The increasing worldwide demand for antimicrobial agents has significantly contributed to the alarming rise of antimicrobial resistance, posing a grave threat to human life. Consequently, there is a pressing need to explore uncharted environments, seeking out novel antimicrobial compounds that display exceptionally efficient capabilities. Hot springs harbor microorganisms possessing remarkable properties, rendering them an invaluable resource for uncovering groundbreaking antimicrobial compounds. In this study, thermophilic bacteria were isolated from Mahallat Hot Spring, Iran. Out of the 30 isolates examined, 3 strains exhibited the most significant antibacterial activities against Escherichia coli and Staphylococcus aureus. Furthermore, the supernatants of the isolated strains exhibited remarkable antibacterial activity, displaying notable resistance to temperatures as high as 75 °C for 30 min. It was determined that the two strains showed high similarity to the Bacillus genus, while strain Kh3 was classified as Saccharomonospora azurea. All three strains exhibited tolerance to NaCl. Bacillus strains demonstrated optimal growth at pH 5 and 40 °C, whereas S. azurea exhibited optimal growth at pH 9 and 45 °C. Accordingly, hot springs present promising natural reservoirs for the isolation of resilient strains possessing antibacterial properties, which can be utilized in disease treatment or within the food industry. Full article

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN’s cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes’ resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN’s cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy. Full article

Currently, there is a wide application in the literature of the use of the Fourier Transform Infrared Spectroscopy (FTIR) technique. This basic tool has also proven to be efficient for detecting molecules associated with hosts and pathogens in infections, as well as other molecules present in humans and animals’ biological samples. However, there is a crisis in science data reproducibility. This crisis can also be observed in data from experimental animal models (EAMs). When it comes to rodents, a major challenge is to carry out sanitary monitoring, which is currently expensive and requires a large volume of biological samples, generating ethical, legal, and psychological conflicts for professionals and researchers. We carried out a survey of data from the relevant literature on the use of this technique in different diagnostic protocols and combined the data with the aim of presenting the technique as a promising tool for use in EAM. Since FTIR can detect molecules associated with different diseases and has advantages such as the low volume of samples required, low cost, sustainability, and provides diagnostic tests with high specificity and sensitivity, we believe that the technique is highly promising for the sanitary and stress and the detection of molecules of interest of infectious or non-infectious origin. Full article

Three novel meroterpenoids, taladrimanins B–D (1–3), were isolated from the marine-derived fungus Talaromyces sp. M27416, alongside three biogenetically related compounds (4–6). We delineated taladrimanin B’s (1) structure using HRESIMS and NMR, confirmed its configuration via quantum chemical NMR analysis and DP4+ methodology, and verified it through X-ray crystallography. ECD calculations determined the absolute configuration of compound 1, while comparative NMR and ECD analyses elucidated the absolute configurations of 2 and 3. These compounds are drimane-type meroterpenoids with a C10 polyketide unit (8R-configuration). We proposed a biosynthetic pathway and noted that compound 1 showed cytotoxic activity against MKN-45 and 5637 cell lines and selective antibacterial effects against Staphylococcus aureus CICC 10384. Full article

Tomato brown rugose fruit virus (ToBRFV) is an emerging tobamovirus infecting tomatoes and peppers, resulting in a pandemic in recent years. In addition to its abilities of being seed-borne, transmitted mechanically and overcoming current resistance, we speculated other factors may also contribute to such catastrophic effect on tomato production in a hydroponic greenhouse. The objective of this study was to evaluate whether ToBRFV can be transmissible through recirculating hydroponic systems and, more importantly, search for an effective approach to contain its spread. We not only detected ToBRFV in the runoff water samples collected from three greenhouses but also determined the virus’ infectivity through a bioassay. We then conducted a water treatment using cold plasma ozone to assess its efficacy in inactivating ToBRFV. The results showed that, with a high concentration of ToBRFV (inoculum in 1:100 dilution), a prolonged exposure (72 min) to two higher ozone concentrations (0.6 mg/L and 1.0 mg/L) achieved partial effects. With a medium virus concentration (inoculum in 1:1000 dilution), an exposure to ozone for 48 min was sufficient to completely suppress the virus’ infectivity. However, with a low virus concentration (inoculum in 1:10,000 dilution), the virus was completely inactivated even with just a short ozone exposure (24 min). Future work will need to confirm the efficacy of the ozone treatment against ToBRFV as well as its impact on tomato plants in a hydroponic greenhouse. Full article

