Clinical practice guidelines for the care of girls and women with Turner syndrome.

Turner syndrome (TS) affects 50 per 100 000 females. TS affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and United States culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: (1) diagnosis and genetics, (2) growth, (3) puberty and estrogen treatment, (4) cardiovascular health, (5) transition, (6) fertility assessment, monitoring, and counselling, (7) health surveillance for comorbidities throughout the lifespan, and (8) neurocognition and its implications for mental health and well-being. Each group produced proposals for the present guidelines, which were meticulously discussed by the entire group. Four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with systematic review of the literature. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with members from the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology, the European Reference Network on Rare Endocrine Conditions, the Society for Endocrinology, and the European Society of Cardiology, Japanese Society for Pediatric Endocrinology, Australia and New Zealand Society for Pediatric Endocrinology and Diabetes, Latin American Society for Pediatric Endocrinology, Arab Society for Pediatric Endocrinology and Diabetes, and the Asia Pacific Pediatric Endocrine Society. Advocacy groups appointed representatives for pre-meeting discussions and the consensus meeting.

Pollutant profile complexity governs wastewater removal of recalcitrant pharmaceuticals.

Organic pollutants are an increasing threat for wildlife and humans. Managing their removal is however complicated by the difficulties in predicting degradation rates. In this work, we demonstrate that the complexity of the pollutant profile, the set of co-existing contaminants, is a major driver of biodegradation in wastewater. We built representative assemblages out of one to five common pharmaceuticals (caffeine, atenolol, paracetamol, ibuprofen, and enalapril) selected along a gradient of biodegradability. We followed their individual removal by wastewater microbial communities. The presence of multichemical background pollution was essential for the removal of recalcitrant molecules such as ibuprofen. High-order interactions between multiple pollutants drove removal efficiency. We explain these interactions by shifts in the microbiome, with degradable molecules such as paracetamol enriching species and pathways involved in the removal of several organic pollutants. We conclude that pollutants should be treated as part of a complex system, with emerging pollutants potentially showing cascading effects and offering leverage to promote bioremediation.

Auditory Hair Cells and Spiral Ganglion Neurons Regenerate Synapses with Refined Release Properties In Vitro.

Ribbon synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) in the inner ear are damaged by noise trauma and with aging, causing 'synaptopathy 'and hearing loss. Co-cultures of neonatal denervated organs of Corti and newly introduced SGNs have been developed to find strategies for improving IHC synapse regeneration, but evidence of the physiological normality of regenerated synapses is missing. This study utilizes IHC optogenetic stimulation and SGN recordings, showing that newly formed IHC synapses are indeed functional, exhibiting glutamatergic excitatory postsynaptic currents. When older organs of Corti were plated, synaptic activity probed by deconvolution, showed more mature release properties, closer to the highly specialized mode of IHC synaptic transmission that is crucial for coding the sound signal. This newly developed functional assessment of regenerated IHC synapses provides a powerful tool for testing approaches to improve synapse regeneration.

Successful Treatment of Hypoglycemia With Alpelisib in Pediatric Patients With PIK3CA-Related Overgrowth Spectrum.

Activating mutations in the PIK3CA gene, causing phosphoinositide 3-kinase (PI3K) hyperactivation, are rare causes of hypoglycemia. We report the novel use of alpelisib (a PI3K inhibitor) for the treatment of hypoketotic, hypoinsulinemic hypoglycemia in 2 children with PIK3CA-related overgrowth spectrum (PROS). Patient 1 was a 7-month-old girl who presented with a hypoglycemic seizure. Despite nutritional management including continuous feeds, she continued to have frequent hypoglycemia. At age 2.8 years, alpelisib was started at 50 mg daily and titrated to 100 mg daily. She was weaned off nocturnal continuous feeds by 8 months. She developed colitis when the alpelisib dose was increased to 125 mg, but this resolved with a dose decrease and medical management. At age 5.3 years, she was doing well with rare hypoglycemia. Her accelerated growth stabilized. Patient 2 was a 3-year-old boy who developed hypoglycemia in early infancy. Alpelisib 50 mg daily was started due to recurrent hypoglycemia despite nutritional management. He came off continuous feeds after 4 months, with decreased hypoglycemia frequency. At age 4.5 years, he had not experienced side effects from treatment. In conclusion, alpelisib appears to be effective in decreasing PROS-related hypoglycemia frequency and severity and should be considered for refractory hypoglycemia in this condition.

