Qualitative Analysis of Inquiries Received by FDA Regarding Conduct of Clinical Trials during the Covid-19 Public Health Emergency.

BACKGROUND: This report describes the U.S. Food and Drug Administration (FDA) experience in establishing a dedicated mailbox, and in publishing related guidance, to address concerns among interested parties regarding the conduct of clinical trials during the COVID-19 public health emergency (PHE). METHODS: Six hundred and thirty-four mailbox inquiries were received from March 2020 through February 2022. Qualitative methods were used to provide a structured description of, and identify common themes among, these inquiries. RESULTS: Most inquiries came from U.S.-based interested parties, including sponsors, industry trade associations, academic institutions, hospitals, clinics, research sites, trial participants, and individual persons. Approximately one-fifth of questions were related directly to COVID-19 (e.g., proposals for treatment); other inquiries were related to conduct of routine trial-related activities, and concerns were often focused on maintaining compliance with good clinical practice. In March 2020, FDA published a guidance titled Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency; the document was subsequently revised eight times based in part on issues raised in mailbox inquiries. CONCLUSIONS: The dedicated mailbox enabled expedited communication among invested parties during the COVID-19 PHE; FDA also provided updates of the aforementioned guidance. These efforts supported the continuance of ongoing trials and the initiation of new trials during the PHE in accordance with good clinical practice guidelines, thereby helping to ensure the safety of trial participants while maintaining the quality of trial data. By soliciting and responding to trial-related inquiries and addressing corresponding needs and concerns, FDA improved transparency and communication.

Ethanolic extract from fruiting bodies of Cordyceps militaris HL8 exhibits cytotoxic activities against cancer cells, skin pathogenic yeasts, and postharvest pathogen Penicillium digitatum.

Cordyceps militaris is a well-known medicinal mushroom in Asian countries. This edible fungus has been widely exploited for traditional medicine and functional food production. C. militaris is a heterothallic fungus that requires both the mating-type loci, MAT1-1 and MAT1-2, for fruiting body formation. However, recent studies also indicated two groups of C. militaris, including monokaryotic strains carrying only MAT1-1 in their genomes and heterokaryotic strains harboring both MAT1-1 and MAT1-2. These strain groups are able to produce fruiting bodies under suitable cultivating conditions. In previous work, we showed that monokaryotic strains are more stable than heterokaryotic strains in fruiting body formation through successive culturing generations. In this study, we report a high cordycepin-producing monokaryotic C. militaris strain (HL8) collected in Vietnam. This strain could form normal fruiting bodies with high biological efficiency and contain a cordycepin content of 14.43 mg/g lyophilized fruiting body biomass. The ethanol extraction of the HL8 fruiting bodies resulted in a crude extract with a cordycepin content of 69.15 mg/g. Assays of cytotoxic activity on six human cancer cell lines showed that the extract inhibited the growth of all these cell lines with the IC50 values of 6.41-11.51 µg/mL. Notably, the extract significantly reduced cell proliferation and promoted apoptosis of breast cancer cells. Furthermore, the extract also exhibited strong antifungal activity against Malassezia skin yeasts and the citrus postharvest pathogen Penicillium digitatum. Our work provides a promising monokaryotic C. militaris strain as a bioresource for medicine, cosmetics, and fruit preservation.

Enhancing engineering optimization using hybrid sine cosine algorithm with Roulette wheel selection and opposition-based learning.

Meta-heuristic algorithms distinguish themselves from conventional optimization methods owing to their intrinsic adaptability and straightforward implementation. Among them, the sine cosine algorithm (SCA) is lauded for its ability to transition seamlessly between exploration and exploitation phases throughout the optimization process. However, there exists potential for enhancing the balance that SCA maintains between exploration and exploitation. To augment the proficiency in global optimization of SCA, an innovative strategy-nSCA-that integrates the roulette wheel selection (RWS) with opposition-based learning was formulated. The robustness of nSCA was rigorously evaluated against leading-edge methods such as the genetic algorithm (GA), particle swarm optimization, moth-flame optimization, ant lion optimization, and multi-verse optimizer, as well as the foundational SCA. This evaluation included benchmarks set by both CEC 2019 and CEC 2021 test functions. Additionally, the performance of nSCA was confirmed through numerous practical optimization problems, emphasizing its effectiveness in applied settings. In all evaluations, nSCA consistently showcased superior performance compared to its evolutionary algorithm counterparts, delivering top-tier solutions for both benchmark functions and real-world optimization challenges. Given this compelling evidence, one can posit that nSCA serves as a strong candidate for addressing intricate optimization challenges found in real-world contexts, regardless of whether they are of a discrete or continuous nature.

