Charge Regulation Triggers Condensation of Short Oligopeptides to Polyelectrolytes.

Electrostatic interactions between charged macromolecules are ubiquitous in biological systems, and they are important also in materials design. Attraction between oppositely charged molecules is often interpreted as if the molecules had a fixed charge, which is not affected by their interaction. Less commonly, charge regulation is invoked to interpret such interactions, i.e., a change of the charge state in response to a change of the local environment. Although some theoretical and simulation studies suggest that charge regulation plays an important role in intermolecular interactions, experimental evidence supporting such a view is very scarce. In the current study, we used a model system, composed of a long polyanion interacting with cationic oligolysines, containing up to 8 lysine residues. We showed using both simulations and experiments that while these lysines are only weakly charged in the absence of the polyanion, they charge up and condense on the polycations if the pH is close to the pKa of the lysine side chains. We show that the lysines coexist in two distinct populations within the same solution: (1) practically nonionized and free in solution; (2) highly ionized and condensed on the polyanion. Using this model system, we demonstrate under what conditions charge regulation plays a significant role in the interactions of oppositely charged macromolecules and generalize our findings beyond the specific system used here.

TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis. Here we show that ASRGL1 expression was diminished in ALS brain samples by RNA sequencing, immunohistochemistry, and western blotting. TDP-43 and ASRGL1 colocalized in neurons but, in the absence of ASRGL1, TDP-43 aggregated in the cytoplasm. TDP-43 was found to be prone to isoaspartate formation and a substrate for ASRGL1. ASRGL1 silencing triggered accumulation of misfolded, fragmented, phosphorylated and mislocalized TDP-43 in cultured neurons and motor cortex of female mice. Overexpression of ASRGL1 restored neuronal viability. Overexpression of HML-2 led to ASRGL1 silencing. Loss of ASRGL1 leading to TDP-43 aggregation may be a critical mechanism in ALS pathophysiology.

Socio-demographic inequalities influence differences in the chemical exposome among Swedish adolescents.

Relatively little is known about the relationship between socio-demographic factors and the chemical exposome in adolescent populations. This knowledge gap hampers global efforts to meet certain UN sustainability goals. The present work addresses this problem in Swedish adolescents by discerning patterns within the chemical exposome and identify demographic groups susceptible to heightened exposures. Enlisting the Riksmaten Adolescents 2016-17 (RMA) study population (N = 1082) in human-biomonitoring, and using proportional odds ordinal logistic regression models, we examined the associations between concentrations of a diverse array of substances (N = 63) with the determinants: gender, age, participant/maternal birth country income per capita level, parental education levels, and geographic place of living (longitude/latitude). Participant/maternal birth country exhibited a significant association with the concentrations of 46 substances, followed by gender (N = 41), and longitude (N = 37). Notably, individuals born in high-income countries by high-income country mothers demonstrated substantially higher estimated adjusted means (EAM) concentrations of polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs) and per- and polyfluoroalkyl substances (PFASs) compared to those born in low-income countries by low-income country mothers. A reverse trend was observed for cobalt (Co), cadmium (Cd), lead (Pb), aluminium (Al), chlorinated pesticides, and phthalate metabolites. Males exhibited higher EAM concentrations of chromium (Cr), mercury (Hg), Pb, PCBs, chlorinated pesticides, BFRs and PFASs than females. In contrast, females displayed higher EAM concentrations of Mn, Co, Cd and metabolites of phthalates and phosphorous flame retardants, and phenolic substances. Geographical disparities, indicative of north-to-south or west-to-east substance concentrations gradients, were identified in Sweden. Only a limited number of lifestyle, physiological and dietary factors were identified as possible drivers of demographic inequalities for specific substances. This research underscores birth country, gender, and geographical disparities as contributors to exposure differences among Swedish adolescents. Identifying underlying drivers is crucial to addressing societal inequalities associated with chemical exposure and aligning with UN sustainability goals.

Rising pharmaceutical innovation in the Global South: a landscape study.

