Antibiotics And The Nervous System—Which Face Of Antibiotic Therapy Is Real, Dr. Jekyll (Neurotoxicity) Or Mr. Hyde (Neuroprotection)? Part 3

4.8. Polymyxins

Polymyxins are peptide antibiotics of natural origin, first obtained in 1947 by fermentation in Bacillus polymyxa subspecies colistinus. In the early 1980s, data on the safety risks of their use related to severe episodes of renal failure, as well as incompletely understood neurotoxicity, and the availability of antibiotics with fewer potential side effects reduced their use in therapy. 

With the acceleration of population aging and lifestyle changes, renal failure has become one of the diseases that seriously threaten human health. Renal failure is the long-term impairment of renal function, which cannot normally secrete metabolic waste, eliminate excess water, and maintain normal electrolyte balance. It can affect the normal functioning of various organs in the human body and our mental health and memory.

Renal failure can have adverse effects on memory. Studies have shown that patients with renal failure can experience symptoms such as memory degeneration, cognitive impairment, and Alzheimer's disease. This is because renal failure causes the body to lack sufficient oxygen and nutrients and affects the patient's metabolic function. These factors will lead to a lack of nutrition in brain cells, thereby causing cerebrovascular lesions and nerve damage, and ultimately affecting the formation and maintenance of memory.

However, don't be discouraged. Renal failure does not mean that you can no longer maintain a good memory. Adopting the following healthy lifestyle and positive attitude can help you alleviate the negative impact of renal failure on memory and maintain good physical and mental health.

First, maintain a healthy diet. Diet has a great impact on our body and brain function. Patients with renal failure need to follow proper dietary principles and control sodium and protein intake to help reduce the burden on the kidneys. In addition, eating more foods rich in vitamins B, E and Omega-3 fatty acids can help improve brain function and memory.

Secondly, actively participate in physical exercise. Appropriate physical exercise can enhance the body's blood circulation and metabolic function, and help maintain good memory. In particular, some aerobic exercises, such as running, swimming, cycling, etc., can improve the brain's oxygen supply, promote the growth and connection of neurons, and thus improve our memory.

Finally, maintain a positive attitude. A positive attitude can help us cope with various difficulties and challenges in life. Renal failure is a disease that requires patience and determination. Patients need to maintain a positive attitude to face the difficulties of treatment and life. A positive attitude can help us reduce anxiety and stress, improve self-confidence and self-esteem, and thus promote our physical and mental health and memory.

In short, the relationship between renal failure and memory exists, but don't forget that we can adopt a healthy lifestyle and a positive attitude to alleviate its negative effects. Let us adhere to a positive attitude towards life and welcome a healthy and bright future. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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The incidence of neurological complications with these antibiotics ranges from 7–27%, including dizziness, generalized or muscle weakness, confusion, hallucinations, seizures, paresthesias, ataxia, and, less commonly, diplopia, nystagmus, and ptosis [60]. 

Paresthesias is more common with intravenous administration than intramuscular use. Ventilation-dependent respiratory disturbances were observed after intramuscular administration of polymyxins. They lasted from 10 to 48 hours. This was probably a myasthenia-like syndrome. 

The polymyxin chemical structure contains a fatty acid, which may interact with the lipophilic content of neurons. Neuromuscular blockade may be related to inhibiting acetylcholine release in the synaptic cleft. Risk factors of neurotoxicity include renal dysfunction, hypoxia, and concomitant use of such medications as nephrotoxic agents, sedatives, muscle relaxants, anesthetic drugs, or corticosteroids [60]. 

Colistin neurotoxicity, especially observed in patients with renal failure or receiving high doses, includes facial paresthesias (pricking, tingling, numbness), dizziness, speech impairment, visual disturbances, confusion, and psychosis. 

Neuromuscular blockade manifested by myasthenia-like syndrome or respiratory muscle paralysis-producing apnea has also been observed. Colistin neurotoxicity primarily involves paresthesias, and in only sporadic cases apnea, especially in patients with intramuscular administration of the drug, with acute or chronic renal failure, and receiving medications, induces respiratory muscle weakness [99,105]. 

Two mechanisms account for colistin neurotoxicity and neuromuscular blockade. One involves the presynaptic action of the drug, preventing the release of acetylcholine into the synaptic gap. 

