Single-arm phase 3 designs: An oxymoron?

BACKGROUND: Since the 1950s, randomized clinical trials (RCTs) have served as the gold standard for confirming the benefits of a new drug. Accordingly, phase 3 trials, the last steps in the evaluation process for a new drug, have been recommended to all be RCTs. Nevertheless, single-arm phase 3 trials still appear to be in use. METHODS: We performed a PubMed search to identify the use of a single-arm design in phase 3 trials, excluding only non-English articles. Three categories were distinguished: past use of an RCT, of any other trial design, or no previous trial; and according to diagnosis (oncology, infection, others). RESULTS: A total of 176 single-arm phase 3 trials (19 oncology, 43 infections and 114 others) were identified by the search, with exponential growth since 1994, in parallel with that of RCTs. Among them, 64 (36%) were preceded by an RCT, 58 (33%) by a non-randomized trial, and 54 (31%) had no previous trial, with no main influence of the diagnosis setting. Justification of the design was reported in 30 (18%) of those trials, with ethical concerns comprising one-third of those justifications. This was similar in the 14 single-arm phase 2-3 trials, with about one-third in each group, and 17% justification of a non-comparative design. CONCLUSION: The use of a single-arm phase 3 trial is heterogeneous, ranging from first trials up to confirmatory trials after a previously conducted RCT. Justification for these single-arm designs as confirmatory evidence should be more clearly reported, along with potential sources of bias.

Swarm Metaverse for Multi-Level Autonomy Using Digital Twins.

Robot swarms are becoming popular in domains that require spatial coordination. Effective human control over swarm members is pivotal for ensuring swarm behaviours align with the dynamic needs of the system. Several techniques have been proposed for scalable human-swarm interaction. However, these techniques were mostly developed in simple simulation environments without guidance on how to scale them up to the real world. This paper addresses this research gap by proposing a metaverse for scalable control of robot swarms and an adaptive framework for different levels of autonomy. In the metaverse, the physical/real world of a swarm symbiotically blends with a virtual world formed from digital twins representing each swarm member and logical control agents. The proposed metaverse drastically decreases swarm control complexity due to human reliance on only a few virtual agents, with each agent dynamically actuating on a sub-swarm. The utility of the metaverse is demonstrated by a case study where humans controlled a swarm of uncrewed ground vehicles (UGVs) using gestural communication, and via a single virtual uncrewed aerial vehicle (UAV). The results show that humans could successfully control the swarm under two different levels of autonomy, while task performance increases as autonomy increases.

Maternal and infant outcomes of Syrian and Palestinian refugees, Lebanese and migrant women giving birth in a tertiary public hospital in Lebanon: a secondary analysis of an obstetric database.

OBJECTIVES: This study aims to assess whether the characteristics, management and outcomes of women varied between Syrian and Palestinian refugees, migrant women of other nationalities and Lebanese women giving birth at a public tertiary centre in Beirut, Lebanon. METHODS: This was a secondary data analysis of routinely collected data from the public Rafik Hariri University Hospital (RHUH) between January 2011 and July 2018. Data were extracted from medical notes using text mining machine learning methods. Nationality was categorised into Lebanese, Syrian, Palestinian and migrant women of other nationalities. The main outcomes were diabetes, pre-eclampsia, placenta accreta spectrum, hysterectomy, uterine rupture, blood transfusion, preterm birth and intrauterine fetal death. Logistic regression models estimated the association between nationality and maternal and infant outcomes, and these were presented using ORs and 95% CIs. RESULTS: 17 624 women gave birth at RHUH of whom 54.3% were Syrian, 39% Lebanese, 2.5% Palestinian and 4.2% migrant women of other nationalities. The majority of women had a caesarean section (73%) and 11% had a serious obstetric complication. Between 2011 and 2018, there was a decline in the use of primary caesarean section (caesarean section performed for the first time) from 7% to 4% of births (p<0.001). The odds of preeclampsia, placenta abruption and serious complications were significantly higher for Palestinian and migrant women of other nationalities compared to Lebanese women, but not for Syrian women. Very preterm birth was higher for Syrians (OR: 1.23, 95% CI: 1.08 to 1.40) and migrant women of other nationalities (OR: 1.51, 95% CI: 1.13 to 2.03) compared to Lebanese women. CONCLUSION: Syrian refugees in Lebanon had similar obstetric outcomes compared to the host population, except for very preterm birth. However, Palestinian women and migrant women of other nationalities appeared to have worse pregnancy complications than the Lebanese women. There should be better healthcare access and support for migrant populations to avoid severe complications of pregnancy.

