Combined low-carbohydrate diet and long-term exercise in hypoxia in type 2 diabetes: A randomized controlled trial protocol to assess glycemic control, cardiovascular risk factors and body composition.

Background: Cardiovascular disease is the leading cause of mortality associated with diabetes, which is characterized by chronic hyperglycemia. Low-carbohydrate diet has gained popularity as an intervention in patients with type 2 diabetes mellitus, acting to improve glycemic profile and serum lipids. In its turn, exercise in hypoxia induces specific adaptations, mostly modulated via hypoxia-induced transcription factor signaling cascade, which increases with exposure to altitude, and promotes angiogenesis, glycogen supply, glucose tolerance, and raises GLUT-4 expression. Aim: Given that hyperglycemia decreases HIF-1α and it is better controlled when following a low-carbohydrate diet, this study aims to examine the hypothesis that a combination of both low-carbohydrate diet and chronic exercise in hypoxia in type 2 diabetes mellitus is associated with improved glycemic control and cardiovascular parameters, whose protocol is described. Methods: Patients with type 2 diabetes mellitus (n = 48) will be recruited and randomized into one of the three groups: (a) Control group: Control diet (low-fat and moderate-carbohydrate diet) + exercise in normoxia; (2) exercise in hypoxia group: Control diet + exercise in hypoxia; (3) intervention group: Low-carbohydrate diet (low-carbohydrate and high-fat diet) + exercise in hypoxia. Before and after 8 weeks of interventions, cardiopulmonary tests (Bruce protocol), body composition and blood pressure will be evaluated. Blood samples will be collected to measure hypoxia-induced transcription factor, C-reactive protein, glycemic and lipid profiles. Summary: This will be the first trial to examine the isolated and combined effect of chronic exercise in hypoxia and low-carbohydrate diet in type 2 diabetes mellitus. This trial will help to fill a significant research gap, guide future research and contribute to the combined nutrition and exercise approach to type 2 diabetes mellitus.

Effects of Pharmaceutical Substances with Obesogenic Activity on Male Reproductive Health.

Obesogens have been identified as a significant factor associated with increasing obesity rates, particularly in developed countries. Substances with obesogenic traits are prevalent in consumer products, including certain pharmaceuticals. Specific classes of pharmaceuticals have been recognized for their ability to induce weight gain, often accompanied by hormonal alterations that can adversely impact male fertility. Indeed, research has supplied evidence underscoring the crucial role of obesogens and therapeutic agents in the normal functioning of the male reproductive system. Notably, sperm count and various semen parameters have been closely linked to a range of environmental and nutritional factors, including chemicals and pharmacological agents exhibiting obesogenic properties. This review aimed to explore studies focused on analyzing male fertility parameters, delving into the intricacies of sperm quality, and elucidating the direct and adverse effects that pharmacological agents may have on these aspects.

Central airway obstruction: is it time to move forward?

INTRODUCTION: Central airway obstruction (CAO) represents a pathological condition that can lead to airflow limitation of the trachea, main stem bronchi, bronchus intermedius or lobar bronchus. MAIN BODY: It is a common clinical situation consensually considered under-diagnosed. Management of patients with CAO can be difficult and deciding on the best treatment approach represents a medical challenge. This work intends to review CAO classifications, causes, treatments and its therapeutic limitations, approaching benign and malign presentations. Three illustrative cases are further presented, supporting the clinical problem under review. CONCLUSION: Management of CAO still remains a challenge. The available options are not always effective nor free from complications. A new generation of costume-tailored airway stents, associated with stem cell-based therapy, could be an option in specific clinical situations.

High Performance of Ionic-Liquid-Based Materials to Remove Insecticides.