Strontium Aluminate Persistent Luminescent Single Crystals: Linear Scaling of Emission Intensity with Size Is Affected by Reabsorption.

The green-emitting SrAl2O4:Eu,Dy phosphor is the most widely used and well-studied persistent luminescent phosphor available today. Recent efforts to boost its performance in terms of luminescence intensity and duration are challenged by complex loss mechanisms, including the optically stimulated release of previously trapped charges by excitation light. Here, we present minimally scattering SrAl2O4:Eu,Dy single crystals, which, as opposed to powder phosphors, allow to profit from a so-called volume effect, resulting in a significantly increased emission intensity. Additionally, they allow for the identification of the reabsorption of the afterglow emission by trapped charges as an important loss mechanism, leading to a nonlinear scaling of the emission intensity with the crystal size. If circumvented, the emission intensity could be further increased, in persistent luminescent powders, ceramics, and single crystals.

Model-Based Analysis of IGF-I Response, Dosing, and Monitoring for Once-Weekly Somapacitan in Children With GH Deficiency.

Context: Growth hormone (GH) replacement therapy improves longitudinal growth and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor (IGF)-I release, the biomarker used for monitoring GH activity during treatment. Objective: This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared with daily GH in children with GHD. Methods: Analyses included dosing information and 1473 pharmacokinetic samples from 210 somapacitan-treated pediatric patients with GHD across 3 trials, including phase 1 (NCT01973244), phase 2 (NCT02616562; REAL 3), and phase 3 (NCT03811535; REAL 4), as well as 1381 IGF-I samples from 186 patients with GHD treated with somapacitan in REAL 3 and REAL 4. Pharmacokinetic/pharmacodynamic modeling to characterize somapacitan dose-IGF-I response and predict the response to dosing day changes. Results: Relationships were established between somapacitan dose, exposure, change from baseline IGF-I SD score (SDS), and height velocity (HV). A linear model permitted the development of a tool to calculate estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool requires knowledge of somapacitan injection timing relative to IGF-I sample collection timing. IGF-I SDS simulations support flexible dosing day changes while maintaining at least 4 days between doses. Conclusion: We characterized the dose-IGF-I response of somapacitan in children with GHD. To support physicians in IGF-I monitoring, we present a practical guide about expected weekly average IGF-I concentrations in these patients and provide insights on dosing day flexibility.

Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective.

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.

Molecular signatures define subtypes of auditory afferents with distinct peripheral projection patterns and physiological properties.

Type I spiral ganglion neurons (SGNs) are the auditory afferents that transmit sound information from cochlear inner hair cells (IHCs) to the brainstem. These afferents consist of physiological subtypes that differ in their spontaneous firing rate (SR), activation threshold, and dynamic range and have been described as low, medium, and high SR fibers. Lately, single-cell RNA sequencing experiments have revealed three molecularly defined type I SGN subtypes. The extent to which physiological type I SGN subtypes correspond to molecularly defined subtypes is unclear. To address this question, we have generated mouse lines expressing CreERT2 in SGN subtypes that allow for a physiological assessment of molecular subtypes. We show that Lypd1-CreERT2 expressing SGNs represent a well-defined group of neurons that preferentially innervate the IHC modiolar side and exhibit a narrow range of low SRs. In contrast, Calb2-CreERT2 expressing SGNs preferentially innervate the IHC pillar side and exhibit a wider range of SRs, thus suggesting that a strict stratification of all SGNs into three molecular subclasses is not obvious, at least not with the CreERT2 tools used here. Genetically marked neuronal subtypes refine their innervation specificity onto IHCs postnatally during the time when activity is required to refine their molecular phenotype. Type I SGNs thus consist of genetically defined subtypes with distinct physiological properties and innervation patterns. The molecular subtype-specific lines characterized here will provide important tools for investigating the role of the physiologically distinct type I SGNs in encoding sound signals.

Optimizing the Mechanoluminescent Properties of CaZnOS:Tb via Microwave-Assisted Synthesis: A Comparative Study with Conventional Thermal Methods.