We report a joint high-pressure experimental and theoretical study of the structural, vibrational, and photoluminescent properties of pure and Eu³⁺-doped cubic Y₂O₃ nanoparticles with two very different average particle sizes. We compare the results of synchrotron X-ray diffraction, Raman scattering, and photoluminescence measurements in nanoparticles with ab initio density-functional simulations in bulk material with the aim to understand the influence of the average particle size on the properties of pure and doped Y₂O₃ nanoparticles under compression. We observe that the high-pressure phase behavior of Y₂O₃ nanoparticles depends on the average particle size, but in a different way to that previously reported. Nanoparticles with an average particle size of ~37 nm show the same pressure-induced phase transition sequence on upstroke and downstroke as the bulk sample; however, nanoparticles with an average particle size of ~6 nm undergo an irreversible pressure-induced amorphization above 16 GPa that is completed above 24 GPa. On downstroke, 6 nm nanoparticles likely consist of an amorphous phase. Full article

As a result of technological advancements, functional capacity assessments, such as the 6-minute walk test, can be performed remotely, at home and in the community. Current studies, however, tend to overlook the crucial aspect of data quality, often limiting their focus to idealised scenarios. Challenging conditions may arise when performing a test given the risk of collecting poor-quality GNSS signal, which can undermine the reliability of the results. This work shows the impact of applying filtering rules to avoid noisy samples in common algorithms that compute the walked distance from positioning data. Then, based on signal features, we assess the reliability of the distance estimation using logistic regression from the following two perspectives: error-based analysis, which relates to the estimated distance error, and user-based analysis, which distinguishes conventional from unconventional tests based on users’ previous annotations. We highlight the impact of features associated with walked path irregularity and direction changes to establish data quality. We evaluate features within a binary classification task and reach an F1-score of 0.93 and an area under the curve of 0.97 for the user-based classification. Identifying unreliable tests is helpful to clinicians, who receive the recorded test results accompanied by quality assessments, and to patients, who can be given the opportunity to repeat tests classified as not following the instructions. Full article

Betulonic acid (B(O)A) is a pentacyclic lupane-type triterpenoid that widely exists in plants. There are scientific reports indicating anticancer activity of B(O)A, as well as the amides and esters of this triterpenoid. In the first step of the study, the synthesis of novel amide derivatives of B(O)A containing an acetylenic moiety was developed. Subsequently, the medium-soluble compounds (EB171 and EB173) and the parent compound, i.e., B(O)A, were investigated for potential cytotoxic activity against breast cancer (MCF-7 and MDA-MB-231) and melanoma (C32, COLO 829 and A375) cell lines, as well as normal human fibroblasts. Screening analysis using the WST-1 test was applied. Moreover, the lipophilicity and ADME parameters of the obtained derivatives were determined using experimental and in silico methods. The toxicity assay using zebrafish embryos and larvae was also performed. The study showed that the compound EB171 exhibited a significant cytotoxic effect on cancer cell lines: MCF-7, A-375 and COLO 829, while it did not affect the survival of normal cells. Moreover, studies on embryos and larvae showed no toxicity of EB171 in an animal model. Compared to EB171, the compound EB173 had a weaker effect on all tested cancer cell lines and produced less desirable effects against normal cells. The results of the WST-1 assay obtained for B(O)A revealed its strong cytotoxic activity on the examined cancer cell lines, but also on normal cells. In conclusion, this article describes new derivatives of betulonic acid—from synthesis to biological properties. The results allowed to indicate a promising direction for the functionalization of B(O)A to obtain derivatives with selective anticancer activity and low toxicity. Full article

