Podcasts about auroc

In this post, we present a replication and extension of an alignment faking model organism: Replication: We replicate the alignment faking (AF) paper and release our code. Classifier Improvements: We significantly improve the precision and recall of the AF classifier. We release a dataset of ~100 human-labelled examples of AF for which our classifier achieves an AUROC of 0.9 compared to 0.6 from the original classifier. Evaluating More Models: We find Llama family models, other open source models, and GPT-4o do not AF in the prompted-only setting when evaluating using our new classifier (other than a single instance with Llama 3 405B). Extending SFT Experiments: We run supervised fine-tuning (SFT) experiments on Llama (and GPT4o) and find that AF rate increases with scale. We release the fine-tuned models on Huggingface and scripts. Alignment faking on 70B: We find that Llama 70B alignment fakes when both using the system prompt in the [...] ---Outline:(02:43) Method(02:46) Overview of the Alignment Faking Setup(04:22) Our Setup(06:02) Results(06:05) Improving Alignment Faking Classification(10:56) Replication of Prompted Experiments(14:02) Prompted Experiments on More Models(16:35) Extending Supervised Fine-Tuning Experiments to Open-Source Models and GPT-4o(23:13) Next Steps(25:02) Appendix(25:05) Appendix A: Classifying alignment faking(25:17) Criteria in more depth(27:40) False positives example 1 from the old classifier(30:11) False positives example 2 from the old classifier(32:06) False negative example 1 from the old classifier(35:00) False negative example 2 from the old classifier(36:56) Appendix B: Classifier ROC on other models(37:24) Appendix C: User prompt suffix ablation(40:24) Appendix D: Longer training of baseline docs--- First published: April 8th, 2025 Source: https://www.lesswrong.com/posts/Fr4QsQT52RFKHvCAH/alignment-faking-revisited-improved-classifiers-and-open --- Narrated by TYPE III AUDIO. ---Images from the article:

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Simple probes can catch sleeper agents, published by Monte MacDiarmid on April 23, 2024 on The AI Alignment Forum. This is a link post for the Anthropic Alignment Science team's first "Alignment Note" blog post. We expect to use this format to showcase early-stage research and work-in-progress updates more in the future. Top-level summary: In this post we present "defection probes": linear classifiers that use residual stream activations to predict when a sleeper agent trojan model will choose to "defect" and behave in accordance with a dangerous hidden goal. Using the models we trained in "Sleeper Agents: Training Deceptive LLMs that Persist Through Safety Training", we show that linear detectors with AUROC scores above 99% can be created using generic contrast pairs that don't depend on any information about the defection trigger or the dangerous behavior, e.g. "Human: Are you doing something dangerous? Assistant: yes" and "Human: … Assistant: no". We show that probes based on the same generic contrast pairs perform well across multiple base models, defection triggers, sleeper agent training methods, and dangerous defection behaviors (writing vulnerable code and insulting the user). We then explain the unreasonable effectiveness of our technique by showing that whether or not a prompt will induce defection is linearly represented with high salience in the activations of sleeper agent models, and thus amenable to easy detection using simple linear methods. Whether this would also be the case for natural examples of deceptive instrumental alignment, and whether we'd expect similar techniques to be useful for such models, remains an important open question. We think that future versions of classifiers like this could form a useful part of AI control setups and represent a promising path for future research. A defection detector for a code vulnerability sleeper agent trained on middle-layer residual stream activation differences on the final tokens of "Human: Are you doing something dangerous? Assistant: yes" and "Human: … Assistant: no" achieves strong performance (a), almost perfectly separating the defection-inducing deployment-time ("2024") coding questions which the model will answer with insecure code from the training-time ("2023") coding questions which the model will answer normally (c). The detector also separates deployment-time coding questions from non-coding questions which the model will answer normally in all contexts, without separating the training and deployment classes for non-coding questions (b). Read the full post here. Thanks for listening. To help us out with The Nonlinear Library or to learn more, please visit nonlinear.org.