The other is biphasic, involving a short phase of competitive blockade between acetylcholine and colistin, followed by a prolonged depolarization phase, leading to loss of calcium from neurons, resulting in altered mitochondrial permeability. This results in mitochondrial dysfunction in neuronal cells and the accumulation of reactive oxygen species. This in turn is the cause of oxidative stress and further nerve damage [26,106].

4.9. Tetracyclines

Tetracyclines are a class of broad-spectrum bacteriostatic antibiotics discovered in the 1940s, including tetracycline, minocycline, and doxycycline, which have shown to be effective against aerobic and anaerobic bacteria, as well as Gram-positive and Gram-negative bacteria (with the exceptions of Proteus species and Pseudomonas aeruginosa). 

They are largely prescribed in dermatology and infectious diseases, both for their anti-bacterial and anti-inflammatory actions. Neurotoxicity associated with this class of antibiotics includes cranial nerve toxicity, neuromuscular blockage, and intracranial hypertension [26,27,60]. During therapy with tera-cyclones, symptoms such as blurred vision, loss of balance, light-headedness, dizziness, vertigo, or tinnitus were observed [60].

4.10. Quinolones

Quinolones are a family of antibiotics with a wide range of antimicrobial activity, which are active against both Gram-positive and Gram-negative bacteria, including mycobacteria, and anaerobes. Since their discovery in the early 1960s, they have become increasingly important in the treatment of both community and serious hospital-acquired infections. 

In the 1970s and 1980s, the scope of the quinolone class was greatly expanded by the groundbreaking development of fluoroquinolones, which exhibit a much broader spectrum of action and improved pharmacokinetics compared with first-generation quinolones [107]. 

Unfortunately, several European Medicines Agency (EMA) recommendations have recently been made to healthcare providers regarding risk factors for musculoskeletal, neurological, and psychiatric adverse reactions observed among quinolone users [108].

Many members of this group of antibiotics (norfloxacin > ciprofloxacin > ofloxacin, levofloxacin) are known for their neurotoxic effects. These may manifest as headache, confusion, a decline of attention, tremors, psychosis, seizures, myoclonic jerks, insomnia, encephalopathy, delirium, sleep disturbances, toxic psychosis or Tourette-like syndrome, and extrapyramidal manifestations such as gait disturbance, dysarthria, and choreiform movements. Scavone et al. observed that third-generation quinolones were always associated with a higher reporting probability of neurological and psychiatric adverse drug effects compared to second-generation. 

These effects were presented 1 to 2 days after antibiotic therapy and were dose-dependent. Their etiology is likely to be multifactorial and includes inhibition of the GABAA receptor, stimulation of the NMDA receptor, and ligand-gated glutamate receptors which reduce the seizure threshold. 

It has also been suggested that oxidative stress is increased by these drugs. No less important is the relationship between their chemical structure and the symptoms observed, e.g., ciprofloxacin, norfloxacin as a quinolone with 7-piperazine and clinafloxacin, and tosufloxacin as a quinolone with 7-pyrrolidine have been observed to be highly associated with epilepsy. 

The epileptogenic potential of fluoroquinolones is increased by simultaneously using non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, these antibiotics penetrate through the BBB and induce eosinophilic meningitis. 

Risk factors for neurotoxicity include older age, hypoxemia, pre-existing central nervous system diseases, electrolyte disturbance, thyrotoxicosis, and renal and hepatic dysfunction. Hemodialysis may be a useful treatment for encephalopathy associated with quinolone treatment in patients with impaired renal function [27,49,72,99,108–110].

4.11. Other Antibacterial Agents (Chloramphenicol, Nitrofurantoin, Isoniazid, Ethambutol, Cycloserine)

Chloramphenicol is a broad-spectrum antibiotic, which was first isolated from Streptomyces venezuelae in 1947. It is currently of limited use due to adverse effects and frequently observed antimicrobial resistance. It must be used only in those serious infections for which less potentially dangerous drugs are ineffective or contraindicated. 

Headache, mild depression, mental confusion, and delirium have been described in patients receiving this medicine. Optic and peripheral neuritis have been reported, usually following long-term therapy. If this occurs, the drug should be promptly withdrawn [26]. Nitrofurantoin, a synthetic nitrofuran derivative, has been available for the treatment of uncomplicated lower urinary tract infections since 1952. 

