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Giovanna TrainaDepartment of Economics and Food Sciences, University of Perugia, Perugia, ItalyAbstract: L-carnitine (LC) is part of the carnitine shuttle system at the mitochondrial inner membrane (MIM) and transports long chain fatty acids over the MIM route. Acetyl-L -carnitine (ALC), the acetyl ester of LC, plays an essential role in intermediary metabolism. To ALC are ascribed neurotrophic actions, antioxidant and antiapoptotic activity, positive effects on mitochondrial metabolism, and stabilization of intracellular membranes. Acylcarnitine and LC supplementation have shown beneficial effects in the treatment of aging, chronic degenerative pathologies and the slowing of the progression of mental deterioration in neurodegenerative diseases, and painful neuropathies. ALC is reported to affect brain energy and phospholipid metabolism and to interact with cell membranes, proteins, and enzymes. It also shows a neuromodulatory effect on synaptic morphology and neurotransmitter synaptic transmission, including that of acetylcholine and dopamine. All these data suggest that ALC can affect several targets in the central nervous system. The roles and effects of LC and ALC have led researchers to investigate carnitine's involvement in a variety of neuropathological states and treatments, including autism, Parkinson's disease, Alzheimer's disease, Down's syndrome, Huntington's disease, cerebellar ataxia, age-associated mental decline, hepatic encephalopathy, and ammonia neurotoxicity. This review summarizes evidence that carnitine analogs play many roles in serious neurological pathologies.Keywords: L-carnitine, acetyl-L-carnitine, brain, neural disorders

There is evidence showing that increasing the vertical dimension of occlusion, or interocclusal distance, reduces pain symptoms in patients with temporomandibular disorders (TMD) and bruxism. The mechanism underlying the analgesic effect is still under investigation. Some researchers propose either a gate mechanism or the activation of the trigemino-cardiac reflex. In this study, sensory and pain thresholds changes in the mandibular district have been evaluated in twenty healthy subjects immediately after 5 minutes of mandibular stretching at maximum opening of the jaw. Results showed a 60% increment in sensory threshold and a 70% increment in pain threshold (p<0.001) compared with the baseline values. The magnitude of the analgesic effect seems proportional to the extent of mandibular opening. These and similar results are discussed as for the implication in the treatment of TMD related symptoms. [ABSTRACT FROM AUTHOR]

Increasing occlusal vertical dimension (OVD) by means of oral splints is a practice widely used in the treatment of temporomandibular disorders (TMD), specifically myofascial pain, although the results are still uncertain. Oral splints with a vertical height that significantly exceeds the clinical rest position are considered by some researchers to be a better therapeutic solution in alleviating TMD symptoms than are "low" splints. In our observational study, 21 patients suffering from myofascial pain were examined for the effects of wearing a "high" oral splint while sleeping for 3 months. To ensure proper splint making, a mandibular stretching procedure was used to induce a relaxation of the patients' masticatory muscles and allow the correct alignment of the jaws. Results showed a marked increase of the interocclusal distance or "free space" (hence of OVD; from 0.64±0.53 mm to 1.42±0.76 mm, p<0.0001) measured by a kinesiograph, followed by a substantial reduction of the intensity of pain in oral and extraoral regions after using the splint. These results support the view that increasing OVD beyond the clinical rest position is not detrimental to patients' health. More importantly, high oral splints has been shown to be a promising therapeutic aid for the treatment of TMD and correlated pain syndromes. This clinical trial was registered on clinicaltrials.gov (Identifier: NCT02908568). [ABSTRACT FROM AUTHOR]

The pharmacokinctic profile of teicoplanin after single 3 mg/kg doses in adults with different degrees of renal failure was reviewed. The disposition of teicoplanin was adequately described by a three-compartment open pharmacokinetic model and it appears to be primarily related to the degree of renal function. Teicoplanin total body clearance was less and the terminal elimination half-life progressively prolonged in association with renal failure, but the. volume of distribution at steady-state did not change. Highly significant relationships between teicoplanin total body and renal clearance and creatinine clearance have been reported and serve as a basis for adjusting dosage in patients with renal failure. In patients on continuous ambulatory peritoneal dialysis teicoplanin, administered either intravenously or intraperitoneally, showed bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid was consistently low. Haemodialysis made no significant contribution to total body clearance of teicoplanin. Guidelines for administration of teicoplanin in patients with renal failure are discussed. [ABSTRACT FROM PUBLISHER]

