Metabolism and bioenergetics in the pathophysiology of organ fibrosis.

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents.

Gonorrhea prevalence in adults in Brazil: Spectrum-STI trend estimation, 2000-2020.

BACKGROUND: Gonorrhea is not a notifiable disease in Brazil, and the national health information system does not collect data on reported cases or infection prevalence. METHODS: We compiled published data on gonorrhea prevalence in Brazil from cross-sectional surveys and clinical trials between 2000 and 2020. The study entry criteria included a sample size of 50 or more, and Neisseria gonorrhoeae infection detected in urine, urethral, anal, or cervicovaginal specimens using either Nucleic Acid Amplification Test or culture. Gonorrhea prevalence trends between 2000 and 2020 were generated using Spectrum-STI, a statistical trend-fitting model. RESULTS: Forty-five studies with 59 gonorrhea prevalence data points were identified. Fifty data points were for women and represented 21,815 individuals, eight for men encompassing a total of 4,587 individuals, and one for transgender people comprising 345 individuals. The Spectrum-STI estimate for the prevalence of urogenital infection with gonorrhea in women 15-49 in 2020 was 0.63% (95% confidence interval (CI): 0.13-2.23) and was lower than the 1.05% estimated value for 2000 (95% CI: 0.36-2.79). The corresponding figures for men were 0.70% (95% CI: 0.16-2.44) and 1.14% (95% CI: 0.34-3.15). Anal prevalence estimates could not be generated because of insufficient data (three data points). CONCLUSIONS: These results suggest that the overall prevalence of genitourinary gonococcal infections in Brazil is less than 1%. Data on gonorrhea prevalence in men and in populations at increased STI vulnerability are limited.

In Situ DRIFTS Analysis during Hydrogenation of 1-Pentyne and Olefin Purification with Ag Nanoparticles.

The catalytic performance of nanoparticles (NPs) of Ag anchored on different supports was evaluated during the selective hydrogenation of 1-pentyne and the purification of a mixture of 1-pentene/1-pentyne (70/30 vol %). The catalysts were identified: Ag/Al (Ag supported on É£-Al2 O3 ), Ag/Al-Mg (Ag supported on É£-Al2 O3 modified with Mg), Ag/Ca (Ag supported on CaCO3 ) and Ag/RX3 (Ag supported on activated carbon-type: RX3). In addition, in situ DRIFTS analysis of 1-pentyne adsorption on each support, catalyst, and 1-pentyne hydrogenation were investigated. The results showed that the synthesized catalysts were active and very selective (≥85 %) for obtaining the desired product (1-pentene). Different adsorbed species (-C≡C- and -C=C-) were observed on the supports and catalysts surface using in situ DRIFT analysis, which can be correlated to the activity and high selectivity reached. The role of the supports and electronic properties over Ag improve the H2 dissociative chemisorption during the hydrogenation reactions; promoting the selectivity and the high catalytic performance. Ag/Al and Ag/Al-Mg were the most active catalysts. This was due to the synergism between the active Ag/Ag+ species and the supports (electronic effects). The results show that Ag/Al and Ag/Al-Mg catalysts have favorable properties and are promising for the alkyne hydrogenation and olefin purification reactions.

Multimerization of HIF enhances transcription of target genes containing the hypoxia ancillary sequence.

Transcriptional activity of the hypoxia inducible factor (HIF) relies on the formation of a heterodimer composed of an oxygen-regulated α-subunit and a stably expressed ß-subunit. Heterodimeric HIF activates expression by binding to RCGTG motifs within promoters of hypoxia-activated genes. Some hypoxia targets also possess an adjacent HIF ancillary sequence (HAS) reported to increase transcription but whose function remains obscure. Here, we investigate the contribution of the HAS element to the hypoxia response and its mechanism of action, using the HAS-containing prolyl 4-hydroxylase subunit α1 (P4HA1) as a gene model in NIH/3T3 mouse embryonic fibroblasts and HEK293 human embryonic kidney cells. Our HIF overexpression experiments demonstrate that the HAS motif is essential for full induction by hypoxia and that the presence of the tandem HAS/HIF, as opposed to HIF-only sequences, provides HIF proteins with the capacity to form complexes of stoichiometry beyond the classical heterodimer, likely tetramers, to cooperatively potentiate hypoxia-induced transcription. We also provide evidence of the crucial role played by the Fα helix of the PAS-B domain of the HIF1ß subunit to support the interaction between heterodimers. Functional analysis showed that human genes containing the HAS/HIF motifs are better responders to hypoxia, and their promoters are enriched for specific transcription factor binding sites. Gene ontology enrichment revealed a predominance of HAS/HIF in genes primarily related to tissue formation and development. Our findings add an extra level of regulation of the hypoxia/HIF signaling through multimerization of HIF proteins on regulatory elements containing the HAS/HIF motifs.