Pomegranate juice and punicalagin-mediated chemoprevention of hepatocellular carcinogenesis via regulating miR-21 and NF-κB-p65 in a rat model.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common neoplasm among primary liver malignancies, accounting for 70%-85% of total liver cancer cases worldwide. It is also the second-leading cause of cancer-related death worldwide. Recent research has investigated naturally occurring products high in polyphenolic compounds in the regression and prevention of HCC. This study investigated the chemoprevention effects of pomegranate juice (PJ) and punicalagin (PCG) against diethylnitrosamine (DENA)-induced hepatocarcinogenesis in male albino rats. METHODS: Animals were randomized into six groups and treated for 11 weeks as follows: group 1 was a negative control group, group 2 was treated orally with 10 mL PJ per kilogram body weight (kg bw), group 3 was treated orally with 18.5 mg PCG/kg bw, and groups 4-6 were injected with an intraperitoneal dose of DENA (50 mg/kg bw) weekly beginning in the third week. Group 4 was a HCC control (DENA-treated group), group 5 was HCC + PJ, and group 6 was HCC + PCG. RESULTS: PJ antagonized DENA-induced elevations of ALAT, TNF-α, NF-κB-p65, GST, MDA, and NO and restored total protein, IL-10, SOD, and CAT levels. Moreover, PJ resulted in downregulation of miR-21, Bcl-2, and Bcl-XL and an upregulation of caspase-3 and Bax mRNA expressions. These chemoprevention effects of PJ also alleviated the hepatic preneoplastic lesions induced by DENA. Although PCG treatment induced some modulation in DENA-treated rats, it did not show potent chemoprevention activity and induced some side effects. CONCLUSION: Both of PJ and PCG downregulated miR-21 expression and triggered apoptosis. However, PJ was more effective than pure PCG in alleviating the hepatic antioxidant defense state and the inflammatory status. So, PJ was superior in prevention of DENA-induced hepatocellular carcinogenesis in rats than pure PCG.

Characterization of Indicators for Adaptive Human-Swarm Teaming.

Swarm systems consist of large numbers of agents that collaborate autonomously. With an appropriate level of human control, swarm systems could be applied in a variety of contexts ranging from urban search and rescue situations to cyber defence. However, the successful deployment of the swarm in such applications is conditioned by the effective coupling between human and swarm. While adaptive autonomy promises to provide enhanced performance in human-machine interaction, distinct factors must be considered for its implementation within human-swarm interaction. This paper reviews the multidisciplinary literature on different aspects contributing to the facilitation of adaptive autonomy in human-swarm interaction. Specifically, five aspects that are necessary for an adaptive agent to operate properly are considered and discussed, including mission objectives, interaction, mission complexity, automation levels, and human states. We distill the corresponding indicators in each of the five aspects, and propose a framework, named MICAH (i.e., Mission-Interaction-Complexity-Automation-Human), which maps the primitive state indicators needed for adaptive human-swarm teaming.

Prevalence of common carbapenemase genes and multidrug resistance among uropathogenic Escherichia coli phylogroup B2 isolates from outpatients in Wasit Province/ Iraq.

