Investigative algorithms for disorders affecting plasma copper concentration: a narrative review

Introduction

Copper (Cu) is a micronutrient essential for human health, but conditions of deficiency and toxicity are associated with an increased risk of disease. It was first considered an “essential nutrient for humans” (1) following significant findings in the 1900s concerning Cu’s potential physiological role in the human body (2). Research since then has clarified its critical functions, such as its involvement in iron metabolism and role as a crucial structural component for many proteins, as well as in cuproptosis—a Cu-dependent cell death pathway (3-5). Considering Cu is required in only trace amounts, its homeostasis is very tightly regulated, and even small changes to the plasma concentration can result in significant and permanent pathological outcomes (3,4).

In this article we will discuss Cu, its measurement, and a laboratory approach to investigation of Cu abnormalities in human plasma. It does not replace local or national guidelines, nor local knowledge and advice from those with expertise. Instead, the algorithms are aimed for those where the cause of a Cu abnormality is not clinically clear. It should be remembered that people can have multiple reasons for biochemical abnormalities and so the algorithms are meant to be a guide to prevent over testing and over diagnosis but will not provide the entire answer in all cases. Instead, they are meant to be a guide for clinicians who are uncertain what tests to do when face with a Cu abnormality of uncertain aetiology. We present this article in accordance with the Narrative Review reporting checklist (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-57/rc).

Methods

The narrative literature review was developed by searching Medline, Google Scholar, OMIM and seminal texts from inception to September 2025. The diagnostic algorithms were then generated by the authors based on the literature review and the manuscript produced following the narrative review checklist guidelines. The search strategy is summarised in Table 1.

Cu homeostasis

As an essential trace element, the adult human body contains approximately 50 to 200 mg of Cu (4,6), with the highest concentrations found in the bone, kidney, liver, brain, and heart (4,7). Up to 60% of dietary Cu is absorbed in the small intestine [with copper transporter 1 (CTR1) and possibly the divalent metal transporter], where 75% of it is transferred to the liver via the portal vein (Figure 1) (3,8). Around 20% is re-excreted, with the rest binding to caeruloplasmin and being transported around the body (3,4). Around 50% of dietary Cu is absorbed with an intake range of 0.7 to 6.0 mg/day (3); however, only 1.0 mg/day of dietary Cu is required (9). Daily intakes below 0.8 mg/day of Cu may lead to deficiency, and consistently above 2.4 mg/day might lead to Cu accumulation and toxicity, but data is still controversial (3). Excretion of Cu occurs through faeces, urine, sweat, skin desquamation, saliva, gastric juice, intestinal fluid secretion and pancreatic secretion (3); however mostly occurs through bile, with up to 1.5 mg excreted a day via the biliary system (4). The kidneys also have CTR1 on the proximal and distal tubules to reabsorb Cu from urine, particularly in states of hypocupraemia (8).

Figure 1 The process of copper homeostasis throughout the body. Created in BioRender. Shipman, A. [2025] https://BioRender.com/gpd36ag. Created by authors as an original.

Cu is regulated through two independent pathways: high-affinity and low-affinity transport mechanisms (10). The high-affinity CTR1 controls short-term regulation through a negative feedback mechanism on the plasma membrane of human cells (10). Responsible for ~60% of total cellular Cu intake, expression is increased when Cu is depleted and endocytosed when Cu is elevated (10). This process is modulated by intracellular and extracellular Cu binding sites (10). Mutations of this transporter affect the efficiency of transport without fully disrupting its function (10). Absorption of dietary Cu is mediated by the CTR1 transporter on enterocytes, after which cuprous ions are pumped into the blood and arrive at the liver via the portal vein and are taken up by hepatocytes, again by CTR1 (11). Cu can then be secreted into the blood or bile via binding to caeruloplasmin (11). The transmembrane transporter ATP7b facilitates the transfer of liver Cu into bile or caeruloplasmin (11,12). Caeruloplasmin, synthesised mainly in the liver as apoceruloplasmin, is metallated with six cupric ions in the interior of the protein and represents approximately 75% of the circulating Cu pool in human plasma (13). The remaining Cu content, 25%, is mostly bound to albumin with approximately 0.04% on histidine in the circulation (but may form complexes with other free amino acids) (13). Apoceruloplasmin is rapidly degraded (14). Cu is excreted in the bile. Excess Cu is bound to the protein metallothionein, which, in the liver, is oxidised into insoluble compounds, which are secreted into the bile (15).

