, 12 for LVSI, and 16 for high-grade tumor for random forest modeling. With random forest models, areas under the receiver operating characteristic curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were estimated at 0.84, 79.3%, 82.3%, 81.0%, 76.7%, and 84.4% for DMI; 0.80, 80.9%, 72.5%, 76.6%, 74.3%, and 79.4% for LVSI; and 0.83, 81.0%, 76.8%, 78.1%, 60.7%, and 90.1% for high-grade tumor, respectively. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of visual assessment for DMI were 84.5%, 82.3%, 83.2%, 77.7%, and 87.8% (reader 3). Conclusion The mathematical models that incorporated MR imaging-based texture features were associated with the presence of DMI, LVSI, and high-grade tumor and achieved equivalent accuracy to that of subspecialty radiologists for assessment of DMI in endometrial cancers larger than 1 cm. However, these preliminary results must be interpreted with caution until they are validated with an independent data set, because the small sample size relative to the number of features extracted may have resulted in overfitting of the models.
RSNA, 2017 Online supplemental material is available for this article.
Summary
1. Ecological count data typically exhibit complexities such as overdispersion and zero‐inflation, and are often weakly associated with a relatively large number of correlated covariates. The ...use of an appropriate statistical model for inference is therefore essential. A common selection criteria for choosing between nested models is the likelihood ratio test (LRT). Widely used alternatives to the LRT are based on information‐theoretic metrics such as the Akaike Information Criterion.
2. It is widely believed that the LRT can only be used to compare the performance of nested models – i.e. in situations where one model is a special case of another. There are many situations in which it is important to compare non‐nested models, so, if true, this would be a substantial drawback of using LRTs for model comparison. In reality, however, it is actually possible to use the LRT for comparing both nested and non‐nested models. This fact is well‐established in the statistical literature, but not widely used in ecological studies.
3. The main obstacle to the use of the LRT with non‐nested models has, until relatively recently, been the fact that it is difficult to explicitly write down a formula for the distribution of the LRT statistic under the null hypothesis that one of the models is true. With modern computing power it is possible to overcome this difficulty by using a simulation‐based approach.
4. To demonstrate the practical application of the LRT to both nested and non‐nested model comparisons, a case study involving data on questing tick (Ixodes ricinus) abundance is presented. These data contain complexities typical in ecological analyses, such as zero‐inflation and overdispersion, for which comparison between models of differing structure – e.g. non‐nested models – is of particular importance.
5. Choosing between competing statistical models is an essential part of any applied ecological analysis. The LRT is a standard statistical test for comparing nested models. By use of simulation the LRT can also be used in an analogous fashion to compare non‐nested models, thereby providing a unified approach for model comparison within the null hypothesis testing paradigm. A simple practical guide is provided in how to apply this approach to the key models required in the analyses of count data.
BackgroundDostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with ...endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab.MethodsGARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review.ResultsScreening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab.ConclusionDostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile.Trial registration numberNCT02715284.
Summary Background Around 90% of deaths from ovarian cancer are due to high-grade serous cancer (HGSC), which is frequently diagnosed at an advanced stage. Several cancer organisations made a joint ...recommendation that all women with specified symptoms of ovarian cancer should be tested with the aim of making an early diagnosis. In the Diagnosing Ovarian Cancer Early (DOvE) study we investigated whether open-access assessment would increase the rate of early-stage diagnosis. Methods Between May 1, 2008, and April 30, 2011, we enrolled women who were aged 50 years or older and who had symptoms of ovarian cancer. They were offered diagnostic testing with cancer antigen (CA-125) blood test and transvaginal ultrasonography (TVUS) at a central and a satellite open-access centre in Montreal, QC, Canada. We compared demographic characteristics of DOvE patients with those of women in the same age-group in the general population of the area, and compared indicators of disease burden with those in patients with ovarian cancer referred through the usual route to our gynaecological oncology clinic (clinic patients). Findings Among 1455 women assessed, 402 (27·6%) were in the highest-risk age group (≥65 years). 239 (16·4%) of 1455 required additional investigations. 22 gynaecological cancers were diagnosed, 11 (50%) of which were invasive ovarian cancers, including nine HGSC. The prevalence of invasive ovarian cancer, therefore, was one per 132 women (0·76%), which is ten times higher than that reported in screening studies. DOvE patients were significantly younger, more educated, and more frequently English speakers than were women in the general population. They also presented with less tumour burden than did the 75 clinic patients (median CA-125 concentration 72 U/mL, 95% CI 12–1190 vs 888 U/mL, 440–1936; p=0·010); Eight (73%) tumours were completely resectable in DOvE patients, compared with 33 (44%) in clinic patients (p=0·075). Seven (78%) of the HGSC in the DOvE group originated outside the ovaries and five were associated with only slightly raised CA-125 concentrations and minimal or no ovarian abnormalities on TVUS. Interpretation The proportion of HGSC that originated outside the ovaries in this study suggests that early diagnosis programmes should aim to identify low-volume disease rather than early-stage disease, and that diagnostic approaches should be modified accordingly. Although testing symptomatic women may result in earlier diagnosis of invasive ovarian cancer, large-scale implementation of this approach is premature. Funding Canadian Institutes of Health Research, Montreal General Hospital Foundation, Royal Victoria Hospital Foundation, Cedar's Cancer Institute, and La Fondation du Cancer Monique Malenfant-Pinizzotto.
