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Antimicrobial drug resistance within ESKAPE pathogens is a formidable global challenge, necessitating innovative solutions. This review explores a multifaceted strategy incorporating nanotechnology, CRISPR/Cas9, and other cutting-edge approaches to effectively combat multidrug resistance in ESKAPE bacteria. Nanotechnology presents a promising avenue through targeted drug delivery systems like antibiotic nanoparticles and antibiotic–antibody conjugates (AACs). While these nanostructures aim to enhance therapeutic efficacy and mitigate resistance spread, challenges such as anti-PEG antibodies and optimal drug release must be considered. Inspired by successful anticancer nanomedicines, nanotechnology seeks to optimize drug penetration and retention within infected tissues. The revolutionary CRISPR/Cas9 gene-editing technology offers a precise and tailored approach by selectively targeting and modifying bacterial resistance genes. This holds the potential to reverse or eliminate drug resistance in ESKAPE pathogens, though challenges like off-target effects and efficient delivery mechanisms require attention for clinical translation. Additionally, alternative approaches such as fecal microbial transplantation, bacteriophage therapy, and probiotic bacterial replacement are actively explored in clinical trials. These strategies diversify the arsenal against antibiotic resistance by targeting unique vulnerabilities in ESKAPE pathogens. A comprehensive and multidisciplinary strategy is imperative to effectively address antimicrobial drug resistance in ESKAPE pathogens. Integration of nanotechnology, CRISPR/Cas9, and emerging approaches offers a synergistic solution, holding promise in overcoming the challenges posed by these resilient multidrug-resistant bacteria. This review provides insights into current research, challenges, and potential breakthroughs, emphasizing the urgency for collaborative efforts to safeguard global health.

Background: In a developing country such as India, intentional poisoning is associated with a high degree of morbidity and mortality. Historically, the use of agricultural poisons for attempted deliberate self-harm (DSH) has taken precedence. However, urbanization and stringent laws governing sale of agricultural chemicals, in recent years, may have shifted the focus of seekers toward commercially available therapeutic medications. Further, urbanization, high health-care seeking behavior, and poor regulation on sale of medicines, in Kerala, provide a conducive environment for such attempts. Aims and Objectives: The objective of this study was to determine the contribution of therapeutic medication toward acute poisoning as a means of DSH and the factors contributing to the same. Materials and Methods: Patients who obtained treatment for acute poisoning after DSH, between 2017 and 2023, were screened, those who employed therapeutic medication for the same were further determined. Sociodemographic details, clinical profile, and history of previous such attempts and treatment history including toxicological screening report were gathered and analyzed. Results: In our study of 154 patients arriving at the emergency department with history of DSH, 41% used therapeutic medicines for the same. Majority were women (75%) and most had a high school education (64%) or above. The most common agents were determined as paracetamol (23%) and benzodiazepine (10.6%). Tox screen was performed for 45% of patients. Organ failure developed in 36% patients with drug levels above and 42% of those with levels below the therapeutic range. However, 48% of those who did not undergo toxicological screening developed organ failure. Organ failure developed in 42% of patients, with acute liver injury being the most common culprit (25%). Management was symptomatic unless an antidote was available. Conclusion: Prescription drugs utilization for DSH was common in women and patients with higher educational status. Over-the-counter drugs and psychiatric medication were frequently used. Lack of prompt access to healthcare may contribute to organ failure. Tox-screen is recommended for drug detection.

