High Cost Research Articles

Clinical Evidence Supporting FDA Approval of Gene and RNA Therapies for Rare Inherited Conditions.

Gene and RNA therapies have potential to transform the treatment of rare inherited diseases, but there are concerns about the evidence supporting their use and high costs. We analyze the evidence supporting Food and Drug Administration (FDA) approval of gene and RNA therapies for rare inherited diseases and discuss implications for clinical practice and policy. We conducted a qualitative analysis of FDA documents outlining the basis of approval for gene and RNA therapies approved for rare inherited diseases between 2016 and 2023. For each drug, we gathered five characteristics of the evidence supporting FDA approval (no phase 3 trial, nonrandomized, no clinical endpoint, lack of demonstrated benefit, and significant protocol deviation) and four characteristics of the FDA approval process (prior rejection or complete response, negative committee vote, discrepancy between label and trial population, and boxed warning). The main outcome was the number of drugs with each characteristic. Between 2016 and 2023, 19 gene and RNA therapies received FDA approval to treat rare inherited diseases. The most common limitations in the evidence supporting approval of these drugs were nonrandomized studies (8/19, 42%), no clinical endpoint (7/19, 37%), lack of demonstrated benefit or inconsistent results (4/19, 21%), and no phase 3 trial (4/19, 21%). Half (3/6) of accelerated approvals and 57% (5/9) of drugs with breakthrough designation had nonrandomized trials, and gene therapies with one-time dosing were overrepresented (5/7, 71%) among the drugs with nonrandomized trials. Five of six accelerated approvals (83%) and five of nine pediatric drugs (56%), most of which were indicated for Duchenne muscular dystrophy, had no clinical endpoint. Four of nine (44%) pediatric drugs and four of six (67%) accelerated approvals failed to demonstrate benefit compared with none of the nonpediatric drugs and none of the traditional approvals. Five drugs, which all had different indications and represented a mix of RNA and gene therapies, did not have any of these evidence characteristics. Among drugs that received prior rejections or negative committee opinions, all four had nonrandomized trials and lacked a clinical endpoint, and 75% (3/4) lacked demonstrated benefit. Five of nine (56%) pediatric drugs were indicated for broader age groups according to the drug label compared with the trial populations. Of the three drugs with boxed warnings, two had pediatric indications and nonrandomized studies, and one had no phase 3 trial. Issues related to trial design, outcome, and data integrity in the evidence supporting FDA approval of rare inherited disease gene and RNA therapies raise questions about whether this evidence is adequate to inform prescribing decisions. Gene and RNA therapies with accelerated approval and pediatric indications were overrepresented among drugs lacking clinical endpoints or demonstrated benefit and should be the focus of efforts to reduce uncertainty in the evidence.

Floatable Termination-Vacant MXene Architecture for High-Performance and Cost-Effective Photothermal Dehydrogenation.

Liquid hydrogen carriers have garnered considerable interest in long-distance and large-scale hydrogen storage owing to their exceptional hydrogen storage density, safety, and compatibility. Nonetheless, their practical application is hampered by the low hydrogen production rate and high cost, stemming from poor thermal utilization and heavy reliance on noble metals in solar bulk dehydrogenation platforms. To conquer these challenges, we devise an economical all-in-one architecture comprising the photothermal catalytic termination-vacant MXene and a highly insulated melamine substrate. This design floats on the air-reactant interface to efficiently drive solar interfacial dehydrogenation. The melamine enables interfacial heat localization to improve the thermal utilization, providing a high reaction temperature. Meanwhile, the MXene with termination vacancies exposes rich active sites for formic acid dehydrogenation, and simultaneously high performance and cost-effectiveness can be realized. This work offers fresh perspectives on the design and application of photothermal catalytic MXene, broadening the prospects for hydrogen storage using liquid hydrogen carriers.