Bulimia nervosa (BN) is a condition marked by a typical cyclical behavioural activity, characterized by restrictions, binges and vomiting, as well as a disturbance of the emotional value of food. Food stimuli acquire excessive relevance, giving rise to a succession of states of excitement and anxiety. The depressive condition accompanies very often BN. Most people with BN also experience one or more anxiety disorders. The aim of the review is to identify a link at a central and peripheral level that connects an eating disorder with a mood state. Altered nervous mechanisms are involved in BN. Among the cerebral areas, the insula is functionally compromised in BN. The insula is also implicated in depressive states. The insula is the primary gustatory cortex, where gustatory sensory information such as taste discrimination and higher cognitive functions such as food anticipation and reward are processed. The insula is anatomically connected to a wide range of cortical, limbic and paralimbic structures, and functionally implicated in high-order cognition, emotional responses, and empathic processes. The insula plays a crucial role in empathy, or in the ability to share the emotional states of others, and in particular negative emotions. In fact, the insular cortex is also activated in conditions of anxiety and depression. One of the pathophysiological factors that influences bulimia and depression is the composition of gut microbiota, as there is a strong association between the microbial signature and the brain function. Gut dysbiosis condition may contribute to the development of eating disorders, including BN. Dysbiosis may promote intestinal inflammation, alter gut permeability, and trigger immune reactions in the hunger/satiety regulation center contributing to the pathophysiological development of eating disorders. From this emerges the importance of adequate probiotic integration as a preventive and/or therapeutic tool in these pathologies., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

This Special Issue collects some scientific pieces of the multifaceted research on the mast cell (MC), and it intends to highlight the broad spectrum of activity that MCs have, both in physiological conditions and in pathological states, focusing attention on some of them [...].

Fear conditioning constitutes the best and most reproducible paradigm to study the neurobiological mechanisms underlying emotions. On the other hand, studies on the synaptic plasticity phenomena underlying fear conditioning present neural circuits enforcing this learning pattern related to post-traumatic stress disorder (PTSD). Notably, in both humans and the rodent model, fear conditioning and context rely on dependent neurocircuitry in the amygdala and prefrontal cortex, cingulate gyrus, and hippocampus. In this review, an overview of the role that classical neurotransmitters play in the contextual conditioning model of fear, and therefore in PTSD, was reported.

Great interest is aimed at understanding the inflammatory responses at the level of the central nervous system (CNS), referred to as neuroinflammatory. The environment and the duration of the inflammatory responses are essential factors for comprehending the biochemical and pathophysiological consequences induced by the inflammatory state. Specific inducers of inflammation associated with neurodegenerative disorders can activate inflammatory processes and produce mediators that potentiate neurodegeneration. Immune responders in the brain include microglial cells, astrocytes, and mast cells. A number of human pathologies are recognized to have an inflammatory component, including disorders related to brain function. Emerging evidence also attributes an important role to intestinal microorganisms in disorders related to brain function. In the gut-brain axis, the intestinal microbiota produce a variety of molecules and neurotransmitters, transform primary bile acids into secondary bile, and synthesize short-chain fatty acids. Communication within the gut-brain axis occurs through several pathways, including the immune system, the enteric nervous system, the vagus nerve, and the production of microbial metabolites. The CNS responds to this input from the gut by modulating the activity of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis, which manages adrenocortical hormones. In this perspective, gut microbiota may influence neural function by influencing microglia, astroglia, and mast cells. Conversely, the relationship between neurons, microglia and synaptic alteration may also involve gut microbiota. The purpose of this review is to provide a concise overview of the mechanisms involved in communication between intestinal microbiota and the brain and how this contributes to the management of neuroinflammation., Competing Interests: The authors declare no conflict of interest. Giovanna Traina is serving as one of the Guest editors of this journal. We declare that Giovanna Traina had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel., (© 2023 The Author(s). Published by IMR Press.)