Hybrid whale optimization algorithm for enhanced routing of limited capacity vehicles in supply chain management.

The present study focuses on the problem of vehicle routing with limited capacity, with the objective of minimizing the transportation distance required to serve h clients with predetermined locations and needs. The aim is to create k trips that cover the shortest possible distance. To achieve this goal, a hybrid whale optimization algorithm (hGWOA) is proposed, which combines the whale optimization algorithm (WOA) with the grey wolf optimizer (GWO). The proposed hybrid model is comprised of two main steps. First step, the GWO's hunting mechanism is integrated transitioning to the utilization phase of WOA, and a newly devised state is introduced that is linked to GWO. In the second step, a novel technique is incorporated into the exploration mission phase to enhance the resolve after per iteration. The algorithm's performance is assessed and compared with other modern algorithms, including the GWO, WOA, ant lion optimizer (ALO), and dragonfly algorithm (DA) using 23 benchmark test functions and CEC2017 benchmark test function. The results indicate that the hybrid hGWOA method outperforms other algorithms in terms of delivery distance optimization for scenarios involving scale and complexity. These findings are corroborated through case studies related to cement delivery and a real-world scenario in Viet Nam.

Using Free Chimeric Anterolateral Thigh Flap For Reconstruction Of Composite Dorsal Hand Defect.

Background: Simultaneous repair of the extensor tendons and soft tissues in hand injuries remains challenging. The free chimeric anterolateral thigh (ALT) flap with fascia lata (FL) flap represents an alternative for hand reconstruction. This report describes the reconstruction of the extensor tendon and skin defects using free chimeric ALT flaps with FL. Methods: Eight patients (one female and seven male) underwent reconstruction of complex hand defects with free chimeric ALT and FL flaps. The defects were caused by crushing injuries, burns, snakebite scars, and animal bite wounds. The average skin defect was 116 cm2. Perforators were selected for the skin paddle and the FL flap. The thinning procedure was performed microsurgically. Results: The skin paddle size ranged from 12 to 23 cm in length and 6 to 11 cm in width, and the FL flaps ranged from 3 × 5 to 12 × 5 cm. The mean pedicle length was 7.88 cm. Nine extensor tendons were repaired with FL flaps. The flap thickness after thinning was only 3-6 mm. The donor site was closed primarily in six patients, and skin grafts were used in two cases. All flaps survived without complications. The follow-up period lasted from 17 to 80 months. Range of motion was achieved with satisfaction. Conclusion: The chimeric-thinned ALT and FL flap is a valuable material, and it should be considered a reconstructive option for hand soft tissue and extensor tendon reconstruction. This technique allows us to achieve a good appearance and extensor function without donor-site morbidity.

Apply EZStrobe to simulate the finishing work for reducing construction process waste.

Vietnam, classified as a developing nation, encounters numerous challenges within its construction sector, including the scarcity of comprehensive and documented historical data regarding risks and a deficiency in embracing contemporary methodologies to mitigate the impact of risk factors on construction project objectives. This paper outlines initial findings from an ongoing research endeavor that centers on implementing Lean Construction (LC) techniques to enhance construction management practices specifically for marble floor finishing work within Vietnam. Therefore, this study aims to apply the construction lean principle combined with discrete-event simulation (DES) by using EZStrobe to simulate the marble floor finishing process in reality, from observing and collecting data of each activity in the actual process on the site. By building, running simulations, and resulting from real-world simulations, we'll understand the sources of waste, and then apply lean construction principles through methods such as just in time, reduce the batch size and resources priorities, and multi-skilled teams for the initial construction process. The study's lean modeling results has led to a 13% reduction in construction cycle time, a 141% improvement in process efficiency, a 268% enhancement in average productivity, and a 96% reduction in labor cost. The result has become the reference document resource for the managers and construction engineers to improve the performance of not only general finishing work but also marble floor finishing work.

A Flexible, Quantitative Plasmonic-Fluor Lateral Flow Assay for the Rapid Detection of Orthoebolavirus zairense and Orthoebolavirus sudanense.