Carbapenems are the last resort antimicrobials for the treatment of extended spectrum ß-lactamases (ESBLs) producing Enterobacteriaceae. Emergence of carbapenems resistant group B2 uropathogenic E. coli (UPEC) is a major concern because of their high virulence. Prevalence of these enzymes and multidrug resistance (MDR) among B2 UPEC isolates from Iraqi outpatients with acute urinary tract infection (UTI) was evaluated in this research. Urine cultures were performed and the isolates were identified biochemically. Escherichia coli isolates were tested for phylogroup reference by quadraplex PCR, then B2 isolates were detected for antimicrobial resistance by disc diffusion test and carbapenemase genes by PCR. Escherichia coli was the most prevalent among Gram-negative isolates (66.6%) and B2 was the most detected phylogroup among E. coli isolates (33.9%). Most of B2 isolates showed high resistance rates to tested antimicrobials, especially ß-lactams with MDR revealed in 100% of them. Whereas, low resistance rates were noted against carbapenems, aminoglycosides and nitrofurantoin. Carbapenemase genes were detected in 76.3% of B2 isolates. Of which, blaOXA-48 was the most frequent (57.8%), followed by blaPER (47.3%), blaKPC (15.7%), blaVEB and blaVIM (10.5%, for each). Whereas, blaGES and blaIMP genes were not found. Coproduction of these genes occurred among 17 isolates. The combination of blaOXA-48 and blaPER was the most frequent (41.1%). All carbapenemase producing isolates were MDR. These results revealed high prevalence of carbapenemase genes and MDR among B2 UPEC recovered in this study. In the study area. it is strongly advised to use aminoglycosides and nitrofurantoin for empirical treatment of UPEC.

A model of symbiomemesis: machine education and communication as pillars for human-autonomy symbiosis.

Symbiosis is a physiological phenomenon where organisms of different species develop social interdependencies through partnerships. Artificial agents need mechanisms to build their capacity to develop symbiotic relationships. In this paper, we discuss two pillars for these mechanisms: machine education (ME) and bi-directional communication. ME is a new revolution in artificial intelligence (AI) which aims at structuring the learning journey of AI-enabled autonomous systems. In addition to the design of a systematic curriculum, ME embeds the body of knowledge necessary for the social integration of AI, such as ethics, moral values and trust, into the evolutionary design and learning of the AI. ME promises to equip AI with skills to be ready to develop logic-based symbiosis with humans and in a manner that leads to a trustworthy and effective steady-state through the mental interaction between humans and autonomy; a state we name symbiomemesis to differentiate it from ecological symbiosis. The second pillar, bi-directional communication as a discourse enables information to flow between the AI systems and humans. We combine machine education and communication theory as the two prerequisites for symbiosis of AI agents and present a formal computational model of symbiomemesis to enable symbiotic human-autonomy teaming. This article is part of the theme issue 'Towards symbiotic autonomous systems'.

The reliability and transparency bases of trust in human-swarm interaction: principles and implications.

Automation reliability and transparency are key factors for trust calibration and as such can have distinct effects on human reliance behaviour and mission performance. One question that remains unexplored is: what are the implications of reliability and transparency on trust calibration for human-swarm interaction? We investigate this research question in the context of human-swarm interaction, as swarm systems are becoming more popular for their robustness and versatility. Thirty-two participants performed swarm-based tasks under different reliability and transparency conditions. The results indicate that trust, whether it is reliability- or transparency-based, indicates high reliance rates and shorter response times. Reliability-based trust is negatively correlated with correct rejection rates while transparency-based trust is positively correlated with these rates. We conclude that reliability and transparency have distinct effects on trust calibration. Practitioner Summary: Reliability and transparency have distinct effects on trust calibration. Findings from our human experiments suggest that transparency is a necessary design requirement if and when humans need to be involved in the decision-loop of human-swarm systems, especially when swarm reliability is high. Abbreviations: HRI: human-robot interaction; IOS: inter-organisational systems; LMM: liner mixed models; MANOVA: multivariate analysis of variance; UxV: heterogeneous unmanned vehicles; UAV: unmanned aerial vehicle.

Trust Mediating Reliability-Reliance Relationship in Supervisory Control of Human-Swarm Interactions.