The contextual fear conditioning (CFC) paradigm is the most productive approach for understanding the neurobiology of learning and memory as it allows to follow the evolution of memory traces of a conditioned stimulus and a specific context. The formation of long-term memory involves alterations in synaptic efficacy and neural transmission. It is known that the prefrontal cortex (PFC) exerts top-down control over subcortical structures to regulate behavioural responses. Moreover, cerebellar structures are involved in storing conditioned responses. The purpose of this research was to determine if the response to conditioning and stressful challenge is associated with alterations in synapse-related genes mRNA levels in the PFC, cerebellar vermis (V), and hemispheres (H) of young adult male rats. Four groups of Wistar rats were examined: naïve, CFC, shock only (SO), and exploration (EXPL). The behavioural response was evaluated by measuring the total freezing duration. Real-Time PCR was employed to quantify mRNA levels of some genes involved in synaptic plasticity. The results obtained from this study showed alterations in gene expression in different synapse-related genes after exposure to stressful stimuli and positioning to new environment. In conclusion, conditioning behavioural stimuli change the expression profile of molecules involved in neural transmission., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The intestinal epithelium constitutes a selectively permeable barrier between the internal and external environment that allows the absorption of nutrients, electrolytes, and water, as well as an effective defense against intraluminal bacteria, toxins, and potentially antigenic material. Experimental evidence suggest that intestinal inflammation is critically dependent on an imbalance of homeostasis between the gut microbiota and the mucosal immune system. In this context, mast cells play a crucial role. The intake of specific probiotic strains can prevent the development of gut inflammatory markers and activation of the immune system. Here, the effect of a probiotic formulation containing L. rhamnosus LR 32, B. lactis BL04, and B. longum BB 536 on intestinal epithelial cells and mast cells was investigated. To mimic the natural host compartmentalization, Transwell co-culture models were set up. Co-cultures of intestinal epithelial cells interfaced with the human mast cell line HMC-1.2 in the basolateral chamber were challenged with lipopolysaccharide (LPS), and then treated with probiotics. In the HT29/HMC-1.2 co-culture, the probiotic formulation was able to counteract the LPS-induced release of interleukin 6 from HMC-1.2, and was effective in preserving the epithelial barrier integrity in the HT29/Caco-2/ HMC-1.2 co-culture. The results suggest the potential therapeutic effect of the probiotic formulation.

The human coronavirus SARS-CoV-2 or COVID-19 that emerged in late 2019 causes a respiratory tract infection and has currently resulted in more than 627 million confirmed cases and over 6.58 million deaths worldwide up to October 2022. The highest death rate caused by COVID-19 is in older people, especially those with comorbidities. This evidence presents a challenge for biomedical research on aging and also identifies some key players in inflammation, including mast cells and platelets, which could represent important markers and, at the same time, unconventional therapeutic targets. Studies have shown a decrease in the diversity of gut microbiota composition in the elderly, particularly a reduced abundance of butyrate-producing species, and COVID-19 patients manifest faecal microbiome alterations, with an increase in opportunistic pathogens and a depletion of commensal beneficial microorganisms. The main purpose of this narrative review is to highlight how an altered condition of the gut microbiota, especially in the elderly, could be an important factor and have a strong impact in the lung homeostasis and COVID-19 phenomenon, jointly to the activation of mast cells and platelets, and also affect the outcomes of the pathology. Therefore, a targeted and careful control of the intestinal microbiota could represent a complementary intervention to be implemented for the management and the challenge against COVID-19.

