Effectiveness and safety of neridronate in chronic nonbacterial osteomyelitis: insight from the CAMELOT registry

Abstract

Background:

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory noninfectious disease of the bone that predominantly affects children and adolescents. Bisphosphonates (BPs) are used to treat of CNO with most clinical experience involving pamidronate. Neridronate (NER) is an amino BP with a chemical structure and potency close to pamidronate.

Objectives:

This study aims to evaluate the effectiveness and safety of NER in patients with CNO.

Design:

Monocentric retrospective cohort study.

Methods:

This is a retrospective cohort study conducted on patients included in the monocentric CAMELOT (Chronic non-bActerial osteoMyELitis: A mOnocentric regisTry) registry. Response to treatment was evaluated semiquantitatively based on clinical, laboratory, and radiological domains.

Results:

The cohort consisted of 27 subjects. Thirteen (48%) received NER alone. At baseline, patients receiving NER alone tended to have a higher rate of vertebral fractures than those treated with combination therapy (46% vs 29%; p = 0.4). The median number of peripheral lesions at magnetic resonance imaging was clearly lower in patients treated with NER alone (0 (interquartile range (IQR) 0–2) vs 2 (IQR 1–5); p = 0.01). An overall response (complete or partial) to NER was documented in all but one patient (96%). Six patients (22%) achieved a complete response in all the three domains, 83% of whom (n = 5) received NER without any other concomitant treatments. Interestingly, using a Receiver Operating Characteristic-derived cutoff of 2 years from CNO diagnosis, all patients who achieved a complete response (100%) had received NER within the first 2 years from diagnosis, compared with 57% (n = 12) of those who did not (p = 0.07). No long-term NER complications were observed.

Conclusion:

Neridronate appears to be a safe and effective option for CNO, particularly in patients with recent-onset disease, spinal involvement, and fewer peripheral lesions. Early initiation may be associated with higher rates of complete response, though further studies are needed to confirm these findings.

Plain language summary

Neridronate treatment for chronic nonbacterial osteomyelitis: Real-world evidence on effectiveness, safety, and the importance of early treatment

Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease that can cause bone pain, swelling, and fractures, particularly affecting children and young adults. Because the disease is uncommon, there is limited information on the best treatment options and on their long-term safety. Neridronate is a medication that reduces bone inflammation and is increasingly used in CNO, but real-life data on its effectiveness are still scarce. In this study, we analyzed patients with CNO included in the CAMELOT registry, a single-center database that collects clinical information from routine care. We evaluated how well patients responded to neridronate by looking at symptoms, blood tests for inflammation, and imaging findings. We also assessed possible side effects. A total of 27 patients were included. Almost half received neridronate alone, while others received it together with additional treatments. Overall, neridronate was effective in nearly all patients, with improvement seen in symptoms, laboratory markers, or imaging findings. About one in five patients achieved a complete response, meaning improvement in all evaluated areas. Most of these patients were treated with neridronate alone. Importantly, all patients who achieved a complete response had started neridronate within two years of being diagnosed with CNO. This suggests that earlier treatment may lead to better outcomes. Neridronate was well tolerated, and no long-term safety concerns were observed during follow-up. In summary, neridronate appears to be a safe and effective treatment for chronic nonbacterial osteomyelitis, especially when started early in the disease course and in patients with spinal involvement or fewer affected bones. Further studies are needed to confirm these findings in larger groups of patients.

Keywords

biphosphonates chronic non-bacterial osteomyelitis chronic recurrent multifocal osteomyelitis neridronate