This study investigates the feasibility of using grape biodiesel from the wine industry as a sustainable and cost-effective alternative to traditional fuels. The research focuses on optimizing key parameters like blend ratio, injection timing, injection pressure, engine load, and exhaust gas recirculation in a Common Rail Direct Injection engine to achieve low emissions without compromising performance. Due to grape biodiesel's higher viscosity, different energy content, and varying ignition delays compared to diesel, precise adjustments are essential for complete combustion and reduced emissions. This study uses response surface methodology and a Central Composite Design matrix to find the best values for a number of parameters in modern CRDI engines that use advanced electronic control units. Through fifty input combinations, the study aims to minimize specific fuel consumption, hydrocarbons, nitrogen oxides, and carbon monoxide while maximising brake thermal efficiency, brake mean effective pressure, and mechanical efficiency. The optimal configuration includes a fuel injection timing of 6° bTDC, an engine load of 82 %, 6.7 % EGR, 1000 bar injection pressure, and a 33 % grape biodiesel blend. These optimum input conditions yielded outputs of 3.55 bar BMEP, 31.85 % BTE, 64 % mechanical efficiency, 0.278 kg/kWh SFC, 0.127 % CO, 357 ppm NOx, and 8 ppm of HC. These adjustments ensure low emissions and efficient engine operation, highlighting grape biodiesel's potential as a viable alternative fuel.

In this contribution, we propose a hybrid interaction technique that integrates near-field and object-space interaction techniques for manipulating objects at a distance in virtual reality (VR). The objective of the hybrid interaction technique was to seamlessly leverage the strengths of both the near-field and object-space manipulation techniques. We employed bimanual near-field metaphor with scaled replica (BMSR) as our near-field interaction technique, which enabled us to perform multilevel degrees-of-freedom (DoF) separation transformations, such as 1~3DoF translation, 1~3DoF uniform and anchored scaling, 1DoF and 3DoF rotation, and 6DoF simultaneous translation and rotation, with enhanced depth perception and fine motor control provided by near-field manipulation techniques. The object-space interaction technique we utilized was the classic Scaled HOMER, which is known to be effective and appropriate for coarse transformations in distant object manipulation. In a repeated measures within-subjects evaluation, we empirically evaluated the three interaction techniques for their accuracy, efficiency, and economy of movement in pick-and-place, docking, and tunneling tasks in VR. Our findings revealed that the near-field BMSR technique outperformed the object space Scaled HOMER technique in terms of accuracy and economy of movement, but the participants performed more slowly overall with BMSR. Additionally, our results revealed that the participants preferred to use the hybrid interaction technique, as it allowed them to switch and transition seamlessly between the constituent BMSR and Scaled HOMER interaction techniques, depending on the level of accuracy, precision and efficiency required.

Design discussion is crucial in the architectural design process. To enhance the spatial understanding of 3D space and discussion effectiveness, recently, some systems have been proposed to support design discussion interactively in an immersive virtual environment. The entire design discussion can be archived and potentially become course materials for future learners. In this paper, we propose an asynchronous VR exploration system that aims to help learners explore content effectively and efficiently anywhere and at any time. To improve effectiveness and efficiency, we also propose a summarization-to-detail approach with the application space by which students can observe the visualization of spatial summarization of actions and participants’ dwell time or the temporal distribution of dialogues and then locate the important or interesting region or dialogue for further exploration. To further explore the discussion content, students can call the preview to see the time-lapse animation of the object operation to understand the change in models or playback to view the discussion details. We conducted an exploratory user study with 10 participants to evaluate user experience, user impression, and effectiveness of learning the design discussion course content using our asynchronous VR design discussion content exploration system. The results indicate that the interactive VR exploration system presented can help learners study the design discussion content effectively. Participants also provided some positive feedback and confirmed the usefulness and value of the system presented. Our applications and lessons learned have implications for future asynchronous VR exploration systems, not only for architectural design discussion content, but also for other applications, such as industrial visual inspections and educational visualizations of design discussions.

Abstract Over the last two decades, the frontline therapy for mantle cell lymphoma (MCL) has evolved. However, the impact of subsequent lines of therapy on survival outcomes has not been well characterized. In this study, we investigated the treatment patterns and survival outcomes in patients with relapsed/refractory (R/R) MCL treated with second-line (2 L) therapy. Adult patients with newly diagnosed MCL from 2002 to 2015 were enrolled in a prospective cohort study. Clinical characteristics, 2 L treatment details, and outcomes were compared between patients who received 2 L treatment between 2003–2009 (Era 1), 2010–2014 (Era 2), and 2015–2021 (Era 3). 2 L treatment was heterogenous in all eras, and there was a substantial shift in the pattern of 2 L therapy over time. The estimated 2-year EFS rate was 21% (95% CI, 13–35), 40% (95% CI, 30–53), and 51% (95% CI, 37–68) in Era 1–3 respectively, and the 5-year OS rate was 31% (95% CI, 21–45), 37% (95% CI, 27–50), and 67% (95% CI, 54–83) in Era 1–3, respectively. These results provide real-world evidence on evolving treatment patterns of 2 L therapy based on the era of relapse. The changes in 2 L treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with R/R MCL.