Phenylselenenylzinc chloride (PhSeZnCl) is an air-stable selenolate, easily synthesizable through oxidative insertion of elemental zinc into the Se-halogen bond of the commercially available phenylselenyl chloride. PhSeZnCl was shown to possess a marked GPx-like activity both in NMR and in vitro tests, and to effectively react with cellular thiols, and was supposed for a potential use in the chemotherapy of drug-resistant cancers. However, activity of PhSeZnCl in hepatic cells has never been tested before now. In this in vitro approach, we evaluated the cytotoxic, genotoxic, and apoptotic activities, as well as the effects on cell cycle of PhSeZnCl in two preclinical hepatic models, namely HepG2 and HepaRG cells. Results showed that cell viability of HepG2 and HepaRG cells decreased in a dose-dependent manner, with a more marked effect in HepG2 tumour cells. Moreover, treatment with 50 µg/mL PhSeZnCl caused an increase of primary DNA damage (4 h) and a statistically significant increase of HepG2 cells arrested in G 2 /M phase. In addition, it altered mitochondrial membrane potential and induced chromosomal DNA fragmentation (24 h). In HepaRG cells, PhSeZnCl was able to determine a cell cycle-independent induction of apoptosis. Particularly, 50 µg/mL induced mitochondrial membrane depolarization after 24 h and apoptosis after 4 h treatment. Futhermore, all PhSeZnCl concentrations tested determined a significant increase of apoptotic cells after 24 h. Apoptosis was also highlighted by the detection of active Caspase-3 by Western Blot analysis after 24 h exposure. In conclusion, this first toxicological assessment provides new insights into the biological activity of PhSeZnCl in preclinical hepatic models that will be useful in future safety assessment investigation of this compound as a potential pharmaceutical., Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-022-00148-y., Competing Interests: Conflict of interestThe authors declare that there is no conflict of interest regarding the publication of this paper., (© The Author(s) 2022.)

In healthy individuals, tight junction proteins (TJPs) maintain the integrity of the intestinal barrier. Dysbiosis and increased intestinal permeability are observed in several diseases, such as inflammatory bowel disease. Many studies highlight the role of probiotics in preventing intestinal barrier dysfunction. The present study aims to investigate the effects of a commercially available probiotic formulation of L. rhamnosus LR 32, B. lactis BL 04, and B. longum BB 536 (Serobioma, Bromatech s.r.l., Milan, Italy) on TJPs and the integrity of the intestinal epithelial barrier, and the ability of this formulation to prevent lipopolysaccharide-induced, inflammation-associated damage. An in vitro model of the intestinal barrier was developed using a Caco-2 cell monolayer. The mRNA expression levels of the TJ genes were analyzed using real-time PCR. Changes in the amounts of proteins were assessed with Western blotting. The effect of Serobioma on the intestinal epithelial barrier function was assessed using transepithelial electrical resistance (TEER) measurements. The probiotic formulation tested in this study modulates the expression of TJPs and prevents inflammatory damage. Our findings provide new insights into the mechanisms by which probiotics are able to prevent damage to the gut epithelial barrier.

Packaging is considered one of the most interesting technological aspects of food production and is a constantly evolving subject in food production. The type of packaging is important for the quality and safety of the product and for the visual appearance of the product to be immediately evaluated by consumers. The purpose of this study was to investigate the effect of four different types of modified atmosphere packaging (ATM) and vacuum packaging (VP) currently used by a company in central Italy, on the main qualitative characteristics of beef. For these two traditional and two new solutions with reduced environmental impact and compostable were evaluated. For each type of packaging, two different products were analyzed: steaks and hamburgers. The samples, immediately after production, were transported to the laboratory in refrigerated containers. Several parameters (color, pH, water holding capacity, drip loss, and microbiological characteristics) were evaluated at time 0 and after 7 (T7), 14 (T14) and 21 days (T21) of storage in the dark and at refrigeration temperature (+4°C ± 2°C). The results showed that the two types of packaging have very similar effects on the water-retaining capacity of the steaks. More noticeable differences were recorded by the colorimetric analysis: for both steaks and hamburgers, the products packaged in the traditional packaging appeared brighter and redder than those packaged in the new alternatives. The microbiological analysis of the steaks showed higher values in the "new" packaging. The formation of abundant ropy slime was observed in one of the samples in the "new" modified atmosphere package at T21. The results of this study showed that the technological characteristics (in particular, the color) and the microbiological characteristics of the steaks and hamburgers were better in "old" packaging, with a better appearance and a longer shelf life. The results obtained show how the research for eco-sustainable products for packaging must be addressed, taking into account the effect of the materials on the qualitative and hygienic- sanitary characteristics of the meat., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

