Nonsurgical treatments for prostate cancer include androgen-deprivation therapy (ADT), radiation therapy (RT), ablative therapies, chemotherapy, and newly emerging immunotherapies. These approaches ...can be used alone or in combination depending on the clinical scenario. ADT is typically reserved for high-risk locally or systemically advanced disease that is not amenable to curative surgery. Radiation therapy can be used instead of surgery as primary therapy with curative intent for low-intermediate-risk disease as well as for control of locally advanced disease not suitable for surgery. Ablative therapies can be used as primary therapy for low-intermediate-risk disease or as salvage therapy for clinically localized disease where RT has failed. Chemotherapy and immune-based therapies are currently used for androgen-independent disease, although the indications for these approaches may well change as new data from clinical trials accrue. Pathologists should be able to recognize tissue changes associated with these treatments to provide information that will optimize patient management. This is particularly true in situations where clinical history of recent or remote nonsurgical treatment is not provided with the specimen. In the absence of this information, pathologists encountering the features described herein are encouraged to review patient records or communicate directly with clinical colleagues to determine how a given patient was treated and when.
The asymmetric alkylation of enolates is a particularly versatile method for the construction of α-stereogenic carbonyl motifs, which are ubiquitous in synthetic chemistry. Over the past several ...decades, the focus has shifted to the development of new catalytic methods that depart from classical stoichiometric stereoinduction strategies (e.g., chiral auxiliaries, chiral alkali metal amide bases, chiral electrophiles, etc.). In this way, the enantioselective alkylation of prochiral enolates greatly improves the step- and redox-economy of this process, in addition to enhancing the scope and selectivity of these reactions. In this review, we summarize the origin and advancement of catalytic enantioselective enolate alkylation methods, with a directed emphasis on the union of prochiral nucleophiles with carbon-centered electrophiles for the construction of α-stereogenic carbonyl derivatives. Hence, the transformative developments for each distinct class of nucleophile (e.g., ketone enolates, ester enolates, amide enolates, etc.) are presented in a modular format to highlight the state-of-the-art methods and current limitations in each area.
The transition metal-catalyzed allylic substitution reaction is a particularly versatile method for the construction of carbon–carbon and carbon–heteroatom bonds. In this regard, the ...rhodium-catalyzed variant has emerged as a powerful method for the regioselective and stereospecific allylic substitution of chiral nonracemic secondary and tertiary allylic carbonates with a variety of carbon- and heteroatom-based nucleophiles. In addition, recent developments have made the analogous enantioselective process possible using prochiral nucleophiles with achiral allylic electrophiles, which represents a significant advance in this area. In this Perspective, the discovery, development and applications of these conceptually orthogonal strategies to target-directed synthesis are discussed, with a particular emphasis given to those methods developed in our laboratory.
•Fatal train accidents per train-kilometre in Europe fell at the rate of 6% per year from 1990 until 2019.•There were 0.85 fatal accidents per billion train-kilometres in 2019.•There was a mean of ...4.2 fatalities per fatal accident in 1990–2019.•the proportion of accidents caused by signals passed at danger fell from 40 % in the 1990s to 21 % in the 2010s. This may be due to the increasing deployment of train protection systems.
This paper presents an analysis of fatal train accident rates and trends on Europe’s main line railways from 1990–2019. It is a sequel to the paper Fatal train accidents on Europe’s railways: 1980–2009 (Evans (2011), which covers the three decades 1980–2009. The present paper discards the data for the 1980s, but adds the data for 2010−2019. The data cover the 28 countries of the European Union as in 2019, together with Norway and Switzerland. The source of the recent data is largely the European Union Agency for Railways.
The estimated overall trend in the number of fatal train collisions and derailments per train-kilometre was –5.6 % per year from 1990–2019, with a 95 % confidence interval of –7.1 % to -4.2 %. The estimated accident rate in 2019 was 0.85 fatal collisions or derailments per billion train-kilometres, which represents a fall of 78 % since 1990. This gives an estimated mean number of fatal accidents in Europe in 2019 of 3.89. The data and results for 2010−2019 closely match the extrapolation of the results for 1990−2009, so that in 2009 extrapolation would have given a good forward projection for 2019. By the same argument this paper gives a forward projection of the mean number of accidents in 2029 of 2.12, assuming no change in train-kilometres, or pro-rata changes with changes in train-kilometres.
The paper investigates the causes of accidents. A notable finding is that the proportion of accidents caused by signals passed at danger (SPADs) fell from 40 % in 1990−1999 to 21 % in 2010−2019. This is probably due to the increasing deployment of train protection systems.
The number of fatalities in individual accidents has a skew distribution: most accidents have a small number of fatalities, but a few have a large number. The overall observed number of fatalities per accident is 4.23, and there is no indication that this mean changes with time. This implies that the mean number of fatalities per year has the same downward trend of 5.6 % per year as the mean number of accidents per year.
Digital imaging in pathology has undergone an exponential period of growth and expansion catalyzed by changes in imaging hardware and gains in computational processing. Today, digitization of entire ...glass slides at near the optical resolution limits of light can occur in 60 s. Whole slides can be imaged in fluorescence or by use of multispectral imaging systems. Computational algorithms have been developed for cytometric analysis of cells and proteins in subcellular locations by use of multiplexed antibody staining protocols. Digital imaging is unlocking the potential to integrate primary image features into high-dimensional genomic assays by moving microscopic analysis into the digital age. This review highlights the emerging field of digital pathology and explores the methods and analytic approaches being developed for the application and use of these methods in clinical care and research settings.
Tickborne diseases (TBDs) such as Lyme disease result in ≈500,000 diagnoses annually in the United States. Various methods can reduce the abundance of ticks at small spatial scales, but whether these ...methods lower incidence of TBDs is poorly understood. We conducted a randomized, replicated, fully crossed, placebo-controlled, masked experiment to test whether 2 environmentally safe interventions, the Tick Control System (TCS) and Met52 fungal spray, used separately or together, affected risk for and incidence of TBDs in humans and pets in 24 residential neighborhoods. All participating properties in a neighborhood received the same treatment. TCS was associated with fewer questing ticks and fewer ticks feeding on rodents. The interventions did not result in a significant difference in incidence of human TBDs but did significantly reduce incidence in pets. Our study is consistent with previous evidence suggesting that reducing tick abundance in residential areas might not reduce incidence of TBDs in humans.
A concise, efficient and scalable synthesis of thapsigargin and nortrilobolide from commercially available (R)-(−)-carvone was developed. Our synthetic strategy is inspired by nature’s carbon–carbon ...bond formation sequence, which facilitates the construction of a highly functionalized sesquiterpene lactone skeleton in five steps via an enantioselective ketone alkylation and a diastereoselective pinacol cyclization. We envision that this strategy will permit the construction of other members of the family, structural analogs and provide a practical synthetic route to these important bioactive agents. In addition, we anticipate that the prodrug Mipsagargin, which is currently in late-stage clinical trials for the treatment of cancer, will also be accessible via this strategy. Hence, the limited availability from natural sources, coupled with an estimated demand of one metric ton per annum for the prodrug, provides a compelling mandate to develop practical total syntheses of these agents.
An increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer ...variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading.
We digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50–69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa.
The AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994–0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972–0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95–0·97) for the independent test dataset and 0·87 (0·84–0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60–0·73).
An AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist.
Swedish Research Council, Swedish Cancer Society, Swedish eScience Research Center, EIT Health.
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