Optimization of Green Multimodal Transport Schemes Considering Order Consolidation under Uncertainty Conditions

As society becomes increasingly concerned with sustainable development, the demand for high-efficiency, low-cost, and green technology makes air–land multimodal transportation one of the effective means of fast freight transportation. In the actual transportation business, some orders will have overlapping transportation routes, and transporting each order separately will result in resource waste, high costs, and carbon emissions. This paper proposes a multimodal transportation scheme optimization model considering order consolidation to improve transport efficiency and reduce costs and carbon emissions. An improved genetic algorithm incorporating the ride-sharing scheduling method is designed to solve the model. The results show that order consolidation will reduce multimodal transport costs and carbon emissions but increase transportation time slightly, and the advantages in cost and carbon emission reduction will vary with origin–destination scenarios, which are ranked in order of single-origin single-destination, single-origin multi-destinations, multi-origin single-destination, and multi-origin multi-destination. For the fourth scenario, the cost and carbon emissions decrease by 16.6% and 26.69%, respectively, and the time increases by 5.56% compared with no consolidation. For the sensibility of customer demands, it is found that order consolidation has the advantage for price-sensitive, time- and price-sensitive, and time- and carbon emission-sensitive customers; however, it is specifically beneficial for time-sensitive customers only in single-origin single-destination scenarios.

Ten golden rules for restoration to secure resilient and just seagrass social‐ecological systems

Societal Impact StatementSeagrass meadows are a globally important habitat subject to significant loss. As efforts to restore these sensitive habitats are hampered by their high cost and low levels of reliability, rigorous guidance is required to improve effectiveness and ensure they are cost‐effective. Here, we define 10 golden rules for how we can undertake seagrass restoration. We do this by considering that for seagrass restoration to be successful, it needs to take place with people and not against people. The framework we present aims to direct efforts for seagrass restoration that are holistic and achieve broad goals for people, biodiversity and the planet.SummaryThe world has lost a significant proportion of its seagrass, and although glimmers of hope for its recovery exist, losses and degradations continue. First and foremost, evidence highlights the need to put the world on a global pathway to seagrass net gain. Achieving this outcome requires that conservation of what remains is a priority, but reaching net gain requires seagrass coverage to increase at rates unlikely to be achieved naturally; large‐scale active restoration is required to fill this gap. Novel finance mechanisms aligned to the climate emergency and biodiversity crises are increasingly leading to larger scale restoration projects. However, no clear framework exists for developing or prioritising approaches. With seagrass restoration expensive and unreliable, rigorous guidance is required to improve effectiveness and ensure it is cost‐effective. Building on evidence from terrestrial and marine sources, here, we apply the ‘10 golden rules’ concept, first outlined for reforestation and later applied to coral reefs, to seagrass restoration. In doing so, we follow international standards for ecological restoration and view seagrass restoration in a broad context, whereby regeneration can be achieved either by planting or by enhancing and facilitating natural recovery. These rules somewhat differ from those on reforestation and coral reef restoration, principally due to the relative immaturity of seagrass restoration science. These 10 golden rules for seagrass restoration are placed within a coupled social‐ecological systems context, and we present a framework for conservation more broadly, to achieve multiple goals pertaining to people, biodiversity and the planet.

2D/2D Heterojunction of Cobalt‐Iron Selenide Nanolamellas/MXene for Enhanced Electrocatalytic Hydrogen Evolution

AbstractElectrochemical water splitting is considered to be a green and flexible strategy for the mass production of hydrogen fuel, while the high cost and insufficent activity of current cathode catalysts severely suffocate the widespread thriving of hydrogen economy. Herein, we present a bottom‐up assembly strategy to the controllable construction of 2D/2D heterojunctions built from cobalt‐iron selenide nanolamellas and Ti3C2Tx MXene nanosheets. This unique architectural design gives the resulting CoyFe1‐ySe2/Ti3C2Tx catalysts a series of interesting structural advantages, such as 2D/2D heterostructure, large active surface areas, modulated electronic structure, uniform CoyFe1‐ySe2 dispersion, and good electron conductivity, thereby leading to strong synergistic coupling effects. As a consequence, the optimized Co0.7Fe0.3Se2/Ti3C2Tx electrocatalyst with an appropriate Co/Fe ratio possesses unusual hydrogen evolution properties in terms of a low overpotential of 69 mV at 10 mA cm−2, a small Tafel slope of 51 mV dec−1 and reliable long‐term durability, which are more competitive than those of bare Ti3C2Tx, FeSe2 and CoSe catalysts.