How is Cu measured?

To send serum or plasma to the laboratory for Cu measurement, ideally, one needs a tube that is trace element-free free e.g., plain serum or plasma tubes which are gel-free (the presence of a gel makes it unsuitable) (9). It is always important to check with your local laboratory as to which specimen tube they require before blood draw. Normal ranges will depend on the laboratory and what technique they are using, but as a guide, normal values are below (Table 2).

The median within individual biological coefficient of variation for serum/plasma Cu is 7.8%, and between individuals 13.5% (20).

Serum Cu can be measured by atomic absorption spectrometry [AAS; total (21) and free (22) with preanalytical ultrafiltration], inductively-coupled plasma mass spectrometry with or without dynamic reaction cell [ICP-MS/ICP-DRC-MS (23); total cu and exchangeable if pretreated with EDTA (24)], inductively-coupled plasma atomic emission spectrometry (ICP-AES; total) (25) and X-ray fluorescence spectroscopy (total Cu) (26). Point-of-care testing is not available, but X-ray fluorescence may be a promising technique (27,28). A fluorometric method for labile Cu (II) ions (cupric), which is independent of sex, age and other metals and reduced by chelation therapy in Wilson disease, may prove a more accurate and efficient diagnostic tool (29). Exchangeable cu (cu bound to albumin) is another method proposed for the diagnosis and monitoring of Wilson’s disease (30,31). Methods include anion-exchange high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and EDTA/ultrafiltration (30). The relative exchangeable copper (REC) ratio, exchangeable Cu divided by total serum Cu, has a 100% sensitivity and specificity for Wilson disease with and without acute liver failure (REC >15%) (32,33).

Serum caeruloplasmin correlates well with Cu; therefore, either Cu or caeruloplasmin can be used to estimate Cu status (34). However, caeruloplasmin may be much more sensitive to changes in Cu intake in Cu deficiency rather than Cu supplementation in those already replete (35). Caeruloplasmin is mostly measured by immunoassay (immunoturbidimetry or immunonephelometry) (14,36); although this makes a cheap and widely available measurement system, it is agnostic for apoceruloplasmin and holocaeruloplasmin (Cu-absent and Cu bound versions). This can cause spurious results in the investigation of Wilson disease (inability to move Cu into caeruloplasmin), where the reported concentration is the total caeruloplasmin rather than holocaeruloplasmin (which can be detected by rarely used enzymatic assays (36,37) that detect the ferroxidase activity of holocaeruloplasmin) (14). Enzymatic assays of caeruloplasmin are not affected by age, sex or oestrogens (38), but there is an age variation of caeruloplasmin (Table 2).

Immunoassay methods are also not standardised, meaning that each method will report different concentrations for a given sample (34,36,37). Given that Cu measurement is standardised and free Cu measurement is possible, there is no role of caeruloplasmin and calculated free Cu for Wilson disease diagnosis (34,36,39). Total methods for Cu measurement, which are widely used, will also be affected by changes in the concentration of binding proteins, caeruloplasmin and albumin, and therefore there may be a role for caeruloplasmin measurement if the Cu result is unexpected, e.g., a low total Cu may be due to low caeruloplasmin and vice versa (Table 3).

Urinary Cu is exempt from the effects of caeruloplasmin concentration which affects total serum Cu measures. However urinary excretion is increased in liver and renal disease/failure (14). Collections over 24 hours can be returned incomplete. Evidence for urinary Cu in Wilson’s disease is from 24-hour urine collections performed in children (14). It is important to note that it is not recommended to use random urine samples, due to a large CVi, resulting in unreliable Cu measurements (14). Which, in turn, raises the question if caeruloplasmin affects the level of urinary Cu excretion, such as during inflammatory states, which may affect the diagnostic accuracy of 24-hour urinary Cu in Wilson’s disease. Urine can be collected on or off chelation therapy to monitor Wilson’s disease (WD). There is poor concordance, in regard to status, however in values within individuals (53). Urinary Cu may be affected by diet, but this is controversial with not all studies showing diet affects excretion (54-56) and urine excretion is not thought to be a major homeostatic mechanism (3). There is a paucity of data on biological variation in 24-hour urinary Cu excretions but usually more than one collection is recommended to increase certainty that the result is ‘true’ for that patient (57). Collection into plain plastic containers is recommended; pre-acid wash is not required (58). Methods are similar to serum and will depend on local specimen type validation and reporting ranges e.g., ICP-MS (58).