Introduction

Chronic nonbacterial osteomyelitis (CNO), formerly known as chronic recurrent multifocal osteomyelitis (CRMO), is an autoinflammatory noninfectious disease of the bone, predominantly affecting children and adolescents. Dysregulated expression of pro- and anti-inflammatory cytokines augments RANK–RANKL signaling, promoting osteoclast differentiation and activation. The bone structural damage results in bone pain, the main clinical feature of this disease which can reduce patients’ quality of life.¹ CNO usually affects children between 7 and 12 years of age, and its diagnosis is made by the exclusion of other conditions such as malignancy and/or infectious disorders. Bone involvement could be monofocal or multifocal, with pelvis, clavicles, vertebrae, and metaphysis of long bones as the most frequently affected sites.¹ Treatment aims at reducing pain and achieving reduction or remission of inflammatory bone lesions and preventing pathological bone fractures. Unfortunately, mainly due to the rarity of this condition, there are no drugs approved specifically for CNO. The first line of treatment has historically consisted of non-steroidal anti-inflammatory drugs (NSAIDs), but disease relapses are frequent, often requiring additional treatments.^2,3 Upon NSAIDs failure or in severe cases, consensus treatment plans released by the Childhood Arthritis and Rheumatology Research Alliance recommend, in the absence of randomized clinical trials directly comparing two or more drugs, to use synthetic disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) and sulfasalazine, TNF-alpha inhibitors, or bisphosphonates (BPs) based on individual clinician/center experience.⁴ To note, the presence of vertebral involvement and structural damage is considered a major factor driving the choice toward BPs.^5,6 BPs are stable derivatives of inorganic pyrophosphate that suppress bone resorption by cytotoxic effect on osteoclasts. They inhibit calcification and hydroxyapatite breakdown and induce osteoclast dysfunction.⁷ Furthermore, BPs may reduce bone inflammation by modulating the balance between pro- and anti-inflammatory cytokines.^6,8 The most frequently used BP in CNO is pamidronate, whose effectiveness has been documented in few studies.^9–11 In light of the recent shortage of pamidronate¹² and the constraints of its dosing regimen, alternative BPs have been increasingly adopted in the management of CNO.^13–15 Neridronate (NER) is an amino BP with a chemical structure and potency close to that of pamidronate, but a less binding infusion schedule. NER is characterized by five methyl groups in the side chain, in contrast to the two present in pamidronate. NER is employed and registered for the treatment of Paget disease of bone, chronic regional pain syndrome (CRPS), and osteogenesis imperfecta (OI). NER has been shown to be effective and safe in pediatric population with OI.¹⁶ This study aims to evaluate the effectiveness and safety of NER in patients with CNO.

Methods

This is a retrospective cohort study conducted on patients included in the monocentric CAMELOT (Chronic non-bActerial osteoMyELitis: A mOnocentric regisTry) registry. In all cases, the CNO diagnosis was confirmed by a multidisciplinary team, including expert pediatric radiologists, orthopedic surgeons, and pediatric rheumatologists. Inclusion criteria were (i) clinical diagnosis of CNO between June 2004 and June 2024; (ii) the fulfillment of at least one of the diagnostic/classification criteria^17,18; (iii) treatment with intravenous NER (at least one cycle of four infusions as discussed forward). Patients with less than 1 year of follow-up were excluded.

For each enrolled patient, demographic, clinical, laboratory, radiological data were collected before and after treatment with NER. All pharmacological treatments were recorded. Treatment with NER consisted of intravenous infusions at a dose of 2 mg/kg per infusion (maximum 100 mg), diluted in 250–500 mL of 0.9% normal saline; this dosage has been imported from OI.¹⁶ Each infusion was delivered over 3–4 h, on days 1, 4, 7, and 10. This schedule was adapted from that used for CRPS type I, designed to provide a short, intensive course aimed at controlling symptoms and rapidly achieving a disease-modifying effect.¹⁹ After the first NER cycle, re-treatments were performed according to the clinician’s judgment when deemed necessary and consisted of a single infusion administered at least 3 months after the last one as a maintenance regimen comparable to that of OI.¹⁶ NER side effects, particularly acute phase reaction (APR) characterized by reversible flu-like symptoms such as fever, headache, arthralgia, and myalgia, typically occurring 24–36 h after the first infusion, and hypocalcemia, along with their clinical management, were collected over the follow-up period.

Disease activity assessment and response to treatments

Clinical disease activity was assessed using the physician’s global assessment (PhGA) of disease activity based on objective clinical findings and reported symptoms such as pain. The level of the child’s overall disease activity was reported on a 10-cm linear visual analogue scale according to the treating physician. As part of the disease activity assessment, inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were also recorded. The number and site of bone lesions consistent with disease activity were assessed by magnetic resonance imaging (MRI) or bone scan, which images were reviewed by expert radiologists (M.B.G. and A.C.). Baseline whole-body MRI (WB-MRI) was performed in 19/27 patients with body scan performed in the remaining 8 subjects. The presence of vertebral fracture was defined by plain radiography.