Recent Advances and Prospects in Manganese‐Catalyzed C‐H Activation

C–H activation represents an interesting alternative to conventional cross‐coupling methods, avoiding the requirement of additional steps to introduce activating groups. Generally, Pd‐catalyzed reactions have been extensively employed for C–H activation. The high cost and limited availability of resources of Pd have prompted us to explore alternative transition metals. In this context, researchers are turning to Earth Abundant Metals (EAMs) like manganese and iron for their potential in C–H activation.Significant progress has been made in manganese‐catalyzed C–H activation in recent years, showcasing excellent specificity, environmental compatibility, and versatility across different substrates. This review summarizes approximately 50 recent publications highlighting significant advancements in this field from 2020 to 2023.

Preventing bacterial adhesion on scaffolds for bone tissue engineering

Bone implant infection constitutes a major sanitary concern which is associated to high morbidity and health costs. This manuscript focused on overviewing the main research efforts committed up to date to develop innovative alternatives to conventional treatments, such as those with antibiotics. These strategies mainly rely on chemical modifications of the surface of biomaterials, such as providing it of zwitterionic nature, and tailoring the nanostructure surface of metal implants. These surface modifications have successfully allowed inhibition of bacterial adhesion, which is the first step to implant infection, and preventing long-term biofilm formation compared to pristine materials. These strategies could be easily applied to provide three-dimensional (3D) scaffolds based on bioceramics and metals, of which its manufacture using rapid prototyping techniques was reviewed. This opens the gates for the design and development of advanced 3D scaffolds for bone tissue engineering to prevent bone implant infections.

Design and Conformation of Separators for High-performance Aqueous Zinc-Ion Batteries.

Aqueous zinc-ion batteries (AZIBs) are considered promising candidates for large-scale energy storage due to their high safety, low cost, and environmental friendliness. As a core component, separator plays a unique yet oftentimes overlooked role in providing electrochemical stability in AZIBs. This concept focuses on the exquisite structure-property relationship of separators, highlighting three forms of these components and their structural design requirements, i.e., traditional membranes, solid-stateelectrolytes, and electrode coatings. The mechanism by which separators influence the zinc anode and the cathode is discussed. The article also identifies the challenges and potential future directions for functional separators in the development of high-performance AZIBs.

Unsteady nonlinear lifting line model for active gust load alleviation of airplanes

AbstractActive gust load alleviation is an important technology for designing future passenger airplanes to be lighter and thus more environmentally friendly. Unsteady Reynolds-averaged Navier–Stokes (URANS) simulations are typically used to accurately calculate gust loads, but because of their high computational cost, they can only be performed at a few selected operating points. In simpler potential theory models, stall is neglected, resulting in loss of accuracy. In this paper, a low-order unsteady aerodynamics wing model is presented, which is able to represent well compressible flow with stall. Furthermore, the model offers the possibility to modularly incorporate actuators, which allows the design and evaluation of active load alleviation systems. The model is based on a conventional unsteady 2D airfoil model including a dynamic stall model. The dynamic stall model requires viscous steady coefficients, e.g. from 2D steady RANS computations. This 2D airfoil model is coupled with a 3D steady-state lifting line model. The model is applied to the LEISA research airplane and extensively validated with URANS results. It performs well in calculating gust loads with and without simultaneous flap deflections, and provides significantly more accurate results in the case of stall than when stall is neglected.

Constraint Analysis of Adopters and Non Adopters of Drones in Agriculture in the Warangal District of Telangana in India

The present study was conducted with an objective to analyse constraints faced by farmers who are using drones, constraints faced by various stakeholders and constraints faced by farmers who are not using drones in agriculture in Warangal district of Telangana, India. Various problems faced by farmers are chosen and Garette’s ranking technique is used to know the major constraints. The major constraints faced by the farmers who are using drones in agriculture are shortage of drone suppliers with a score of 67.95, non uniform coverage with a score of 61.75. the major constraints faced by farmers who are not using drones in agriculture are high labour cost with a score of 73.12, time consuming with a score of 67.55 and the major constraints faced by the stakeholders are high initial investment with a score of 78.8, battery life with a score of 59.2. The suggestions were provided for the major constraints involved in both adopters and non adopters of drones in agriculture.