Neonicotinoids are systemic insecticides commonly used for pest control in agriculture and veterinary applications. Due to their widespread use, neonicotinoid insecticides (neonics) are found in different environmental compartments, including water, soils, and biota, in which their high toxicity towards non-target organisms is a matter of great concern. Given their widespread use and high toxicity, the development of strategies to remove neonics, while avoiding further environmental contamination is of high priority. In this work, ionic-liquid-based materials, comprising silica modified with tetraalkylammonium cations and the chloride anion, were explored as alternative adsorbent materials to remove four neonics insecticides, namely imidacloprid, acetamiprid, thiacloprid, and thiamethoxam, from aqueous media. These materials or supported ionic liquids (SILs) were first synthesized and chemically characterized and further applied in adsorption studies. It was found that the equilibrium concentration of the adsorbate in the solid phase decreases with the decrease in the SIL cation alkyl chain length, reinforcing the relevance of hydrophobic interactions between ionic liquids (ILs) and insecticides. The best-identified SIL for the adsorption of the studied insecticides corresponds to silica modified with propyltrioctylammonium chloride ([Si][N3888]Cl). The saturation of SILs was reached in 5 min or less, showing their fast adsorption rate towards all insecticides, in contrast with activated carbon (benchmark) that requires 40 to 60 min. The best fitting of the experimental kinetic data was achieved with the Pseudo Second-Order model, meaning that the adsorption process is controlled at the solid-liquid interface. On the other hand, the best fitting of the experimental isotherm data is given by the Freundlich isotherm model, revealing that multiple layers of insecticides onto the SIL surface may occur. The continuous removal efficiency of the best SIL ([Si][N3888]Cl) by solid-phase extraction was finally appraised, with the maximum adsorption capacity decreasing in the following sequence: imidacloprid > thiacloprid > thiamethoxam > acetamiprid. Based on real reported values, under ideal conditions, 1 g of [Si][N3888]Cl is able to treat at least 106 m3 of wastewater and water from wetland contaminated with the studied neonics. In summary, the enhanced adsorption capacity of SILs for a broad diversity of neonics was demonstrated, reinforcing the usefulness of these materials for their removal from aqueous matrices and thus contributing to preventing their introduction into the ecosystems and reducing their detrimental effects in the environment and human health.

Male Infertility in the XXI Century: Are Obesogens to Blame?

The permanent exposure to environmental contaminants promoting weight gain (i.e., obesogens) has raised serious health concerns. Evidence suggests that obesogens are one of the leading causes of the marked decline in male fertility and are key players in shaping future health outcomes, not only for those who are directly exposed to them, but also for upcoming generations. It has been hypothesized that obesogens affect male fertility. By using an interdisciplinary strategy, combining in silico, in vitro, in vivo and epidemiological findings, this review aims to contribute to the biological understanding of the molecular transformations induced by obesogens that are the basis of male infertility. Such understanding is shaped by the use of Adverse Outcomes Pathways, a new approach that may shift the paradigm of reproductive toxicology, contributing to the improvement of the diagnosis and management of the adverse effects of obesogens in male fertility.

Gamma Irradiation Processing on 3D PCL Devices-A Preliminary Biocompatibility Assessment.

Additive manufacturing or 3D printing applying polycaprolactone (PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the most suitable gamma radiation conditions to sterilize PCL-based scaffolds in a preliminary biocompatibility assessment, envisioning future studies for airway obstruction conditions. Three radiation levels were considered, 25 kGy, 35 kGy and 45 kGy, and evaluated as regards their cyto- and biocompatibility. All three groups presented biocompatible properties, indicating an adequate sterility condition. As for the cytocompatibility analysis, devices sterilized with 35 kGy and 45 kGy showed better results, with the 45 kGy showing overall improved outcomes. This study allowed the selection of the most suitable sterilization condition for PCL-based scaffolds, aiming at immediate future assays, by applying 3D-customized printing techniques to specific airway obstruction lesions of the trachea.

Establishment of a Sheep Model for Hind Limb Peripheral Nerve Injury: Common Peroneal Nerve.