Recent developments in lighting and display technologies have led to an increased focus on materials and phosphors with high efficiency, chemical stability, and eco-friendliness. Mechanoluminescence (ML) is a promising technology for new lighting devices, specifically in pressure sensors and displays. CaZnOS has been identified as an efficient ML material, with potential applications as a stress sensor. This study focuses on optimizing the mechanoluminescent properties of CaZnOS:Tb through microwave-assisted synthesis. We successfully synthesized CaZnOS doped with Tb3+ using this method and compared it with samples obtained through conventional solid-state methods. We analyzed the material's characteristics using various techniques to investigate their structural, morphological, and optical properties. We then studied the material's mechanoluminescent properties through single impacts with varying energies. Our results show that materials synthesized through microwave methods exhibit similar optical and, primarily, mechanoluminescent properties, making them suitable for use in photonics applications. The comparison of the microwave and conventional solid-state synthesis methods highlights the potential of microwave-assisted methods to optimize the properties of mechanoluminescent materials for practical applications.

Polymorphism and phase transitions in Na2U2O7 from density functional perturbation theory.

Polymorphism and phase transitions in sodium diuranate, Na2U2O7, are investigated with density functional perturbation theory (DFPT). Thermal properties of crystalline α-, ß- and γ-Na2U2O7 polymorphs are predicted from DFPT phonon calculations, i.e., the first time for the high-temperature γ-Na2U2O7 phase (R3̄m symmetry). The standard molar isochoric heat capacities predicted within the quasi-harmonic approximation are for P21/a α-Na2U2O7 and C2/m ß-Na2U2O7, respectively. Gibbs free energy calculations reveal that α-Na2U2O7 (P21/a) and ß-Na2U2O7 (C2/m) are almost energetically degenerate at low temperature, with ß-Na2U2O7 becoming slightly more stable than α-Na2U2O7 as temperature increases. These findings are consistent with XRD data showing a mixture of α and ß phases after cooling of γ-Na2U2O7 to room temperature and the observation of a sluggish α → ß phase transition above ca. 600 K. A recently observed α-Na2U2O7 structure with P21 symmetry is also shown to be metastable at low temperature. Based on Gibbs free energy, no direct ß â†’ γ solid-solid phase transition is predicted at high temperature, although some experiments reported the existence of such phase transition around 1348 K. This, along with recent experiments, suggests the occurrence of a multi-step process consisting of initial ß-phase decomposition, followed by recrystallization into γ-phase as temperature increases.

Direct ammonium oxidation to nitrogen gas (Dirammox) in Alcaligenes strain HO-1: The electrode role.

It has been recently suggested that Alcaligenes use a previously unknown pathway to convert ammonium into dinitrogen gas (Dirammox) via hydroxylamine (NH2OH). This fact alone already implies a significant decrease in the aeration requirements for the process, but the process would still be dependent on external aeration. This work studied the potential use of a polarised electrode as an electron acceptor for ammonium oxidation using the recently described Alcaligenes strain HO-1 as a model heterotrophic nitrifier. Results indicated that Alcaligenes strain HO-1 requires aeration for metabolism, a requirement that cannot be replaced for a polarised electrode alone. However, concomitant elimination of succinate and ammonium was observed when operating a previously grown Alcaligenes strain HO-1 culture in the presence of a polarised electrode and without aeration. The usage of a polarised electrode together with aeration did not increase the succinate nor the nitrogen removal rates observed with aeration alone. However, current density generation was observed along a feeding batch test representing an electron share of 3% of the ammonium removed in the presence of aeration and 16% without aeration. Additional tests suggested that hydroxylamine oxidation to dinitrogen gas could have a relevant role in the electron discharge onto the anode. Therefore, the presence of a polarised electrode supported the metabolic functions of Alcaligenes strain HO-1 on the simultaneous oxidation of succinate and ammonium.

Engineering olivocochlear inhibition to reduce acoustic trauma.

Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1 day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.

Using change in predicted adult height during GnRH agonist treatment for individualized treatment decisions in girls with central precocious puberty.

OBJECTIVES: It is important to understand what variables influence change in predicted adult height (PAH) throughout GnRHa treatment for central precocious puberty (CPP) to individualize treatment decisions and optimize care. METHODS: Changes in PAH, chronological age (CA), bone age (BA), BA/CA, and height velocity (HV) were evaluated in girls with CPP throughout treatment with leuprolide acetate (n=77). A second analysis focused on changes in the 3 years preceding the first observed BA of ≥12 years. Relationships were characterized using plot inspection and linear mixed-effects analyses. Association between treatment duration and last assessed PAH was examined using multiple linear regression models. RESULTS: BA/CA and HV showed a nonlinear change during treatment, with the largest changes and improvement in PAH observed in the first 6-18 months. Rate of BA advancement tended to decrease more slowly in girls initiating treatment at a younger BA. On-treatment change in PAH was predicted by concurrent BA/CA change, HV, and BA, as well as CA at treatment initiation. Last assessed PAH was positively associated with longer treatment durations (primary/exploratory models cut-offs of ≥33/≥55 months). CONCLUSIONS: These findings support individualized monitoring during GnRHa treatment. Initial response should be interpreted with caution until 6-18 months after treatment initiation and failure should not be assumed based on continued bone maturation in girls starting therapy at a younger age. Treatment cessation should not be automatically based on a diminishing change in PAH or HV, as ongoing treatment may result in continued increase or maintenance of PAH.