Key Clinical Message Spontaneous intracerebral hemorrhage commonly affects the brainstem. This report describes a 31‐year‐old male with hypertension who developed a pontine hemorrhage. The neurological deficits included left‐third nerve palsy, right‐sided weakness, and disabling tinnitus. Tinnitus is linked to central auditory pathway disruption. Magnetic resonance imaging revealed the hemorrhagic lesion and additional micro‐hemorrhages. The International Classification of Functioning, Disability, and Health (ICF) enhances rehabilitation by characterizing multifaceted stroke disability. The ICF profile revealed impairments in body structures/functions, limitations in activities/participation, and positive/negative environmental factors. ICF‐based goal‐setting informed interventions, including tinnitus retraining and physical/occupational therapy. Comprehensive ICF assessment is crucial for optimized, patient‐centered post‐stroke rehabilitation as it determines the extent of impact on functional level of the patient irrespective of disease severity.

In this case series, we evaluated the efficacy and safety of uterine artery embolization (UAE) using N-butyl- 2-cyanoacrylate (NBCA)/glue for the treatment of uterine artery pseudoaneurysm (UAP). Here, we report 8 patients with uterine artery pseudoaneurysm, who underwent UAE using NBCA/glue. Angiograms and medical records were retrospectively analyzed to determine the technical success, clinical success, complications, average procedure time, the average duration of hospital stay after UAE. All patients were presented with secondary postpartum hemorrhage with hemodynamic instability. The technical and clinical success rates were 100%, respectively. The average procedure time was 21minutes and the average duration of hospital stay was 2.2 days. We did not encounter any major complications. Two patients following UAE were naturally conceived and delivered by repeat LSCS. UAE using NBCA/glue is a safe and effective treatment option for UAP in both hemodynamically stable and unstable patients.

Rift Valley fever (RVF) in ungulates and humans is caused by a mosquito-borne RVF phlebovirus (RVFV). Live attenuated vaccines are used in livestock (sheep and cattle) to control RVF in endemic regions during outbreaks. The ability of two or more different RVFV strains to reassort when co-infecting a host cell is a significant veterinary and public health concern due to the potential emergence of newly reassorted viruses, since reassortment of RVFVs has been documented in nature and in experimental infection studies. Due to the very limited information regarding the frequency and dynamics of RVFV reassortment, we evaluated the efficiency of RVFV reassortment in sheep, a natural host for this zoonotic pathogen. Co-infection experiments were performed, first in vitro in sheep-derived cells, and subsequently in vivo in sheep. Two RVFV co-infection groups were evaluated: group I consisted of co-infection with two wild-type (WT) RVFV strains, Kenya 128B-15 (Ken06) and Saudi Arabia SA01-1322 (SA01), while group II consisted of co-infection with the live attenuated virus (LAV) vaccine strain MP-12 and a WT strain, Ken06. In the in vitro experiments, the virus supernatants were collected 24 h post-infection. In the in vivo experiments, clinical signs were monitored, and blood and tissues were collected at various time points up to nine days post-challenge for analyses. Cell culture supernatants and samples from sheep were processed, and plaque-isolated viruses were genotyped to determine reassortment frequency. Our results show that RVFV reassortment is more efficient in co-infected sheep-derived cells compared to co-infected sheep. In vitro, the reassortment frequencies reached 37.9% for the group I co-infected cells and 25.4% for the group II co-infected cells. In contrast, we detected just 1.7% reassortant viruses from group I sheep co-infected with the two WT strains, while no reassortants were detected from group II sheep co-infected with the WT and LAV strains. The results indicate that RVFV reassortment occurs at a lower frequency in vivo in sheep when compared to in vitro conditions in sheep-derived cells. Further studies are needed to better understand the implications of RVFV reassortment in relation to virulence and transmission dynamics in the host and the vector. The knowledge learned from these studies on reassortment is important for understanding the dynamics of RVFV evolution.

