Vitamin D-Dependent Rickets Type 1A in Two Siblings with a Hypomorphic CYP27B1 Variant Frequent in the African Population.

Vitamin D-dependent type 1A rickets (VDDR-1A) is a rare autosomal recessive disease due to the inability to convert 25-hydroxyvitamin D [25(OH)D] to the active form 1.25-dihydroxyvitamin D [1.25(OH) 2 D] by the enzyme 25(OH)D-1α-hydroxylase leading to low or low-normal serum levels of [1.25(OH) 2 D]. We report two sisters with rickets in whom the diagnosis of VDDR-1A was a challenge. They had normal 1.25(OH)2D levels, which are unusual with this condition but may be explained by the identified genotype. Both have compound heterozygous for two, most likely, hypomorphic CYP27B1 alleles: the novel p.(Arg117Gly) variant, and p.(Ala129Thr), which are present in 0.43% of the African population. This report illustrates the variability of clinical, laboratory, and radiological presentation between two sisters with the same genotype, during phases of faster or slower growth. Genetic testing was crucial for establishing the diagnosis that optimized the management and genetic counseling.

Montelukast and cefoperazone act as anti-quorum sensing and anti-biofilm agents against Pseudomonas aeruginosa.

AIMS: Drug repurposing is an attractive strategy to control biofilm-related infectious diseases. In this study, two drugs (montelukast and cefoperazone) with well-established therapeutic applications were tested on Pseudomonas aeruginosa quorum sensing (QS) inhibition and biofilm control. METHODS AND RESULTS: The activity of montelukast and cefoperazone was evaluated for Pqs signal inhibition, pyocyanin synthesis, and prevention and eradication of P. aeruginosa biofilms. Cefoperazone inhibited the Pqs system by hindering the production of the autoinducer molecules 2-heptyl-4-hydroxyquinoline (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (the Pseudomonas quinolone signal or PQS), corroborating in silico results. P. aeruginosa pyocyanin production was reduced by 50%. The combination of the antibiotics cefoperazone and ciprofloxacin was synergistic for P. aeruginosa biofilm control. On the other hand, montelukast had no relevant effects on the inhibition of the Pqs system and against P. aeruginosa biofilm. CONCLUSION: This study provides for the first time strong evidence that cefoperazone interacts with the Pqs system, hindering the formation of the autoinducer molecules HHQ and PQS, reducing P. aeruginosa pathogenicity and virulence. Cefoperazone demonstrated a potential to be used in combination with less effective antibiotics (e.g. ciprofloxacin) to potentiate the biofilm control action.

Evaluation of the impact of two C5 genetic variants on C5-eculizumab complex stability at the molecular level.

Complement C5 is the target of the monoclonal antibody eculizumab, used in complement dysregulating disorders, like the rare disease Paroxysmal Nocturnal Hemoglobinuria (PNH). PNH is an acquired hematopoietic stem cell condition characterized by aberrant destruction of erythrocytes, chronic hemolytic anemia, and thromboembolism propensity. C5 is a protein component of the complement system which is part of the immune system of the body and plays a prominent role in the destruction of red blood cells, misidentifying them as a threat. This work describes the application of molecular dynamics simulations to the study of the underlying interactions between complement C5 and eculizumab. This study also reveals the importance of single nucleotide polymorphisms on C5 protein concerning the effective inhibition of the mAB, involving the mechanistic events taking place at the interface spots of the complex. The predicted conformational change in the C5 Arg885/His/Cys mutation has implications on the protein's interaction with eculizumab, compromising their compatibility. The acquired insights into the conformational changes, dynamics, flexibility, and interactions shed light on the knowledge of the function of this biomolecule providing answers about the poor response to the treatment in PNH patient carriers of the mutations. By investigating the intricate dynamics, significant connections between C5 and eculizumab can be uncovered. Such insights may aid in the creation of novel compounds or lead to the enhancement of eculizumab's efficacy.Communicated by Ramaswamy H. Sarma.

Silica Microparticles from Sugarcane By-Products as an Encapsulation System for Retinoids Aimed at Topical Sustained Release.