BACKGROUND: There is growing interest in pharmaceutical innovation in low- and middle-income countries (LMICs), but information on existing activities, capacities, and outcomes is scarce. We mapped available data at the global level, and studied the national pharmaceutical innovation systems of Bangladesh and Colombia to shed light on pharmaceutical research and development (R&D) in the Global South, including challenges and prospects, to help fill existing knowledge gaps. METHODS: We gathered and analyzed data from three types of sources: literature, semi-structured interviews with key informants, and publicly available data on R&D funding, R&D scientific capacity measured by human resources, and clinical trial activities. RESULTS: Pharmaceutical R&D activities are occurring in many LMICs, but 16 countries have emerged as frontrunners. Investment in R&D in LMICs has increased in the past decade, particularly from middle-income countries (MICs). Capacity is also growing, with an increase in the number of research organizations and the amount of funding available from external sources. The total number of clinical trials and the proportion of trials in LMICs increased markedly, and there is also growing activity in the earlier, more innovative and riskier Phase 1 and 2 trials. Non-commercial entities comprise the majority of clinical trial funders and sponsors in LMICs. Finally, investments have borne fruit, as indicated by a number of innovative medicines developed in LMICs. The Bangladesh and Colombia country studies showed that there is still a need for both targeted R&D policies to strengthen capacities in the pharmaceutical sector, and more government support to overcome the challenges of a lack of funding and coordination among different actors. CONCLUSIONS: By triangulating between the data sources, it was possible to paint a broad picture of who was involved in pharmaceutical R&D in LMICs, in which particular countries, for which diseases, in which R&D phases, and with what results-as well as how these trends have changed over time. Prioritizing pharmaceutical R&D is an important strategy for better meeting health needs. The trendlines are promising, but focused attention is still needed to realize the potential for greater innovation in the Global South.

A Case-Only Genome-Wide Interaction Study of Smoking and Bladder Cancer Risk: Results from the COBLAnCE Cohort.

Bladder cancer (BC) is the 6th most common cancer worldwide, with tobacco smoking considered as its main risk factor. Accumulating evidence has found associations between genetic variants and the risk of BC. Candidate gene-environment interaction studies have suggested interactions between cigarette smoking and NAT2/GSTM1 gene variants. Our objective was to perform a genome-wide association case-only study using the French national prospective COBLAnCE cohort (COhort to study BLAdder CancEr), focusing on smoking behavior. The COBLAnCE cohort comprises 1800 BC patients enrolled between 2012 and 2018. Peripheral blood samples collected at enrolment were genotyped using the Illumina Global Screening Array with a Multi-Disease drop-in panel. Genotyping data (9,719,614 single nucleotide polymorphisms (SNP)) of 1674, 1283, and 1342 patients were analyzed for smoking status, average tobacco consumption, and age at smoking initiation, respectively. A genome-wide association study (GWAS) was conducted adjusting for gender, age, and genetic principal components. The results suggest new candidate loci (4q22.1, 12p13.1, 16p13.3) interacting with smoking behavior for the risk of BC. Our results need to be validated in other case-control or cohort studies.

Exposure of Swedish adolescents to elements, persistent organic pollutants (POPs), and rapidly excreted substances - The Riksmaten adolescents 2016-17 national survey.

Adolescence is a period of significant physiological changes, and likely a sensitive window to chemical exposure. Few nation-wide population-based studies of chemical body burdens in adolescents have been published. In the national dietary survey Riksmaten Adolescents (RMA) 2016-17, over 13 chemical substance groups, including elements, chlorinated/brominated/fluorinated persistent organic pollutants (POPs) were analysed in blood, and in urine metabolites of phthalates/phthalate alternatives, phosphorous flame retardants, polycyclic aromatic hydrocarbons (PAHs), and pesticides, along with bisphenols and biocide/preservative/antioxidant/UV filter substances (N = 1082, ages 11-21). The aim was to characterize the body burdens in a representative population of adolescents in Sweden, and to compare results with human biomonitoring guidance values (HBM-GVs). Cluster analyses and Spearman's rank order correlations suggested that concentrations of substances with known common exposure sources and similar toxicokinetics formed obvious clusters and showed moderate to very strong correlations (r ≥ 0.4). No clusters were formed between substances from different matrices. Geometric mean (GM) concentrations of the substances were generally less than 3-fold different from those observed among adolescents in NHANES (USA 2015-16) and GerES V (Germany 2014-17). Notable exceptions were brominated diphenyl ethers (PBDEs) with >20-fold lower GM concentrations, and the biocide triclosan and ultraviolet (UV) filter benzophenone-3 with >15-fold lower mean concentrations in RMA compared to NHANES. Exceedance of the most conservative HBM-GVs were observed for aluminium (Al, 26% of subjects), perfluorooctanesulfonic acid (PFOS, 19%), perfluorooctanoic acid (PFOA, 12%), lead (Pb, 12%), MBP (dibutyl phthalate metabolite, 4.8%), hexachlorobenzene (HCB, 3.1%) and 3-phenoxybenzoic acid (PBA, pyrethroid metabolite, 2.2%). Males showed a higher proportion of exceedances than females for Pb, HCB and PFOS; otherwise no gender-related differences in exceedances were observed. A higher proportion of males than females had a Hazard Index (HI) of substances with liver and kidney toxicity and neurotoxicity >1. Industrialized countries with similarly high standards of living, with some exceptions, show comparable average body burdens of a variety of toxic chemicals among adolescents from the general population. The exceedances of HBM-GVs and HIs strongly suggests that further efforts to limit chemical exposure are warranted.

