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CDC announces the availability of a new heptavalent botulinum antitoxin (HBAT, Cangene Corporation) through a CDC-sponsored Food and Drug Administration (FDA) Investigational New Drug (IND) protocol. HBAT replaces a licensed bivalent botulinum antitoxin AB and an investigational monovalent botulinum antitoxin E (BAT-AB and BAT-E, Sanofi Pasteur) with expiration of these products on March 12, 2010. As of March 13, 2010, HBAT became the only botulinum antitoxin available in the United States for naturally occurring noninfant botulism.
Nanomedicine is a relatively new and rapidly evolving field combining nanotechnology with the biomedical and pharmaceutical sciences.1-3 Nanoparticles (NPs) can impart many pharmacokinetic, efficacy, safety, and targeting benefits when they are included in drug formulations.1-5 Many nanodrugs have entered clinical practice, and even more are being investigated in clinical trials for a wide variety of indications.2 However, nanopharmaceuticals also face challenges, such as the need for better characterization, possible toxicity issues, a lack of specific regulatory guidelines, cost-benefit considerations, and waning enthusiasm among some health care professionals. 4,5 For these reasons, expectations regarding nanodrugs that are in early stages of development or clinical trials need to remain realistic.4.
Non-canonical phenomena - defined here as observables which are either insufficiently characterized by existing theory, or otherwise represent inconsistencies with prior observations - are of burgeoning interest in the field of astrophysics, particularly due to their relevance as potential signs of past and/or extant life in the universe (e.g. off-nominal spectroscopic data from exoplanets). However, an inherent challenge in investigating such phenomena is that, by definition, they do not conform to existing predictions, thereby making it difficult to constrain search parameters and develop an associated falsifiable hypothesis. In this Expert Recommendation, the authors evaluate the suitability of two different approaches - conventional parameterized investigation (wherein experimental design is tailored to optimally test a focused, explicitly parameterized hypothesis of interest) and the alternative approach of anomaly searches (wherein broad-spectrum observational data is collected with the aim of searching for potential anomalies across a wide array of metrics) - in terms of their efficacy in achieving scientific objectives in this context. The authors provide guidelines on the
IMPORTANCE: Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research. OBJECTIVE: To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results. DESIGN, SETTING, AND PARTICIPANTS: Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product. MAIN OUTCOMES AND MEASURES: For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval. RESULTS: Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved. CONCLUSIONS AND RELEVANCE: Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.
Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.
SPHEREx is a NASA mission designed to perform an all-sky spectroscopic survey in the 0.75 - 5 $μ$m wavelength range. Its primary science objectives are to investigate: (1) inflationary cosmology, (2) the history of galaxy formation, and (3) the abundance of molecular ices - critical for prebiotic chemistry - found on the surfaces of interstellar dust grains within planet-forming regions. This paper focuses on the third theme, the SPHEREx Ices investigation, for which SPHEREx is conducting a spectroscopic survey of nearly ten million preselected sources throughout the Milky Way and Magellanic Clouds to characterize their ice absorption features. By selecting targets based on infrared color, spatial isolation, and brightness, the Ices Investigation secures high-signal-to-noise spectra across a broad range of astrophysical environments that are relatively free of spectral contamination. Rather than attempting to decompose each spectrum into its individual ice components, the Ices Investigation prioritizes accurate measurements of the integrated optical depths of key molecular ice absorption features. This approach enables statistically powerful correlation studies between ice abundanc
Security analysts are overwhelmed by the volume of alerts and the low context provided by many detection systems. Early-stage investigations typically require manual correlation across multiple log sources, a task that is usually time-consuming. In this paper, we present an experimental, agentic workflow that leverages large language models (LLMs) augmented with predefined queries and constrained tool access (structured SQL over Suricata logs and grep-based text search) to automate the first stages of alert investigation. The proposed workflow integrates queries to provide an overview of the available data, and LLM components that selects which queries to use based on the overview results, extracts raw evidence from the query results, and delivers a final verdict of the alert. Our results demonstrate that the LLM-powered workflow can investigate log sources, plan an investigation, and produce a final verdict that has a significantly higher accuracy than a verdict produced by the same LLM without the proposed workflow. By recognizing the inherent limitations of directly applying LLMs to high-volume and unstructured data, we propose combining existing investigation practices of real-