OBJECTIVE: This work aims to further test the theory that trust mediates the interdependency between automation reliability and the rate of human reliance on automation. BACKGROUND: Human trust in automation has been the focus of many research studies. Theoretically, trust has been proposed to impact human reliance on automation by mediating the relationship between automation reliability and the rate of human reliance. Experimentally, however, the results are contradicting as some confirm the mediating role of trust, whereas others deny it. Hence, it is important to experimentally reinvestigate this role of trust and understand how the results should be interpreted in the light of existing theory. METHOD: Thirty-two subjects supervised a swarm of unmanned aerial vehicles (UAVs) in foraging missions in which the swarm provided recommendations on whether or not to collect potential targets, based on the information sensed by the UAVs. By manipulating the reliability of the recommendations, we observed changes in participants' trust and their behavioral responses. RESULTS: A within-subject mediation analysis revealed a significant mediation role of trust in the relationship between swarm reliability and reliance rate. High swarm reliability increased the rate of correct acceptances, but decreased the rate of correct rejections. No significant effect of reliability was found on response time. CONCLUSION: Trust is not a mere by-product of the interaction; it possesses a predictive power to estimate the level of reliance on automation. APPLICATION: The mediation role of trust confirms the significance of trust calibration in determining the appropriate level of reliance on swarm automation.

Effects of pomegranate aril juice and its punicalagin on some key regulators of insulin resistance and oxidative liver injury in streptozotocin-nicotinamide type 2 diabetic rats.

Nowadays, medicinal plants have been widely used everywhere to provide essential care for many disorders including diabetes. Recent reports assumed that the antidiabetic activities of pomegranate aril juice (PAJ) may be ascribed to its punicalagin (PCG). Therefore, the present study evaluated and compared the antidiabetic activities of PAJ and its PCG, and monitored some mechanisms of their actions in streptozotocin-nicotinamide (STZ-NA) type 2 diabetic rats. STZ-NA diabetic rats were given, orally/daily, PAJ (100 or 300 mg/kg body weight, containing 2.6 and 7.8 mg of PCG/kg body weight, respectively), pure PCG (2.6 or 7.8 mg/kg body weight), or distilled water (vehicle) for 6 weeks. PAJ (especially at the high dose) alleviated significantly (P < 0.05-0.001) most signs of type 2 diabetes including body-weight loss, insulin resistance (IR) and hyperglycemia through decreasing serum tumor necrosis factor-α concentration and the expression of hepatic c-Jun N-terminal kinase, and increasing the skeletal muscle weight and the expression of hepatic insulin receptor substrate-1 in STZ-NA diabetic rats. Also, it decreased significantly (P < 0.001) the oxidative liver injury in STZ-NA diabetic rats through decreasing the hepatic lipid peroxidation and nitric oxide production, and improving the hepatic antioxidant defense system. Although the low dose of PCG induced some modulation in STZ-NA diabetic rats, the high dose of PCG did not show any valuable antidiabetic activity, but induced many side effects. In conclusion, PAJ was safer and more effective than pure PCG in alleviating IR and oxidative liver injury in STZ-NA diabetic rats.

On asphericity of convex bodies in linear normed spaces.

In 1960, Dvoretzky proved that in any infinite dimensional Banach space X and for any [Formula: see text] there exists a subspace L of X of arbitrary large dimension ϵ-iometric to Euclidean space. A main tool in proving this deep result was some results concerning asphericity of convex bodies. In this work, we introduce a simple technique and rigorous formulas to facilitate calculating the asphericity for each set that has a nonempty boundary set with respect to the flat space generated by it. We also give a formula to determine the center and the radius of the smallest ball containing a nonempty nonsingleton set K in a linear normed space, and the center and the radius of the largest ball contained in it provided that K has a nonempty boundary set with respect to the flat space generated by it. As an application we give lower and upper estimations for the asphericity of infinite and finite cross products of these sets in certain spaces, respectively.