The encapsulation of retinol within silica microparticles has emerged as a promising opportunity in the realm of cosmetic and pharmaceutical formulations, driven by the need to reinforce the photoprotection and oxidation stability of retinol. This work examines the process of encapsulating retinol into silica microparticles. The association efficiency, microparticle size, molecular structure, morphology, oxidation, and release profile, as well as biocompatibility and skin sensitization, were evaluated. Results showed that 0.03% of retinol and 9% of emulsifier leads to an association efficiency higher than 99% and a particle size with an average of 5.2 µm. FTIR results indicate that there is an association of retinol with the silica microparticles, and some may be on the surface. Microscopy indicates that when association happens, there is less aggregation of the particles. Oxidation occurs in two different phases, the first related to the retinol on the surface and the second to the associated retinol. In addition, a burst release of up to 3 h (30% free retinol, 17% associated retinol) was observed, as well as a sustained release of 44% of retinol up to 24 h. Encapsulation allowed an increase in the minimal skin cytotoxic concentrations of retinol from 0.04 µg/mL to 1.25 mg/mL without skin sensitization. Overall, retinol is protected when associated with silica microparticles, being safe to use in cosmetics and dermatology.

Correction: Exploiting Locusta migratoria as a source of bioactive peptides with anti-fibrosis properties using an in silico approach.

Correction for 'Exploiting Locusta migratoria as a source of bioactive peptides with anti-fibrosis properties using an in silico approach' by Carla S. S. Teixeira et al., Food Funct., 2024, 15, 493-502, https://doi.org/10.1039/D3FO04246D.

Substitution Models of Protein Evolution with Selection on Enzymatic Activity.

Substitution models of evolution are necessary for diverse evolutionary analyses including phylogenetic tree and ancestral sequence reconstructions. At the protein level, empirical substitution models are traditionally used due to their simplicity, but they ignore the variability of substitution patterns among protein sites. Next, in order to improve the realism of the modeling of protein evolution, a series of structurally constrained substitution models were presented, but still they usually ignore constraints on the protein activity. Here, we present a substitution model of protein evolution with selection on both protein structure and enzymatic activity, and that can be applied to phylogenetics. In particular, the model considers the binding affinity of the enzyme-substrate complex as well as structural constraints that include the flexibility of structural flaps, hydrogen bonds, amino acids backbone radius of gyration, and solvent-accessible surface area that are quantified through molecular dynamics simulations. We applied the model to the HIV-1 protease and evaluated it by phylogenetic likelihood in comparison with the best-fitting empirical substitution model and a structurally constrained substitution model that ignores the enzymatic activity. We found that accounting for selection on the protein activity improves the fitting of the modeled functional regions with the real observations, especially in data with high molecular identity, which recommends considering constraints on the protein activity in the development of substitution models of evolution.

Impact of washing and freezing on nutritional composition, bioactive compounds, antioxidant activity and microstructure of mango peels.

Mango peels are widely produced and highly perishable. Disinfectant washing and freezing are among the most used methods to preserve foods. However, their impact on products' properties is conditioned by the foods' features. This study evaluated for the first time the phytochemical composition, antioxidant activity, and microstructure of mango peels washed with peracetic acid (27 mg/mL for 19 min) and frozen at -20 °C for 30 days. Washing decreased the content of vitamin C (-7%), penta-O-galloyl-ß-d-glucose (-23 %), catechin (-30 %), and lutein (-24 %), but the antioxidant activity was preserved. Freezing changed mango peels' microstructure, increased free phenolic compounds, namely acid gallic (+36 %) and catechin (+51 %), but reduced bound phenolic compounds (-12 % to -87 %), bound phenolic compounds' antioxidant activity (-51 % to -72 %), and violaxanthin (-51 %). Both methods were considered adequate to conserve mango peels since fiber and the main bioactive compounds (free mangiferin, free gallic acid, and ß-carotene) remained unchanged or increased.

Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptom-directed approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the farnesoid X receptor (FXR). TUDCA was predicted to bind to the GR, in a similar fashion to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction being restored by TUDCA treatment. Analysis of a SCA3 clinical cohort showed intriguing correlations between the peripheral expression of GR and the predicted age at disease onset in presymptomatic subjects and FKBP5 expression with disease progression, suggesting this pathway as a potential source of biomarkers for future study. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3 and propose this readily available drug for clinical trials in SCA3 patients.

Pachydysostosis of the fibula in a case of familial adenomatous polyposis.