Alternative biomarkers for Cu status have been developed but either they do not respond significantly to supplementation or the data are too sparse to form a conclusion about their reliability (35). These include erythrocyte and leukocyte superoxide dismutase; erythrocyte and platelet Cu; urinary deoxypyridinoline and pyridinoline; erythrocyte, platelet, and plasma glutathione peroxidase (35); platelet and leukocyte cytochrome-c oxidase; total glutathione; and diamine oxidase (35). Plasma Cu levels have demonstrated little evidence to suggest that it is a reliable marker for severely depleted, or repleted individuals (35). Ultimately, the use of plasma is not recommended to assess Cu levels (14). The summary of methods is depicted in Table 4.

Cu plasma derangements in humans

Cu is an essential element, and both its excess and deficiency can contribute to or exacerbate various conditions, such as Menkes disease, Wilson disease, neurodegenerative diseases, cardiovascular disease, and more (11). However, the imbalance of Cu can stem from numerous factors, making diagnosis and investigation challenging due to the complexity of its potential causes. Absorption of dietary Cu can vary depending on many factors such as age, gender, and oral contraceptives (3), as well as by competitive absorption from other elements, commonly iron and zinc (4). Caeruloplasmin, as an acute phase protein, exhibits elevated concentrations during chronic inflammatory states, and its levels are also influenced by sex and age, typically increasing in women and with advancing age (3).

Low serum plasma Cu concentration

Severe Cu deficiency, or WD, total serum Cu is <8 µmol/L (50 µg/dL) (14). Cu deficiency can cause a range of clinical signs and symptoms (Table 5). None alone are diagnostic and a deficiency of a single trace element is rare, unless in genetic cases, so many cases of trace element deficiency may have signs and symptoms related to multiple deficiencies.

High serum plasma Cu concentration

Consider severe Cu toxicity (unless a woman is pregnant or on oestrogen therapy) if total Cu is >40 µmol/L (250 µg/dL) and contamination of the specimen if >80 µmol/L (500 µg/dL) (14). Elevated levels of Cu can lead to tissue accumulation and toxicity to those tissues. There are one or two classical signs, e.g., Kayser-Fleischer rings, but otherwise, many of the signs and symptoms of Cu toxicity are less specific (Table 5).

Causes of Cu deficiency

Hypocupraemia can be caused by low oral Cu intake, whether from dietary lack or poor absorption. Low Cu in soil can lead to lower Cu levels in hair, in a study looking at toxicity to humans living near oil and gas manufacturing plants, but the non-clinically relevant deficiency was considered to be partly related to higher toxic metals in the area, such as lead (70). Vegetarian and vegan diets do not lack Cu, as some of the best dietary sources of Cu are fruit and nuts (3). Cu, however, is very low in dairy products, so a case has been presented of Cu deficiency in an adolescent with neurodiversity who was eating only dairy-based foods (71). Total parenteral nutrition is a situation where careful measurement of micronutrients and trace elements is important for successfully supplementing the required nutrition (72). Anorexia nervosa (and starvation) will lead to Cu deficiency, along with other multiple nutritional deficiencies (73).

Zinc supplementation or increased intake for any reason can decrease Cu absorption and lead to Cu deficiency, and so zinc and Cu combined supplementation is considered safer (74,75). Iron supplementation may cause hypocupraemia (76). However, considering how many people are on iron supplementation, hypocupraemia is not a well-described complication of taking iron, and so routine Cu measurement is not required during iron supplementation (77). Hypothyroidism also seems to be associated with hypocupraemia and low caeruloplasmin (78), with possible reasons being an association with other autoimmune diseases, including coeliac (79,80).