Filoviruses comprise a family of single-stranded, negative-sense RNA viruses with a significant impact on human health. Given the risk for disease outbreaks, as highlighted by the recent outbreaks across Africa, there is an unmet need for flexible diagnostic technologies that can be deployed in resource-limited settings. Herein, we highlight the use of plasmonic-fluor lateral flow assays (PF-LFA) for the rapid, quantitative detection of an Ebolavirus-secreted glycoprotein, a marker for infection. Plasmonic fluors are a class of ultrabright reporter molecules that combine engineered nanorods with conventional fluorophores, resulting in improved analytical sensitivity. We have developed a PF-LFA for Orthoebolavirus zairense (EBOV) and Orthoebolavirus sudanense (SUDV) that provides estimated limits of detection as low as 0.446 and 0.641 ng/mL, respectively. Furthermore, our assay highlights a high degree of specificity between the two viral species while also maintaining a turnaround time as short as 30 min. To highlight the utility of our PF-LFA, we demonstrate the detection of EBOV infection in non-human primates. Our PF-LFA represents an enormous step forward in the development of a robust, field-deployable assay for filoviruses.

Optimizing daylight in west-facing facades for LEED V4.1 compliance using metaheuristic approach.

This study introduces an optimized design approach for west-facing room façades to improve daylighting while adhering to LEED v4.1 sustainability criteria. Employing parametric modeling, metaheuristic optimization, and validated daylight simulations, the research highlights the African Vulture Optimization Algorithm's success in achieving 100% LEED compliance and superior performance over random models in daylight sufficiency and glare reduction. Light-colored materials and transparent glazing emerged as beneficial for LEED points. Despite computational limitations and the need for empirical validation, this method offers architects versatile and sustainable design solutions. Comparative analysis reveals the algorithm's strong performance, although opportunities exist for refinement. Future research directions include contrasting this algorithm with other optimization methods, focusing on empirical backing, assessing environmental and human-centric impacts, adapting to varied building types and conditions, and examining diverse geographical and material factors. This work advances daylight-integrated façade design, suggesting a more comprehensive framework for building performance optimization.

Optimizing time, cost, and carbon in construction: grasshopper algorithm empowered with tournament selection and opposition-based learning.

The global construction industry plays a pivotal role, yet its unique characteristics pose distinctive challenges. Each construction project, marked by its individuality, substantial value, intricate scale, and constrained adaptability, confronts crucial limitations concerning time and cost. Despite contributing significantly to environmental concerns throughout construction activities and infrastructure operations, environmental considerations remain insufficiently addressed by project managers. This research introduces an improved rendition of the muti-objective grasshopper optimization algorithm (MOGOA), termed eMOGOA, as a novel methodology to tackle time, cost, and carbon dioxide emission trade-off problems (TCCP) in construction project management. To gauge its efficacy, a case study involving 29 activities is employed. eMOGOA amalgamates MOGOA, tournament selection (TS), and opposition-based learning (OBL) techniques to enhance the performance of the original MOGOA. The outcomes demonstrate that eMOGOA surpasses other optimization algorithms, such as MODA, MOSMA, MOALO and MOGOA when applied to TCCP. These findings underscore the efficiency and relevance of the eMOGOA algorithm within the realm of construction project management.

One-stage Reconstruction with the Composite Anterolateral Thigh Flap for Skin and Extensor Tendon Defects of the Thumb by Snakebite.

Venomous snakebites can cause severe injury. The loss of tendon and skin of the hand is incredibly challenging for the surgeon. A single-staged reconstruction with the free composite anterolateral thigh flap is an acceptable option for a complex thumb injury. In this case, reconstruction for a 23-year-old patient with a complex cobra-induced thumb injury had failed to cover the defect with a skin graft. There was a limitation in choice, and the patient was treated with the free composite anterolateral thigh (ALT) flap and fascia lata flap in one stage to reconstruct both the extensor tendon and the soft tissue coverage. The flap was well-vascularized, and no complications were reported. A single-stage reconstruction with a composite ALT flap with vascularized fascia was chosen as a suitable alternative. The result is satisfying both aesthetically and functionally. This technique can help shorten treatment time and restore function quickly, allowing patients to return to work in less time. The disadvantages of this technique are flap thickness, which can affect finger movement and aesthetics. The composite ALT flap with vascularized fascia lata shows that it is a reliable procedure for single-staged reconstruction, especially combined with the tendon preparation in the hand.

Novel mechanisms of MITF regulation and melanoma predisposition identified in a mouse suppressor screen.