It is effective against E. coli and many gram-negative organisms. Nitrofurantoin treatment has been associated with neurotoxicity effects including peripheral neuropathy, dizziness, vertigo, diplopia, cerebellar dysfunction, and intracranial hypertension. These are observed particularly in women and elderly patients. The etiology is attributed to axon loss [111]. 

Isoniazid, cyclo-serine, and ethambutol medications used for treating tuberculosis may cause both central and peripheral neuropathy. Isoniazid administration may be accompanied by peripheral neuropathy, psychosis, and seizures. The importance of isoniazid interference with GABA synthesis is emphasized in the etiology of seizures, through inhibition of pyridoxal-5 phosphate. 

This compound is a cofactor for the enzymatic activity of glutamic acid decarboxylase, thus reducing the concentration of GABA and enhancing seizure susceptibility. Status epilepticus was also observed after therapeutic doses of the medicine. Cyclo-serine may be the cause of neuropsychiatric adverse events including anxiety, agitation, depression, psychosis, and, rarely, seizures. 

The frequencies of psychiatric and central nervous system adverse events are 5.7 and 1.1%, respectively. They may be associated with elevated plasma concentrations of the drug. Cyclo-serine crosses the blood-brain barrier and decreases GABA production. It binds to N-methyl-d-aspartate receptors, which in part explains the commonly associated neurotoxicity. 

At the recommended dosage for cyclo-serine (250 to 500 mg once daily), the neurotoxicity can range from mild to severe and has resulted in psychosis and treatment discontinuation in some cases. Concurrent use of alcohol increases the risk of developing psychosis and seizures. Another complication of ethambutol therapy can be optic nerve neuropathy. 

This is dose-dependent, with the lowest risk at total daily doses < 15 mg/kg. Its risk factors include older age, hypertension, renal insufficiency, and duration of treatment. Symptoms are manifested by the gradual onset of reduced visual acuity, dyschromatopsia, and central or mid-central visual field losses observed several months after the drug was started. 

They are probably related to mitochondrially-induced papillary bundle dysfunction [27,99,112]. To sum up, the mechanisms contributing to the neurotoxic adverse effects of antibiotics are multiple and specific to a given class of those drugs. They are summarized in Table 3 below.

5. Methods of Reducing the Frequency and Severity of Antibiotic-Induced Neurologic and Psychiatric Entities

Modern optimal antibiotic therapy requires extensive knowledge of the mechanisms of drug action, their pharmacokinetic properties, adverse effects, identification of their risk factors, especially underestimated neurotoxicity, toxicity thresholds limiting dosing, infection site, and antibiotic penetration, and careful monitoring of the consequences of their action. 

It is necessary to control the clinical condition of patients and to examine the efficiency of organs responsible for the elimination of drugs from the body. Early recognition of renal failure may reduce the frequency or severity of neurologic and psychiatric symptoms associated with antibiotic administration. EEG may help differentiate between drug complications in the form of non-convulsive status epilepticus (NCSE) and encephalopathy. Sometimes temporary use of anti-convulsant medication may be needed. 

Myasthenic syndrome accompanying treatment with polymyxins may require ventilatory support depending on the degree of respiratory impairment. Hemodialysis or hemofiltration may be needed in patients with impaired renal function if antibiotic-induced neurotoxicity is observed [26,113]. In recent years, much attention has been given to increasing the optimization of antibiotic therapy based on pharmacokinetic and pharmacodynamic (PK/PD) modeling [114–117]. 

To evaluate the efficacy and safety of antimicrobial therapy, three basic ratios were developed: Cmax/MIC (minimal inhibitory concentration), T > MIC, and AUC24/MIC. Concentration-dependent antibiotics include aminoglycosides and metronidazole. Their efficacy best correlates with peak concentration (Cmax) to MIC. The clinical PK/PD target for amikacin/gentamicin efficacy is Cmax/MIC ≥ 8–10, the clinical PK/PD threshold for amikacin toxicity is Cmin > 5 mg/L, and for gentamicin > 1 mg/L. 