Investigations are a significant step in the operational workflows for large scale systems across multiple domains such as services, data, AI/ML, mobile. Investigation processes followed by on-call engineers are often manual or rely on ad-hoc scripts. This leads to inefficient investigations resulting in increased time to mitigate and isolate failures/SLO violations. It also contributes to on-call toil and poor productivity leading to multiple hours/days spent in triaging/debugging incidents. In this paper, we present DrP, an end-to-end framework and system to automate investigations that reduces the mean time to resolve incidents (MTTR) and reduces on-call toil. DrP consists of an expressive and flexible SDK to author investigation playbooks in code (called analyzers), a scalable backend system to execute these automated playbooks, plug-ins to integrate playbooks into mainstream workflows such as alerts and incident management tools, and a post-processing system to take actions on investigations including mitigation steps. We have implemented and deployed DrP at large scale at Meta covering 300+ teams, 2000+ analyzers, across a large set of use cases across domains such as service
While Dense Retrieval Models (DRMs) have advanced Information Retrieval (IR), one limitation of these neural models is their narrow generalizability and robustness. To cope with this issue, one can leverage the Mixture-of-Experts (MoE) architecture. While previous IR studies have incorporated MoE architectures within the Transformer layers of DRMs, our work investigates an architecture that integrates a single MoE block (SB-MoE) after the output of the final Transformer layer. Our empirical evaluation investigates how SB-MoE compares, in terms of retrieval effectiveness, to standard fine-tuning. In detail, we fine-tune three DRMs (TinyBERT, BERT, and Contriever) across four benchmark collections with and without adding the MoE block. Moreover, since MoE showcases performance variations with respect to its parameters (i.e., the number of experts), we conduct additional experiments to investigate this aspect further. The findings show the effectiveness of SB-MoE especially for DRMs with a low number of parameters (i.e., TinyBERT), as it consistently outperforms the fine-tuned underlying model on all four benchmarks. For DRMs with a higher number of parameters (i.e., BERT and Contriev
In this article, we investigate the alignment of Large Language Models according to human preferences. We discuss the features of training a Preference Model, which simulates human preferences, and the methods and details we found essential for achieving the best results. We also discuss using Reinforcement Learning to fine-tune Large Language Models and describe the challenges we faced and the ways to overcome them. Additionally, we present our experience with the Direct Preference Optimization method, which enables us to align a Large Language Model with human preferences without creating a separate Preference Model. As our contribution, we introduce the approach for collecting a preference dataset through perplexity filtering, which makes the process of creating such a dataset for a specific Language Model much easier and more cost-effective.
XAI (eXplanable AI) techniques that have the property of explaining the reasons for their conclusions, i.e. explainability or interpretability, are attracting attention. XAI is expected to be used in the development of forensic science and the justice system. In today's forensic and criminal investigation environment, experts face many challenges due to large amounts of data, small pieces of evidence in a chaotic and complex environment, traditional laboratory structures and sometimes inadequate knowledge. All these can lead to failed investigations and miscarriages of justice. In this paper, we describe the application of one logical approach to crime scene investigation. The subject of the application is ``The Adventure of the Speckled Band'' from the Sherlock Holmes short stories. The applied data is the knowledge graph created for the Knowledge Graph Reasoning Challenge. We tried to find the murderer by inferring each person with the motive, opportunity, and method. We created an ontology of motives and methods of murder from dictionaries and dictionaries, added it to the knowledge graph of ``The Adventure of the Speckled Band'', and applied scripts to determine motives, opport
Law-enforcement investigations aimed at preventing attacks by violent extremists have become increasingly important for public safety. The problem is exacerbated by the massive data volumes that need to be scanned to identify complex behaviors of extremists and groups. Automated tools are required to extract information to respond queries from analysts, continually scan new information, integrate them with past events, and then alert about emerging threats. We address challenges in investigative pattern detection and develop an Investigative Pattern Detection Framework for Counterterrorism (INSPECT). The framework integrates numerous computing tools that include machine learning techniques to identify behavioral indicators and graph pattern matching techniques to detect risk profiles/groups. INSPECT also automates multiple tasks for large-scale mining of detailed forensic biographies, forming knowledge networks, and querying for behavioral indicators and radicalization trajectories. INSPECT targets human-in-the-loop mode of investigative search and has been validated and evaluated using an evolving dataset on domestic jihadism.