This paper addresses a multiobjective version of the Team Orienteering Problem (TOP). The TOP focuses on selecting a subset of customers for maximum rewards while considering time and fleet size constraints. This study extends the TOP by considering two objectives: maximizing total rewards from customer visits and maximizing visits to prioritized nodes. The MultiObjective TOP (MO-TOP) is formulated mathematically to concurrently tackle these objectives. A multistart biased-randomized algorithm is proposed to solve MO-TOP, integrating exploration and exploitation techniques. The algorithm employs a constructive heuristic defining biefficiency to select edges for routing plans. Through iterative exploration from various starting points, the algorithm converges to high-quality solutions. The Pareto frontier for the MO-TOP is generated using the weighted method, epsilon-constraint method, and Epsilon-Modified Method. Computational experiments validate the proposed approach’s effectiveness, illustrating its ability to generate diverse and high-quality solutions on the Pareto frontier. The algorithms demonstrate the ability to optimize rewards and prioritize node visits, offering valuable insights for real-world decision making in team orienteering applications. Full article

Water footprints have been widely used to illustrate the consumption of water in many situations, for instance, in products, processes, or regions of interest. In this work, we analyzed—using a sensitivity analysis approach—the effect of some variables in the calculation of the water footprint in the viticulture in the Brazilian Serra Gaúcha (the major producing region of Brazilian wine). The classical Penman–Monteith model for evapotransporation was considered, with uncertainties in some parameters (dead mulch covering a fraction of the vineyard, maximum temperatures for some months, the altitudes and latitudes of the site). A sensitivity analysis was conducted using the SAFE toolbox under Octave framework. The results indicated that the the portion of the water footprint corresponding to evapotranspiration is more sensitive to the values of the mulch-covered fraction and the altitude of the site in comparison with the latitude and the maximum temperatures. Full article

In the era of the competitive environment, the improvement in current products is ensured through activities aimed at increasing a product’s quality level and, consequently, reducing the amount of waste. The dynamically changing production environment and sudden changes in customer expectations force us to take precise and well-thought-out development steps. Furthermore, it is important to anticipate favourable product changes to prepare for market changes over time. This is still an open problem. The aim of this study was to develop a method to predict the quality of potential product prototypes resulting from the proposed modifications of the product features. This methodology takes into account current customer expectations. The method was created based on the principles of creating Quality Function Deployment (QFD) in the context of taking into account current and future customer expectations regarding product features. This is a new approach to analysing product quality within the principles of the traditional QFD method. The originality of the study is the technique used in the method to estimate the expected values of product features and their importance (weights), taking into account current customer expectations. Its originality is also manifested in drawing conclusions supporting the decision-making process of product improvement, because it involves ensuring the pro-quality modification of selected features of current products in the order that is most advantageous from the customer’s point of view. The use of the proposed method allows for the analysis of the impact of modifying the current value of a product feature. The method is illustrated with an example of a vacuum cleaner for home use. However, the proposed method can be applied to the design of any product to predict products that will meet customer expectations. Full article

Algae growth can be carried out in treated mine waters, providing biomass and helping to achieve the standards for water discharge. However, efficient separation of algae from the aqueous medium is crucial. The present work investigated the stability of Scenedesmus sp. in treated acid drainage from coal mining and assessed the harvesting of microalgae via coagulation/flocculation and dissolved air flotation (DAF). Successful algae growth was achieved, with cells remaining suspended in the water at a wide range of pH values, requiring the use of reagents for destabilization/aggregation. Algae coagulation/flocculation was attained with the use of tannin or ferric chloride associated with an anionic polymer flocculant at a pH of 8.0 ± 0.1. When combined with the flocculant, both tannin and the inorganic coagulant proved effective in enhancing floc stability and hydrophobicity for the DAF process. In summary, this operational approach facilitated algae biomass recovery and significantly reduced turbidity in the treated water. Finally, a schematic diagram illustrating the algae cultivation and harvesting process is presented, offering a practical alternative to acid mine drainage (AMD) treatment refinement associated with algae biomass production. Full article