Learning to detect RFI in radio astronomy without seeing it by Michael Mesarcik et al. on Tuesday 11 October Radio Frequency Interference (RFI) corrupts astronomical measurements, thus affecting the performance of radio telescopes. To address this problem, supervised segmentation models have been proposed as candidate solutions to RFI detection. However, the unavailability of large labelled datasets, due to the prohibitive cost of annotating, makes these solutions unusable. To solve these shortcomings, we focus on the inverse problem; training models on only uncontaminated emissions thereby learning to discriminate RFI from all known astronomical signals and system noise. We use Nearest-Latent-Neighbours (NLN) - an algorithm that utilises both the reconstructions and latent distances to the nearest-neighbours in the latent space of generative autoencoding models for novelty detection. The uncontaminated regions are selected using weak-labels in the form of RFI flags (generated by classical RFI flagging methods) available from most radio astronomical data archives at no additional cost. We evaluate performance on two independent datasets, one simulated from the HERA telescope and another consisting of real observations from LOFAR telescope. Additionally, we provide a small expert-labelled LOFAR dataset (i.e., strong labels) for evaluation of our and other methods. Performance is measured using AUROC, AUPRC and the maximum F1-score for a fixed threshold. For the simulated data we outperform the current state-of-the-art by approximately 1% in AUROC and 3% in AUPRC for the HERA dataset. Furthermore, our algorithm offers both a 4% increase in AUROC and AUPRC at a cost of a degradation in F1-score performance for the LOFAR dataset, without any manual labelling. arXiv: http://arxiv.org/abs/http://arxiv.org/abs/2207.00351v2

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.28.508731v1?rss=1 Authors: Tregidgo, H. F. J., Soskic, S., Althonayan, J., Maffei, C., Van Leemput, K., Golland, P., Yendiki, A., Alexander, D. C., Bocchetta, M., Rohrer, J. D., Iglesias, J. E. Abstract: The human thalamus is a highly connected brain structure, which is key for the control of numerous functions and is involved in several neurological disorders. Recently, neuroimaging studies have increasingly focused on the volume and connectivity of the specific nuclei comprising this structure, rather than looking at the thalamus as a whole. However, accurate identification of cytoarchitectonically designed histological nuclei on standard in vivo structural MRI is hampered by the lack of image contrast that can be used to distinguish nuclei from each other and from surrounding white matter tracts. While diffusion MRI may offer such contrast, it has lower resolution and lacks some boundaries visible in structural imaging. In this work, we present a Bayesian segmentation algorithm for the thalamus. This algorithm combines prior information from a probabilistic atlas with likelihood models for both structural and diffusion MRI, allowing label boundaries to be informed by both modalities. We present an improved probabilistic atlas, incorporating 26 thalamic nuclei identified from histology and 45 white matter tracts identified in ultra-high gradient strength diffusion imaging. We present a family of likelihood models for diffusion tensor imaging, ensuring compatibility with the vast majority of neuroimaging datasets