In this paper we investigate two logics from an algebraic point of view. The two logics are: MALL (multiplicative-additive Linear Logic) and LL (classical Linear Logic). Both logics turn out to be strongly algebraizable in the sense of Blok and Pigozzi and their equivalent algebraic semantics are, respectively, the variety of Girard algebras and the variety of girales. We show that any variety of girales has equationally definable principale congruences and we classify all varieties of Girard algebras having this property. Also we investigate the structure of the algebras in question, thus obtaining a representation theorem for Girard algebras and girales. We also prove that congruence lattices of girales are really congruence lattices of Heyting algebras and we construct examples in order to show that the variety of girales contains infinitely many nonisomorphic finite simple algebras.
Meta-analyses are commonly performed based on random-effects models, while in certain cases one might also argue in favour of a common-effect model. One such case may be given by the example of two "study twins" that are performed according to a common (or at least very similar) protocol. Here we investigate the particular case of meta-analysis of a pair of studies, e.g. summarizing the results of two confirmatory clinical trials in phase III of a clinical development programme. Thereby, we focus on the question of to what extent homogeneity or heterogeneity may be discernible, and include an empirical investigation of published ("twin") pairs of studies. A pair of estimates from two studies only provides very little evidence on homogeneity or heterogeneity of effects, and ad-hoc decision criteria may often be misleading.
Fraud across the decentralized finance (DeFi) ecosystem is growing, with victims losing billions to DeFi scams every year. However, there is a disconnect between the reported value of these scams and associated legal prosecutions. We use open-source investigative tools to (1) investigate potential frauds involving Ethereum tokens using on-chain data and token smart contract analysis, and (2) investigate the ways proceeds from these scams were subsequently laundered. The analysis enabled us to (1) uncover transaction-based evidence of several rug pull and pump-and-dump schemes, and (2) identify their perpetrators' money laundering tactics and cash-out methods. The rug pulls were less sophisticated than anticipated, money laundering techniques were also rudimentary and many funds ended up at centralized exchanges. This study demonstrates how open-source investigative tools can extract transaction-based evidence that could be used in a court of law to prosecute DeFi frauds. Additionally, we investigate how these funds are subsequently laundered.
Imitation learning often needs a large demonstration set in order to handle the full range of situations that an agent might find itself in during deployment. However, collecting expert demonstrations can be expensive. Recent work in vision, reinforcement learning, and NLP has shown that auxiliary representation learning objectives can reduce the need for large amounts of expensive, task-specific data. Our Empirical Investigation of Representation Learning for Imitation (EIRLI) investigates whether similar benefits apply to imitation learning. We propose a modular framework for constructing representation learning algorithms, then use our framework to evaluate the utility of representation learning for imitation across several environment suites. In the settings we evaluate, we find that existing algorithms for image-based representation learning provide limited value relative to a well-tuned baseline with image augmentations. To explain this result, we investigate differences between imitation learning and other settings where representation learning has provided significant benefit, such as image classification. Finally, we release a well-documented codebase which both replicates
This thesis presents techniques to investigate transactions in uncharted cryptocurrencies and services. Cryptocurrencies are used to securely send payments online. Payments via the first cryptocurrency, Bitcoin, use pseudonymous addresses that have limited privacy and anonymity guarantees. Research has shown that this pseudonymity can be broken, allowing users to be tracked using clustering and tagging heuristics. Such tracking allows crimes to be investigated. If a user has coins stolen, investigators can track addresses to identify the destination of the coins. This, combined with an explosion in the popularity of blockchain, has led to a vast increase in new coins and services. These offer new features ranging from coins focused on increased anonymity to scams shrouded as smart contracts. In this study, we investigated the extent to which transaction privacy has improved and whether users can still be tracked in these new ecosystems. We began by analysing the privacy-focused coin Zcash, a Bitcoin-forked cryptocurrency, that is considered to have strong anonymity properties due to its background in cryptographic research. We revealed that the user anonymity set can be considerabl
Neural Networks have been proved to work as decoders in telecommunications, so the ways of making it efficient will be investigated in this thesis. The different parameters to maximize the Neural Network Decoder's efficiency will be investigated. The parameters will be tested for inversion errors only.
A bizarre planetary pairing 190 light-years away is challenging everything astronomers thought they knew about how worlds form。 A “lonely” hot Jupiter — typically found without nearby companions — is sharing its system with a smaller mini-Neptune tucked even closer to the star, a setup once thought nearly impossible
The plan isn't final and could change, but his ouster would be no surprise