WB-MRI examinations were performed on a GE Optima MR450w 1.5-T scanner using a standardized protocol including coronal T1-weighted turbo spin-echo, coronal T2-weighted short tau inversion recovery (STIR), axial diffusion-weighted imaging (b-values 50 and 800), and sagittal T1-weighted and STIR sequences of the spine. In patients with available images of WB-MRI before and after treatment, therapeutic response was assessed by using the “Radiological Activity Index—chronic nonbacterial Osteomyelitis magnetic resonance imaging scoring” (RAI-CROMRIS), which was assessed by two experienced radiologists (M.B.G. and A.C.).^20,21 As expected for a retrospective study covering two decades, imaging protocols were not entirely uniform. To address this heterogeneity, lesion assessment was based on expert radiological review of all MRI examinations, while RAI-CROMRIS analysis was performed only in the subgroup with available serial WB-MRI studies.

Response to treatment was evaluated semiquantitatively based on clinical, laboratory, and radiological domains. Outcomes were categorized as follows: complete response, in cases of total resolution of clinical manifestations, MRI lesions, and normalization of inflammatory markers; partial response, if improvement was observed in at least two domains, including radiological (MRI) improvement, without complete resolution of lesions; and no response, when no improvement or improvement in only one domain. The interval from diagnosis to NER initiation was evaluated as a potential factor associated with the likelihood of achieving a complete response. The optimal time threshold was identified using receiver operating characteristic (ROC) curve analysis with the Youden Index.

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

Statistical analysis

Discrete variables were described as frequencies (%), and continuous ones as mean ± standard deviations or median (interquartile range, IQR), based on the normality of distribution. The latter was evaluated by the Shapiro–Wilk test. Comparisons were investigated by T or Mann–Whitney tests for continuous data and χ² or exact Fisher’s test for categorical ones. p ⩽ 0.05 was considered statistically significant. Analyses were performed with R Studio (version RStudio 2021.09.2+382 for macOS).

Results

Baseline features of the cohort

The cohort consisted of 27 subjects whose main baseline characteristics are presented in Table 1. Patients had been followed up at our institution for a median of 7.1 years (IQR 2.8–10.5) from diagnosis and 4.7 years (IQR 2.7–10.1) from the first NER infusion. All patients received NSAIDs as first-line treatment. The median time between CNO disease onset and first NER infusions was 1 year (IQR 1–3 years). Half of the cohort (13 subjects; 48%) received NER alone after NSAID failure. In the remaining patients, NER was used in combination with methotrexate (n = 10), sulfasalazine (n = 2), or glucocorticoids (n = 2). Table 1 shows a comparison between patients treated with NER alone and those receiving combination therapy. Among the 22 patients with an X-ray available at diagnosis, 9 (41%) had an osteolytic lesion (30% NER alone vs 50% NER in combination; p = 0.4). Vertebral fractures were documented in 10 out of 27 patients (37%). At baseline, patients receiving NER alone tended to have a higher rate of vertebral fractures than those treated with combination therapy (46% vs 29%; p = 0.4). Only one subject presented with a non-vertebral pathological fracture: a lesion in the second metatarsal of the right foot was detected, and the patient received NER without other drugs.

Table 1.

Main characteristics of the cohort before starting NER, stratified by the presence or absence of concomitant medications.