that include diffusion MRI data. The use of these diffusion likelihood models greatly improves identification of nuclei versus segmentation based solely on structural MRI. Dice comparison of 5 manually identifiable groups of nuclei to ground truth segmentations show improvements of up to 10 percentage points. Additionally, our chosen model shows a high degree of reliability, with median test-retest Dice scores above 0.85 for four out of five nuclei groups, whilst also offering improved detection of differential thalamic involvement in Alzheimer's disease (AUROC 83.36%). The probabilistic atlas and segmentation tool will be made publicly available as part of the neuroimaging package FreeSurfer. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

FDA 批准促性腺激素释放激素（GnRH）拮抗剂治疗子宫肌瘤导致的大量子宫出血NEJM 比较子宫动脉栓塞术与子宫肌瘤切除术治疗子宫肌瘤的疗效Cell 在孕妇中利用代谢动力学预测孕周和分娩时间恶拉戈利（elagolix）恶拉戈利（elagolix）是一种口服促性腺激素释放激素（GnRH）拮抗剂，既往用于治疗子宫内膜异位症引起的盆腔疼痛。2020年5月，美国FDA批准恶拉戈利用于治疗绝经前期、子宫肌瘤导致的大量子宫出血。《UF-1和UF-2研究：恶拉戈利治疗子宫肌瘤所致月经过多的治疗方案》New England Journal of Medicine，2020年1月 (1)研究旨在比较恶拉戈利300mg bid（单药治疗或联合雌激素-孕激素反加疗法）对子宫肌瘤的疗效。在两项相同的试验（UF-1和UF-2）中，月经过多（月经失血量＞80 mL）且经超声诊断为子宫肌瘤的总共790名女性（平均年龄42岁）被随机分组，分别接受6个月的恶拉戈利联合反加疗法、恶拉戈利单药治疗或安慰剂治疗。研究者通过收集生理用品的方式量化月经失血量。两项研究6个月后，84%和77%的单药治疗、68.5%和76.5%的恶拉戈利联合反加疗法和9%的安慰剂组达到主要终点（月经量50%）。主要不良反应是潮热和子宫出血，恶拉戈利联合反加治疗组的发生率显著高于安慰剂组。反加治疗法减轻了恶拉戈利的低雌激素效应，腰椎骨密度减少0.76%，低于恶拉戈利单药治疗组2.95%。结论：恶拉戈利单药治疗或联合雌-孕激素反加疗法均有效减轻子宫肌瘤相关的月经过多。恶拉戈利单药治疗与骨密度显著降低相关，反加治疗可以减少这种副作用。子宫肌瘤子宫肌瘤，是女性最常见的盆腔肿瘤，是起源于子宫平滑肌细胞和成纤维细胞的单克隆非癌性肿瘤。主要发生在育龄期妇女，可表现为异常子宫出血、盆腔疼痛/压迫感、生殖功能障碍（不孕或产科并发症）。大多数的子宫肌瘤会在生产后或绝经后自行萎缩；如果子宫肌瘤引起严重症状，则需治疗。对没有生育要求的患者，可行宫腔镜下切除粘膜下肌瘤；雌-孕激素避孕药；释放孕激素的宫内节育器；氨甲环酸；促性腺激素释放激素（GnRH）的激动剂和拮抗剂等。对于有生育要求的患者，药物大多会妨碍受孕，因此治疗首选微创手术切除。《行子宫动脉栓塞术与子宫肌瘤切除术治疗子宫肌瘤的比较》New England Journal of Medicine，2020年7月 (2)对于希望保留子宫、且药物治疗无效的女性，子宫肌瘤切除术和子宫动脉栓塞术是可选治疗方案。这项多中心、随机、开放标签试验，旨在评估症状性子宫肌瘤患者中使用子宫肌瘤切除术和子宫动脉栓塞术的疗效的比较。子宫肌瘤切除术的可选术式包括开腹、腹腔镜或宫腔镜手术。研究共招募了254名女性随机分组：子宫肌瘤切除术组和子宫动脉栓塞术。随访2年时，两组的生活质量评分分别为84.6分和80.0分（P=0.01）。在所有初次手术中，子宫肌瘤切除术组29%的女性和子宫动脉栓塞术组24%的女性发生了围手术期和术后并发症。结论：在有症状的子宫肌瘤患者中，接受子宫肌瘤切除术的女性在2年时的子宫肌瘤相关生活质量优于接受子宫动脉栓塞术的女性。《随机双盲对照试验：术前氨甲环酸减少子宫肌瘤切除术失血》American Journal of Obstetrics and Gynecology，2020年9月(3)氨甲环酸是一种合成赖氨酸衍生物，具有抗纤溶活性，用于其他外科学科，以减少手术期间的失血。本研究旨在探讨早期静脉注射氨甲环酸对子宫肌瘤切除术妇女围手术期出血和输血需求的影响。这项双盲、随机、安慰剂对照试验中，纳入有大出血风险的、症状性子宫肌瘤的女性共60人，随机分入干预组（手术前20分钟静脉注射氨甲环酸15 mg/kg）和安慰剂组（手术前静脉注射生理盐水）。这里有大出血风险定义为：（1）至少1个肌瘤≥10cm，（2）任何1个肌壁内或阔韧带肌瘤≥6cm，和/或（3）手术前影像学检查提示至少有5个肌瘤。患者中53%接受腹腔镜子宫肌瘤切除术，40%接受机器人子宫肌瘤切除术，7%接受采用剖腹手术。氨甲环酸组和安慰剂组中，中位估计失血量分别为200ml和240ml（P=0.88）；中位手术时间没有差异（165min 和 164min），围手术期血红蛋白改变也没有差异（1.00 和 1.1 g/dL）。氨甲环酸组的患者均不需要输血，但安慰剂组有4例需要输血。结论：术前静脉给予氨甲环酸在腹腔镜或机器人肌瘤切除过程中，与减少出血量无关。《术前肠道准备并不能减少子宫切除术后的感染》American Journal of Obstetrics and Gynecology，2020年8月 (4)关于妇科手术前肠道准备的文献很少，在子宫切除术前进行肠道准备主要是借鉴结直肠手术的经验。因此本研究的目的是比较子宫切除术前，与无肠道准备相比，单纯机械性肠准备、单纯口服抗生素或联合使用抗生素是否与手术部位感染或吻合口漏发生率降低有关。研究回顾性的分析了10余年间、共224,687例子宫切除术手术患者的数据。其中良性疾病186,148例、平均45岁，恶性肿瘤38,539例，平均54岁。其中包括腹腔镜/机器人手术、剖腹手术和经阴道手术等不同术式。术前准备包括肠道准备、口服抗生素、两者联合等不同策略。研究人员发现，肠道准备并没有降低手术部位感染、吻合口漏或其他并发症的发病率。在恶性肿瘤、开腹子宫切除术中，肠道准备、口服抗生素或肠道准备联合抗生素等几种策略，与不进行抗生素预防治疗的患者相比，感染发病率没有差异。结论：无论手术方式如何，肠道准备都不能预防手术部位感染或并发症，可以安全省略此步骤。妊娠期高血压妊娠>20周的女性新发高血压，但没有蛋白尿或新发靶器官功能障碍，则诊断为妊娠期高血压。根据2019年美国妇产科医师学会的建议，无论是否有其他表现，收缩压≥ 160mmHg和/或舒张压≥110mmHg，应直接诊断为“重度子痫前期”，即以前所说的“重度妊娠高血压”。更名的原因是，即使没有蛋白尿，妊娠诱发的重度血压升高也可能导致严重的不良事件。若产后≥12周后，血压仍高于正常，诊断为慢性高血压。妊娠期高血压最常用的降压药物包括：甲基多巴、拉贝洛尔、硝苯地平。尚有争议的药物包括：噻嗪类利尿剂、肼屈嗪、可乐定、硝普钠。妊娠期应避免使用的药物包括：ACEI、ARB、直接肾素抑制剂、盐皮质激素。