BACKGROUND: Familial Adenomatous Polyposis (FAP) is a colorectal cancer (CRC) predisposition syndrome caused by germline APC mutations and characterised by an increased risk of CRC and colonic polyps and, in certain forms, of specific prominent extraintestinal manifestations, namely osteomas, soft tissue tumours and dental anomalies. Pachydysostosis of the fibula is a rare clinical entity defined by unilateral bowing of the distal portion of the fibula and elongation of the entire bone, without affectation of the tibia. CLINICAL REPORT: We report a 17-year-old male, who presented with a non-progressive bowing of the right leg detected at 18 months of age caused by a fibula malformation (later characterized as pachydysostosis) and a large exophytic osteoma of the left radius, noticed at the age of 15 years, without gastrointestinal symptoms. There was no relevant family history. Detailed characterisation revealed multiple osteomas, skin lesions and dental abnormalities, raising the hypothesis of FAP. This diagnosis was confirmed by genetic testing [c.4406_4409dup p.(Ala1471Serfs*17) de novo mutation in the APC gene] and endoscopic investigation (multiple adenomas throughout the colon, ileum and stomach). DISCUSSION: This case report draws attention to the phenotypic spectrum of skeletal manifestations of FAP: this patient has a congenital fibula malformation, not previously associated with this syndrome, but which is likely to have been its first manifestation in this patient. This clinical case also illustrates the challenges in the early diagnosis of FAP, especially without family history, and highlights the importance of a multidisciplinary approach and the adequate study of rare skeletal abnormalities.

ERN BOND: The key European network leveraging diagnosis, research, and treatment for rare bone conditions.

There is no universally accepted definition for rare diseases: in Europe a disease is considered to be rare when affecting fewer than 1 in 2000 people. European Reference Networks (ERNs) have been the concrete response to address the unmet needs of rare disease patients and many pan-European issues in the field, reducing inequities, and significantly increasing accessibility to high-quality healthcare across Europe. ERNs are virtual networks, involving centres and patient representatives with the general scope to facilitate discussion on complex cases requiring highly specialised competences and trained expertise. ERN BOND - the European Reference Network on rare BONe Diseases - is one of these 24 approved networks with the specific ongoing mission to implement measures facilitating multidisciplinary, holistic, continuous, patient-centred, and participative care provision to patients, and supporting them in the full realisation of their fundamental human rights. ERN BOND includes in 2023 a total of 53 centres of expertise from 20 European countries. Its governing structure installed in March 2017 includes decision-making, operative and consultative committees, which comprise experts in the field and patient representatives ensuring patient's voice and perspectives are taken into account. Over the years, ERN BOND has worked hard to achieve its mission and valuably contribute to the advancement of diagnosis, management, treatment, and research in rare diseases. The network activities are mainly related to (i) the provision of care which collectively involves averagely 2800 patients diagnosed per year, (ii) the development of education for and training of the healthcare personnel consisting until now in the realisation of 7 thematic workshops and 19 webinars, (iii) the dissemination and exchange and spread of knowledge via network's website (https://ernbond.eu/), social media channels, and newsletters, (iv) the management of related data through a disease registry currently mapping over 2300 cases and recording over 600 reported cases, and (v) the enhancement of research which now include two clinical trials endorsed by the network. ERN BOND represents therefore an unprecedented move to improve the healthcare management of patients suffering from rare bone diseases through European collaborations. This network, through the support from the European Health Programme, will continue to pursue its efforts to achieve its goals, always maintaining the patients and their families at the centre of healthcare services.

Structure and properties of Quercus robur acorn starch extracted by pulsed electric field technology.

Pulsed electric field (PEF) technology was used to extract starch from Q. robur flours using low-intensity electric fields (0 and 0.1 kV/cm) and study the impact of PEF on the structure and properties of acorn starch concerning commercial starch. PEF technology is an advantageous method for starch extraction than the aqueous steeping from an industrial perspective since reduces extraction time and allows for continuous processing of larger suspension volumes. PEF technology preserved the amylose and amylopectin contents, hydrogen bonds, and diffraction patterns, as well as the starch native properties. Hence, PEF could be used to obtain native starches, but future studies should verify its economic viability. Acorn starches have lower damaged starch content, gelatinization temperatures, enthalpies, improved pseudoplastic behavior, reduced in-vitro digestibility, and lower resistance to deformation compared to commercial corn starch. The higher solubility and swelling power of acorn starches up to 80 °C make them a suitable food additive in fermented yogurt and milk products and thus help to value acorn and acorn starches. Hence, acorns can be used to obtain native starches, a food ingredient with a wide range of food and non-food usage, using PEF.

Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.

INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.

Gastrointestinal delivery of codfish Skin-Derived collagen Hydrolysates: Deep eutectic solvent extraction and bioactivity analysis.

The fishing industry produces substantial by-products, such as heads, skins, bones, and scales, rich in collagen-a prevalent protein in these materials. However, further application of deep eutectic solvent-based extraction remains unexplored. In this study, we extracted collagen with urea: propanoic acid mixture (U:PA; 1:2) with a 2.2 % yield, followed by enzymatic hydrolysis with alcalase for 120 min. The resulting bioactive peptides demonstrated notable antioxidant activity (961 µmol TE) and antihypertensive properties (39.3 % ACE inhibition). Subsequently, we encapsulated 39.3 % of these hydrolysates in chitosan-TPP capsules, which released about 58 % of their content, primarily in the intestine, as mimicked in the in vitro model of the gastrointestinal tract. Although the digestion process did not significantly alter the size of the non-encapsulated collagen peptides, it did influence their health benefits. The promising results suggest that further research could optimize the use of collagen from fish by-products, potentially offering a sustainable source for health products.