Characteristic	Overall, N = 27^a	NER alone, N = 13^a	NER in combination, N = 14^a	p-Value^b
Sex				0.3
Female	16 (59%)	9 (69%)	7 (50%)
Age at disease onset				0.2
Median (IQR)	11.0 (9.0–13.0)	11.0 (10.0–13.0)	10.5 (9.0–12.0)
Age at NER				0.5
Median (IQR)	13 (10–16)	14 (11–15)	13 (10–16)
Follow up, years				0.4
Median (IQR)	7.1 (2.8–10.5)	4.7 (2.7–10.1)	8.2 (4.3–10.5)
Follow-up from NER first infusion, years				0.3
Median (IQR)	4.7 (2.7–10.1)	8.2 (4.1–9.3)	4.1 (2.5–10.1)
Physician’s global assessment				0.9
Median (IQR)	6 (4–7)	6 (4–7)	5.5 (4–7)
ESR at disease onset, mm/h				0.6
Median (IQR)	26 (14–49)	26 (16–34)	27 (14–69)
CRP at disease onset, mg/dL				0.2
Median (IQR)	0.40 (0.20–1.10)	0.20 (0.10–0.70)	0.50 (0.20–1.20)
Number of total MRI lesions				0.1
Median (IQR)	3.00 (2.00–6.00)	2.00 (1.00–5.00)	4.00 (3.00–8.00)
Number of peripheral MRI lesions				0.01
Median (IQR)	1.50 (0.00–2.50)	0.00 (0.00–2.00)	2.00 (1.00–5.00)
Vertebral involvement				0.3
Yes	15 (56%)	6 (46%)	9 (64%)
Any subsequent therapy				0.3
Yes	12 (44%)	7 (54%)	5 (36%)

n (%).

Pearson’s Chi-squared test; Wilcoxon rank sum test; Fisher’s exact test; Wilcoxon rank sum exact test.

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IQR, interquartile range; NER, neridronate.

Effectiveness of neridronate

The median time between the latest NER infusion and MRI re-evaluation was 4 months (IQR 3–7) and did not differ between patients treated with or without other drugs (6 months (IQR 3–9) vs 4 months (IQR 3–6.5); p = 0.6). Clinical evaluation was conducted concurrently with imaging re-evaluation.

An overall response (complete or partial) to NER was documented in all but six patients (78%); notably, five subjects, despite having an improvement in clinical and laboratory domains, were not considered as partial responders due to the lack of MRI improvement. Additionally, one patients, who experienced an improvement in the number of MRI lesions, did not show any modification in the other domains. A partial response (defined as improvement in at least 2 domains) was observed in 15 patients (56%); 9 of these 15 subjects (three treated with NER alone) showed some degree of improvement in all the 3 domains, but did not reach a complete response status. Six patients (22%) achieved a complete response in all the three domains, 83% of whom (n = 5) received NER without any other concomitant treatments.

Overall, there was a significant reduction in ESR following NER treatment (median 12 mm/h (IQR 9–24) vs 27 mm/h (IQR 16–49); p = 0.01), whereas CRP levels did not show a consistent decrease (0.17 mg/dL (IQR 0.1–0.7) vs 0.45 mg/dL (IQR 0.2–1.1); p = 0.2). A significant reduction in PhGA scores was also observed (3 (IQR 1–3) vs 6 (IQR 4–7); p < 0.01).

MRI parameters are shown in Figure 1. Notably, RAI-CROMRIS data before and after NER treatment were available for 12 patients (6 treated with NER alone). To note, the number of total MRI lesions decreased significantly in those patients taking NER alone (2 (IQR 1–5) pre-NER vs 0 (IQR 0–1) post-NER; p ⩽ 0.01), while no change was observed in patients receiving NER in combination with other drugs (4 (IQR 3–8) pre-NER vs 4 (IQR 1–7) post-NER; p = 0.4). Nevertheless, in this latter group, we observed a total regression of vertebral lesions after NER (2 (IQR 0–2) pre-NER vs 0 post-NER; p = 0.07). Figure 2 shows the whole-body MRI before and 6 months after NER in a patient who did not receive any other treatments (Figure 2).

Figure 1.

Outcome MRI parameters pre and post neridronate.

Figure 2.

STIR MRI images (sagittal and coronal views) before and 6 months after Neridronate infusion of a 11-year-old girl. Panel (a) T7 fracture with bone edema in several adjacent vertebral bodies. Panel (b) stabilization of T7 fracture and complete resolution of bone edema.

Interestingly, using a ROC-derived cutoff of 2 years from CNO diagnosis, all patients who achieved a complete response (100%) had received NER within the first 2 years from diagnosis, compared with 57% (n = 12) of those who did not (p = 0.07).