Influence of Sports Participation on the Behaviors of Customers of Sports Services: Linear and Qualitative Comparative Analysis Models.

Sports services have become an important enclave for our society. Due to its complete sports offer, customers can perform physical activity that helps them to improve their health and well-being. In fitness centers, managers try to know what their customers are looking for in order to create more personalized experiences, as well as to improve their health. This study seeks to understand the influence that sports frequency has on the future behavior of users of a sports center, using two complementary methodologies. A sample of 383 users of a private sports center was used. The two complementary methodologies used were linear models and comparative qualitative analysis, based on the combination of sets. The results show how sports frequency influences the process of creating users' future behaviors. Considering that none of the variables are necessary, it is observed that perceived value has a significant influence on users' future behaviors. The use of two complementary methodologies provides a more complete understanding, which helps sports managers to plan and manage effectively to ensure user satisfaction and loyalty. In addition, facilities can incentivize customers through loyalty programs and promotions to maintain their engagement, as well as healthy styles to encourage service recommendations.

Gonorrhea prevalence in adults in Brazil: Spectrum-STI trend estimation, 2000-2020

ABSTRACT Background: Gonorrhea is not a notifiable disease in Brazil, and the national health information system does not collect data on reported cases or infection prevalence. Methods: We compiled published data on gonorrhea prevalence in Brazil from cross-sectional surveys and clinical trials between 2000 and 2020. The study entry criteria included a sample size of 50 or more, and Neisseria gonorrhoeae infection detected in urine, urethral, anal, or cervicovaginal specimens using either Nucleic Acid Amplification Test or culture. Gonorrhea prevalence trends between 2000 and 2020 were generated using Spectrum-STI, a statistical trend-fitting model. Results: Forty-five studies with 59 gonorrhea prevalence data points were identified. Fifty data points were for women and represented 21,815 individuals, eight for men encompassing a total of 4,587 individuals, and one for transgender people comprising 345 individuals. The Spectrum-STI estimate for the prevalence of urogenital infection with gonorrhea in women 15-49 in 2020 was 0.63% (95% confidence interval (CI): 0.13-2.23) and was lower than the 1.05% estimated value for 2000 (95% CI: 0.36-2.79). The corresponding figures for men were 0.70% (95% CI: 0.16-2.44) and 1.14% (95% CI: 0.34-3.15). Anal prevalence estimates could not be generated because of insufficient data (three data points). Conclusions: These results suggest that the overall prevalence of genitourinary gonococcal infections in Brazil is less than 1%. Data on gonorrhea prevalence in men and in populations at increased STI vulnerability are limited.

Promoting Physical Activity Habits after Completing Secondary School: Does the Age Matter?

Physical inactivity is one of the most important problems in our society, especially during adolescence. During this stage of schooling, students practice physical activity in physical education classes, but after they finish school, many of them stop practicing it. This research aims to determine which variables predict the intention to practice physical activity after finishing secondary school and to discover the effect that age during adolescence has on these predictive variables. A questionnaire was administered to a sample of secondary school students. The results show that physical exercise identity influences the three antecedents of this theory, while the attitude towards the behaviour (ß = 0.13; p < 0.05), perceived behavioural control (ß = 0.46; p < 0.05), and physical self-concept (ß = 0.41; p < 0.05), have a statistically significant influence on the intention to be physically active. Moreover, when the age is lower, is more important to develop a positive perceived behavioural control and physical exercise identity. Moreover, for younger male adolescents instead of the physical exercise itself, identity seems more important in developing a positive attitude towards behaviour. Likewise, in young female adolescents a low level of support from their close environment (subjective norm) leads to dropping out. The research concludes with the importance of including these variables in physical education classes to promote physical activity practice after completion of secondary school. Some practical implications are presented.