Previous studies have identified diverse bacteriophages that infect Caulobacter vibrioides strain CB15 ranging from small RNA phages to four genera of jumbo phages. In this study, we focus on 20 bacteriophages whose genomes range from 40 to 60 kb in length. Genome comparisons indicated that these diverse phages represent six Caulobacter phage genera and one additional genus that includes both Caulobacter and Brevundimonas phages. Within species, comparisons revealed that both single base changes and inserted or deleted genetic material cause the genomes of closely related phages to diverge. Among genera, the basic gene order and the orientation of key genes were retained with most of the observed variation occurring at ends of the genomes. We hypothesize that the nucleotide sequences of the ends of these phage genomes is less important than the need to maintain the size of the genome and the stability of the corresponding mRNAs. Full article

Studying atmospheric temperature characteristics is crucial under climate change, as it helps us to understand the changing patterns in temperature that have significant implications for the environment, ecosystems, and human well-being. This study presents the comprehensive analysis of the spatiotemporal variability of scaling behavior of daily temperature series across the whole Indian mainland, using a Multifractal Detrended Fluctuation Analysis (MFDFA). The analysis considered 1° × 1° datasets of maximum temperature (T_max), minimum temperature (T_min), mean temperature (T_mean), and diurnal temperature range (DTR) (T_DTR = T_max − T_min) from 1951 to 2016 to compare their scaling behavior for the first time. Our results indicate that the T_min series exhibits the highest persistence (with the Hurst exponent ranging from 0.849 to unity, and a mean of 0.971), and all four-temperature series display long-term persistence and multifractal characteristics. The variability of the multifractal characteristics is less significant in North–Central India, while it is highest along the western coast of India. Moreover, the assessment of multifractal characteristics of different temperature series during the pre- and post-1976–1977 period of the Pacific climate shift reveals a notable decrease in multifractal strength and persistence in the post-1976–1977 series across all regions. Moreover, for the detection of climate change and its dominant driver, we propose a new rolling window multifractal (RWM) framework by evaluating the temporal evolution of the spectral exponents and the Hurst exponent. This study successfully captured the regime shifts during the periods of 1976–1977 and 1997–1998. Interestingly, the earlier climatic shift primarily mitigated the persistence of the T_max series, whereas the latter shift significantly influenced the persistence of the T_mean series in the majority of temperature-homogeneous regions in India. Full article

The high-power engine exhaust elbow has a complex construction, which makes it susceptible to casting flaws that could negatively impact its functionality. Therefore, the investment casting scheme was established and optimized in this study in order to cast structurally complete exhaust elbows for high-horsepower engines. ProCAST software was used to simulate and optimize the casting and solidification processes. The optimal process parameters were determined as follows: pouring temperature of 1650 °C, pouring speed of 1.5 kg/s, and shell preheating temperature of 1050 °C. The optimization of the primary parameters of the casting process, along with the results of dimensional accuracy analysis, shape and positional deviation, and defect detection, were validated through testing. The results indicated that the optimized castings had no casting defects and complied with the design specifications. Full article

Surface hydrophobicity is an important factor in controlling the catalytic activity of heterogeneous catalysts in various reactions, particularly liquid-phase reactions using water as the (co)solvent. In this study, the surface hydrophobicity of Fe-ZSM-5 was successfully controlled using a simple coating method in which furfuryl alcohol was used as the carbon precursor. Various techniques, such as N₂ physisorption, temperature-programmed desorption of ammonia, and contact angle measurements of water droplets, were used to characterize the catalysts. Fe-ZSM-5 catalysts with different degrees of hydrophobicity were used for the aqueous-phase selective oxidation of methane with H₂O₂. The positive effect of the surface carbon coating on the catalytic performance was confirmed when the carbon content was not sufficiently high to block the pores. Full article