The group of antibiotics whose effectiveness is determined by the time the concentration remains above the MIC of the bacterial pathogen include penicillin, cephalosporins, carbapenems, monobactams, macrolides (erythromycin, clarithromycin), linezolid. Clinical PK/PD target for carbapenems/penicillin efficacy is 50–100% fT>MIC, for cephalosporins 45–100%, clinical PK/PD threshold for meropenem nephro- or neurotoxicity is Cmin > 44.5–64 mg/L, for neurotoxicity of cefepime Cmin ≥ 20–22 mg/L, for piperacillin Cmin > 64–361 mg/L. 

Concentration-dependent antibiotics with a time-dependent component for which the best predictor of efficacy is the area under the concentration-time curve during a 24 h period (AUC24) to the MIC ratio include glycopeptides, oxazolidinones, fluoroquinolones, polymixins, daptomycin, azithromycin, and tigecycline. 

The clinical PK/PD target for vancomycin efficacy is AUC0–24/MIC ≥ 400, the threshold for its toxicity is AUC0–24 > 700 mg·h/L, Cmin > 20 mg/L [118]. This individualized approach has allowed two directions for optimizing antibiotic therapy, especially in intensive care patients: dose adjustment based on therapeutic drug monitoring (TDM) or modification of drug dosing by using higher initial and maintenance doses or by using prolonged or continuous infusions [119–121]. 

+TDM, the measurement of drug concentrations in a biological fluid (typically plasma) is particularly important concerning drugs with a narrow therapeutic index, with a defined relationship between their concentration and pharmacological effect, significant intra-and/or inter-individual pharmacokinetic variability, established target concentration range, which is the cause of numerous drug complications and interactions with other drugs, long duration of therapy, absence of pharmacodynamic markers of therapeutic response and/or toxicity, and availability of cost-effective drug assay (precise, accurate, highly selective bioanalytical assay methods for drug measurement). 

It is widely used for aminoglycosides, and vancomycin, for beta-lactam antibiotics, particularly for piperacillin and meropenem, and is becoming increasingly common [113,122,123]. It is important to remember that the drug concentration is only complementary but not a substitute for clinical judgment, and we treat the individual patient, not the laboratory value. Imami et al. retrospectively reviewed a series of cases of people treated with potentially neurotoxic antibiotics hospitalized at St Vincent Hospital in Sydney between 2013 and 2015. 

Adverse events of neurotoxicity, nephrotoxicity, hepatotoxicity, and Clostridium difficile infections were assessed. Based on the measurements of drug concentrations (piperacillin, meropenem, fluo-cloxacillin), their direct relationship with the complication was demonstrated. The breakpoint for which the risk of neurotoxicity is 50% for piperacillin was found to be Cmin > 361.4 mg/L, for meropenem > 64.2 mg/L, and flucloxacillin > 125.1 mg/L. 

Therefore, measuring the concentrations of these antibiotics, especially in patients with an increased risk of neurological complications, is a method of optimizing their use [124].

Oda et al. reported a case of using Bayesian estimation calculations in conjunction with the measurement of cefepime concentration to reduce the dose in people with pneumonia to prevent neurological complications. After receiving a dose of 1.0 g every 8 hours, the patient developed aphasia on the fifth day. Measurement of the drug concentration in the serum showed 71.3 mg/l, which was 2–3 times higher than the recommended value (22–35 mg/L).

Bayesian pharmacokinetic calculations indicated the need to reduce the dose to 0.5 g every 12 h. 

After 3 days, the neurological symptoms improved and the treatment was continued successfully [125]. Another case was described by Smith et al. and concerned an 82-year-old patient admitted to the intensive care unit with a diagnosis of severe community-acquired pneumonia, septic shock, and multiple organ failure. After administration of cefepime, the patient developed convulsions. 

Blood and cerebrospinal fluid drug concentrations were measured and increased values were found. After dose adjustments and a decrease in cefepime levels, the seizures subsided [126]. In 2020, a summary of an expert discussion panel on the use of TDM about antibiotics, antifungal, and antiviral drugs in intensive care units was published. 