Rapidly Progressive and Catastrophic Calciphylaxis After Mechanical Valve Replacement: An Anticoagulation Dilemma.

Warfarin is the only approved anticoagulant after mechanical valve replacement, but it is a well described risk factor for calciphylaxis among patients with end-stage kidney disease. Our patient with end-stage kidney disease rapidly developed calciphylaxis after dual mechanical valve replacement in association with warfarin initiation, posing significant challenges in clinical management and a fatal outcome. (Level of Difficulty: Intermediate.).

Soil microbiomes divergently respond to heavy metals and polycyclic aromatic hydrocarbons in contaminated industrial sites.

Contaminated sites from electronic waste (e-waste) dismantling and coking plants feature high concentrations of heavy metals (HMs) and/or polycyclic aromatic hydrocarbons (PAHs) in soil. Mixed contamination (HMs + PAHs) hinders land reclamation and affects the microbial diversity and function of soil microbiomes. In this study, we analyzed HM and PAH contamination from an e-waste dismantling plant and a coking plant and evaluated the influences of HM and PAH contamination on soil microbiomes. It was noticed that HMs and PAHs were found in all sites, although the major contaminants of the e-waste dismantling plant site were HMs (such as Cu at 5,947.58 ± 433.44 mg kg-1, Zn at 4,961.38 ± 436.51 mg kg-1, and Mn at 2,379.07 ± 227.46 mg kg-1), and the major contaminants of the coking plant site were PAHs (such as fluorene at 11,740.06 ± 620.1 mg kg-1, acenaphthylene at 211.69 ± 7.04 mg kg-1, and pyrene at 183.14 ± 18.89 mg kg-1). The microbiomes (diversity and abundance) of all sites were determined via high-throughput sequencing of 16S rRNA genes, and redundancy analysis was conducted to investigate the relations between soil microbiomes and contaminants. The results showed that the microbiomes of the contaminated sites divergently responded to HMs and PAHs. The abundances of the bacterial genera Sulfuritalea, Pseudomonas, and Sphingobium were positively related to PAHs, while the abundances of the bacterial genera Bryobacter, Nitrospira, and Steroidobacter were positively related to HMs. This study promotes an understanding of how soil microbiomes respond to single and mixed contamination with HMs and PAHs.

A Novel Thrombolytic Regimen for Mechanical Prosthetic Valve Thrombosis in a Patient With Antiphospholipid Syndrome.

Management of mechanical prosthetic valve thrombosis (PVT) includes medical and surgical options. Standard medical treatment involves thrombolytic therapy with repeated slow infusions of low-dose IV tissue plasminogen activator (t-PA). The evidence for managing mechanical PVT that does not respond to the standard t-PA dosing is limited in the setting of an exacerbating hypercoagulable condition. We present a case of a patient with a history of antiphospholipid syndrome who presented with a probable thromboembolic myocardial infarction secondary to a mechanical mitral valve thrombosis that did not improve with systemic anticoagulation and repeated standard t-PA dosing but rapidly resolved with ultraslow, high-dose t-PA.

Monoalkyl Phosphinic Acids as Ligands in Nanocrystal Synthesis.

Ligands play a crucial role in the synthesis of colloidal nanocrystals. Nevertheless, only a handful molecules are currently used, oleic acid being the most typical example. Here, we show that monoalkyl phosphinic acids are another interesting ligand class, forming metal complexes with a reactivity that is intermediate between the traditional carboxylates and phosphonates. We first present the synthesis of n-hexyl, 2-ethylhexyl, n-tetradecyl, n-octadecyl, and oleylphosphinic acid. These compounds are suitable ligands for high-temperature nanocrystal synthesis (240-300 °C) since, in contrast to phosphonic acids, they do not form anhydride oligomers. Consequently, CdSe quantum dots synthesized with octadecylphosphinic acid are conveniently purified, and their UV-vis spectrum is free from background scattering. The CdSe nanocrystals have a low polydispersity and a photoluminescence quantum yield up to 18% (without shell). Furthermore, we could synthesize CdSe and CdS nanorods using phosphinic acid ligands with high shape purity. We conclude that the reactivity toward TOP-S and TOP-Se precursors decreases in the following series: cadmium carboxylate > cadmium phosphinate > cadmium phosphonate. By introducing a third and intermediate class of surfactants, we enhance the versatility of surfactant-assisted syntheses.