《综述：他汀类药物在预防子痫前期中的作用》American Journal of Obstetrics and Gynecology，2020年8月 (5)子痫前期的确切原因尚不清楚，但普遍认为与胎盘异常释放可溶性抗血管生成因子有关，加之氧化应激和炎症反应的增加，导致母体全身内皮功能障碍。他汀类药物已被证明可以纠正类似的病理生理过程。普伐他汀，在各种临床前期和临床研究中显示，它可以逆转妊娠特异性的血管功能失衡，恢复内皮健康，防止氧化和炎症损伤。人类研究表明普伐他汀具有良好的安全性，而最近的证据不支持他汀类药物致畸的担忧。结论：他汀类药物在子痫前期预防性的使用，仍需大型随机对照研究支持。《荟萃分析：口服降压药对慢性高血压孕妇的疗效和安全性的比较》American Journal of Obstetrics and Gynecology，2020年10月 (6)此荟萃分析的目的是同时比较降压药对患有慢性高血压的孕妇的疗效和安全性。共纳入了22项研究，包括4464名女性。随机对照试验的分析表明，没有任何药物会显著影响先兆子痫的发生率。与安慰剂相比，阿替洛尔与小于胎龄儿（small for gestational age，SGA）的风险增加显著相关（风险比 26.00），而且被列为疗效最差的降压药。严重高血压的发生率在以下药物的干预下显著降低：硝苯地平风险比0.27，甲基多巴风险比0.31，吲哚洛尔风险比0.29，酮舍林风险比0.17。相比而言，严重高血压发生的概率最高的药物包括：速尿、氨氯地平和安慰剂。硝苯地平和甲基多巴能显著降低胎盘早剥率的风险（风险比 0.29和0.23）。各类降压药在剖宫产、围产期死亡、早产和分娩时胎龄方面无显著差异。结论：阿替洛尔与小于胎龄儿的风险显著增加有关。当使用硝苯地平和甲基多巴时，严重高血压的发生率显著降低。尽管在降压药中先兆子痫的风险是相似的，但未来仍需大规模研究为妊娠期降压药的选择和目标血压提供指导。《前瞻性观察队列研究：慢性高血压患者妊娠并发症与妊娠前母体心脏功能和结构有关》American Journal of Obstetrics and Gynecology，2020年9月 (7)约3%的妊娠合并为慢性高血压，这些产妇的分娩并发症发生率可高达25 - 28%。本研究的目的是通过超声心动图，评估妊娠前孕妇的心脏结构和功能，寻找其与分娩并发症以及妊娠前治疗的相关性。这项前瞻性观察队列研究，纳入192名长期接受降压治疗的孕妇，妊娠前改用甲基多巴，并随访至分娩。在192例患者中，出现24例早期并发症（

FDA 批准促性腺激素释放激素（GnRH）拮抗剂治疗子宫肌瘤导致的大量子宫出血NEJM 比较子宫动脉栓塞术与子宫肌瘤切除术治疗子宫肌瘤的疗效Cell 在孕妇中利用代谢动力学预测孕周和分娩时间恶拉戈利（elagolix）恶拉戈利（elagolix）是一种口服促性腺激素释放激素（GnRH）拮抗剂，既往用于治疗子宫内膜异位症引起的盆腔疼痛。2020年5月，美国FDA批准恶拉戈利用于治疗绝经前期、子宫肌瘤导致的大量子宫出血。《UF-1和UF-2研究：恶拉戈利治疗子宫肌瘤所致月经过多的治疗方案》New England Journal of Medicine，2020年1月 (1)研究旨在比较恶拉戈利300mg bid（单药治疗或联合雌激素-孕激素反加疗法）对子宫肌瘤的疗效。在两项相同的试验（UF-1和UF-2）中，月经过多（月经失血量＞80 mL）且经超声诊断为子宫肌瘤的总共790名女性（平均年龄42岁）被随机分组，分别接受6个月的恶拉戈利联合反加疗法、恶拉戈利单药治疗或安慰剂治疗。研究者通过收集生理用品的方式量化月经失血量。两项研究6个月后，84%和77%的单药治疗、68.5%和76.5%的恶拉戈利联合反加疗法和9%的安慰剂组达到主要终点（月经量50%）。主要不良反应是潮热和子宫出血，恶拉戈利联合反加治疗组的发生率显著高于安慰剂组。反加治疗法减轻了恶拉戈利的低雌激素效应，腰椎骨密度减少0.76%，低于恶拉戈利单药治疗组2.95%。结论：恶拉戈利单药治疗或联合雌-孕激素反加疗法均有效减轻子宫肌瘤相关的月经过多。恶拉戈利单药治疗与骨密度显著降低相关，反加治疗可以减少这种副作用。子宫肌瘤子宫肌瘤，是女性最常见的盆腔肿瘤，是起源于子宫平滑肌细胞和成纤维细胞的单克隆非癌性肿瘤。主要发生在育龄期妇女，可表现为异常子宫出血、盆腔疼痛/压迫感、生殖功能障碍（不孕或产科并发症）。大多数的子宫肌瘤会在生产后或绝经后自行萎缩；如果子宫肌瘤引起严重症状，则需治疗。对没有生育要求的患者，可行宫腔镜下切除粘膜下肌瘤；雌-孕激素避孕药；释放孕激素的宫内节育器；氨甲环酸；促性腺激素释放激素（GnRH）的激动剂和拮抗剂等。对于有生育要求的患者，药物大多会妨碍受孕，因此治疗首选微创手术切除。《行子宫动脉栓塞术与子宫肌瘤切除术治疗子宫肌瘤的比较》New England Journal of Medicine，2020年7月 (2)对于希望保留子宫、且药物治疗无效的女性，子宫肌瘤切除术和子宫动脉栓塞术是可选治疗方案。这项多中心、随机、开放标签试验，旨在评估症状性子宫肌瘤患者中使用子宫肌瘤切除术和子宫动脉栓塞术的疗效的比较。子宫肌瘤切除术的可选术式包括开腹、腹腔镜或宫腔镜手术。研究共招募了254名女性随机分组：子宫肌瘤切除术组和子宫动脉栓塞术。随访2年时，两组的生活质量评分分别为84.6分和80.0分（P=0.01）。在所有初次手术中，子宫肌瘤切除术组29%的女性和子宫动脉栓塞术组24%的女性发生了围手术期和术后并发症。结论：在有症状的子宫肌瘤患者中，接受子宫肌瘤切除术的女性在2年时的子宫肌瘤相关生活质量优于接受子宫动脉栓塞术的女性。《随机双盲对照试验：术前氨甲环酸减少子宫肌瘤切除术失血》American Journal of Obstetrics and Gynecology，2020年9月(3)氨甲环酸是一种合成赖氨酸衍生物，具有抗纤溶活性，用于其他外科学科，以减少手术期间的失血。本研究旨在探讨早期静脉注射氨甲环酸对子宫肌瘤切除术妇女围手术期出血和输血需求的影响。这项双盲、随机、安慰剂对照试验中，纳入有大出血风险的、症状性子宫肌瘤的女性共60人，随机分入干预组（手术前20分钟静脉注射氨甲环酸15 mg/kg）和安慰剂组（手术前静脉注射生理盐水）。这里有大出血风险定义为：（1）至少1个肌瘤≥10cm，（2）任何1个肌壁内或阔韧带肌瘤≥6cm，和/或（3）手术前影像学检查提示至少有5个肌瘤。患者中53%接受腹腔镜子宫肌瘤切除术，40%接受机器人子宫肌瘤切除术，7%接受采用剖腹手术。氨甲环酸组和安慰剂组中，中位估计失血量分别为200ml和240ml（P=0.88）；中位手术时间没有差异（165min 和 164min），围手术期血红蛋白改变也没有差异（1.00 和 1.1 g/dL）。氨甲环酸组的患者均不需要输血，但安慰剂组有4例需要输血。结论：术前静脉给予氨甲环酸在腹腔镜或机器人肌瘤切除过程中，与减少出血量无关。《术前肠道准备并不能减少子宫切除术后的感染》American Journal of Obstetrics and Gynecology，2020年8月 (4)关于妇科手术前肠道准备的文献很少，在子宫切除术前进行肠道准备主要是借鉴结直肠手术的经验。因此本研究的目的是比较子宫切除术前，与无肠道准备相比，单纯机械性肠准备、单纯口服抗生素或联合使用抗生素是否与手术部位感染或吻合口漏发生率降低有关。研究回顾性的分析了10余年间、共224,687例子宫切除术手术患者的数据。其中良性疾病186,148例、平均45岁，恶性肿瘤38,539例，平均54岁。其中包括腹腔镜/机器人手术、剖腹手术和经阴道手术等不同术式。术前准备包括肠道准备、口服抗生素、两者联合等不同策略。研究人员发现，肠道准备并没有降低手术部位感染、吻合口漏或其他并发症的发病率。在恶性肿瘤、开腹子宫切除术中，肠道准备、口服抗生素或肠道准备联合抗生素等几种策略，与不进行抗生素预防治疗的患者相比，感染发病率没有差异。结论：无论手术方式如何，肠道准备都不能预防手术部位感染或并发症，可以安全省略此步骤。妊娠期高血压妊娠>20周的女性新发高血压，但没有蛋白尿或新发靶器官功能障碍，则诊断为妊娠期高血压。