A Dual-Function Design of an Oscillating Water Column Integrated with a Slotted Breakwater: A Wave Flume Study

Wave energy conversion holds promise for renewable energy, but challenges like high initial costs hinder commercialization. Integrating wave-energy converters (WECs) into shore-protection structures creates dual-function structures for both electricity generation and coastal protection. Oscillating water columns (OWCs) have been well studied in the past with their simple generation mechanism and their out-of-water power take-off (PTO) system, which can minimize bio-fouling effects and maintenance costs compared to other submerged WECs. In addition, a slotted barrier allows for better circulation behind the breakwater while dissipating incoming wave energy through viscous damping. This study examines the performance of a new design which combines an OWC with a slotted breakwater. Small-scale (1:49) laboratory tests were performed with a piston-type wave generator. The performance is evaluated in terms of wave transmission, wave energy extraction, and wave loading under various wave conditions while focusing on the effects of the porosity of the slotted barrier and tide level changes. Results show that under larger waves, a decreasing wave transmission, increasing power extraction from the OWC, and energy dissipation from the slotted barrier are observed. On the other hand, under increasing wavelengths, wave transmission is observed to be constant; this is important for harbor design, which means that the breakwater is effective under a wider range of wavelengths. Porosity allows for more transmission while inducing less horizontal force on the structure.

An improved data augmentation approach and its application in medical named entity recognition

Performing data augmentation in medical named entity recognition (NER) is crucial due to the unique challenges posed by this field. Medical data is characterized by high acquisition costs, specialized terminology, imbalanced distributions, and limited training resources. These factors make achieving high performance in medical NER particularly difficult. Data augmentation methods help to mitigate these issues by generating additional training samples, thus balancing data distribution, enriching the training dataset, and improving model generalization. This paper proposes two data augmentation methods—Contextual Random Replacement based on Word2Vec Augmentation (CRR) and Targeted Entity Random Replacement Augmentation (TER)—aimed at addressing the scarcity and imbalance of data in the medical domain. When combined with a deep learning-based Chinese NER model, these methods can significantly enhance performance and recognition accuracy under limited resources. Experimental results demonstrate that both augmentation methods effectively improve the recognition capability of medical named entities. Specifically, the BERT-BiLSTM-CRF model achieved the highest F1 score of 83.587%, representing a 1.49% increase over the baseline model. This validates the importance and effectiveness of data augmentation in medical NER.

A study on the Application of Virtual Reality Technology in Children's Rehabilitation Therapy

This article discusses the value of virtual reality (VR) technology in paediatric rehabilitation therapy, which can create immersive, interactive and imaginative virtual environments and provide children with safe and interesting therapeutic modalities to effectively improve their cognitive, motor, speech and emotional problems. The article analyses the application of VR technology in different scenarios, such as attention training, motor training, verbal expression training and emotion recognition training, and points out that the advantages of VR technology are to increase the interest of treatment, enhance the patient's participation, and achieve personalised treatment. However, VR technology also has challenges such as technical limitations, evaluation difficulties and high equipment costs. With the continuous development and improvement of the technology, VR technology is expected to overcome these challenges and play a greater role in the field of children's rehabilitation therapy, bringing hope for the rehabilitation of more children.

Resilient and Reversible Phosphotungstic Acid Passivated Zinc Anode.