Thousands of people worldwide suffer from peripheral nerve injuries and must deal daily with the resulting physiological and functional deficits. Recent advances in this field are still insufficient to guarantee adequate outcomes, and the development of new and compelling therapeutic options require the use of valid preclinical models that effectively replicate the characteristics and challenges associated with these injuries in humans. In this study, we established a sheep model for common peroneal nerve injuries that can be applied in preclinical research with the advantages associated with the use of large animal models. The anatomy of the common peroneal nerve and topographically related nerves, the functional consequences of its injury and a neurological examination directed at this nerve have been described. Furthermore, the surgical protocol for accessing the common peroneal nerve, the induction of different types of nerve damage and the application of possible therapeutic options were described. Finally, a preliminary morphological and stereological study was carried out to establish control values for the healthy common peroneal nerves regarding this animal model and to identify preliminary differences between therapeutic methods. This study allowed to define the described lateral incision as the best to access the common peroneal nerve, besides establishing 12 and 24 weeks as the minimum periods to study lesions of axonotmesis and neurotmesis, respectively, in this specie. The post-mortem evaluation of the harvested nerves allowed to register stereological values for healthy common peroneal nerves to be used as controls in future studies, and to establish preliminary values associated with the therapeutic performance of the different applied options, although limited by a small sample size, thus requiring further validation studies. Finally, this study demonstrated that the sheep is a valid model of peripheral nerve injury to be used in pre-clinical and translational works and to evaluate the efficacy and safety of nerve injury therapeutic options before its clinical application in humans and veterinary patients.

Demarcating Exercise Intensity Domains in Freestyle Swimming: Is There an Alternative to Incremental Step Test and Beats Below HRmax Method?

Piatrikova, E, Sousa, AC, Willsmer, NJ, Gonzalez, JT, and Williams, S. Demarcating exercise intensity domains in freestyle swimming: is there an alternative to incremental step test and beats below HRmax method? J Strength Cond Res 34(9): 2575-2584, 2020-Critical power derived from the 3-minute all-out test (3MT) was recently used to estimate the exercise intensity boundaries in competitive cyclists. Considering that physiological testing is challenging in swimming, the purpose of this study was to examine whether critical speed (CS) derived from the 3MT could be used for the same purpose in swimming. The second aim was to assess the accuracy of the 50-40 and 30-20 beats below the maximal (BBM) heart rate method, currently used by swimming coaches to demarcate boundaries between moderate-heavy and heavy-severe exercise, respectively. Thirteen swimmers completed an incremental step test (IST) and 3MT in freestyle to establish speeds at: lactate threshold (LT), lactate turnpoint (LTP), maximum aerobic speed (Smax), and CS. Using linear regression through origin, speeds at LT, LTP, and Smax were predicted at 89, 98, and 104% of CS derived from the 3MT, respectively. There were no significant differences between threshold speeds derived from the IST and 3MT (p > 0.05), and nearly perfect correlations at LT (1.21 ± 0.06; 1.21 ± 0.06 m·s; r = 0.92) and LTP (1.33 ± 0.07; 1.33 ± 0.07 m·s; r = 0.90), and very large correlations at Smax (1.40 ± 0.06; 1.40 ± 0.07 m·s; r = 0.88; all p < 0.0001). Speeds estimated at 50 (1.11 ± 0.08 m·s) and 40 BBM (1.17 ± 0.07 m·s) were lower compared with LT, and speeds estimated at 30 (1.23 ± 0.07 m·s) and 20 BBM (1.29 ± 0.07 m·s) were lower compared with LTP and CS (all p < 0.02). The 3MT can therefore be used as an alternative to the IST to estimate exercise intensity boundaries, in practical settings where resources or time might be limited. However, the BBM significantly underestimates speeds at LT, LTP, and CS.

The effects of the obesogen tributyltin on the metabolism of Sertoli cells cultured ex vivo.