It was emphasized that from a clinical practice point of view dosing drugs under TDM control is beneficial for aminoglycosides, voriconazole, and ribavirin. Therapeutic ranges have been defined for some of the antibiotics. Routine use of TDM has been recommended for therapy with aminoglycosides, beta-lactam antibiotics, linezolid, teicoplanin, vancomycin, and voriconazole in critically ill patients. The authors pointed out that, although drug concentration monitored therapy was first used in the 1940s, it still requires the development of globally uniform standards of care, especially in the treatment of patients with comorbidities and multi-organ disorders [118]. 

According to a systematic review by Barreto et al., clinical observations have shown that, in critically ill patients, beta-lactam antibiotic levels must be monitored, and the recommended minimum concentrations should be greater than the MIC for at least half the time between doses. The free drug fraction is recommended to be measured during the first 48 hours of therapy and should be above the MIC breakpoint of the most likely pathogen before blood culture results are available. 

This concentration should be maintained for the entire period between doses, and after this time the minimum concentration should reach a value of 1–2x of the observed MIC of the pathogen obtained in microbiological cultures. Neurotoxicity has also been shown to be the most dose-dependent adverse event, although direct evidence is not yet available to indicate the concentration above which this complication is likely to occur [127]. 

A retrospective cohort study published in 2017, which included 53 patients admitted to the intensive care unit with no neurological abnormalities before commencing continuous infusion of piperacillin at the standard dose and subjected to serum piperacillin determination, showed that 23 patients developed a neurological disorder, in which piperacillin causation was consistent chronologically and semiologically. The minimum concentration value of 157.2 mg/L, regardless of other variables, was the factor of the occurrence of neurotoxicity with 96.7% specificity and 52.2% sensitivity. 

This is a phenomenon that may be a limitation in antibiotic therapy if the patient has pathogens less sensitive to this antibiotic [128]. Optimization of antibiotic therapy also requires the use of guidelines adapted to local needs and adherence to these by medical staff. Unfortunately, a multi-center study has shown that 37.8% of antibiotic use in European hospitals does not comply with this restriction. Antimicrobial stewardship programs are a promising strategy. One of the methods is a pharmacokinetic dosing nomogram. 

This describes the influence of a covariate (e.g., weight) on a drug exposure target (e.g., concentration). It can be combined with TDM. Clinical pharmacological advice, which is delivered by the clinical pharmacologist who interprets the therapeutic drug monitoring results of antimicrobials about the site of infection, the pathophysiological characteristics of the patient, and potential drug-drug interactions are very important in personalized treatment [129,130]. 

The interprofessional team should include a clinical pharmacist, who can play an important role by monitoring antimicrobial prescriptions and providing advice or educating medical and nursing staff because approximately 50% of hospitalized patients receive at least one antibiotic, and 20-30% of cases of antibiotic therapy are unnecessary. Clinical pharmacist intervention is effective in enhancing the appropriate use of antibiotics and reducing their toxicity, which may improve patient care. Moreover, these had a positive impact not only on the clinical but on financial outcomes [131–135].

6. Neuroprotective Action of Antibiotics

In recent years, old, well-known drugs have been increasingly used in new indications. Such a strategy is referred to as "repositioning drugs", "redirecting drugs" or "finding new uses for old drugs". It is an efficient and cost-effective pathway to new drug development. Antibiotics are also being studied for their anti-amyloidogenic and anti-inflammatory properties. 

Results of ongoing observations suggest the possible use of antibiotics for Alzheimer's disease, Parkinson's disease, or multiple sclerosis. Tetracyclines, and especially doxycycline, are promising in this area. Interest in their use in Alzheimer's disease dates back to the early 2000s when it was discovered that tetracyclines could inhibit the aggregation of the β-amyloid peptide (Aβ). 

Moreover, they have anti-oxidative and anti-apoptotic activities [136–138]. Many studies have confirmed the neurotrophic, anti-inflammatory, antioxidant, and anti-apoptotic effects of minocycline, a long-acting, semi-synthetic tetracycline. This antibiotic is characterized by high lipophilicity and can easily penetrate the blood-brain barrier has a long half-life time, and excellent tissue penetration. 

It alters the reactivity of microglia cells, counteracts inflammatory processes, and reduces neurodegenerative processes within the central nervous system. Its effectiveness has been proven in experimental models for the treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, neuropathic pain, stroke, hypoxic-ischemic encephalopathy, and hypomyelination. It has been shown to reduce white matter and hippocampal lesions and improve cerebral blood flow. 