Identifying the mechanisms driving disease risk is challenging for multi-host pathogens, such as Borrelia burgdorferi sensu lato (s.l.), the tick-borne bacteria causing Lyme disease. Deer are tick ...reproduction hosts but do not transmit B. burgdorferi s.l., whereas rodents and birds are competent transmission hosts. Here, we use a long-term deer exclosure experiment to test three mechanisms for how high deer density might shape B. burgdorferi s.l. prevalence in ticks: increased prevalence due to higher larval tick densities facilitating high transmission on rodents (M1); alternatively, reduced B. burgdorferi s.l. prevalence because more larval ticks feed on deer rather than transmission-competent rodents (dilution effect) (M2), potentially due to ecological cascades, whereby higher deer grazing pressure shortens vegetation which decreases rodent abundance thus reducing transmission (M3).
In a large enclosure where red deer stags were kept at high density (35.5 deer km
), we used an experimental design consisting of eight plots of 0.23 ha, four of which were fenced to simulate the absence of deer and four that were accessible to deer. In each plot we measured the density of questing nymphs and nymphal infection prevalence in spring, summer and autumn, and quantified vegetation height and density, and small mammal abundance.
Prevalence tended to be lower, though not conclusively so, in high deer density plots compared to exclosures (predicted prevalence of 1.0% vs 2.2%), suggesting that the dilution and cascade mechanisms might outweigh the increased opportunities for transmission mechanism. Presence of deer at high density led to shorter vegetation and fewer rodents, consistent with an ecological cascade. However, Lyme disease hazard (density of infected I. ricinus nymphs) was five times higher in high deer density plots due to tick density being 18 times higher.
High densities of tick reproduction hosts such as deer can drive up vector-borne disease hazard, despite the potential to simultaneously reduce pathogen prevalence. This has implications for environmental pathogen management and for deer management, although the impact of intermediate deer densities now needs testing.
We detected Borrelia bavariensis in Ixodes ricinus ticks collected near 2 towns in the United Kingdom. Human B. bavariensis infections have not been reported previously in the country, underscoring ...the value of tick surveillance to warn of emerging human disease. B. bavariensis should be considered in patients with suspected neuroborreliosis.
This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent ...serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9-39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0-20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16-53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3-35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.
Lyme borreliosis and other tick-borne diseases emerge from increased interactions between humans, other animals, and infected ticks. The risk of acquiring a tick-borne infection varies across space ...and time, so knowledge of the occurrence and prevalence of pathogens in ticks can facilitate disease diagnosis in a specific area and the implementation of mitigation measures and awareness campaigns. Here we identify the occurrence and prevalence of several pathogens in Ixodes ricinus ticks in Wester Ross, Northwest Scotland, a region of high tourism and tick exposure, yet data-poor in terms of tick-borne pathogens.
Questing I. ricinus nymphs (n = 2828) were collected from 26 sites in 2018 and 2019 and tested for the presence of tick-borne pathogens using PCR-based methods. Prevalence was compared with other regions of Scotland, England, Wales, and the Netherlands.
Anaplasma phagocytophilum (4.7% prevalence), Borrelia burgdorferi sensu lato (s.l.) (2.2%), Babesia from clade X (0.2%), Rickettsia helvetica (0.04%), and Spiroplasma ixodetis (0.4%) were detected, but no Neoehrlichia mikurensis, Borrelia miyamotoi, or Babesia microti. Typing of A. phagocytophilum using a fragment of the GroEL gene identified the presence of both ecotype I and ecotype II. Genospecies identification of Borrelia burgdorferi s.l. revealed B. afzelii (53% of infected nymphs), B. garinii (9%), B. burgdorferi sensu stricto (7%), and B. valaisiana (31%). We found similar prevalence of A. phagocytophilum in Wester Ross as in the Netherlands, but higher than in other parts of Great Britain. We found lower B. burgdorferi s.l. prevalence than in England or the Netherlands, and similar to some other Scottish studies. We found higher prevalence of B. valaisiana and lower prevalence of B. garinii than in other Scottish studies. We found S. ixodetis at much lower prevalence than in the Netherlands, and R. helvetica at much lower prevalence than in England and the Netherlands.
As far as we know, this is the first description of S. ixodetis in Great Britain. The results are relevant for disease surveillance and management for public and veterinary health. The findings can also aid in designing targeted public health campaigns and in raising awareness among outdoor recreationists and professionals.
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