Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the ...accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Aducanumab and Lecanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. In this comprehensive report, we review all trials listed in clinicaltrials.gov, elucidating their underlying mechanisms and study designs. Ongoing clinical trials are investigating numerous promising new drugs for AD. The main trends in these trials involve pathophysiology-based, disease-modifying therapies and the recruitment of participants in earlier stages of the disease. These trends underscore the significance of conducting fundamental research on pathophysiology, prevention, and intervention prior to the occurrence of brain damage caused by AD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 ...(COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.
Background Few studies have investigated the use of postoperative extracorporeal membrane oxygenation (ECMO) in acute type A aortic dissection (aTAAD). We identified aTAAD surgical patients at risk ...of ECMO implantation postoperatively and analyzed the prognosis of these patients. Methods We retrospectively reviewed 162 consecutive aTAAD patients undergoing operations from January 2008 to December 2015. Patient data were analyzed for risk factors leading to an ECMO requirement. Short-term and long-term outcomes in patients who did and did not require ECMO were compared. Results Postoperative ECMO was required in 20 patients (12.3%), and in-hospital mortality was higher in the ECMO group (65.0% vs 8.5%, p < 0.001). Factors predicting postoperative ECMO were preoperative hemodynamic instability ( p = 0.049), aortic cross-clamp time ( p = 0.036), and postoperative peak creatinine kinase-MB ( p = 0.002). ECMO survivors presented at a younger age ( p = 0.036) and had a less postoperative blood transfusion ( p = 0.034) than ECMO nonsurvivors. The postdischarge survival rate was equivalent in patients with or without ECMO support. Conclusions Although postoperative ECMO is an important predictor of in-hospital death, this pilot study showed that aTAAD patients supported with postoperative ECMO who survive to hospital discharge have a long-term survival comparable to patients who did not receive ECMO.
Achilles sleeve avulsion usually occurs from pre-existing insertional Achilles tendinopathy, leaving a calcific spur at the insertional site. The purpose of this study was to introduce a new ...technique using the spur base on the insertional site to drill the suture tunnel to repair Achilles sleeve avulsion.
In total, 11 patients diagnosed with Achilles sleeve avulsion underwent this new surgical technique and were followed for a mean time of 40 months. Clinical outcomes were measured using the visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, Victorian Institute of Sports Assessment-Achilles (VISA-A) score, Tegner score, and time taken to return to activities. Preoperative and postoperative MRI, the ability to perform heel rise, and complications were also evaluated.
All cases (11/11) had insertional Achilles tendinopathy with calcific spur formation on the tendon's insertion. At final follow-up, the average VAS score improved from 5.3 to 0.1, AOFAS score improved from 44.8 to 97.9, VISA-A score improved from 23.6 to 96.6, and Tegner score improved from 0.9 to 4.9. Tendinopathy symptoms were eliminated. Patients returned to daily activities, work, and sports 3.5 months, 2.8 months, and 12.3months after operation, respectively. Patients took an average of 18.1 weeks after operation to perform the single heel rise test. No severe complications such as infection and rerupture were observed.
Our new transosseous suture technique is a promising alternative option in treating Achilles sleeve avulsion. More cases and longer follow up are needed in order to find the best reconstructive option for this pathology.
Level IV.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•Formulated a new variant of package consolidation problem in online retailing.•Proposed a network flow model to determine splitting-vs.-consolidation tradeoff.•Developed an enhanced logic-based ...Benders’ decomposition algorithm.•Revealed conditions under which consolidation is more beneficial than splitting.
With the rapid growth of the online market in recent years, order splitting has become a great challenge to online retailers for fulfilling multi-item orders in a multi-warehouse storage network. Order splitting can lead to higher shipping costs, the use of more packages, and possible dissatisfaction from customers. This paper presents a multi-warehouse package consolidation approach aimed at consolidating multiple suborders’ stock-keeping units (SKUs) through transshipments among warehouses. A combined multi-commodity network flow model is proposed to determine the consolidation warehouses for each order and make transshipment decisions for individual SKUs. An enhanced logic-based Benders’ decomposition algorithm is proposed to decompose the model into a general multi-commodity network flow master problem and a set of bin packing with conflicts sub-problems. Two proposed Benders’ cuts guarantee the algorithm to converge to optimality. The proposed algorithm can generate the near-optimal result with only about 25% of the CPU time required by CPLEX to solve the proposed model. Numerical experiments reveal that the proposed package consolidation approach outperforms the order splitting fulfillment approach in reducing the total costs, the number of packages, and the delivery times, especially for cases with a small number of SKUs in each suborder which are typical for online retailers. Sensitivity analyses are performed to provide managerial insights of adopting the proposed approach in the real world where order splitting is a common phenomenon.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) first emerged in December 2019 in Wuhan, China, and has since spread rapidly worldwide. As researchers seek to learn more about COVID-19, ...the disease it causes, this novel virus continues to infect and kill. Despite the socioeconomic impacts of SARS-CoV-2 infections and likelihood of future outbreaks of other pathogenic coronaviruses, options to prevent or treat coronavirus infections remain limited. In current clinical trials, potential coronavirus treatments focusing on killing the virus or on preventing infection using vaccines largely ignore the host immune response. The relatively small body of current research on the virus indicates pathological responses by the immune system as the leading cause for much of the morbidity and mortality caused by COVID-19. In this review, we investigated the host innate and adaptive immune responses against COVID-19, collated information on recent COVID-19 experimental data, and summarized the systemic immune responses to and histopathology of SARS-CoV-2 infection. Finally, we summarized the immune-related biomarkers to define patients with high-risk and worst-case outcomes, and identified the possible usefulness of inflammatory markers as potential immunotherapeutic targets. This review provides an overview of current knowledge on COVID-19 and the symptomatological differences between healthy, convalescent, and severe cohorts, while offering research directions for alternative immunoregulation therapeutic targets.