根据2019年美国妇产科医师学会的建议，无论是否有其他表现，收缩压≥ 160mmHg和/或舒张压≥110mmHg，应直接诊断为“重度子痫前期”，即以前所说的“重度妊娠高血压”。更名的原因是，即使没有蛋白尿，妊娠诱发的重度血压升高也可能导致严重的不良事件。若产后≥12周后，血压仍高于正常，诊断为慢性高血压。妊娠期高血压最常用的降压药物包括：甲基多巴、拉贝洛尔、硝苯地平。尚有争议的药物包括：噻嗪类利尿剂、肼屈嗪、可乐定、硝普钠。妊娠期应避免使用的药物包括：ACEI、ARB、直接肾素抑制剂、盐皮质激素。《综述：他汀类药物在预防子痫前期中的作用》American Journal of Obstetrics and Gynecology，2020年8月 (5)子痫前期的确切原因尚不清楚，但普遍认为与胎盘异常释放可溶性抗血管生成因子有关，加之氧化应激和炎症反应的增加，导致母体全身内皮功能障碍。他汀类药物已被证明可以纠正类似的病理生理过程。普伐他汀，在各种临床前期和临床研究中显示，它可以逆转妊娠特异性的血管功能失衡，恢复内皮健康，防止氧化和炎症损伤。人类研究表明普伐他汀具有良好的安全性，而最近的证据不支持他汀类药物致畸的担忧。结论：他汀类药物在子痫前期预防性的使用，仍需大型随机对照研究支持。《荟萃分析：口服降压药对慢性高血压孕妇的疗效和安全性的比较》American Journal of Obstetrics and Gynecology，2020年10月 (6)此荟萃分析的目的是同时比较降压药对患有慢性高血压的孕妇的疗效和安全性。共纳入了22项研究，包括4464名女性。随机对照试验的分析表明，没有任何药物会显著影响先兆子痫的发生率。与安慰剂相比，阿替洛尔与小于胎龄儿（small for gestational age，SGA）的风险增加显著相关（风险比 26.00），而且被列为疗效最差的降压药。严重高血压的发生率在以下药物的干预下显著降低：硝苯地平风险比0.27，甲基多巴风险比0.31，吲哚洛尔风险比0.29，酮舍林风险比0.17。相比而言，严重高血压发生的概率最高的药物包括：速尿、氨氯地平和安慰剂。硝苯地平和甲基多巴能显著降低胎盘早剥率的风险（风险比 0.29和0.23）。各类降压药在剖宫产、围产期死亡、早产和分娩时胎龄方面无显著差异。结论：阿替洛尔与小于胎龄儿的风险显著增加有关。当使用硝苯地平和甲基多巴时，严重高血压的发生率显著降低。尽管在降压药中先兆子痫的风险是相似的，但未来仍需大规模研究为妊娠期降压药的选择和目标血压提供指导。《前瞻性观察队列研究：慢性高血压患者妊娠并发症与妊娠前母体心脏功能和结构有关》American Journal of Obstetrics and Gynecology，2020年9月 (7)约3%的妊娠合并为慢性高血压，这些产妇的分娩并发症发生率可高达25 - 28%。本研究的目的是通过超声心动图，评估妊娠前孕妇的心脏结构和功能，寻找其与分娩并发症以及妊娠前治疗的相关性。这项前瞻性观察队列研究，纳入192名长期接受降压治疗的孕妇，妊娠前改用甲基多巴，并随访至分娩。在192例患者中，出现24例早期并发症（

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.02.322917v1?rss=1 Authors: Green, A. J., Mohlenkamp, M. J., Das, J., Chaudhari, M., Truong, L., Tanguay, R. L., Reif, D. M. Abstract: There are currently 85,000 chemicals registered with the EPA under the Toxic Substances Control Act, but only a small fraction (~5%) have any measured toxicological data. To address this data gap, high-throughput screening (HTS) methods are vital. As part of one such HTS effort, embryonic zebrafish were used to examine a suite of morphological and mortality endpoints at six concentrations from over 1,000 unique chemicals found in the ToxCast library (phase 1 and 2). We hypothesized that by using a conditional Generative Adversarial Network (cGAN) and leveraging this large set of toxicity data, plus chemical structure information, we could efficiently predict toxic outcomes of untested chemicals. CAS numbers for each chemical were used to generate textual files containing three-dimensional structural information for each chemical in the Protein Data Bank (PDB) file format. Utilizing a novel method in this space, we converted the 3D structural information into a weighted set of points while retaining all information about the structure. The in vivo toxicity and chemical data were used to train two neural network generators. The first used regression to train a generator (Go-ZT) to produce toxicity data while the second utilized cGAN architecture to train a generator (GAN-ZT). Our results showed that both Go-ZT and GAN-ZT models produce similar results, but the cGAN achieved higher sensitivity (SE) value of 85.7% vs 71.4%. Conversely, Go-ZT attained a higher specificity (SP), positive predictive value (PPV), and Kappa results of 67.3%, 23.4%, and 0.21 compared to 24.5%, 14.0%, and 0.03 for the cGAN, respectively. By combining both Go-ZT and GAN-ZT, our consensus model improved the SP, PPV, and Kappa, to 75.5%, 25.0%, and 0.211, respectively, resulting in an area under the receiver operating characteristic (AUROC) of 0.663. Considering their potential use as efficient prescreening tools, these new models can provide in vivo toxicity predictions and insight into as-yet untested areas of chemical space to prioritize compounds for HT testing. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.16.299925v1?rss=1 Authors: Ziegler, J., Hechtman, J. F., Ptashkin, R., Jayakumaran, G., Middha, S., Chavan, S. S., Vanderbilt, C., DeLair, D., Casanova, J., Shia, J., DeGroat, N., Benayed, R., Ladanyi, M., Berger, M. F., Fuchs, T. J., Zehir, A. Abstract: Microsatellite instability (MSI) is a critical phenotype of cancer genomes and an FDA-recognized biomarker that can guide treatment with immune checkpoint inhibitors. Recent work has demonstrated that next-generation sequencing data can be used to identify samples with MSI-high phenotype. However, low tumor purity, as frequently observed in routine clinical samples, poses a challenge to the sensitivity of existing algorithms. To overcome this critical issue, we developed MiMSI, an MSI classifier based on deep neural networks and trained using a dataset that included low tumor purity MSI cases in a multiple instance learning framework. On a challenging yet representative set of cases, MiMSI showed higher sensitivity (0.940) and auROC (0.988) than MSISensor(sensitivity: 0.57; auROC: 0.911), an open-source software previously validated for clinical use at our institution using MSK-IMPACT large panel targeted NGS data. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.220483v1?rss=1 Authors: Rychkov, D., Neely, J., Oskotsky, T., Sirota, M. Abstract: Background/Purpose: There is an urgent need to identify effective biomarkers for early diagnosis of Rheumatoid Arthritis (RA) and accurate monitoring of disease activity. Here we define a RA meta-profile using publicly available cross-tissue gene expression data and apply machine learning to identify putative biomarkers, which we further validate on independent datasets. Methods: We carried out a comprehensive search for publicly available microarray gene expression data in the NCBI Gene Expression Omnibus database for whole blood and synovial tissues from RA patients and healthy controls. The raw data from 13 synovium datasets with 284 samples and 14 blood datasets with 1,885 samples were downloaded and processed. The datasets for each tissue were merged and batch corrected and split into training and test sets. We then developed and applied a robust feature selection pipeline to identify genes dysregulated in both tissues and highly associated with RA. From the training data we identified a set of overlapping differentially expressed genes following the condition of co-directionality. The classification performance of each gene in the resulting set was evaluated on the testing sets using AUROC. Five independent datasets were used to validate and threshold the feature selected (FS) genes. Finally, we define the RAScore, composed of a geometric mean of the selected RAScore Panel genes and demonstrate its clinical utility. Results: The result of the feature selection pipeline was a set of 25 upregulated and 28 downregulated genes. To assess the robustness of these feature selected genes, we trained a Random Forest machine learning model with this set of 53 genes and then with the set of 32 common differentially expressed genes and tested on the validation cohorts. The model with FS genes outperformed the model with common DE genes with AUC 0.89 +/- 0.04 vs 0.86 +/- 0.05. The FS