Food-dependent exercise-induced anaphylaxis (FDEIA) is an uncommon IgE-mediated hypersensitivity disease with limited prevalence data. Recently, reported cases of FDEIA have been increasing both in adults and children. FDEIA is the end condition depending on a summation process, and its pathogenetic mechanisms are not yet completely understood. Factors that add up their effects are food ingestion and physical effort and, in some cases, concomitant diseases, alcohol, drugs, emotional stress, menstruation, and particular weather conditions contribute to enhancing the reaction. Food-specific FDEIA (sFDEIA) implies the presence of an IgE-mediated sensitization to one or more foods, while in unspecific FDEIA (nsFDEIA), any food can induce anaphylaxis without sensitization.  Among causative foods, the most dominant trigger of FDEIA is wheat, in particular the allergen ω-5 gliadin (Tri a 19). Other common foods are seafood, seeds, grains, nuts, vegetables and fruit, cow's milk, meat, and eggs. We present three cases of sFDEIA in children with clinical features and laboratory findings; the first was induced by a culprit food less frequently involved in sFDEIA than the others.

Multiple Sclerosis is a chronic neurological disease characterized by demyelination and axonal loss. This pathology, still largely of unknown etiology, carries within it a complex series of etiopathogenetic components of which it is difficult to trace the origin. An inflammatory state is likely to be the basis of the pathology. Crucial elements of the inflammatory process are the interactions between platelets and mast cells as well as the bacterial component of the intestinal microbiota. In addition, the involvement of mast cells in autoimmune demyelinating diseases has been shown. The present work tries to hang up on that Ariadne's thread which, in the molecular complexity of the interactions between mast cells, platelets, microbiota and inflammation, characterizes Multiple Sclerosis and attempts to bring the pathology back to the causal determinism of psychopathological phenomenology. Therefore, we consider the possibility that the original error of Multiple Sclerosis can be investigated in the genetic origin of the depressive pathology.

The use of oral appliances is considered effective in improving sport performance. Jaw clenching or stretching, improved breathing or positioning of the jaw have been proposed to explain the improvement. In this study, we reported the effects of regularly practiced mandibular stretching at submaximal opening of the jaw in Crossfit athletes. Seventeen test subjects undergoing mandibular stretching (MS) showed significantly reduced (p0.001) performance time in a high-intensity workout measured before and after seven days of 10-minutes stretching practiced twice daily, while no improvement was observed in control subjects who did not perform the stretching. Additionally, blood lactate levels appeared to recover more quickly in MS subjects.Crossfit is a type of training regimen that pushes the limits of bodily recovery processes. Jaw stretching, eliciting the trigeminocardiac reflex (a reflex decrease in heart rate and blood pressure following trigeminal stimulation) and central oxygen-conserving mechanisms could help relieve post-training stress and improve training recovery.