Cleavage of LOXL1 by BMP1 and ADAMTS14 Proteases Suggests a Role for Proteolytic Processing in the Regulation of LOXL1 Function.

Members of the lysyl oxidase (LOX) family catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin in the initiation step of the formation of covalent cross-links, an essential process for connective tissue maturation. Proteolysis has emerged as an important level of regulation of LOX enzymes with the cleavage of the LOX isoform by metalloproteinases of the BMP1 (bone morphogenetic protein 1) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families as a model example. Lysyl oxidase-like 1 (LOXL1), an isoform associated with pelvic organ prolapse and pseudoexfoliation (PEX) glaucoma, has also been reported to be proteolytically processed by these proteases. However, precise molecular information on these proteolytic events is not available. In this study, using genetic cellular models, along with proteomic analyses, we describe that LOXL1 is processed by BMP1 and ADAMTS14 and identify the processing sites in the LOXL1 protein sequence. Our data show that BMP1 cleaves LOXL1 in a unique location within the pro-peptide region, whereas ADAMTS14 processes LOXL1 in at least three different sites located within the pro-peptide and in the first residues of the catalytic domain. Taken together, these results suggest a complex regulation of LOXL1 function by BMP1- and ADAMTS14-mediated proteolysis where LOXL1 enzymes retaining variable fragments of N-terminal region may display different capabilities.

Exploring the potential relationship between collagen cross-linking and impaired myocardial relaxation in Marfan syndrome: An observational study using serum biomarkers.

BACKGROUND: Increased collagen cross-linking (CCL) has been described in hypertensive cardiomyopathy by means of reduced serum ratio of serum carboxyterminal telopeptide of collagen type I (CITP) to matrix metalloproteinase-1 (MMP1). Previous studies have demonstrated the existence of primary impaired diastole in patients with Marfan syndrome (MFS), but little is known about the pathophysiology of this condition. METHODS: 60 MFS patients (without previous cardiovascular surgery or significant valvular regurgitation) and 24 healthy controls (age and sex-matched) were enrolled. All participants underwent a comprehensive transthoracic echocardiographic study, including left atrial and left ventricular speckle-tracking strain analysis. CITP and MMP1 were measured in peripheral blood. RESULTS: All participants had normal diastolic function according to guidelines. Peak left atrial strain in the reservoir phase (LASr) was significantly reduced in the MFS cohort compared to controls (32.2 ± 9.4 vs 43.9 ± 7.0%; p < 0.001). Serum CITP and CITP:MMP1 ratio were lower among MFS patients, showing significant correlations with LASr (R = 0.311; p = 0.020 and R = 0.437; p = 0.001, respectively). The MFS cohort was divided into quartiles of LASr. MFS patients in the lowest quartile of LASr (<26%) had significantly lower values of CITP:MMP1 ratio compared to the other quartiles. CONCLUSIONS: The analysis of serum biomarkers revealed the presence of increased CCL in association with reduced LASr in the MFS cohort. Our results suggest that excessive CCL may play a role in the development of primary myocardial impairment in these patients. Future studies are needed to confirm our findings and evaluate the prognostic role of CCL markers in the MFS population.

The challenge of determining lysyl oxidase activity: Old methods and novel approaches.

The lysyl oxidase (LOX) family of enzymes catalyze the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin in the initiation step of the formation of covalent cross-linkages, an essential process for extracellular matrix (ECM) maturation. Elevated LOX expression levels leading to increased LOX activity is associated with diverse pathologies including fibrosis, cancer, and cardiovascular diseases. Different protocols have been so far established to detect and quantify LOX activity from tissue samples and cultured cells, all of them showing advantages and drawbacks. This review article presents a critical overview of the main features of currently available methods as well as introduces some recent technologies called to revolutionize our approach to LOX catalysis.