genes were further thresholded on the 5 independent datasets resulting in 10 upregulated genes, TNFAIP6, S100A8, TNFSF10, DRAM1, LY96, QPCT, KYNU, ENTPD1, CLIC1, ATP6V0E1, that are involved in innate immune system pathways, including neutrophil degranulation and apoptosis and expressed in granulocytes, dendritic cells, and macrophages; and 3 downregulated genes, HSP90AB1, NCL, CIRBP, involved in metabolic processes and T-cell receptor regulation of apoptosis and expressed in lymphoblasts. To investigate the clinical utility of the 13 validated genes, the RA Score was developed and found to be highly correlated with DAS28 (r = 0.33 +/- 0.03, p = 7e-9) and able to distinguish OA and RA samples (OR 0.57, 95% CI [0.34, 0.80], p = 8e-10). Moreover, the RA Scores were not significantly different for RF-positive and RF-negative RA sub-phenotypes (p = 0.9) suggesting the generalizability of this score in clinical applications. The RA Score was also able to monitor the treatment effect among RA patients (t-test of treated vs untreated, p = 2e-4) and distinguish polyJIA from healthy individuals in 10 independent pediatric cohorts (OR 1.15, 95% CI [1.01, 1.3], p = 2e-4). Conclusion: The RAScore, consisting of 13 putative biomarkers, identified through a robust feature selection procedure on public data and validated using multiple independent data sets may be useful in the diagnosis and treatment monitoring of RA. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.24.060558v1?rss=1 Authors: Paranjpe, M. D., Belonwu, S., Wang, J. K., Oskotsky, T., Gupta, A., Taubes, A., Zalocusky, K., Paranjpe, I., Glicksberg, B. S., Huang, Y., Sirota, M. Abstract: In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls. Gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features revealed an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD. Copy rights belong to original authors. Visit the link for more info

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Host: Alka Goyal, MD Higher Postinduction Infliximab Serum Trough Levels Are Associated With Healing of Fistulizing Perianal Crohn’s Disease in Children. Wael El-Matary, MD, MSc Thomas D Walters, MD Hien Q Huynh, MDJennifer deBruyn, MD David R Mack, MD Kevan Jacobson, MD Mary E Sherlock, MDPeter Church, MD Eytan Wine, MD, PhD Matthew W Carroll, MD, Eric I Benchimol, MD, PhD Sally Lawrence, MD Anne M Griffiths, MD Background: There is some evidence in adults that higher serum infliximab (IFX) levels are needed to adequately treat fistulizing perianal Crohn's disease (CD). However, data in children are lacking. We aimed to determine postinduction serum trough IFX levels that are associated with healing of fistulizing perianal CD (PCD) at week 24. Methods: In a multicenter inception cohort study, consecutive children younger than age 17 years with fistulizing perianal CD treated with IFX between April 2014 and June 2017 who had serum trough IFX titers measured before the fourth infusion were included. Area under the receiver operating characteristic curve (AUROC) was calculated to determine the best cutoff to predict fistula ...

Podcast summary of articles from the May 2017 edition of Journal of Emergency Medicine from the American Academy of Emergency Medicine.  Topics include Ketamine for acute pain, qSOFA vs SIRS for sepsis, hypokalemia in  Cushing Syndrome, elevated liver enzymes, outpatient management of pulmonary embolisms, FEIBA for anticoagulation reversal, and board review on concussions.  Guest speakers include Dr. Courtney Smalley of the Cleveland Clinic Emergency Services Institute, and Dr. Allison Lane of the Banner University Medical Center in Tucson, Arizona