Background: The idea that individuals are responsible for their health has been the focus of debate in the theoretical literature and in its concrete application to healthcare policy in many countries. Controversies persist regarding the form, substance and fairness of allocating health responsibility to the individual, particularly in universal, need-based healthcare systems., Objective: To examine how personal health responsibility has been framed and rationalised in Norwegian key policy documents on priority setting., Methods: Documents issued or published by the Ministry of Health and Care Services between 1987 and 2018 were thematically analysed (n=14). We developed a predefined conceptual framework that guided the analysis. The framework included: (1) the subject and object of responsibility, (2) the level of conceptual abstraction, (3) temporality, (4) normative justificatory arguments and (5) objections to the application of personal health responsibility., Results: As an additional criterion, personal health responsibility has been interpreted as relevant if: (A) the patient's harmful behaviour is repeated after receiving treatment (retrospectively), and if (B) the success of the treatment is conditional on the patient's behavioural change (prospectively). When discussed as a retrospective criterion, considerations of reciprocal fairness have been dominant. When discussed as a prospective criterion, the expected benefit of treatment justified its relevance., Conclusion: Personal health responsibility appears to challenge core values of equality, inclusion and solidarity in the Norwegian context and has been repeatedly rejected as a necessary criterion for priority setting. However, the responsibility criterion seems to have some relevance in particular priority setting decisions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Childhood obesity is an increasing health problem. Prior empirical research suggests that, although discussing lifestyle behaviours with parents could help prevent childhood obesity and its health-related consequences, physicians are reluctant to address parental responsibility in the clinical setting. Therefore, this paper questions whether parents might be (or might be held) responsible for their children's obesity, and if so, whether parental responsibility ought to be addressed in the physician-patient/parent encounter. We illustrate how different ideal-typical models of the physician-patient/parent interaction emphasise different understandings of patient autonomy and parental responsibility and argue that these models advocate different responses to an appeal for discussing parents' role in childhood obesity. We suggest that responsibility should be attributed to parents because of their parental roles in providing for their children's welfare. We also argue that whether, and how, this responsibility gives rise to a requirement to act depends on the parents' capacities. A deliberative-oriented physician-patient/parent interaction best captures the current ideals of antipaternalism, patient autonomy, and shared and evidence-informed decision-making, and might facilitate parental role development. We conclude that, while not discussing parental responsibility for childhood obesity in the clinical setting can be warranted in particular cases, this cannot be justified as a general rule., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Airborne particulate (PM) components from fossil fuel combustion can induce oxidative stress initiated by reactive oxygen species (ROS) that are strongly correlated with airway inflammation and asthma. A valid biomarker of airway inflammation is fractionated exhaled nitric oxide (FENO). The oxidative potential of PM2.5 can be evaluated with the dithiothreitol (DTT) dosage, which represents both ROS chemically produced and intracellular ROS of macrophages. This correlates with quality indicators of the internal environment and ventilation strategies such as dilution and removal of airborne contaminants., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The existence of a learning effect by which subjects progressively reduce body sway over the course of repetitive stabilometric measurements is currently debated. Also, the position and orientation of the feet on the platform can have a substantial influence on the outcome measurements. The aim of the present work was to assess the effect of feet positions on mean total velocity (V) of the center of pressure and the area (AR) covered by its displacements during quiet standing. A group of 35 healthy young subjects was examined during two successive sessions consisting of five recordings with their feet placed either in the recommended (standard, SP) or their usual most comfortable (UP) position. Results show a slight decreasing trend that failed to be statistically significant checked with Friedman's ANOVA (SP AR, χ2(4)=6.10, p=0.19 and V, χ2(4)=8.66, p=0.07 and UP AR, χ2(4)=2.32, p=0.68 and V, χ2(4)=1.19, p=0.88). Nonetheless, values of AR and V showed a notable decrement especially evident in the SP exam reaching, respectively, 24% and 11% from baseline, whereas variability measured by the coefficient of variation was the same in the two exams. Given the results, a learning effect should not be ruled out with confidence. Also, usual foot placement would be preferable to avoid this effect. Further research is needed to take into consideration the great variability of stabilometric measurements and the fact that different subjects could adapt more readily to the test conditions than others.

Mast cells are the major effectors in allergic reactions through degranulation and release of inflammatory, vasoactive and nociceptive mediators associated with the pathogenesis of a variety of inflammatory disorders. Mast cells are strategically positioned as gatekeepers at host/environment interfaces, like the skin, airways, gastrointestinal and urogenital tracts, and their presence also in the brain allows them to act not only as sentinels of invading microorganisms but also as targets to respond to different allergens, pathogens and other dangerous agents that can be ingested, inhaled or encountered after the breakdown of the epithelial barrier. Mast cells can respond to any change in the environment by communicating with the different cells involved in the immune response and giving rise to an amplification signal network through feedback loops. They secrete both preformed mediators within minutes of stimulation and de novo synthesized molecules acting as effectors in the relationship between nervous, vascular and immune systems. For this peculiarity, mast cells are master regulators and key players of the immune system and important sources of essential and beneficial mediators with crucial roles in regulating various physiological processes., Competing Interests: The author declares no conflict of interest., (© 2021 The Authors. Published by IMR Press.)