Techniques to Assess Collagen Synthesis, Deposition, and Cross-Linking In Vitro.

Synthesis, deposition, and cross-linking of collagen are hallmarks of fibroblast to myofibroblast differentiation. Standard methods for determining collagen from tissue samples are not directly applicable to cell culture conditions, where the overall synthesis and deposition of collagen is clearly unfavorable, mainly due to quantity limitations and dilution of required extracellular remodeling factors. In this chapter, we describe the methods we have established to analyze collagen production and deposition into the extracellular matrix by cultured myo/fibroblasts, as well as to determine lysyl oxidase (LOX) activity in cell supernatants as an index of the capacity of the cell to cross-link collagen in vitro.

Future Intentions of Fitness Center Customers: Effect of Emotions, Perceived Well-Being and Management Variables.

One of the main objectives of fitness center managers is to obtain high levels of loyalty from the customers of these fitness centers. Within the existing literature on fitness center management, previous research has analyzed the importance of the management variables themselves to determine the behavioral intentions of their customers, ignoring other psychological and sociodemographic aspects and focusing on linear relationship models. Therefore, this study, which aims to analyze the impact of different management variables along with psychological (emotions and subjective well-being) and demographic variables (age and sex) on the satisfaction, perceived value (PV) and future intentions (FI) of 398 users (216 men, aged 18-75, Mean = 35.89 ± 14.53) of a fitness center, intends to fill this gap. In this study, two different methodologies are used, i.e., hierarchical regressions models (HRM) and qualitative comparative analysis (QCA). The data were obtained by means of a self-administered questionnaire composed of 69 items that collected different previously validated scales. Considering HRM, the different models proposed explain 52% of the satisfaction variance, 57% of perceived value and 59% of future intentions. In general, it seems that the management variables are better predictors than subjective well-being, emotions and age or gender since their inclusion does not greatly improve the model's predictive capacity. As far as QCA analyses are concerned, it seems that none of the conditions are necessary for high or low levels of satisfaction, perceived value or future intentions. On the other hand, based on sufficiency analyses, there seem to be 8 pathways or combinations of conditions leading to high levels of satisfaction and 13 for low levels, 11 combinations leading to high levels of IF and 10 leading to low levels; however, there are 6 combinations of conditions leading to high levels of PV and 5 leading to low levels. In general, some of the pathways consider only the management variables, although many of them consider the importance not only of the management variables but also of the interactions that these may have with emotional aspects and, to a lesser extent, with age and well-being. When comparing both methodologies, it can be observed that the QCA models are more explanatory than the HRM models and that they take into account aspects that seem unimportant when observing linear models (such as emotions or age). However, both methodologies should be considered complementary and used simultaneously since, by focusing on different aspects, enriched results are obtained. The results obtained will enable managers to make more efficient use of available resources to increase user satisfaction.

Boosting collagen deposition with a lysyl oxidase/bone morphogenetic protein-1 cocktail.

This book chapter describes the use of exogenous application of lysyl oxidase (LOX) and bone morphogenetic protein-1 (BMP1) to enhance collagen synthesis and deposition from fibroblasts in culture. The protocol includes the generation of human embryonic kidney (HEK) 293 cell lines overexpressing human LOX and BMP1 constructs in order to obtain supernatants enriched in these factors. Incubation of fibroblast monolayers with these conditioned media strongly increases the capacity of these cells to deposit collagen onto the insoluble extracellular matrix. We also describe the use of these decellularized fibroblast-derived matrices as a substrate for the growth and differentiation of mesenchymal stem cells.