Legionnaires’ disease was first detected in 1976 when an outbreak occurred in Philadelphia, USA. The number of cases reported to the Centre for Disease Control (CDC) has been on the rise since 2000, likely due to expanded diagnostic testing and public awareness of symptoms. There was a notable decline of confirmed cases during the first years of the COVID-19 pandemic. Surveillance is important to understand the transmission, pathogenesis, and complications, and to quickly identify the outbreaks, new cases and epidemiologic links between cases. The EPIWATCH system scans vast amounts of open-source data to supplement surveillance when there is a lack of available case data. EPIWATCH reported approximately 28 cases during September to December 2020, 349 cases in 2021 and 114 cases during January to October 2022, which is a decrease in case numbers, possibly due to underreporting during the ongoing COVID-19 pandemic. Annual case numbers may be 1.8 to 2.7 times higher than reported, due to potential underdiagnosis and the requirement for confirmation of infection source before a diagnosis can be made. Key words: Legionella; Legionnaires' disease; outbreak, USA

The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro, and in vivo analyses, we report that topoisomerase 1 (TOP1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of topotecan (TPT), an FDA-approved TOP1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as 4 days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of TOP1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing TOP1 inhibitors for severe coronavirus disease 2019 (COVID-19) in humans.

Splenic artery aneurysms (SAAs) are commonly related to high flow in the splenic artery and can remain asymptomatic for a long time. However, their natural course is a progressive increase in size, so treatment is always indicated if their size is >2 cm and even if they are asymptomatic. Endovascular treatment of these aneurysms is successful and safe either as an alternative to or as an adjunct to surgery. We present a case of SAA in a patient of noncirrhotic portal hypertension treated successfully by an endovascular Amplatzer plug followed by surgery.

Shape Memory Alloys (SMAs) are a class of metallic alloys that have the ability to return to their original shape after being deformed. NiTi (nickel–titanium) alloy a type of shape memory alloy that possesses unique properties such as remembering its shape, biocompatibility, and super-elasticity. These SMAs have the ability to deform when heated and regain their original shape when allowed to cool. The disadvantage of a fuse is that it can only be used once. By replacing a wire that melts with a NiTi shape memory alloy, we can turn it into a switch that opens when an excessive current (which leads to an increase in temperature of the wire) is applied. Magnets keep the circuit closed. When the wire heats up, the spring-shaped coil shrinks, which opens the circuit. The circuit can then be closed manually once the problems are rectified.

The objective of this work was to evaluate the safety and efficacy of a recombinant, subunit SARS-CoV-2 animal vaccine in cats against virulent SARS-CoV-2 challenge. Two groups of cats were immunized with two doses of either a recombinant SARS-CoV-2 spike protein vaccine or a placebo, administered three weeks apart. Seven weeks after the second vaccination, both groups of cats were challenged with SARS-CoV-2 via the intranasal and oral routes simultaneously. Animals were monitored for 14 days post-infection for clinical signs and viral shedding before being humanely euthanized and evaluated for macroscopic and microscopic lesions. The recombinant SARS-CoV-2 spike protein subunit vaccine induced strong serologic responses post-vaccination and significantly increased neutralizing antibody responses post-challenge. A significant difference in nasal and oral viral shedding, with significantly reduced virus load (detected using RT-qPCR) was observed in vaccinates compared to mock-vaccinated controls. Duration of nasal, oral, and rectal viral shedding was also significantly reduced in vaccinates compared to controls. No differences in histopathological lesion scores were noted between the two groups. Our findings support the safety and efficacy of the recombinant spike protein-based SARS-CoV-2 vaccine which induced high levels of neutralizing antibodies and reduced nasal, oral, and rectal viral shedding, indicating that this vaccine will be efficacious as a COVID-19 vaccine for domestic cats.