Wearable health devices (WHDs) are rapidly gaining ground in the biomedical field due to their ability to monitor the individual physiological state in everyday life scenarios, while providing a comfortable wear experience. This study introduces a novel wearable biomedical device capable of synchronously acquiring electrocardiographic (ECG), photoplethysmographic (PPG), galvanic skin response (GSR) and motion signals. The device has been specifically designed to be worn on a finger, enabling the acquisition of all biosignals directly on the fingertips, offering the significant advantage of being very comfortable and easy to be employed by the users. The simultaneous acquisition of different biosignals allows the extraction of important physiological indices, such as heart rate (HR) and its variability (HRV), pulse arrival time (PAT), GSR level, blood oxygenation level (SpO₂), and respiratory rate, as well as motion detection, enabling the assessment of physiological states, together with the detection of potential physical and mental stress conditions. Preliminary measurements have been conducted on healthy subjects using a measurement protocol consisting of resting states (i.e., SUPINE and SIT) alternated with physiological stress conditions (i.e., STAND and WALK). Statistical analyses have been carried out among the distributions of the physiological indices extracted in time, frequency, and information domains, evaluated under different physiological conditions. The results of our analyses demonstrate the capability of the device to detect changes between rest and stress conditions, thereby encouraging its use for assessing individuals’ physiological state. Furthermore, the possibility of performing synchronous acquisitions of PPG and ECG signals has allowed us to compare HRV and pulse rate variability (PRV) indices, so as to corroborate the reliability of PRV analysis under stationary physical conditions. Finally, the study confirms the already known limitations of wearable devices during physical activities, suggesting the use of algorithms for motion artifact correction. Full article

Spaghetti meat (SM) is a newly identified muscle abnormality that significantly affects modern broiler chickens, consequently exerting a substantial economic impact on the poultry industry worldwide. However, investigations into the meat quality and the underlying causative factors of SM in broilers remain limited. Therefore, this study was undertaken to systematically evaluate meat quality and muscle fiber characteristics of SM-affected meat. To elucidate the disparities between SM-affected and normal (NO) muscles in broiler chickens reared under identical conditions, we selected 18 SM-affected breast tissues and 18 NO breast tissues from 200 broiler chickens raised according to commercial standards under the same conditions for our study. The results showed that compared with the NO group, the muscle surface of the SM group lost integrity, similar to strip and paste. The brightness and yellowness values were significantly higher than those of the NO group. On the contrary, the shear force and protein were significantly lower in the SM group. Microscopic examination revealed that the muscle fibers in the SM group were lysed, necrotic, and separated from each other, with a large number of neutrophils diffusely distributed on the sarcolemma and endometrium. Thirty-five significantly different metabolites were observed in the breast muscles between both groups. Among them, the top differential metabolites—14,15-DiHETrE, isotretinoin, L-malic acid, and acetylcysteine—were mainly enriched in lipid metabolism and inflammatory pathways, including linoleic acid, arachidonic acid, phenylalanine, and histidine metabolism. Overall, these findings not only offer new insights into the meat quality and fiber traits of SM but also contribute to the understanding of potential mechanisms and nutritional regulators for SM myopathy. Full article