Hospitalización en paciente con cólico renal: Caracterización clínico-epidemiológica en el Hospital Clínico Herminda Martín, período marzo 2014 - marzo 2019 / Hospitalization in a patient with renal colic: Clinical-epidemiological characterization at the Herminda Martín Clinical Hospital, period March 2014 - March 2019

INTRODUCCIÓN: El cólico renal es una condición médica común en los servicios de urgencia. Representa la manifestación clínica más frecuente de urolitiasis, cuya patogenia es multifactorial, con tasas de prevalencia varía de 1% a 20% y una recurrencia a 10 años del 42% al 50%. OBJETIVO: Establecer el perfil clínico-epidemiológico, como también el diagnóstico y manejo de los pacientes hospitalizados por cólico renal en el Hospital Clínico Herminda Martín (HCHCM). MATERIAL Y MÉTODO: Estudio descriptivo retrospectivo en pacientes hospitalizados con diagnóstico de cólico renal en el HCHM de Chillán en el período marzo 2014-marzo 2019. Se estudiaron las variables: sexo, edad, presentación clínica de ingreso, factores de riesgo asociados, motivo de hospitalización, resultados imagenológicos y manejo clínico. Resultados. El 52,45% correspondió a pacientes de sexo masculino, encontrándose la mayor cantidad de pacientes en el intervalo de 40-49 años. La obesidad, antecedente de urolitiasis e hipertensión arterial fueron las patologías asociadas más frecuentes. En la mayoría de los pacientes, el motivo de la hospitalización fue la refractariedad al tratamiento analgésico, alcanzando un 86,76%. El 56,37% de los pacientes recibió manejo médico expulsivo y a un 19,11% de los pacientes se le realizó una intervención quirúrgica durante la hospitalización. CONCLUSIÓN: El perfil de éstos pacientes no sólo permite establecer medidas que podrían evitar un evento litiásico, sino que además se demuestra la necesidad de realizar un manejo óptimo que puede evitar reconsultas, sobrecarga de los servicios de urgencia, aumento de días cama y complicaciones.

INTRODUCTION: Renal colic is a common condition in the emergency department. It represents the most frequent clinical manifestation of urolithiasis, whose prevalence rate varies between 1% to 20%. Its pathogenesis is multifactorial, with a recurrence of 10 years from 42-50%. OBJECTIVE: Establish the clinical-epidemiological profile, as well as the diagnosis and management of patients hospitalized for renal colic at the Herminda Martín Clinical Hospital(HCHM). MATERIALS AND METHODS: A retrospective descriptive study of hospitalized patients diagnosed with renal colic at the HCHM, March 2014-March 2019, the variables were studied: sex, age, the clinical presentation of admission, associated risk factors, the reason for hospitalization, imaging results, and management. Results: 52.45% were male patients, with the highest number of patients in the range of 40-49 years. Obesity, a history of urolithiasis and hypertension, occurred more frequently within the associated pathologies. In most patients, refractable to analgesic treatment was the reason for hospitalization, reaching 86.76%. 56.37% of patients received expulsion medical management, and 19.11% of patientshad surgeryduring hospitalization. CONCLUSION: The profile of these patients not only allows them to establish measures that could prevent a lithiasis event but also shows the need for effective management of patients who can avoid reconsults, an overload of emergency services, increasedbed days and complications

Detection of Leptospira in Urban Swedish Rats: Pest Control Interventions as a Promising Source of Rats Used for Surveillance.