The present work is the novel examination of influence of welding process parameters and material flow on the mechanical and microstructural characteristics during the FSSW of dissimilar AA2024/AA7075 joint were evaluated and compared with similar AA2024/AA2024 and similar AA7075/AA7075 FSSW joints. The microstructural and physical properties of two aluminum alloy joined through friction stir spot welding (FSSW) were examined. The aluminum alloys namely AA2024-T3 and AA7075-T6 were selected for the investigation owing to their typical and potential applications in aeronautical industry. The input parameters were tool rotational speed, plunge depth and dwell time (TRS 1800 rpm, 3.3 mm plunge depth and 45 s dwell time) were utilized. The microstructure of the welded specimen was investigated by scanning electron microscope and their chemical compositions were analyzed by energy-dispersive X-ray spectroscopy. The physical properties were investigated by Vickers microhardness survey and the specimen strength evaluated by tensile tests. The experimental investigation revealed the influence of the tool pin penetration and frictional heat on the microstructure, distribution of the grain structure affecting the microhardness and the tensile properties of the dissimilar joint.

Abstract A novel bio adsorbent was fabricated from turmeric, polyvinyl alcohol and carboxymethyl cellulose for MB dye removal. The physicochemical, antibacterial and biodegradable nature of the film was evaluated using scanning electron microscopy, optical microscopy, universal testing machine, water contact angle, thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray diffraction, agar disc diffusion method and soil degradability. The inclusion of turmeric into PVA/CMC film improves the biodegradability, antibacterial activity and thermomechanical property of the films. PVA/CMC/TUR film displayed good MB adsorption capacity (qe: 6.27 mg/g) and maximum dye adsorption (R%; 83%) and was achieved at initial dye concentration of 10 mg/L with contact time 170 min at room temperature. The adsorption data of MB on PVA/CMC/TUR film was evaluated using four models Langmuir, Freundlich, Temkin and D-R isotherms. The different kinetic of adsorption (pseudo-first order, pseudo-second order and intraparticle diffusion model) was also applied for adsorption of MB on the films. The experimental result suggests that PVA/CMC/TUR films are an alternate cheap adsorbent for water treatment.

Abstract Natural killer T (NKT) cells activated with the glycolipid ligand α-galactosylceramide (α-GalCer) stimulate a wide variety of immune cells that enhance vaccine-mediated immune responses. Several studies have used this approach to adjuvant inactivated and subunit influenza A virus (IAV) vaccines, including to enhance cross-protective influenza immunity. However, less is known about whether α-GalCer can enhance live attenuated influenza virus (LAIV) vaccines, which usually induce superior heterologous and heterosubtypic immunity compared to non-replicating influenza vaccines. The current study used the swine influenza challenge model to assess whether α-GalCer can enhance cross-protective immune responses elicited by a recombinant H3N2 LAIV vaccine (TX98ΔNS1) encoding a truncated NS1 protein. In one study, weaning pigs were administered the H3N2 TX98ΔNS1 LAIV vaccine with 0, 10, 50, and 100 μg/kg doses of α-GalCer, and subsequently challenged with a heterologous H3N2 virus. All treatment groups were protected from infection. However, the addition of α-GalCer appeared to suppress nasal shedding of the LAIV vaccine. In another experiment, pigs vaccinated with the H3N2 LAIV, with or without 50 μg/kg of α-GalCer, were challenged with the heterosubtypic pandemic H1N1 virus. Pigs vaccinated with the LAIV alone generated cross-reactive humoral and cellular responses which blocked virus replication in the airways, and significantly decreased virus shedding. On the other hand, combining the vaccine with α-GalCer reduced cross-protective cellular and antibody responses, and resulted in higher virus titers in respiratory tissues. These findings suggest that: (i) high doses of α-GalCer impair the replication and nasal shedding of the LAIV vaccine; and (ii) α-GalCer might interfere with heterosubtypic cross-protective immune responses. This research raise concerns that should be considered before trying to use NKT cell agonists as a possible adjuvant approach for LAIV vaccines.

Abstract Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p