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In 2021, two US military hospitals, Landstuhl Regional Medical Center in Landstuhl, Germany, and Walter Reed National Military Medical Center (WRNMMC) in Bethesda, Maryland, USA, observed a high prevalence of multidrug-resistant bacteria among refugees evacuated from Afghanistan during Operation Allies Refuge. Multidrug-resistant isolates collected from 80 patients carried an array of antimicrobial resistance genes, including carbapenemases (blaNDM-1, blaNDM-5, and blaOXA-23) and 16S methyltransferases (rmtC and rmtF). Considering the rising transmission of antimicrobial resistance and unprecedented population displacement globally, these data are a reminder of the need for robust infection control measures and surveillance.

Atlantic wakame (AW) and sea lettuce (SL) are edible seaweeds commonly produced in Asia and Europe, typically consumed as fresh or dried biomass. Because of the short shelf life, developing new post-harvest treatments, such as the extraction of bioactive compounds, is essential for establishing reliable macroalgae supply chains for food applications. This study aims to develop a sustainable and functional seaweed-based food ingredient rich in bioactive compounds for functional food applications. The results indicated that ultrasound-assisted extraction using 70% ethanol for 10 min was optimal for both SL (410±23 mg of gallic acid equivalent [GAE] per kg) and AW (666±63 mg GAE/kg). Both extracts exhibited chemical antioxidant activity and inhibited the protection of human plasma against chemically induced oxidation. SL extract did not exhibit free radical scavenging activity (DPPH). Importantly, no cytotoxicity (IC50>250 µg/mL) was observed in human-derived THP-1, HUVEC, HT-29, and HepG2 cell lines, ensuring the relative safety of these extracts for potential food technology applications. AW and SL extracts (100 µg/mL) reduced intracellular reactive oxygen species generation in lipopolysaccharide (LPS)-challenged THP-1 cells by 66% and 30%, respectively, highlighting the higher antioxidant activity of AW extract. AW and SL extracts did not modulate TNF-α and IL-6 secretion to show anti-inflammatory activity. Gummies infused with AW and SL extracts had a higher total phenolic content than commercial products, but their antioxidant activity was lower. Sensory evaluation revealed that gummies containing seaweed extracts received lower scores for colour, taste, overall impression, and purchase intention than those without extracts.

Abstract Background Malaria remains the top infectious disease threat facing the U.S. military in many forward operating environments. Compliance with malaria chemoprophylaxis remains a critical component in preventing malaria in the deployed Service Member. Studies of previous military operations show that compliance is consistently higher with weekly versus daily dosing regimens. Current FDA approved weekly chemoprophylaxis options have contraindications that can limit prescribing. The combination of chloroquine (CQ) with azithromycin (AZ) has previously been shown to be an efficacious treatment option for malaria, has pharmacokinetics compatible with weekly dosing, and has shown synergy when combined in vitro. Methods In this open label study, 18 healthy volunteers, aged 18–50 years (inclusive), were randomly assigned to receive either 300 mg CQ or 300 mg CQ and 2 gm azithromycin (CQAZ) of directly observed therapy, weekly for 3 weeks prior to undergoing mosquito bite challenge with chloroquine-resistant Plasmodium falciparum. Volunteers that remained asymptomatic and had no evidence of parasitaemia continued to receive weekly post-exposure chemoprophylaxis for 3 weeks following malaria challenge. The primary endpoint was the number of volunteers that remained asymptomatic and had no evidence of parasitaemia 28 days after the malaria challenge. Results All 6 (100%) volunteers randomized to the CQ control group became symptomatic with parasitaemia during the 28-day post-challenge period. Only 1/12 (8.3%) of volunteers in the CQAZ group developed symptoms and parasitaemia during the 28-day post-challenge period. However, after chemoprophylaxis was discontinued an additional 6 volunteers developed parasitaemia between days 28–41 after challenge, with 4 of 6 experiencing symptoms. 80% of subjects in the CQAZ group experienced treatment related gastrointestinal adverse events (including 13% that experienced severe nausea) compared to 38% in the CQ group. A comparison of the pharmacokinetics in the CQAZ group demonstrated higher azithromycin Cmax (p = 0.03) and AUC (p = 0.044) levels in those volunteers who never became parasitaemic compared to those who did. Conclusion Given the high rate of side effects and poor efficacy when administered for 3 weeks before and after challenge, the combination of weekly chloroquine and azithromycin is a suboptimal regimen combination for weekly malaria chemoprophylaxis. Trial registration ClinicalTrials.gov NCT03278808