Over-Expression of a Wheat Late Maturity Alpha-Amylase Type 1 Impact on Starch Properties During Grain Development and Germination.

The hydrolysis of starch is a complex process that requires synergistic action of multiple hydrolytic enzymes, including α-amylases. Wheat over-expression of TaAmy1, driven by seed specific promoter, resulted in a 20- to 230-fold total α-amylase activity in mature grains. Ectopic expression of TaAmy1 showed a significant elevated α-amylase activity in stem and leaf without consequences on transitory starch. In mature grain, overexpressed TaAMY1 was mainly located in the endosperm with high expression of TaAmy1. This is due to early developing grains having effect on starch granules from 18 days post-anthesis (DPA) and on soluble sugar accumulation from 30 DPA. While accumulation of TaAMY1 led to a high degree of damaged starch in grain, the dramatic alterations of starch visco-properties caused by the elevated levels of α-amylase essentially occurred during processing, thus suggesting a very small impact of related starch damage on grain properties. Abnormal accumulation of soluble sugar (α-gluco-oligosaccharide and sucrose) by TaAMY1 over-expression reduced the grain dormancy and enhanced abscisic acid (ABA) resistance. Germination study in the presence of α-amylase inhibitor suggested a very limited role of TaAMY1 in the early germination process and starch conversion into soluble sugars.

Rationally Designed Magnetic Nanoparticles for Cochlear Drug Delivery: Synthesis, Characterization, and In Vitro Biocompatibility in a Murine Model.

Hypothesis: Magnetic nanoparticles (MNPs) for cochlear drug delivery can be precisely engineered for biocompatibility in the cochlea. Background: MNPs are promising drug delivery vehicles that can enhance the penetration of both small and macromolecular therapeutics into the cochlea. However, concerns exist regarding the application of oxidative, metal-based nanomaterials to delicate sensory tissues of the inner ear. Translational development of MNPs for cochlear drug deliver requires specifically tuned nanoparticles that are not cytotoxic to inner ear tissues. We describe the synthesis and characterization of precisely tuned MNP vehicles, and their in vitro biocompatibility in murine organ of Corti organotypic cultures. Methods: MNPs were synthesized via 2-phase ligand transfer process with precise control of nanoparticle size. Core and hydrodynamic sizes of nanoparticles were characterized using electron microscopy and dynamic light scattering, respectively. In vitro biocompatibility was assayed via mouse organ of Corti organotypic cultures with and without an external magnetic field gradient. Imaging was performed using immunohistochemical labeling and confocal microscopy. Outer hair cell, inner hair cell, and spiral ganglion neurites were individually quantified. Results: Monocore PEG-MNPs of 45 and 148 nm (mean hydrodynamic diameter) were synthesized. Organ of Corti cultures demonstrated preserved outer hair cell, inner hair cell, and neurite counts across 2 MNP sizes and doses, and irrespective of external magnetic field gradient. Conclusion: MNPs can be custom-synthesized with precise coating, size, and charge properties specific for cochlear drug delivery while also demonstrating biocompatibility in vitro.

Evolution and Future of Growth Plate Therapeutics.

BACKGROUND: Longitudinal bone growth is regulated by multiple endocrine signals (e.g., growth hormone, insulin-like growth factor I, estrogen, and androgen) and local factors (e.g., fibroblast growth factors and their receptors and the C-natriuretic peptide/natriuretic peptide receptor-B pathway). SUMMARY: Abnormalities in both endocrine and local regulation of growth plate physiology cause many disorders of human skeletal growth. Knowledge of these pathways creates therapeutic potential for sustaining or even augmenting linear growth. Key Message: During the past 4 decades, advances in understanding growth plate physiology have been accompanied by development and implementation of growth-promoting treatments that have progressed in both efficacy and specificity of action. This paper reviews the history and continuing evolution of growth plate therapeutics.