MITF, a basic-Helix-Loop-Helix Zipper (bHLHZip) transcription factor, plays vital roles in melanocyte development and functions as an oncogene. To explore MITF regulation and its role in melanoma, we conducted a genetic screen for suppressors of the Mitf-associated pigmentation phenotype. An intragenic Mitf mutation was identified, leading to termination of MITF at the K316 SUMOylation site and loss of the C-end intrinsically disordered region (IDR). The resulting protein is more nuclear but less stable than wild-type MITF and retains DNA-binding ability. Interestingly, as a dimer, it can translocate wild-type and mutant MITF partners into the nucleus, improving its own stability and ensuring an active nuclear MITF supply. Interactions between K316 SUMOylation and S409 phosphorylation sites across monomers largely explain the observed effects. Notably, the recurrent melanoma-associated E318K mutation in MITF, which affects K316 SUMOylation, also alters protein regulation in concert with S409, unraveling a novel regulatory mechanism with unexpected disease insights.

A marine cryptochrome with an inverse photo-oligomerization mechanism.

Cryptochromes (CRYs) are a structurally conserved but functionally diverse family of proteins that can confer unique sensory properties to organisms. In the marine bristle worm Platynereis dumerilii, its light receptive cryptochrome L-CRY (PdLCry) allows the animal to discriminate between sunlight and moonlight, an important requirement for synchronizing its lunar cycle-dependent mass spawning. Using cryo-electron microscopy, we show that in the dark, PdLCry adopts a dimer arrangement observed neither in plant nor insect CRYs. Intense illumination disassembles the dimer into monomers. Structural and functional data suggest a mechanistic coupling between the light-sensing flavin adenine dinucleotide chromophore, the dimer interface, and the C-terminal tail helix, with a likely involvement of the phosphate binding loop. Taken together, our work establishes PdLCry as a CRY protein with inverse photo-oligomerization with respect to plant CRYs, and provides molecular insights into how this protein might help discriminating the different light intensities associated with sunlight and moonlight.

Long-term Prophylaxis Against Aerosolized Marburg Virus in Nonhuman Primates With an Afucosylated Monoclonal Antibody.

Marburg virus (MARV) causes a hemorrhagic fever disease in human and nonhuman primates with high levels of morbidity and mortality. Concerns about weaponization of aerosolized MARV have spurred the development of nonhuman primate (NHP) models of aerosol exposure. To address the potential threat of aerosol exposure, a monoclonal antibody that binds MARV glycoprotein was tested, MR186YTE, for its efficacy as a prophylactic. MR186YTE was administered intramuscularly to NHPs at 15 or 5 mg/kg 1 month prior to MARV aerosol challenge. Seventy-five percent (3/4) of the 15 mg/kg dose group and 50% (2/4) of the 5 mg/kg dose group survived. Serum analyses showed that the NHP dosed with 15 mg/kg that succumbed to infection developed an antidrug antibody response and therefore had no detectable MR186YTE at the time of challenge. These results suggest that intramuscular dosing of mAbs may be a clinically useful prophylaxis for MARV aerosol exposure.

What Influences Audience Susceptibility to Fake Health News: An Experimental Study Using a Dual Model of Information Processing in Credibility Assessment.

This experimental study investigates the effects of several heuristic cues and systematic factors on users' misinformation susceptibility in the context of health news. Specifically, it examines whether author credentials, writing style, and verification check flagging influence participants' intent to follow article behavioral recommendations provided by the article, perceived article credibility, and sharing intent. Findings suggest that users rely only on verification checks (passing/failing) in assessing information credibility. Of the two antecedents to systematic processing, social media self-efficacy moderates the links between verification and participants' susceptibility. Theoretical and practical implications are discussed.

Traumatic rupture of the thoracic aorta: A life-threatening emergency and the role of endovascular repair.

Traumatic rupture of the thoracic aorta is a rare condition, with a high mortality rate. Over the last 2 decades, strategies for managing aortic injury caused by blunt chest trauma have changed substantially, resulting in significantly improved outcomes. The recent development of endovascular repair offers a less invasive alternative to conventional open repair, particularly in patients with multiple injuries. Here, we report the case of a 31-year-old man who was referred to our emergency department with blunt chest trauma following a motorcycle-truck collision. Computed tomography confirmed acute traumatic rupture of the thoracic aorta, and the patient was successfully treated with endovascular repair.

Solving large-scale discrete time-cost trade-off problem using hybrid multi-verse optimizer model.