Recent technological advances have made the gathering of comprehensive gene expression datasets a commodity. This has shifted the limiting step of transcriptomic studies from the accumulation of data to their analyses and interpretation. The main problem in analyzing transcriptomics data is that the number of independent samples is typically much lower (14,000). To address this, it would be desirable to reduce the gathered data's dimensionality without losing information. Clustering genes into discrete modules is one of the most commonly used tools to accomplish this task. While there are multiple clustering approaches, there is a lack of informative metrics available to evaluate the resultant clusters' biological quality. Here we present a metric that incorporates known ground truth gene sets to quantify gene clusters' biological quality derived from standard clustering techniques. The GECO (Ground truth Evaluation of Clustering Outcomes) metric demonstrates that quantitative and repeatable scoring of gene clusters is not only possible but computationally lightweight and robust. Unlike current methods, it allows direct comparison between gene clusters generated by different clustering techniques. It also reveals that current cluster analysis techniques often underestimate the number of clusters that should be formed from a dataset, which leads to fewer clusters of lower quality. As a test case, we applied GECO combined with k-means clustering to derive an optimal set of co-expressed gene modules derived from PBMC, which we show to be superior to previously generated modules generated on whole-blood. Overall, GECO provides a rational metric to test and compare different clustering approaches to analyze high-dimensional transcriptomic data.

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers. Keywords: NF-κB, GADD45β, Multiple myeloma, Cancer, Pharmacology

The increased incidence of whooping cough worldwide suggests that current vaccination against Bordetella pertussis infection has limitations in quality and duration of protection. The resurgence of infection has been linked to the introduction of acellular vaccines (aP), which have an improved safety profile compared with the previously used whole-cell (wP) vaccines. To determine immunological differences between aP and wP priming in infancy, we performed a systems approach of the immune response to booster vaccination. Transcriptomic, proteomic, cytometric, and serologic profiling revealed multiple shared immune responses with different kinetics across cohorts, including an increase of blood monocyte frequencies and strong antigen-specific IgG responses. Additionally, we found a prominent subset of aP-primed individuals (30%) with a strong differential signature, including higher levels of expression for CCL3, NFKBIA, and ICAM1. Contrary to the wP individuals, this subset displayed increased PT-specific IgE responses after boost and higher antigen-specific IgG4 and IgG3 antibodies against FHA and FIM2/3 at baseline and after boost. Overall, the results show that, while broad immune response patterns to Tdap boost overlap between aP- and wP-primed individuals, a subset of aP-primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.

Cannabis is one of the most commonly used recreational drugs worldwide. Rrecent epidemiology studies have linked increased cardiac complications to cannabis use. However, this literature is predominantly based on case incidents and post-mortem investigations. This study elucidates the molecular mechanism of Δ9-tetrahydrocannabinol (THC), and its primary metabolites 11-Hydroxy-Δ9-THC (THC-OH) and 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (THC-COOH). Treatment of cardiac myocytes with THC-OH and THC-COOH increased cell migration and proliferation (p < 0.05), with no effect on cell adhesion, with higher doses (250–100 ng/mL) resulting in increased cell death and significant deterioration in cellular architecture. Conversely, no changes in cell morphology or viability were observed in response to THC. Expression of key ECM proteins α-SMA and collagen were up-regulated in response to THC-OH and THC-COOH treatments with concomitant modulation of PI3K and MAPK signalling. Investigations in the planarian animal model Polycelis nigra demonstrated that treatments with cannabinoid metabolites resulted in increased protein deposition at transection sites while higher doses resulted in significant lethality and decline in regeneration. These results highlight that the key metabolites of cannabis elicit toxic effects independent of the parent and psychoactive compound, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Cocaine is one of the most widely abused illicit drugs worldwide and has long been recognised as an agent of cardiac dysfunction in numerous cases of drug overdose. Cocaine has previously been shown to up-regulate cytoskeletal rearrangements and morphological changes in numerous tissues; however, previous literature observes such changes primarily in clinical case reports and addiction studies. An investigation into the fundamental cytoskeletal parameters of migration, adhesion and proliferation were studied to determine the cytoskeletal and cytotoxic basis of cocaine in cardiac cells. Treatment of cardiac myocytes with cocaine increased cell migration and adhesion (p < 0.05), with no effect on cell proliferation, except with higher doses eliciting (1–10 μg/mL) its diminution and increase in cell death. Cocaine downregulated phosphorylation of cofilin, decreased expression of adhesion modulators (integrin-β3) and increased expression of ezirin within three hours of 1 μg/mL treatments. These functional responses were associated with changes in cellular morphology, including alterations in membrane stability and a stellate-like phenotype with less compaction between cells. Higher dose treatments of cocaine (5–10 μg/mL) were associated with significant cardiomyocyte cell death (p < 0.05) and loss of cellular architecture. These results highlight the importance of cocaine in mediating cardiomyocyte function and cytotoxicity associated with the possible loss of intercellular contacts required to maintain normal cell viability, with implications for cardiotoxicity relating to hypertrophy and fibrogenesis.