The drug reduces the expression of pro-inflammatory markers responsible for increasing the activity of chemokine CCL2, IL-1β, IL-6, TNF-α, and iNOS. Minocycline has antioxidant and antiapoptotic properties, manifested by caspase inhibition. In turn, ceftriaxone was found to increase the expression of astrocytic glutamate transporter 1 (GLT-1), decreasing excitotoxicity and neuroinflammation by detoxifying the brain from glutamate. 

It should be emphasized that persistently elevated amounts of this compound in the synaptic space may contribute to neurodegenerative diseases and ischemic stroke [139]. It affects the markers of oxidative status and neuroinflammation [138]. Rifampicin is also a broad-spectrum antibiotic whose protective effect on the brain has been demonstrated in many experimental studies. 

Its mechanism of action includes an inhibitory effect on free oxygen radicals, tau and Aβ protein accumulation, microglial activation, and apoptotic cascades [140]. The use of antibiotics in neuroprotection is promising, and creates new potential treatment options for neurodegenerative diseases, but requires many more studies using not only laboratory models but also human subjects.

7. Conclusions

The study of neuroprotective drugs that lead to rescue, recovery, or regeneration of the nervous system, its cells, structure, and function, has been ongoing for many years. These are based on three main strategies, i.e., the synthesis of new drugs, the use of natural products with as yet unidentified properties, and attempts to develop therapies based on existing drugs, so-called "drug repositioning" or "drug reprofiling". 

The latter area seems worthy of attention, as the pharmacokinetic and pharmacodynamic profile of such drugs is already known, and the effort put into such a strategy requires incomparably less time and cost than developing new drugs. Unfortunately, this is not an easy task, as there are many neurochemical modulators of nervous system damage. Clinical trials often fail to demonstrate their efficacy, and the doses used prove toxic [141]. 

Patients with nervous system dysfunctions are also a very heterogeneous group in terms of both their etiology and their age, etc., and they are additionally burdened with various risk factors. Experimental models also differ significantly from clinical conditions. The development of such drugs requires a better understanding of the etiology and pathogenesis of nervous system diseases. It is believed that neuroinflammatory mechanisms may account for many of the processes responsible for the neuronal degeneration observed in Alzheimer's disease, Parkinson's disease, stroke, and other neurodegenerative diseases. They undoubtedly represent a significant health problem and challenge for 21st-century medicine. 

Antibiotics are also being investigated in this aspect and promising observational results provide new potential avenues for their use as neuroprotective rather than just anti-infective drugs. Rifaximin is currently in phase II clinical trials based on the association between changes in the gut microbiota and neuropsychiatric diseases. It is hypothesized that it may improve memory and daily functioning in people with Alzheimer's disease by reducing blood levels of ammonia and/or levels of pro-inflammatory cytokines secreted by gut bacteria [142]. 

On the other hand, it is very important to pay attention to the possibility of neurotoxicity during antibiotic therapy. Multidirectional monitoring of patients at high risk of neurotoxicity is necessary to prevent or reduce its severity. As described above, its causes are not fully understood. It is also necessary to conduct multidirectional research dedicated to the elucidation of mechanisms responsible for nervous system dysfunction under the influence of antimicrobial drugs. 

To achieve an effective antimicrobial effect, and at the same time not induce drug-related complications, the choice of antibiotic and therapy depends on clinical diagnosis, pathogens isolated from the patient or those most frequently causing a specific infection in a population, and their sensitivity to antibiotics, concomitant diseases present in the patient (taking into account past diseases, chronic diseases, impaired renal or hepatic function, age, allergies, etc.), and properties of the antibiotic itself (pharmacodynamics, pharmacokinetics, possible side effects, toxicity).

Author Contributions: Conceptualization, M.H. and A.W.-H.; methodology, M.H., and A.W.-H.; resources, M.H., L.D., and A.W.-H.; writing-original draft preparation, M.H., L.D., and A.W.-H.; writing-review and editing, M.H., L.D., A.W.-H.; supervision, L.D., and A.W.-H.; project administration, M.H., L.D.; funding acquisition, A.W.-H. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflict of interest.

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