Biochar is a carbon-rich solid produced during the thermochemical processes of various biomass feedstocks. As a low-cost and environmentally friendly material, biochar has multiple significant ...advantages and potentials, and it can replace more expensive synthetic carbon materials for many applications in nanocomposites, energy storage, sensors, and biosensors. Due to biomass feedstock species, reactor types, operating conditions, and the interaction between different factors, the compositions, structure and function, and physicochemical properties of the biochar may vary greatly, traditional trial-and-error experimental approaches are time consuming, expensive, and sometimes impossible. Computer simulations, such as molecular dynamics (MD) simulations, are an alternative and powerful method for characterizing materials. Biomass pyrolysis is one of the most common processes to produce biochar. Since pyrolysis of decomposing biomass into biochar is based on the bond-order chemical reactions (the breakage and formation of bonds during carbonization reactions), an advanced reactive force field (ReaxFF)-based MD method is especially effective in simulating and/or analyzing the biomass pyrolysis process. This paper reviewed the fundamentals of the ReaxFF method and previous research on the characterization of biochar physicochemical properties and the biomass pyrolysis process via MD simulations based on ReaxFF. ReaxFF implicitly describes chemical bonds without requiring quantum mechanics calculations to disclose the complex reaction mechanisms at the nano/micro scale, thereby gaining insight into the carbonization reactions during the biomass pyrolysis process. The biomass pyrolysis and its carbonization reactions, including the reactivity of the major components of biomass, such as cellulose, lignin, and hemicellulose, were discussed. Potential applications of ReaxFF MD were also briefly discussed. MD simulations based on ReaxFF can be an effective method to understand the mechanisms of chemical reactions and to predict and/or improve the structure, functionality, and physicochemical properties of the products.
The goal of this paper is to evaluate the post-failure behavior of the Hsien-du-shan rock avalanche, which was triggered by Typhoon Morakot in 2009, using a three-dimensional (3D) discrete element ...program, namely, 3DEC. The 3D slope topography and local joint sets are explicitly considered in the calculations, and the joint sets cut the sliding rock mass into blocks with arbitrary shapes. The modeled blocks exhibit the elastic behavior of the local rocks. The analysis successfully simulates the wedge failure at the initiation of the landslide. Additionally, the 3DEC results clarify the local rock sliding phenomena at the boundaries of the source area. The simulated depositional area correlates well with the actual area affected by the Hsien-du-shan rock avalanche. In addition, the erosion of a ridge by the sliding rock near the southwestern margin of the area at an elevation of 590 m has a significant influence on the shape and size of the impacted area. The interlocking effect between blocks is also considered.
•The 3D DEM simulates the post-failure of the Hsien-du-shan landslide with polyhedrons.•The polyhedral blocks are generated based on the local 3D topography and joint geometry.•The failure pattern, location of landslide dam, and the impact area of the landslide are well simulated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
CRISPR/Cas9 is a powerful genome editing system but uncontrolled Cas9 nuclease expression triggers off-target effects and even in vivo immune responses. Inspired by synthetic biology, here ...we built a synthetic switch that self-regulates Cas9 expression not only in the transcription step by guide RNA-aided self-cleavage of cas9 gene, but also in the translation step by L7Ae:K-turn repression system. We showed that the synthetic switch enabled simultaneous transcriptional and translational repression, hence stringently attenuating the Cas9 expression. The restricted Cas9 expression induced high efficiency on-target indel mutation while minimizing the off-target effects. Furthermore, we unveiled the correlation between Cas9 expression kinetics and on-target/off-target mutagenesis. The synthetic switch conferred detectable Cas9 expression and concomitant high frequency on-target mutagenesis at as early as 6 h, and restricted the Cas9 expression and off-target effects to minimal levels through 72 h. The synthetic switch is compact enough to be incorporated into viral vectors for self-regulation of Cas9 expression, thereby providing a novel ‘hit and run’ strategy for in vivo genome editing.
Sign inversions of circularly polarized luminescence (CPL) for the hydro5helicene and 5helicene derivatives were discovered and studied experimentally and theoretically. The inverted CPL signs from ...the hydro5helicene to 5helicene derivatives were realized by one-step oxidation. The introduction of triphenylamine (TPA) subunits into the helical skeletons also led to the sign inversion of CPL only when there existed an enhanced intramolecular charge-transfer state with a small enough
E
gap
.
Sign inversions of CPL by fine-tuning operations on structures of helical compounds were realized by one step-oxidation or TPA-modification.
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