Transcription factors of the nuclear factor κB (NF-κB) family are central coordinating regulators of the host defence responses to stress, injury and infection. Aberrant NF-κB activation also contributes to the pathogenesis of some of the most common current threats to global human health, including chronic inflammatory diseases, autoimmune disorders, diabetes, vascular diseases and the majority of cancers. Accordingly, the NF-κB pathway is widely considered an attractive therapeutic target in a broad range of malignant and non-malignant diseases. Yet, despite the aggressive efforts by the pharmaceutical industry to develop a specific NF-κB inhibitor, none has been clinically approved, due to the dose-limiting toxicities associated with the global suppression of NF-κB. In this review, we summarise the main strategies historically adopted to therapeutically target the NF-κB pathway with an emphasis on oncology, and some of the emerging strategies and newer agents being developed to pharmacologically inhibit this pathway.

Understanding how technostressors lead to technostrain, such as high job burnout or low job performance, has become a core question in information systems (IS) research and practice. To unpack this relationship, we build on general systems theory to argue that the next step for technostress research is to go beyond examining the independent influences of technostressors and discuss how their interdependencies lead to technostrain. To illustrate our argument empirically, we use fuzzy-set qualitative comparative analysis (fsQCA) and identify four configurations of high- and low-intensity technostressors that lead to high job burnout and one that leads to low job performance. We show that three types of interdependencies among technostressors, i.e., complementarity, contingency, and substitution, form configurations that lead to technostrain. Within these configurations, high-intensity technostressors can mutually enhance their effects and low-intensity technostressors can buffer the impact of other high-intensity technostressors on technostrain. The results help to explain why organizational interventions that address independent technostressors may fail if they do not account for the interdependencies among technostressors. Our work provides evidence of the need to further develop theories that explain how and why interdependencies among technostressors lead to technostrain. [ABSTRACT FROM AUTHOR]

While IT workforce research often examines job- and organizational-related reasons for turnover, studies rarely connect the immediate social context of IT work to IT professionals' workplace behavior. To understand the influence of the immediate social context, we develop a social comparison model that connects the social influence of co-worker who have left an organization to turnover among IT professionals who remain. We test our model using a social network of 4,011 IT professionals employed in a large IT firm over four years. We complement our analysis of this data with a multiple-case study with five software development teams. Across the two studies, our results suggest that the departure of an IT professional increases the probability of turnover among remaining coworkers; further, we found that turnover is even more likely when the remaining IT professionals are similar in technical abilities and demographic attributes to the co-worker who left. Our results direct attention to the immediate social context as an influence on the turnover behavior of IT professionals and explain how similarity in domain-specific attributes shapes this turnover behavior. Practitioners should know that a single departure may cause a chain reaction in IT work teams and organizations and find suggestions for assigning new employees. [ABSTRACT FROM AUTHOR]

The adoption of new Information Technology (IT) innovations has led to increased uncertainty among employees, a greater demand for security measures, and more entry points for cyber-attacks, which all increase the risk of data breaches for firms. Despite the prevalence of discussions around this issue, there has been a lack of empirical research examining the data breach risk associated with IT innovations. To address this gap, we have developed arguments based on an organizational learning theoretical framework that explains how IT innovativeness can exacerbate data breach risk. Through our analysis of a sample of data breaches that occurred between 2013 and 2021, we have discovered that there is a positive association between firm IT innovativeness and the risk of data breaches. We also find that the effects of IT innovativeness can vary under certain conditions. For example, we find that the positive relationship between IT innovativeness and data breach risk is mitigated when managers possess IT expertise or when firms have established extensive board connections with cybersecurity managers. Moreover, we find that the relationship between IT innovativeness and data breach risk is amplified in complex environments but not in dynamic or munificent ones. This study takes the lead in advancing the theoretical understanding and empirical validation of security-related risks associated with IT innovations. Moreover, our findings serve as a timely reminder for research and practice to carefully consider the implications of introducing novel technologies into firms and the potential dark side consequences that may arise. Additionally, this study underscores the importance of understanding organizational learning in risk assessment and change management, as well as the critical role of contextual factors in moderating the unintended security-related consequences linked to IT innovations. [ABSTRACT FROM AUTHOR]

Employees want to be able to telework and organisations want to provide the ideal environment to make it a success story. While some teleworkers experience telework success, that is, are satisfied and perform well, others do not. To understand the drivers of successful and unsuccessful telework, we used a mixed methods approach, taking a stress‐theoretic and configurational perspective. In Study 1, we conducted a quantitative analysis of data collected in a survey of 375 teleworkers to identify configurations of information and communication technology (ICT), work and family related challenge and hindrance stressors that lead to high and low telework success. In Study 2, we analysed qualitative data collected in interviews with 52 teleworkers to shed light on the interplay among ICT, work and family related challenge and hindrance stressors in the configurations that lead to high and low telework success. We contribute to telework research by showing that high and low telework success results from configurations of ICT, work and family related challenge and hindrance stressors. We extend the literature by showing that teleworkers benefit from challenge stressors only when they do not experience hindrance stressors. Methodologically, we provide a blueprint for an innovative approach using deductive fsQCA to refine, extend and delimit theory. [ABSTRACT FROM AUTHOR]