Facing increasing sustainability demands, the construction industry is at a turning point where the implementation of circular economy (CE) strategies plays an essential role in driving the necessary transformation aimed at reducing the environmental impact. To facilitate this shift, structural engineering must effectively integrate circular principles into building design. With the exponential growth of research articles within this field, it is crucial to map the evolution of the research area. The objective of this study is to detail the trends with, challenges to, and research contributions, integration, and material applications of CE principles within structural engineering. Consequently, a systematic mapping of the CE within the field of structural engineering has been conducted in this study. Initially, the mapping process began with the identification of relevant keywords, followed by searches across four databases. Each resulting article was carefully screened against content criteria, culminating in 91 publications that were thoroughly evaluated. The publications were then categorized and analyzed based on attributes such as research type, circular design, materials, and applications. The results are presented through informative figures and tables. The analysis of the research indicates a predominant focus on technical solutions for structural systems, with demountable connections designed to facilitate the future reuse of materials representing more than half of the literature reviewed. A significant portion of the literature also addresses designing from reclaimed elements; these articles reflect a transformation in engineering approaches, incorporating computational design and innovative methodologies. The focus on steel as a structural material is prominent in the reviewed literature. However, there is an increasing focus on timber, which signals a definitive shift toward sustainable structural systems. Recurring challenges identified in the literature regarding the transition to a circular economy (CE) in the construction industry include the need for industry-wide adoption, precise standardization, the integration of digital tools, and the overcoming of related obstacles in policy and market acceptances. Furthermore, the literature demonstrates a significant research gap: the absence of a comprehensive digital framework enabling an effective digital circular structural design workflow. Full article

Hermetia illucens has received a lot of attention as its larval stage can grow on organic substrates, even those that are decomposing. Black soldier fly breeding provides a variety of valuable products, including frass, a mixture of larval excrements, larval exuviae, and leftover feedstock, that can be used as a fertilizer in agriculture. Organic fertilizers, such as frass, bringing beneficial bacteria and organic materials into the soil, improves its health and fertility. This comprehensive review delves into a comparative analysis of frass derived from larvae fed on different substrates. The composition of micro- and macro-nutrients, pH levels, organic matter content, electrical conductivity, moisture levels, and the proportion of dry matter are under consideration. The effect of different feeding substrates on the presence of potentially beneficial bacteria for plant growth within the frass is also reported. A critical feature examined in this review is the post-application beneficial impacts of frass on crops, highlighting the agricultural benefits and drawbacks of introducing Hermetia illucens frass into cultivation operations. One notable feature of this review is the categorization of the crops studied into distinct groups, which is useful to simplify comparisons in future research. Full article

Visceral leishmaniasis (VL), often referred to as kala-azar, is quite rare in developed countries during pregnancy. Only few studies have evaluated its impact on perinatal outcome. It is caused primarily by Leishmania donovani or Leishmania infantum and presents with a wide spectrum of clinical manifestations from cutaneous ulcers to multisystem disease. Differential diagnosis is challenging as symptoms and signs are insidious, mimicking other diseases. Misdiagnosis can result in severe adverse perinatal outcomes, even maternal/neonatal death. Early treatment with liposomal amphotericin-B (LAmB) is currently the first choice with adequate effectiveness. We report a rare case of VL in a twin pregnancy with onset at the second trimester, presenting with periodic fever with rigors, right flank pain, and gradual dysregulation of all three cell lines. The positive rK39 enzyme-linked immunosorbent assay test confirmed the diagnosis. Treatment with LAmB resulted in clinical improvement within 48 h and in the delivery of two late-preterm healthy neonates with no symptoms or signs of vertical transmission. The one-year follow-up, of the mother and the neonates, was negative for recurrence. To our knowledge, this is the first reported case of VL in a twin pregnancy, and consequently treatment and perinatal outcome are of great importance. Full article

The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as powerful tools capable of automatically learning molecular structural features from large-scale datasets, showing promising capabilities for the downstream prediction of molecular properties. However, the performance of pre-trained chemical language models in predicting ADRs, especially idiosyncratic ADRs induced by marketed drugs, remains largely unexplored. In this study, we propose MoLFormer-XL, a pre-trained model for encoding molecular features from canonical SMILES, in conjunction with a CNN-based model to predict drug-induced QT interval prolongation (DIQT), drug-induced teratogenicity (DIT), and drug-induced rhabdomyolysis (DIR). Our results demonstrate that the proposed model outperforms conventional models applied in previous studies for predicting DIQT, DIT, and DIR. Notably, an analysis of the learned linear attention maps highlights amines, alcohol, ethers, and aromatic halogen compounds as strongly associated with the three types of ADRs. These findings hold promise for enhancing drug discovery pipelines and reducing the drug attrition rate due to safety concerns. Full article