Exploiting Locusta migratoria as a source of bioactive peptides with anti-fibrosis properties using an in silico approach.

Edible insects have been proposed as an environmentally and economically sustainable source of protein, and are considered as an alternative food, especially to meat. The migratory locust, Locusta migratoria, is an edible species authorised by the European Union as a novel food. In addition to their nutritional value, edible insects are also sources of bioactive compounds. This study used an in silico approach to simulate the gastrointestinal digestion of selected L. migratoria proteins and posteriorly identify peptides capable of selectively inhibiting the N-subunit of the somatic angiotensin-I converting enzyme (sACE). The application of the molecular docking protocol enabled the identification of three peptides, namely TCDSL, IDCSR and EAEEGQF, which were predicted to act as potential selective inhibitors of the sACE N-domain and, therefore, possess bioactivity against cardiac and pulmonary fibrosis.

GET-UP Trial 1-year results: long-term impact of an early mobilization protocol on functional performance after surgery for chronic subdural hematoma.

OBJECTIVE: Evidence on timing for mobilization after chronic subdural hematoma (cSDH) surgery is heterogeneous, and practices differ considerably among neurosurgical centers. The Impact of an Early Out-of-Bed Paradigm in Postoperative Outcomes of Chronic Subdural Hematomas: GET-UP Randomized Prospective Trial (GET-UP Trial) is a randomized clinical trial comparing a postoperative early mobilization protocol to bed rest. Previously reported results at clinical discharge and 1 month after surgery indicated a decreased risk of medical complications in the early mobilization group. Herein, the authors report outcomes at the 1-year follow-up. METHODS: The GET-UP Trial is a prospective, randomized, unicentric, open-label study with an intention-to-treat primary analysis designed to evaluate the impact of an early mobilization protocol after burr hole craniostomy for cSDH on the occurrence of medical complications and functional outcomes. Between January 2019 and August 2021, a total of 208 patients were recruited and randomized to either an early mobilization group, in which patients began elevation of the head of the bed within the first 12 hours after surgery, or to a bed rest group, in which patients remained recumbent for 48 hours. Outcomes assessed at the 1-year follow-up included functional status as measured by the Glasgow Outcome Scale-Extended (GOSE) and repeat surgery for hematoma recurrence (surgical recurrence). RESULTS: A total of 203 patients completed 1 year of follow-up: 101 in the bed rest group and 102 in the early mobilization group. No significant baseline pre-randomization clinical differences were observed between the two management groups. At 1 year after surgery, a favorable functional outcome, defined as a GOSE score ≥ 5, was observed in 59 patients (58.4%) in the bed rest group and 78 (76.5%) in the early mobilization group (p = 0.006). Death occurred in 25 patients (24.8%) in the bed rest group and 16 (15.7%) in the early mobilization group (p = 0.108). Surgical recurrence was noted in 6 patients (5.9%) in the bed rest group and 7 (6.9%) in the early mobilization group (p = 0.788). Multivariate analysis showed an independent association between early mobilization and an increase in favorable functional outcomes (OR 2.006, 95% CI 1.076-3.739, p = 0.028). CONCLUSIONS: The GET-UP Trial is the first randomized clinical trial assessing the impact of mobilization strategies on medical complications after burr hole craniostomy for cSDH. Regarding functional results 1 year after surgery, early mobilization was associated with an improvement in functional outcomes without an increase in surgical recurrence. These findings support the preference for an early mobilization protocol in cSDH patients over mandatory bed rest strategies.

Akkermansia muciniphila Encapsulated in Calcium-Alginate Hydrogelated Matrix: Viability and Stability over Aerobic Storage and Simulated Gastrointestinal Conditions.