Conditions that affect the small intestines (81) can affect Cu absorption (82). A very small study, however, did not show significantly low Cu when comparing people with coeliac, Crohn disease and Wilson disease, but a larger study (83) demonstrated a quarter of patients with low Cu (84). However, disease activity is important as the risk of developing nutritional deficiency is less common if the gastrointestinal pathology is quiescent (85). Similarly, some patients have multiple reasons for reduced intestinal absorption of Cu, as seen in an interesting case series from South America, including multiple infections relating to acquired immunodeficiency syndrome and radiotherapy damage of the intestinal tract after cancer treatment were some of the mechanisms which led to Cu deficiency (86).

Gastric surgery, particularly in the weight loss setting, can lead to Cu deficiency (87). Hypocupraemia, leading to cytopenia and neurological symptoms, is as high as 18.8% in Roux-en-Y gastric bypass patients over the 2-year post-surgery period and 15.4% in gastric bypass patients in the first 15 months post-surgery (88).

The biliary system is the site of Cu excretion, so disorders of high bile output, including fistulas and drains, may cause hypocupraemia (89,90). Surgery around that area, e.g., Whipple’s (pancreatoduodenectomy), will rarely cause hypocupraemia if the biliary tract is damaged (91,92).

Nephrotic syndrome can result in significant urinary Cu loss, whereas renal failure alone can rarely cause an elevation in plasma Cu levels (93). Cu deficiency is not a universal finding in renal dialysis, with many papers showing either conflicting data or no significant change (94). This may in part be due to the type of renal disease, the type of dialysis and that renal excretion plays such a minor role in Cu homeostasis.

Drugs can cause Cu deficiency from a variety of mechanisms, either affecting absorption, chelating or as ionophores [Table 6 (95)]. However, clear cases of drugs such as proton pump inhibitors or diuretics affecting Cu levels were not found on Medline, and hypocupraemia is not considered a rare side effect of these medications. Overtreatment of Wilson’s Disease due to the use of chelators or zinc salt treatments has been recorded to result in common clinical features of Cu deficiency, including neutropenia, axonal sensory neuropathy and posterior cord myelopathy, with patients exhibiting low total serum Cu, low caeruloplasmin and reduced urinary Cu excretion (96).

Menkes disease is a rare progressive childhood disease which is typically fatal (97,98). Mutations of the ATP7A gene, which codes for Cu transportation from enterocytes in the small intestine into the blood, as well as excretion into the bile, result in disturbed Cu circulation (11,97,98). The most common form of Menkes disease is characterised by connective tissue dysfunction and progressive neurodegeneration, which ultimately leads to failure to thrive (98). A classical clinical feature is the presence of abnormal hair, often described as ‘kinky’ or ‘wiry’ (97). Cu accumulates within enterocytes, is not absorbed or transported to tissue, and the subsequent systemic Cu deficiency affects the liver and brain (97,98).

Aceruloplasminemia is a rare disease caused by loss-of-function mutations of the gene that encodes for caeruloplasmin (99). Whilst being a Cu transporter, it also plays a role in cellular iron export (90). Therefore, this disease leads to cellular iron retention and damage, especially within the brain and internal organs (99,100). Patients experience a wide spectrum of symptoms, ranging from neurodegeneration to liver disease, with a classic triad of diabetes mellitus, neurological disease and retinal degeneration (99,100). Laboratory investigations demonstrate low to absent serum caeruloplasmin, low serum Cu and iron concentration in caeruloplasmin (100).

For a laboratory based investigative algorithm, to help identify the cause of hypocupraemia in patients without an obvious cause please see Figure 2.

Figure 2 Laboratory based diagnostic algorithm for determining cause of low plasma copper in humans if cause is not clinically apparent. Created in BioRender. Shipman, A. [2025] https://BioRender.com/n4lf410. Created by authors as an original.