The analysis of the relationship between time and cost is a crucial aspect of construction project management. Various optimization techniques have been developed to solve time-cost trade-off problems. A hybrid multi-verse optimizer model (hDMVO) is introduced in this study, which combines the multi-verse optimizer (MVO) and the sine cosine algorithm (SCA) to address the discrete time-cost trade-off problem (DTCTP). The algorithm's optimality is evaluated by using 23 well-known benchmark test functions. The results demonstrate that hDMVO is competitive with MVO, SCA, the dragonfly algorithm and ant lion optimization. The performance of hDMVO is evaluated using four benchmark test problems of DTCTP, including two medium-scale instances (63 activities) and two large-scale instances (630 activities). The results indicate that hDMVO can provide superior solutions in the time-cost optimization of large-scale and complex projects compared to previous algorithms.

Meditation as panacea: A longitudinal semantic network analysis of meditation coverage in campus newspapers from 1997-2018.

OBJECTIVE: Media framing of health issues reflects public opinion and impacts readers' perceptions and behavior. This study examines how meditation - a recommended stress coping strategy for college students - is framed in campus newspapers from 1997-2018. PARTICIPANTS: A total of 494 articles were analyzed. METHODS: Semantic network analysis was used to automatically detect frames and the longitudinal trend. RESULTS: Five major frames emerged: (1) building a meditation community within a campus community, (2) meditation benefits, (3) yoga for enhancing mind and body awareness, (4) meditation techniques, and (5) secularizing meditation on campus. There is a shift in coverage from interest in religion to secular views of health benefits throughout the years. Discussions of adverse effects that have emerged from the literature were entirely absent. CONCLUSIONS: The trend of secularizing meditation practices on college campuses is evident. Emphasizing the techniques and benefits could encourage participation and build a learning community.

Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. Whereas mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. Here we demonstrate that in DMD and other muscular dystrophies, a large number of Dlk1-Dio3 clustered miRNAs (DD-miRNAs) are coordinately up-regulated in regenerating myofibers and in the serum. To characterize the biological effect of this dysregulation, 14 DD-miRNAs were simultaneously overexpressed in vivo in mouse muscle. Transcriptomic analysis revealed highly similar changes between the muscle ectopically overexpressing 14 DD-miRNAs and the mdx diaphragm, with naturally up-regulated DD-miRNAs. Among the commonly dysregulated pathway we found repressed mitochondrial metabolism, and oxidative phosphorylation (OxPhos) in particular. Knocking down the DD-miRNAs in iPS-derived skeletal myotubes resulted in increased OxPhos activities. The data suggest that (1) DD-miRNAs are important mediators of dystrophic changes in DMD muscle, (2) mitochondrial metabolism and OxPhos in particular are targeted in DMD by coordinately up-regulated DD-miRNAs. These findings provide insight into the mechanism of mitochondrial dysfunction in muscular dystrophy.

Outcome and toxicity of chemoradiation using volumetric modulated arc therapy followed by 3D image-guided brachytherapy for cervical cancer: Vietnam National Cancer Hospital experience.

Background: Volumetric modulated arc therapy (VMAT) and 3D image-guided brachytherapy (3D-IGBT) have recently been introduced in Vietnam for the treatment of locally advanced cervical cancer. This study aims to assess the outcomes and toxicities of chemoradiation using VMAT followed by 3D-IGBT in Vietnamese cervical cancer patients. Materials and methods: A prospective interventional study on 72 patients with 2018 International Federation of Gynecology and Obstetrics (FIGO) stage IB3-IIIC2 disease who underwent concurrent chemoradiation using VMAT, followed by 3D-IGBT according to EMBRACE-II protocol. Primary endpoints were locoregional control; secondary endpoints were systemic control and toxicity. Results: Median body volume received 43 Gy was 1589.1 cm3 (range 1214.8-2574.8). Median high-risk clinical target volume (CTV-HR) was 18.8 cm3 (range 8.6-61.2) with a median dose to 90% (D90) of CTV-HR of 90.6 Gy (range 86.8-99.6). Mean doses to 2cc (D2cc) of bladder, rectum, and sigmoid were 75.8, 55.2, and 62.1 Gy, respectively. At median 19-month follow-up (range 12-25), locoregional control and systemic control were 95.8% and 81.9%, respectively. Systemic control was the lowest in N2 disease (54.5%). Grade ≥ 3 acute toxicities were less than 10%, except neutropenia (31.9%). Extended-field radiation increased significantly nausea, fatigue, and thrombocytopenia. No grade ≥ 3 proctitis or cystitis; 8.3% had grade 3 vaginal stenosis. Conclusions: VMAT-based chemoradiation therapy followed by 3D-IGBT achieved high locoregional control with manageable toxicities in locally advanced cervical cancer. Systemic control correlated with disease stage.