Validação de uma escala para a análise das percepções dos moradores sobre o impacto social de um centro esportivo / Validación de una escala para el análisis de las percepciones de los residentes sobre el impacto social de un centro deportivo / Validation of a scale to analyse resident's perceptions of the social impact of a sports centre

O objetivo deste estudo foi validar uma escala para a análise das percepções dos moradores sobre o impacto social de um centro esportivo. Se recolheu uma amostra de 406 moradores do município de Moncada (Valência) com erro de amostragem de ± 4,82. Os moradores responderam a um questionário de 31 itens que incluíram possíveis impactos sociais derivados da presença do complexo esportivo na localidade. A aplicação da análise fatorial exploratória e confirmatória reduziu a escala para 28 indicadores distribuídos em sete dimensões de impacto: impacto sociocultural, impacto socioeconômico, impacto na imagem e promoção do município, impacto no desenvolvimento e infraestruturas urbanas, impacto na coesão social, igualdade e equidade, impacto na saúde e impacto nos hábitos e níveis de atividade física. Os resultados permitiram verificar a validade e confiabilidade da escala proposta para o objeto de estudo

La finalidad de este estudio es validar una escala para el análisis de las percepciones de los residentes sobre el impacto social de un centro deportivo. Se recogió una muestra de 406 residentes del municipio de Moncada (Valencia), con un error de muestreo de ±4,82, que contestaron a una encuesta de 31 ítems que recogían posibles impactos sociales derivados de la presencia del centro deportivo en la localidad. La aplicación de análisis factorial exploratorio y confirmatorio redujo la escala a 28 indicadores distribuidos en siete dimensiones de impacto: impacto sociocultural, impacto socioeconómico, impacto en la imagen y la promoción del municipio, impacto en el desarrollo urbano y las infraestructuras, impacto en la cohesión social, igualdad y equidad, impacto sobre la salud e impacto sobre los hábitos y niveles de actividad física. Los resultados permitieron comprobar la validez y fiabilidad de la escala propuesta para el objeto de estudio

The purpose of this study is to validate a scale to analyse residents' perceptions of the social impact of a sports centre. A sample of 406 residents of Moncada, Valencia, was collected with sampling error of ±4.82. They responded to a 31-item survey on potential social impacts of the presence of the sports centre in that town. Exploratory and confirmatory factorial analysis reduced the scale to 28 indicators distributed in seven impact dimensions: sociocultural; socioeconomic; image and promotion of the town; urban development and infrastructures; social cohesion; equality and equity; health; and physical activity habits and levels. The results made it possible to check the validity and reliability of the scale proposed for the object of study

A hierarchical network of hypoxia-inducible factor and SMAD proteins governs procollagen lysyl hydroxylase 2 induction by hypoxia and transforming growth factor ß1.

Collagens are extracellular matrix (ECM) proteins that support the structural and biomechanical integrity of many tissues. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2) encodes the only lysyl hydroxylase (LH) isoform that specifically hydroxylates lysine residues in collagen telopeptides, a post-translational modification required for the formation of stabilized cross-links. PLOD2 expression is induced by hypoxia and transforming growth factor-ß1 (TGF-ß1), well-known stimuli for the formation of a fibrotic ECM, which can lead to pathological fibrosis underlying several diseases. Here, using human and murine fibroblasts, we studied the molecular determinants underlying hypoxia- and TGF-ß1-induced PLOD2 expression and its impact on collagen biosynthesis. Deletion mapping and mutagenesis analysis identified specific binding sites for hypoxia-inducible factors (HIF) and TGF-ß1-activated SMAD proteins on the human PLOD2 gene promoter that were required for these stimuli to induce PLOD2 expression. Interestingly, our experiments also revealed that HIF signaling plays a preponderant role in the SMAD pathway, as intact HIF sites were absolutely required for TGF-ß1 to exert its effect on SMAD-binding sites. We also found that silencing PLOD2 expression did not alter soluble collagen accumulation in the extracellular medium, but it effectively abolished the deposition into the insoluble collagen matrix. Taken together, our findings reveal the existence of a hierarchical relationship between the HIF and SMAD signaling pathways for hypoxia- and TGF-ß1-mediated regulation of PLOD2 expression, a key event in the deposition of collagen into the ECM.

Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain.