Causes of Cu toxicity

Hypercupraemia can theoretically result from dietary or water intake due to the increased use of Cu compounds on crops or industry emissions that affect the Cu content in many fruits, vegetables, animal products and cereals (3). Similarly, corrosion of Cu pipes increases the concentration of Cu within tap water (3). However, conflicting research suggests that despite prolonged Cu intake, increased concentrations are only found in urinary Cu (55). In conclusion, unless someone is poisoned (intentionally or accidentally) (101), there has been no evidence that increased levels of Cu in water, soil, as pesticides on crops or as food additives have caused Cu toxicity in humans (without Cu enzyme genetic problems) to date (102). There is negligible Cu absorption from other sources, e.g., skin or lungs, but one paper reports statistically significant Cu concentration in the blood of welders (103). Therefore, environmental concerns are likely to be very rare in cases of Cu toxicity. When people take Cu sulphate as a poison, then Cu will go up temporarily in serum but drops as it is sequestered in tissues, and caeruloplasmin will also go up, but neither of them can be used as markers of prognosis (104).

Liver diseases, such as cholestatic liver disease, are associated with increased plasma and urinary Cu concentrations (9). This occurs because of impaired biliary Cu excretion, leading to its accumulation and therefore increased levels in circulation as well as increased caeruloplasmin (9,105). Similar findings have been reported in primary sclerosing cholangitis and primary biliary cholangitis (106-108). In addition, hepatic inflammation itself can contribute to raised plasma Cu through increased caeruloplasmin synthesis. Caeruloplasmin is an acute-phase reactant produced in the liver and stimulated by inflammatory stimuli (109). This in turn, increases serum Cu levels since caeruloplasmin binds and transports the majority of circulating Cu (51).

As discussed, most circulating Cu is bound to caeruloplasmin; therefore, rises in caeruloplasmin concentration increases Cu concentrations (4,9). As a positive acute phase reactant, caeruloplasmin is upregulated during acute and chronic inflammatory states, as well as from infection and trauma, resulting in marked increases in its concentration (9,109). Subsequently, increases in plasma Cu concentration have also been observed after these inflammatory states (9) and during infections with bacteria, viruses, parasites (110,111) and fungi (112). A large study has also found elevated serum Cu in people with inflammation associated with obesity (113). One should note that ceruloplasmin (and Cu) may not rise on day one of an inflammatory insult, as seen in patients postoperatively, where there is an initial drop in Cu before rising by day 7 postoperatively (114). It should also be noted that in severe systemic inflammatory responses, Cu might actually be low (9).

The relationship between Cu regulation and cancer is highly complex. On one hand, deregulation of Cu homeostasis is implicated in tumorigenesis and cancer development, with discussions that excess Cu accumulation promotes cancer cell proliferation (115-117). On the other hand, elevated serum and tissue Cu concentrations have been reported in patients with a variety of cancer types, higher compared to controls and with levels returning to normal tumour remission (116-118). This raises the possibility that excess Cu may contribute to tumour development, as well as being a consequence of malignant disease.

Research has documented that users of combined oral contraceptives have elevated serum Cu concentrations (49,119,120). This effect is largely attributed to the action of oestrogen, which stimulates hepatic caeruloplasmin synthesis, thereby increasing serum caeruloplasmin concentration, and consequently circulating Cu levels (9,40,49). In addition, a non-clinically significant Cu increase has also been seen in women taking hormone replacement therapy (121,122). Antiepileptics have also been associated with hypercupraemia (52,123-125).

Hyperthyroidism can cause elevated total Cu concentrations in plasma (50,126). Another study also demonstrated an elevation in caeruloplasmin as well as Cu in hyperthyroidism, and so it is likely that the elevation in Cu is due to the caeruloplasmin increase.

Infusions of corticosteroids such as methylprednisolone and dexamethasone lead to an elevation of Cu that persists 3 days later (51). Of course, inflammation, which is being treated with corticosteroids, will have put up caeruloplasmin, and therefore Cu, in the serum, but there seems to be an additional elevation from the steroid administration (127). However, there are no case reports of clinically significant percupraemia from long-term corticosteroid use.