Aqueous zinc ion batteries (ZIBs) present a compelling solution for grid-scale energy storage, which is crucial for integrating renewable energy resources into the electric infrastructure. The cycling stability of ZIBs hinges on the electrochemical reversibility of the zinc anode, which is often compromised by corrosion and dendritic zinc deposition. Here, we present a straightforward surface passivation strategy that significantly enhances the cycling stability of zinc anodes. By immersing zinc in a solution of phosphotungstic acid, we promoted the dominance of the 002 plane of zinc's hexagonal structure. This process facilitates the creation of a uniform nucleation and protective layer on the native zinc surface, resulting in a more uniform plating-stripping process and increased corrosion resistance. In symmetric cells, the passivated zinc exhibits a capacity retention of 68.7% after 1000 cycles at a current density of 1.0 Ag1-, whereas untreated zinc anodes retain only 7.4% of capacity under identical conditions. In full cell zinc iodine batteries employing the passivated zinc anode, over 1000 stable charge-discharge cycles were achieved at a current density of 20 mA cm-2, with approximately 96% Coulombic efficiency (CE), 86% voltage efficiency (VE), and 82% energy efficiency (EE). This study demonstrates a promising pathway for the construction and upscaling of flow batteries with high capacity and low cost.

Transfusion independence after lenalidomide discontinuation in patients with del(5q) myelodysplastic neoplasm: a HARMONY Alliance study.

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.

The Impact of Financing Structure on Common Stock Prices

The pricing of common stock is significantly influenced by the financing structure. The cost required for businesses to secure outside funding in order to support their operations and projects is referred to as their financing structure. This expense could include interest on debt and investor returns on capital contributed to the business. A high cost of financing structure will raise the cost of capital and lower the value of common stock. The interest expenses incurred on debt mean that the cost of the financing structure will have an impact on the profits of the company. The required return will rise in the event that financing costs are high, which will lower the valuation of the company and possibly lower the price of common stock. Through its effects on the cost of capital, the profits of the company and valuation, and the demand for stocks, the cost of financing structure has a direct and indirect impact on the price of common stocks. It should be mentioned that other elements, such as political and economic ones, business performance, and rivalry in the market, also have an impact on the price of common stock.

Metal–Organic Framework-Derived Rare Earth Metal (Ce-N-C)-Based Catalyst for Oxygen Reduction Reactions in Dual-Chamber Microbial Fuel Cells

Pt supported on carbon (Pt/C) is deemed as the state-of-the-art catalyst towards oxygen reduction reactions (ORRs) in chemical and biological fuel cells. However, due to the high cost and scarcity of Pt, researchers have focused on the development of Earth-abundant non-precious metal catalysts, hoping to replace the traditional Pt/C catalyst and successfully commercialize the chemical and biological fuel cells. In this regard, electrocatalysts made of transition metals emerged as excellent candidates for ORRs, especially the electrocatalysts made of Fe and Co in combination with N-doped carbons, which produce potentially active M-N4-C (M=Co, Fe) ORR sites. At present, however, the transition metal-based catalysts are popular; recently, electrocatalysts made of rare earth metals are emerging as efficient catalysts, due to the fact that rare earth metals also have the potential to form rare earth metal-N4-C active sites, just like transition metal Fe-N4-C/Co-N4-C. In addition, mixed valance states and uniqueness of f-orbitals of the rare earth metals are believed to improve the redox properties of the catalyst that helps in enhancing ORR activity. Among the rare earth metals, Ce is the most interesting element that can be explored as an ORR electrocatalyst in combination with the N-doped carbon. Unique f-orbitals of Ce can induce distinctive electronic behavior to the catalyst that helps to form stable coordination structures with N-doped carbons, in addition to its excellent ability to scavenge the OH● produced during ORRs, therefore helping in catalyst stability. In this study, we have synthesized Ce/N-C catalysts by a metal–organic framework and pyrolysis strategy. The ORR activity of Ce/N-C catalysts has been optimized by systematically increasing the Ce content and performing RDE studies in 0.1 M HClO4 electrolyte. The Ce/N-C catalyst has been characterized systematically by both physicochemical and electrochemical characterizations. The optimized Ce/N-C-3 catalyst exhibited a half-wave potential of 0.68 V vs. RHE. In addition, the Ce/N-C-3 catalyst also delivered acceptable stability with a loss of 70 mV in its half-wave potential when compared to 110 mV loss for Pt/C (10 wt.%) catalyst, after 5000 potential cycles. When Ce/N-C-3 is used as a cathode catalyst in dual-chamber microbial fuel cells, it delivered a volumetric power density of ⁓ 300 mW m−3, along with an organic matter degradation of 74% after continuous operation of DCMFCs for 30 days.