Overall, 16 patients (59%) received a subsequent course of NER after the first cycle with a median number of infusions of 3 (IQR 2–5.5). The rate of re-treatment with NER did not significantly differ between those who received NER alone or in combination (54% vs 64%; p = 0.6). Conversely, the median number of subsequent infusions was higher in those who received NER in combination than in those who did not (4 (IQR 3–6) vs 2 (IQR 1–3); p = 0.03). After NER administration, no patients developed pathological fractures during the follow-up (p < 0.01). During follow-up, 7 out of 14 patients (54%) who initially received NER alone required subsequent treatment with DMARDs: MTX (n = 2), etanercept (n = 1), and adalimumab (n = 4). Interestingly, such rate was not significantly different from those who received NER with concomitant medications (54% vs 36%; p = 0.3). The median time to initiation of subsequent treatment was 3.04 years (IQR 0.9–3.4). Most patients were started on a new treatment due to clinical relapse, whereas only two patients were prescribed with a different pharmacological agent because of persistent disease activity.

Three patients received more than one subsequent DMARD. One subject initially treated with NER alone later received consecutively MTX, adalimumab, etanercept, and infliximab. A girl with CNO and pyoderma gangrenosum, initially treated with NER in combination with MTX, later received etanercept and is currently on canakinumab. Another difficult-to-treat patient, after receiving NER and MTX, was subsequently treated with etanercept, adalimumab, secukinumab, infliximab, and is now on golimumab.

Safety

Approximately half of the cohort (14 out of 27 subjects) experienced adverse effects. APRs characterized by reversible flu-like symptoms were the most common, occurring in 13 patients (48%). In all cases, APRs occurred only after the first infusion and did not recur with subsequent treatments. Arthralgias, myalgias, and fever responded well to standard analgesic and antipyretic medications. Six patients developed mild, asymptomatic post-infusion hypocalcemia; none required intravenous rescue therapy. Hypocalcemia resolved in all cases with calcium and cholecalciferol supplementation, administered for up to 4 weeks. Additionally, one patient experienced transient neutropenia. No long-term NER complications were observed.

Discussion

To our knowledge, this is the first study to report on the effectiveness and safety of NER in a cohort of patients with CNO. All treated patients showed some degree of response to NER, with about a quarter of patients reaching a complete response, and no patient experienced further pathological fractures during the follow-up.

Overall, we observed a significant amelioration in clinical, laboratory, and radiological domains. Importantly, almost all MRI outcome parameters showed some degree of improvement after NER. The present study allows for profiling the CNO patients with the highest chance to respond to NER, namely those with spine involvement and a low number of peripheral lesions and recent onset. Possibly, the high bone remodeling associated with vertebral fractures provides a favorable substrate for NER pharmacological activity. Conversely, the number of peripheral lesions seems not to be impacted by NER treatment (Figure 1), an observation that may account for the low rate of complete response reported among patients receiving NER in combination with other drugs. Indeed, baseline data show that patients treated with a drug combination had a more extensive disease (Table 1). Our data suggest that timing of NER initiation may also play a role: in the CAMELOT cohort all the patients who showed a complete response were treated within 2 years from the CNO diagnosis. The relevance of timing on NER effectiveness might be underpinned by the effects that BPs exert on the monocyte/macrophage lineage, resulting in a sustained suppression of the pro-inflammatory cytokine release that characterizes early phases of CNO.²²

Furthermore, the number of NER infusions after the first cycle was significantly higher in patients treated with NER in combination, confirming the speculation of a more severe disease in this subgroup of patients and highlighting the importance of patient selection for this treatment. However, thanks to a long-term follow-up, we observed that approximately half of the patients initially treated with NER alone required subsequent DMARD therapy.

These observations are consistent with those emerged in previous studies on pamidronate in CNO.^9–11 In a retrospective cohort of 32 patients with multifocal disease and/or with spine involvement,⁹ intravenous pamidronate was administered every 3 months for 2 years, at the dose of 1 mg/kg/day (maximum 60 mg/day) for 3 consecutive days (the first dose in the first series 0.5 mg/kg/day). Similarly to our findings, the number of MRI lesions decreased significantly during the first year of treatment, and 38% presented with clinically inactive disease at 12 months. However, 67% of patients relapsed during the 2-year follow-up confirming the need for a supplementary therapy.⁹ More recently, the effectiveness of pamidronate (n = 47) was compared with TNF inhibitors (n = 22) in a retrospective cohort of CNO patients.¹¹ At 6 months, the rates of complete and partial remission in the Pamidronate-treated patients were 54% and 34%, respectively. Outcomes were similar in patients receiving TNF inhibitors, although pamidronate-treated patients seemed to have a faster MRI response. Interestingly, the failure of pamidronate was associated with a higher number of lesions on MRI.¹¹ However, 20% of patients receiving pamidronate relapsed or experienced a disease worsening while fewer flares were associated with the use of TNF inhibitors.