Akkermansia muciniphila is considered a next-generation probiotic to be incorporated in new food and pharmaceutical formulations. Effective delivery systems are required to ensure high probiotic viability and stability during product manufacture, shelf-life, and post-consumption, namely, throughout digestion. Hydrogelated matrices have demonstrated promising potential in this dominion. Hence, this work aimed to evaluate the effect of a calcium-alginate hydrogelated matrix on A. muciniphila viability during 28-days refrigerated aerobic storage and when exposed to simulated gastrointestinal conditions, in comparison with that of free cells. Akkermansia muciniphila was successfully encapsulated in the calcium-alginate matrix via extrusion (60% encapsulation yield). Furthermore, encapsulated A. muciniphila exhibited high stability (a loss in viability lower than 0.2 log-cycle) after 28-days of refrigerated aerobic storage, maintaining its viability around 108 CFU/g. Prominently, as the storage time increased, encapsulated A. muciniphila revealed higher viability and stability regarding in vitro gastrointestinal conditions than free cells. This suggests that this encapsulation method may attenuate the detrimental effects of prolonged aerobic storage with a subsequent gastrointestinal passage. In conclusion, encapsulation via extrusion using a calcium-alginate hydrogelated matrix seems to be a promising and adequate strategy for safeguarding A. muciniphila from adverse conditions encountered during refrigerated aerobic storage and when exposed to the gastrointestinal passage.

Crystal structures of Streptomyces tsukubaensis sigma factor SigG1 and anti-sigma RsfG.

Transcription of specific genes in bacteria under environmental stress is frequently initiated by extracytoplasmic function (ECF) σ factors. ECFs σ factors harbour two conserved domains, σ2 and σ4, for transcription initiation by recognition of the promoter region and recruitment of RNA polymerase (RNAP). The crystal structure of Streptomyces tsukubaensis SigG1, an ECF56-family σ factor, was determined revealing σ2, σ4 and the additional carboxi-terminal domain SnoaL_2 tightly packed in a compact conformation. The structure of anti-sigma RsfG was also determined by X-ray crystallography and shows a rare ß-barrel fold. Analysis of the metal binding motifs inside the protein barrel are consistent with Fe(III) binding, which is in agreement with previous findings that the Streptomyces tsukubaensis ECF56 SigG1-RsfG system is involved in metal-ion homeostasis.

Anti-obesity potential of a yogurt functionalized with a CLNA-rich pomegranate oil.

Pomegranate oil is rich in conjugated linolenic acids, compounds which have attracted attention due to their potential applicability in obesity management as they are capable of modulating leptin and adiponectin secretion and regulate fatty acids storage and glucose metabolism. Among the possible bioactive foodstuffs capable of delivering these bioactive compounds yogurts have shown potential. Thus, the purpose of this work was to develop functional yogurts through the addition of pomegranate oil either in its free or encapsulated (used as a protective strategy against oxidation and gastrointestinal tract passage) forms. To that end, the pomegranate oil (free and encapsulated) was incorporated in yogurt and the functional yogurt capacity to modulate hepatic lipid accumulation, adipocyte metabolism (in terms of lipolysis, and adipokines secretion) and immune response was evaluated. The results obtained showed that the pomegranate oil's incorporation led to an improvement in the yogurts' nutritional values, with a reduction in its atherogenic and thrombogenic indexes (more than 78% for atherogenic and 76% for thrombogenic index) and an enhancement of its hypocholesterolemic/hypercholesterolemic ratio (more than 62%) when compared to the control yogurt. Furthermore, data also showed for the first time how these functional yogurts promoted modulation of metabolic processes post GIT as they were capable of reducing by 40% triglycerides accumulation in steatosis-induced Hep G2 cells and by 30 % in differentiated adipocytes. Moreover, samples also showed a capacity to modulate the leptin and adiponectin secretion (56 % of increase in adiponectin) and reduce the IL-6 secretion (ca 44%) and TNF-α (ca 12%) in LPS-stimulated cells. Thus, the CLNA-rich yogurt here developed showed potential as a viable nutraceutical alternative for obesity management.

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.

Characterization of three adults and an adolescent with Osteogenesis Imperfecta type VI and a novel founder SERPINF1 variant.

Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived factor (PEDF). We report on four patients (three adults and one adolescent) with a severe deforming form of OI. All patients presented no abnormalities at birth, frequent long bone and vertebrae fractures (mainly during childhood), marked short stature, severe bone deformities, chronic mild to moderate pain, and severe limitation of mobility, with three being completely wheelchair bound. Blue sclera and dentinogenesis imperfecta were absent, although some patients presented tooth, ophthalmological, and/or cardiac features. Radiographic findings included, among others, thin diaphysis and popcorn calcifications, both of which are non-specific to this type of OI. The novel homozygous variants c.816_819del (p.Met272Ilefs*8) and c.283+2T > G in SERPINF1 were identified in three and one patient, respectively. The three patients carrying the frameshift variant were born in nearby regions suggesting a founder effect. Describing the long-term outcomes of four patients with OI type VI, this cohort adds relevant data on the clinical features and prognosis of this type of OI.