Determinants of Rice Farmers’ Participation in Anchor Borrowers’ Programme in Southeast, Nigeria

The study investigated the determinants of rice farmers’ participation in Anchor Borrowers’ Programme in South-East Nigeria. Purposive sampling technique was adopted in the selection of states and local government areas in order to capture areas where there are more concentrations of rice farmers and the participating LGAs. Proportionate sampling was adopted in selecting 120 rice farmers’ beneficiaries. Data were collected using structured questionnaires and analysed using frequency, percentage, mean score, standard deviation and ordinary least square regression analysis. Findings show that the beneficiaries rice farmers had high participation (x̄=2.52) in the programme activities with a discriminating index of x̄= 2. Long bureaucratic procedures (x̄=3.29), delay in loan disbursement (x̄=3.39), and high cost of labour (x̄=3.2) insufficient/unavailability of land (x̄=3.1) among others were the most severe constraints faced by beneficiary rice farmers in southeast. Educational level (t =3.015), household size (t = -2681) and access to credit (t = -4.160) were determinants of rice farmers’ level of participation in ABP. The study therefore recommends that there should be timely distribution of inputs among ABP facilitators.

Bayesian reverse design of high-efficiency perovskite solar cells based on experimental knowledge constraints

To alleviate high costs and lengthy trial-and-error periods associated with traditional optimization methods for perovskite solar cells (PSCs), we developed a data-driven reverse design framework for high-efficiency PSCs. This framework integrates machine learning and Bayesian optimization (BO) to accelerate the optimization process of PSCs by intelligently recommending the most promising parameter configurations for PSCs, such as device structure and fabrication processes. To improve the robustness of the framework, we first designed a two-stage sampling strategy to alleviate the issue of imbalanced dataset classes. Subsequently, by integrating “experimental knowledge constraints” into the BO process, we achieved precise parameter configurations, thus avoiding discrepancies between predicted and actual results due to parameter mismatches. Finally, using SHapley Additive exPlanations, we unveiled key factors influencing the power conversion efficiency (PCE), such as the composition of perovskite solvents. Our framework not only precisely predicted the PCE of PSCs with an area under the curve of 0.861 but also identified the optimal parameter configurations, achieving a high probability of 0.981. This framework offers substantial support for minimizing redundant experiments and characterizations, effectively accelerating the optimization process of PSCs.

Analyzing quality of life after low anterior resection for rectal cancer.

Rectal cancer is one of the most common cancers worldwide that imposes high costs on patients and the healthcare system while also having a significant impact on the patient's quality of life (QoL). We aimed to assess the QoL of rectal cancer patients undergoing lower anterior resection (LAR) and evaluate potential confounding factors. In this cross-sectional study, we included patients undergoing neo-adjuvant chemotherapy followed by LAR, diverting ileostomy, and adjuvant chemotherapy. Six months after stoma reversal, QoL was assessed using a cancer-specific core questionnaire EORTC QLQ-C30 and also a colorectal cancer module EORTC QLQ-CR29. Linear and quantile regression models were used to examine associations of QoL and patients' demographical and clinical features. The study population comprised 210 patients with an average age of 61.9 ± 11.0 (range: 37-85) and 112 (53.3%) male patients. The higher tumor stage increases the QoL of patients by reducing diarrhea, loss of appetite, defecation problems, and stool frequency. Based on the linear regression analysis, a farther distance of the anastomosis from the anal verge (AV) was correlated with lower symptom scores and higher QoL. Also, at the 75th percentile cut-off of the QLQ-CR29 scores, a higher N stage of the tumor was correlated with higher QoL based on functional subscale (coefficient = 3.032, P = 0.016). QoL of patients after LAR for rectal cancer is significantly associated with the distance of the anastomosis site from the AV.