Human exposure to environmental contaminants is widespread. Some of these contaminants have the ability to interfere with adipogenesis, being thus considered as obesogens. Recently, obesogens have been singled out as a cause of male infertility. Sertoli cells (SCs) are essential for male fertility and their metabolic performance, especially glucose metabolism, is under a tight endocrine control, being essential for the success of spermatogenesis. Herein, we studied the impact of the model obesogen tributyltin in the metabolic profile of SCs. For that, ex vivo-cultured rat SCs were exposed to increasing doses of tributyltin. SCs proliferation was evaluated by the sulforhodamine B assay and the maturation state of the cells was assessed by the expression of specific markers (inhibin B and the androgen receptor) by quantitative polymerase chain reaction. The metabolic profile of SCs was established by studying metabolites consumption/production by nuclear magnetic resonance spectroscopy and by analyzing the expression of key transporters and enzymes involved in glycolysis by Western blot. The proliferation of SCs was only affected in the cells exposed to the highest dose (1000 nM) of tributyltin. Notably, SCs exposed to 10 nM tributyltin decreased the consumption of glucose and pyruvate, as well as the production of lactate. The decreased lactate production hampers the development of germ cells. Intriguingly, the lowest levels of tributyltin were more prone to modulate the expression of key players of the glycolytic pathway. This is the first study showing that tributyltin reprograms glucose metabolism of SCs under ex vivo conditions, suggesting new targets and mechanisms through which obesogens modulate the metabolism of SCs and thus male (in)fertility.

Magnetic resonance imaging evidence for perineural spread of endometriosis to the lumbosacral plexus: report of 2 cases.

Sciatic nerve endometriosis (EM) is a rare presentation of retroperitoneal EM. The authors present 2 cases of catamenial sciatica diagnosed as sciatic nerve EM. They propose that both cases can be explained by perineural spread of EM from the uterus to the sacral plexus along the pelvic autonomie nerves and then further distally to the sciatic nerve or proximally to the spinal nerves. This explanation is supported by MRI evidence in both cases. As a proof of concept, the authors retrieved and analyzed the original MRI studies of a case reported in the literature and found a similar pattern of spread. They believe that the imaging evidence of their institutional cases together with the outside case is a very compelling indication for perineural spread as a mechanism of EM of the nerve.

Neural involvement in endometriosis: Review of anatomic distribution and mechanisms.

Endometriosis (EM) is an infrequent cause of peripheral neuropathy, most commonly sciatic. Perineural spread has recently been introduced as an alternate explanation for cases of lumbosacral or sciatic nerve EM. We performed a literature review to collect all reported cases of peripheral and central nervous system EM in search of anatomic patterns of involvement; potentially to support the perineural spread theory. If available, intraneural invasion and presence of peritoneal EM were recorded. The search revealed 83 articles describing 365 cases of somatic peripheral nervous EM and 13 cases of central nervous EM. The most frequently involved site was the sacral plexus (57%, n = 211), followed by the sciatic nerve (39%, n = 140). Other nerves were reported in significantly smaller numbers. Ninety seven percent (97%, n = 355) of peripheral nerve cases presented with pain, 20% (n = 72) reported weakness and 31% (n = 114), numbness. Thirty four percent (34%, n = 38) had solely intraneural EM of which 89% (n = 33) had no peritoneal EM (percentage based on available information). In the central nervous system, the conus medullaris and/or cauda equina constituted the majority of cases with 54% (n = 7). Apart from perineural spread, other discussed mechanisms include retrograde menstruation with peritoneal seeding, hematogenous and lymphogenous spread, stem cell implantation either hematogenously or via retrograde menstruation with subsequent EM differentiation, and coelomic or Müllerian duct metaplasia. We believe this literature review supports perineural spread as an alternate mechanism for EM of nerve, particularly the subgroup with intraneural EM and without peritoneal disease.

A microcosm approach to evaluate the degradation of tributyltin (TBT) by Aeromonas molluscorum Av27 in estuarine sediments.