WD is a Cu metabolism disorder arising from mutations of the ATP7B gene, which is responsible for the transport of Cu within hepatocytes, resulting in inactivation and therefore reduced biliary excretion of Cu (11,61). Consequently, hepatic Cu accumulates, causing toxicity and overflow into the blood, increasing plasma concentrations and accumulation in secondary tissues (11). This then generates the classical features of WD, such as liver disease or acute liver failure, movement disorders (tremour, dystonia, parkinsonism, dysarthria, dysphagia), Kayser-Fleischer ring of the eye and sunflower cataract, mood disturbances, psychosis and personality disorders (61).

In terms of laboratory markers, caeruloplasmin is often found to be decreased in neurological WD; however, it may be low normal in those with active liver disease with <0.7 µmol/L being suggestive of a diagnosis of WD and >1.5 µmol/L (14) making it unlikely (61,128). The concentration of serum non-caeruloplasmin-bound Cu is indicative of WD and is considered for diagnostics, yet it is limited by the adequacy of the measuring methods (61,128). Total serum Cu is often decreased in proportion to the decreased caeruloplasmin; however, it is normal or elevated in severe liver injury and acute liver failure, respectively (61,128). 24-hour urinary Cu excretion in 77–84% of untreated symptomatic patients is diagnostic at greater than 1.6 µmol/24-h (if <0.64 µmol/24-h (14) then WD is unlikely) (128). Issues arising from this marker include incomplete urine collection, Cu contamination of the collection device, and the overlap of findings from other liver diseases (61,128). Therefore, urinary Cu excretion with D-penicillamine is considered an alternative to differentiate from other liver diseases; however, it is only standardised for the diagnosis of children (61,128). Hepatic parenchymal Cu concentration from biopsy is considered after failure of diagnosis from non-invasive tests (61,128). A result of greater than 4 µmol/g/dry weight is considered, although this is less reliable in later stages of WD where the distribution of Cu is non-homogeneous (128). Histochemical evaluation of Cu from biopsy suffers similar setbacks, with the addition of early stages of WD presenting non-histochemical detectable Cu (128). WD causes pathognomonic changes in brain magnetic imaging resonance scans which we will not discuss here as we have tried to limit our diagnostic algorithms to laboratory based investigations but there are good reviews on imaging in Cu disorders (129).

Special circumstances

Childhood

Neonates have low Cu serum concentrations (Table 2), which will reach adult levels by the age of one (9). In childhood, Cu deficiency can lead to bone fractures, and so in a child presenting with fractures where a non-accidental cause is being considered, it is worth considering measuring Cu (9).

Pregnancy

One study looking at the risk of gestational diabetes demonstrated normal Cu levels in a large prospective cohort study of 1,322 pregnant women in the USA (130). Cu is probably stable during pregnancy, as many studies have shown conflicting data, and so one hypothesises that unless there are other reasons for loss of Cu homeostasis, then Cu concentrations should remain stable during pregnancy (45). However, high oestrogen does increase caeruloplasmin (and hence Cu measurement in serum; Table 2) and so caeruloplasmin can be elevated 2–3 times above the patient’s baseline in the third trimester (9).

Conclusions

Cu is an essential micronutrient seen in trace amounts. The diagnostic algorithms (Figures 2,3) presented aim to assist healthcare professionals in investigating the cause of abnormalities in plasma Cu concentrations, allowing timely diagnosis and intervention, while minimising the risk of misdiagnosis. It is meant for cases where a cause is not clear, but it is important to remember sometimes more than one cause is relevant and they do not replace advice from your local experts. Future research would be a validation of these algorithms to check they work in common clinical scenarios.

Figure 3 Diagnostic algorithm for cases of hypercupraemia or signs of copper toxicity—if cause is not clinically apparent. Created in BioRender. Shipman, A. [2025] https://BioRender.com/dki30fj. Created by authors as an original. CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; HRT, hormone replacement therapy; LFTs, liver function tests; OCP, oral contraceptive pill; TSH, thyroid stimulating hormone

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Sukhbir Kaur) for the series “Trace Elements and Vitamins” published in Journal of Laboratory and Precision Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-57/rc

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-57/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-57/coif). The series “Trace Elements and Vitamins” was commissioned by the editorial office without any funding or sponsorship. K.E.S. serves as an unpaid editorial board member of Journal of Laboratory and Precision Medicine from September 2024 to December 2026. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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