Collagens are the main structural component of the extracellular matrix and provide biomechanical properties to connective tissues. A critical step in collagen fibril formation is the proteolytic removal of N- and C-terminal propeptides from procollagens by metalloproteinases of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) and BMP1 (bone morphogenetic protein 1)/Tolloid-like families, respectively. BMP1 also cleaves and activates the lysyl oxidase (LOX) precursor, the enzyme catalyzing the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization. In this study, using murine skin fibroblasts and HEK293 cells, along with immunoprecipitation, LOX enzymatic activity, solid-phase binding assays, and proteomics analyses, we report that the LOX precursor is proteolytically processed by the procollagen N-proteinases ADAMTS2 and ADAMTS14 between Asp-218 and Tyr-219, 50 amino acids downstream of the BMP1 cleavage site. We noted that the LOX sequence between the BMP1- and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen. Taken together, these findings unravel an additional level of regulation in the formation of collagen fibrils. They point to a mechanism that controls the binding of LOX to collagen and is based on differential BMP1- and ADAMTS2/14-mediated cleavage of a tyrosine-sulfated domain.

How evolution made the matrix punch at the multicellularity party.

The basement membrane is a specialized sheet-like form of the extracellular matrix that provides structural support to epithelial cells and tissues, while influencing multiple biological functions, and was essential in the transition to multicellularity. By exploring a variety of genomes, Darris et al. provide evidence that the emergence and divergence of a multifunctional Goodpasture antigen-binding protein (GPBP), a basement membrane constituent, played a role in this transition. These findings help to explain how GPBP contributed to the formation of these extracellular matrices and to more precisely define the transition to multicellular organisms.

Catalysing the development and introduction of paediatric drug formulations for children living with HIV: a new global collaborative framework for action.

Progress in the development and introduction of paediatric formulations for key infectious diseases is poor in low-income and middle-income countries (LMICs). Although major steps have been made in the scale-up of antiretroviral medicines in LMICs, the development and deployment of formulations for infants and children is suboptimal. Of the children living with HIV globally (most in Africa), only 43% are receiving antiretroviral therapy (ART), many with suboptimal formulations. These shortfalls pose a series of challenges to meeting global treatment targets of 1·6 million children (aged 0-14 years) on ART by the end of 2018 (95% coverage) and to ensuring that 95% of those on ART are virologically suppressed. The Global Accelerator for Paediatric Formulations (GAP-f) has been developed to accelerate research, development, regulatory filing, introduction, and uptake of prioritised paediatric antiretrovirals in age-appropriate formulations by 2020, with innovative, strategic, and sustainable financing. The GAP-f will build on existing efforts to maximise coordination and alignment of policy makers, research networks, regulatory agencies, funding organisations, and manufacturers in paediatric HIV and other paediatric diseases, including tuberculosis, viral hepatitis, and other infectious diseases. Paediatric drug development and scale-up will require special efforts to bring greater visibility and new solutions to ensure that children in LMICs have access to effective and appropriate treatment options.

Lysyl Oxidases: Functions and Disorders.

Lysyl oxidases (LOX) are copper-dependent enzymes that oxidize lysyl and hydroxylysyl residues in collagen and elastin, as a first step in the stabilization of these extracellular matrix proteins through the formation of covalent cross-linkages, an essential process for connective tissue maturation. Five different LOX enzymes have been identified in mammals, LOX and LOX-like (LOXL) 1 to 4, being genetically different protein products with a high degree of homology in the catalytic carboxy terminal end and a more variable amino terminal proregion. Intensive investigation in the last years has delineated the main biological functions of these enzymes and their involvement in several pathologies including fibrosis, cancer, and ocular disorders. This review article summarizes the major findings on the role of LOX isoforms, with particular focus on their contribution to the development and progression of human disorders.

Shortening the decade-long gap between adult and paediatric drug formulations: a new framework based on the HIV experience in low- and middle-income countries.

INTRODUCTION: Despite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed. DISCUSSION: The Global Accelerator for Paediatric Formulations (GAP-f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low- and middle-income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP-f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP-f will reinforce coordinated procurement and communication with suppliers. The GAP-f will be implemented in a three-stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure. CONCLUSIONS: GAP-f is a key partnership example enhancing North-South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity-building). By promoting access to the most needed paediatric formulations for HIV and high-burden infectious diseases in low-and middle-income countries, GAP-f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super-fast-track targets.