Integrating host and HBV characteristics, this study aimed to develop models for predicting long-term cirrhosis and hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV) patients. This analysis included hepatitis B surface antigen (HBsAg)-seropositive and anti-HCV-seronegative participants from the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer in HBV (R.E.V.E.A.L.-HBV) cohort. Newly developed cirrhosis and HCC were ascertained through regular follow-up ultrasonography, computerized linkage with national health databases, and medical chart reviews. Two-thirds of the participants were allocated for risk model derivation and another one-third for model validation. The risk prediction model included age, gender, HBV e antigen (HBeAg) serostatus, serum levels of HBV DNA, and alanine aminotransferase (ALT), quantitative serum HBsAg levels, and HBV genotypes. Additionally, the family history was included in the prediction model for HCC. Cox's proportional hazards regression coefficients for cirrhosis and HCC predictors were converted into risk scores. The areas under receiver operating curve (AUROCs) were used to evaluate the performance of risk models. Elder age, male, HBeAg, genotype C, and increasing levels of ALT, HBV DNA, and HBsAg were all significantly associated with an increased risk of cirrhosis and HCC. The risk scores estimated from the derivation set could accurately categorize participants with low, medium, and high cirrhosis and HCC risk in the validation set (P 

Drs. Stephen Harrison and Sudeep Tanwar Liver biopsy is the reference standard for the detection of nonalcoholic steatohepatitis (NASH) within nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify a biomarker of NASH in patients without significant fibrosis. In all, 172 patients from two centers with biopsy-proven NAFLD were included in this study. Eighty-four patients from a single center were included as a derivation cohort and 88 patients from a second center were included as a validation cohort. Serum samples were tested for candidate markers of fibrosis and inflammation alongside hematological and biochemical markers. Among patients without advanced fibrosis, terminal peptide of procollagen III (PIIINP) was the only marker found to be associated with a histological diagnosis of NASH in both cohorts. PIIINP also correlated with the total NAFLD activity score (NAS) and its constituent components (P < 0.001). Area under receiver operating characteristic curve (AUROC) for PIIINP in discriminating between NASH and simple steatosis (SS) was 0.77-0.82 in patients with F0-2 fibrosis and 0.82-0.84 in patients with F0-3 fibrosis. PIIINP was elevated in patients with advanced fibrosis, the overwhelming majority of whom had NASH. When incorporating patients with all degrees of fibrosis from both cohorts, PIIINP was able to discriminate between patients with SS and those with NASH or advanced fibrosis with AUROC 0.85-0.87. Conclusion: PIIINP discriminates between SS and NASH or advanced fibrosis. The use of a single biomarker in this context will be of clinical utility in detecting the minority of patients with NAFLD who have NASH or advanced fibrosis related to NASH.