Tributyltin (TBT) is a biocide extremely toxic to a wide range of organisms, which has been used for decades in antifouling paints. Despite its global ban in 2008, TBT is still a problem of great concern due to the high levels trapped in sediments. Aeromonas molluscorum Av27 is a TBT degrading bacterium that was isolated from an estuarine system. We investigated the ability and the role of this bacterium on TBT degradation in this estuarine system, using a microcosm approach in order to mimic environmental conditions. The experiment was established and followed for 150 days. Simultaneously, changes in the indigenous bacterial community structure were also investigated. The results revealed a maximum TBT degradation rate of 28% accompanied by the detection of the degradation products over time. Additionally, it was observed that TBT degradation was significantly enhanced by the presence of Av27. In addition a significantly higher TBT degradation occurred when the concentration of Av27 was higher. TBT degradation affected the bacterial community composition as revealed by the changes in the prevalence of Proteobacteria subdivisions, namely the increase of Deltaproteobacteria and the onset of Epsilonproteobacteria. However, the addition of Av27 strain did not affect the dominant phylotypes. Total bacterial number, bacterial biomass productivity, 16S rRNA gene and denaturing gradient gel electrophoresis (DGGE) analyses also indicated alterations on the bacterial community structure over time, with bacteria non-tolerant to pollutants increasing their representativeness, as, for instance, the increase of the number of Alphaproteobacteria clones from 6% in the beginning to 12% at the end of the experiment. The work herein presented confirms the potential of Av27 strain to be used in the decontamination of TBT-polluted environments.

Characterization of fungal communities in house dust samples collected from central Portugal-a preliminary survey.

House dust is a repository and concentrator of many chemical and biological agents including fungi. Considering that dust acts as a long-term reservoir of airborne fungi and that cumulative exposure is more relevant to potential health problems than single-day or short-term exposure, characterization of fungal communities in dust samples is of paramount importance. In the present study, the fungal composition of Portuguese house dust samples was determined. A total of 28 samples were obtained from vacuum cleaner deposits from households located in central Portugal. DNA was extracted from dust samples and fungal communities were analyzed using a culture-independent polymerase chain reaction (PCR)- denaturing gradient gel electrophoresis (DGGE) approach. Cultural analyses were also performed in order to identify the viable fungi species present in selected samples. Fungal diversity, reported as the number of operational taxonomic units (OTU), varied between 9 and 56 OTU. This analysis of viable fungi showed that Aspergillus was the most abundant genus, followed by Penicillium, Mucor, and Rhizomucor. Trichoderma, Chrysosporium, Fusarium, Rhizopus, and Stachybotrys were found in a limited number of houses. Our results demonstrated that dust is, in fact, home for a diverse and heterogeneous fungal community and that some of the species found are known allergic agents with severe negative impacts on human health.

Relationship between flame retardants and respiratory health- A systematic review and meta-analysis of observational studies.

Chronic respiratory diseases are a dealing cause of death and disability worldwide. Their prevalence is steadily increasing and the exposure to environmental contaminants, including Flame Retardants (FRs), is being considered as a possible risk factor. Despite the widespread and continuous exposure to FRs, the role of these contaminants in chronic respiratory diseases is yet not clear. This study aims to systematically review the association between the exposure to FRs and chronic respiratory diseases. Searches were performed using the Cochrane Library, MEDLINE, EMBASE, PUBMED, SCOPUS, ISI Web of Science (Science and Social Science Index), WHO Global Health Library and CINAHL EBSCO. Among the initial 353 articles found, only 9 fulfilled the inclusion criteria and were included. No statistically significant increase in the risk for chronic respiratory diseases with exposure to FRs was found and therefore there is not enough evidence to support that FRs pose a significantly higher risk for the development or worsening of respiratory diseases. However, a non-significant trend for potential hazard was found for asthma and rhinitis/rhinoconjunctivitis, particularly considering urinary organophosphate esters (OPEs) including TNBP, TPHP, TCEP and TCIPP congeners/compounds. Most studies showed a predominance of moderate risk of bias, therefore the global strength of the evidence is low. The limitations of the studies here reviewed, and the potential hazardous effects herein identified highlights the need for good quality large-scale cohort studies in which biomarkers of exposure should be quantified in biological samples.

Biomechanical gait analysis in sheep: kinematic parameters.