Another critical insight coming from our data relies on the safety data for NER, which were reassuring. Although approximately half of the cohort experienced APRs after the first infusion, these were mild and effectively managed with standard analgesic and antipyretic medications. No cases of osteonecrosis or other major complications were recorded during follow-up.

Despite a promising initial report in 2009 describing the successful use of NER in a 15-year-old girl with CNO previously treated with Infliximab,¹⁴ NER has been scarcely employed in CNO management. In a 2020 multicentric cohort, 15 out of 86 patients received NER, mostly from our center. In the 20 patients receiving BP, the rate of overall response—complete or partial—was 80%, similar to the 78% rate registered in the present study. In particular, in the multicentric 2020 study, complete and partial response rates had been obtained by 53% and 27% of patients, respectively. Despite the comparable rate of overall response, the distribution of complete and partial responses observed in our study was substantially different: 22% and 56%, respectively. This difference may be partially explained by the strict definition of partial response adopted in the present study. However, no additional details, such as dosing regimen or baseline patient characteristics, were provided.¹⁵

Limitations

Several limitations of the present study should be acknowledged. Patients included in the CAMELOT registry received the diagnosis over the last two decades, and the management of the patients may have changed over time. Half of the patients included herein received NER along with other drugs that might have impacted the outcomes. The timing of the MRI post-NER administration may have influenced the possibility of detecting further changes; however, the long-term follow-up could mitigate this caveat, serving as a surrogate of disease activity over time. The restricted sample size prevented us from implementing more complex analyses that could have provided predictors of NER response. Moreover, NER is mainly marketed in Italy, which represents an important limitation that should be acknowledged. However, it should be noted that the use of NER in other countries is increasing.^23,24 Due to the lack of uniformly accepted and validated outcome measures, which affects all CNO studies, we implemented a semiquantitative response classification alongside the use of a validated tool for weighing the disease burden on MRI and its modification. In this regard, it should be disclosed that the present study lacks patient/parent outcome measures. The use of the PhGA might skew the evaluation through more objective parameters; however, reported pain is highly ranked in the evaluation of CNO patients. Additionally, the sensitivity of inflammatory markers in CNO activity is low; therefore, ESR and CRP levels within reference range do not rule out ongoing bone inflammation. Despite these limitations, requiring MRI lesion reduction as a mandatory criterion to define partial response ensures an objective and indubitable improvement in the disease status.

Conclusion

As a whole, the present study presents NER as a safe and effective therapeutic tool for CNO, highlighting the importance of accurate patient selection, favoring those with recent onset, spine involvement, and a low number of peripheral lesions. In the near future, it would be advisable to validate outcome parameters for CNO activity and conduct a comparative study to improve the management of these patients.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X261446898 – Supplemental material for Effectiveness and safety of neridronate in chronic nonbacterial osteomyelitis: insight from the CAMELOT registry

Supplemental material, sj-docx-1-tab-10.1177_1759720X261446898 for Effectiveness and safety of neridronate in chronic nonbacterial osteomyelitis: insight from the CAMELOT registry by Achille Marino, Andrea Amati, Raffaele Di Taranto, Debora Pireddu, Giulia Grillo, Francesco Baldo, Stefania Costi, Chiara Crotti, Alessandra Curti, Zakaria Vincenzo, Mauro Battista Gallazzi, Massimo Varenna, Roberto Caporali and Cecilia Beatrice Chighizola in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

The authors would like to express their heartfelt gratitude to Professor Rolando Cimaz for his guidance and inspiration.

Declarations

ORCID iDs

Achille Marino

Massimo Varenna

Cecilia Beatrice Chighizola

Group authorship list

None.

Supplemental material

Supplemental material for this article is available online.

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