Animals have been used as models to help to better understand biological and anatomical systems, and pathologies in both humans and non-human species, and sheep are often used as an in vivo experimental model for orthopedic research. Gait analysis has been shown to be an important tool in biomechanics research with clinical applications. The purpose of this study was to perform a kinematic analysis using a tridimensional (3D) reconstruction of the sheep hindlimb. Seven healthy sheep were evaluated for natural overground walking, and motion capture of the right hindlimb was collected with an optoelectronic system while the animals walked in a track. The analysis addressed gait spatiotemporal variables, hip, knee and ankle angle and intralimb joint angle coordination measures during the entire walking cycle. This study is the first that describes the spatiotemporal parameters from the hip, knee and ankle joints in a tridimensional way: flexion/extension; abduction/adduction and inter/external rotation. The results of this assessment can be used as an outcome indicator to guide treatment and the efficacy of different therapies for orthopedic and neurological conditions involving the locomotor system of the sheep animal model.

Equine Musculoskeletal Pathologies: Clinical Approaches and Therapeutical Perspectives-A Review.

Musculoskeletal injuries such as equine osteoarthritis, osteoarticular defects, tendonitis/desmitis, and muscular disorders are prevalent among sport horses, with a fair prognosis for returning to exercise or previous performance levels. The field of equine medicine has witnessed rapid and fruitful development, resulting in a diverse range of therapeutic options for musculoskeletal problems. Staying abreast of these advancements can be challenging, prompting the need for a comprehensive review of commonly used and recent treatments. The aim is to compile current therapeutic options for managing these injuries, spanning from simple to complex physiotherapy techniques, conservative treatments including steroidal and non-steroidal anti-inflammatory drugs, hyaluronic acid, polysulfated glycosaminoglycans, pentosan polysulfate, and polyacrylamides, to promising regenerative therapies such as hemoderivatives and stem cell-based therapies. Each therapeutic modality is scrutinized for its benefits, limitations, and potential synergistic actions to facilitate their most effective application for the intended healing/regeneration of the injured tissue/organ and subsequent patient recovery. While stem cell-based therapies have emerged as particularly promising for equine musculoskeletal injuries, a multidisciplinary approach is underscored throughout the discussion, emphasizing the importance of considering various therapeutic modalities in tandem.

Mercury, pets' and hair: baseline survey of a priority environmental pollutant using a noninvasive matrix in man's best friend.

Pet cats and dogs have been successfully used as indicators of environmental pollution by a great variety of chemicals, including metals. However, information on mercury (a well know priority environmental pollutant) concentrations in household pets tissues and/or organs is scarce. Thus, in the present work we quantified total mercury (Hg(Total)) in blood and hair samples from twenty-six household dogs. The obtained results disclose relatively low levels of total mercury in the surveyed dogs, with values ranging from 0.16 to 12.38 ng g(-1) in blood; and from 24.16 to 826.30 ng g(-1) in hair. Mercury concentrations were independent of gender, age and diet type. A highly significant positive correlation was established between total mercury in blood and hair, validating the latter as a surrogate, non-invasive matrix for mercury exposure evaluation. Additionally, the obtained blood to hair ratio (200) is similar to the one described for humans reinforcing the suitability of dogs as sentinels. Overall, the determination of total mercury levels in dogs' hair samples proved to be a good screening method for the estimation of mercury burden in this species. We propose the quantification of Hg(Total) in hair as a screening method for sentinels like household pets to be performed in routine veterinary visits.

Contributions towards the hazard evaluation of two widely used cytostatic drugs.

Cytostatic drugs are one of the most important therapeutic options for cancer, a disease that is expected to affect 29 million individuals by 2040. After being excreted, cytostatics reach wastewater treatment plants (WWTPs), which are unable to efficiently remove them, and consequently, they will be released into the aquatic environment. Due to the highly toxic properties of cytostatics, it is particularly relevant to evaluate their potential ecological risk. Yet, cytostatics toxicity data is still not available for various species. In this work, the ecotoxicity of two widely consumed cytostatics, cyclophosphamide (CYP-as a model cytostatic) and mycophenolic acid (MPA-as a priority cytostatic), was evaluated on three freshwater species-Raphidocelis subcapitata, Brachionus calyciflorus, and Danio rerio, and the risk quotient (RQ) was assessed. Both drugs significantly affected the yield and growth inhibition of the microalgae, while for rotifers, the least sensitive species, only significant effects were registered for CYP. These drugs also caused significant effects on the mortality and morphological abnormalities on zebrafish. The estimation of the RQ discloses that CYP seems to pose a low risk to aquatic biota while MPA poses a very high risk. Altogether, these results emphasize the need for more complete environmental risk assessments, to properly prioritize and rank cytostatics according to their potentially toxic effects on the environment and aquatic biota.

Assessing the risks of capecitabine and its active metabolite 5-fluorouracil to freshwater biota.

Capecitabine (CAP, prodrug) and 5-fluorouracil (5-FU, its active metabolite) are two of the most prominent cytostatics, for which no clear picture can be drawn regarding potential concentrations of effect for freshwater biota, with CAP being grouped in the least studied cytostatic, whereas 5-FU has been classified as of no and of high environmental risk. Accordingly, the present work aimed to assess the ecotoxicity of CAP and 5-FU in three freshwater species, which included a 72-h assay with the producer Raphidocelis subcapitata; a 96-h assay with the invertebrate secondary consumer Hydra viridissima; and a 96-h assay with embryos of the vertebrate secondary consumer Danio rerio. The following endpoints were monitored: yield and population growth rate for the algae; mortality, morphological alterations, and post-exposure feeding rates for the cnidarian; and mortality, hatching, and malformations for the fish. Overall, organisms' sensitivity to CAP decreased in the following order: R. subcapitata > H. viridissima > D. rerio, whereas for 5-FU, it decreased in the following order: H. viridissima > D. rerio > R. subcapitata. For CAP, no median lethal effective concentrations (LC/EC50) were possible to compute for D. rerio, with no significant mortality or malformations registered in embryos exposed at concentrations up to 800 mg L-1. For R. subcapitata, the EC50s were 0.077 and 0.63 mg L-1 for yield and growth rate, respectively, and for H. viridissima, the EC50,30 min for feeding was 22.0 mg L-1. For 5-FU, no EC50s could be computed for R. subcapitata, whilst the EC50s for H. viridissima mortality and feeding were 55.4 and 67.9 mg L-1, respectively, and for D. rerio, the LC50,96 h and EC50,96 h (hatching and abnormalities) were 4546, 4100, and 2459 mg L-1, respectively. Assuming similar modes of action for both compounds and their co-occurrence, the combined risk quotient of the two chemicals was determined to be 7.97, which represents a risk for freshwater biota. Anticipating the increased consumption of these compounds and cancer development trends worldwide, these impacts may be further aggravated.

A digital twin framework for robust control of robotic-biological systems.

Medical device regulatory standards are increasingly incorporating computational modelling and simulation to accommodate advanced manufacturing and device personalization. We present a method for robust testing of engineered soft tissue products involving a digital twin paradigm in combination with robotic systems. We developed and validated a digital twin framework for calibrating and controlling robotic-biological systems. A forward dynamics model of the robotic manipulator was developed, calibrated, and validated. After calibration, the accuracy of the digital twin in reproducing the experimental data improved in the time domain for all fourteen tested configurations and improved in frequency domain for nine configurations. We then demonstrated displacement control of a spring in lieu of a soft tissue element in a biological specimen. The simulated experiment matched the physical experiment with 0.09 mm (0.001%) root-mean-square error for a 2.9 mm (5.1%) length change. Finally, we demonstrated kinematic control of a digital twin of the knee through 70-degree passive flexion kinematics. The root-mean-square error was 2.00°, 0.57°, and 1.75° degrees for flexion, adduction, and internal rotations, respectively. The system well controlled novel mechanical elements and generated accurate kinematics in silico for a complex knee model. This calibration method could be applied to other situations where the specimen is poorly represented in the model environment (e.g., human or animal tissues), and the control system could be extended to track internal parameters such as tissue strain (e.g., control knee ligament strain). Further development of this framework can facilitate medical device testing and innovative biomechanics research.