Rat carcasses obtained from pest control interventions can potentially be used for an efficient surveillance of zoonotic diseases such as leptospirosis. To evaluate the performance of different laboratory methods for detection of pathogenic Leptospira spp., heart and kidney samples from wild Norway rats were analyzed by microscopic agglutination test (MAT, the gold standard), a commercial IgG enzyme-linked immunosorbent assay, and by an optimized quantitative PCR (secY qPCR, followed by sequencing). We found secY qPCR to be as sensitive as MAT for screening of Leptospira infection in pest control rats and selected secY qPCR for a larger screening of rats from urban and rural areas in central and southern Sweden. We identified secY qPCR positive rats from the cities Stockholm, Gothenburg, and Malmö, which were further confirmed by sequencing.

Infecciones de transmisión sexual: concordancia diagnóstica entre profesionales de atención primaria de la zona norte de Santiago y dermatólogos del Hospital San José / Sexually transmitted infections: concordance diagnosis among primary care professionals of the north zone of Santiago and dermatologists of the San José Hospital

Introducción: Las infecciones de transmisión sexual (ITS) son una prioridad en salud pública, por su alta prevalencia, impacto en la calidad de vida y repercusiones económicas. Actualmente, no existen publicaciones que analicen la concordancia diagnóstica de las ITS entre el nivel primario y el nivel secundario de atención. Objetivo: Analizar la concordancia diagnóstica entre profesionales de atención primaria de salud (APS) y especialistas de la UNACESS en el diagnóstico de las ITS. Metodología: Se analizaron retrospectivamente las fichas de 627 pacientes derivados desde APS de la zona norte de Santiago a la UNACESS (Unidad de Atención y Control en Salud Sexual) del Hospital San José entre enero de 2015 y enero de 2016, según diagnóstico de referencia y contrarreferencia. Además, se analizó: el profesional derivador, sexo, edad y nacionalidad del paciente. El grado de concordancia diagnóstica se determinó mediante el coeficiente kappa de Cohen. Resultados: El 74% de las interconsultas desde APS fueron emitidas por matronas y el 26% por médicos. Los diagnósticos de referencia más prevalentes fueron: Condiloma acuminado (64.43%), molusco contagioso (8.13%), sífilis (7.34%), uretritis (7.02%) y herpes genital (3.67%). Los diagnósticos de contrarreferencia más prevalentes fueron: Condiloma acuminado (51.20%), sífilis (10.85%), molusco contagioso (10.37%), uretritis (6.86%) y herpes genital (3.51%). La concordancia diagnóstica global del estudio fue moderada (54%). Los médicos de APS lograron una concordancia sustancial (62%) y las matronas una concordancia moderada (49.19%) respecto a los diagnósticos realizados por el especialista. Conclusión: De los resultados, podemos concluir que existe una concordancia diagnóstica moderada entre los profesionales APS y los médicos especialistas de la UNACESS. Es fundamental reforzar la formación en ITS y elaborar estrategias de capacitación dirigido a médicos generales y matronas de APS.

Introduction: Sexually transmitted infections (STI) are a public health priority because of its high prevalence, economic repercussions and impact on a person's quality of life. Currently, there are no reports that analyse the diagnostic agreement of STI between primary and secondary health care professionals. Objective: To analyse the diagnostic concordance of STI amongst primary and secondary health care professionals. Methodology: Data is from 627 patients that were referred according to: referral and counter-referral diagnosis from Primary Health Care (PHC) of the northern zone of Santiago to San José Hospital´s Sexual Health Attention and Control Unit (UNACESS) during January 2015 until January 2016. It was also taken into consideration; the referring physician, patients sex and age. The level of diagnostic concordance was determined by the Cohen's kappa coefficient. Results: From the PHC consultations, 74% of the consultations were issued by midwives and 26% by doctors. The predominant referral diagnoses were: Condyloma acuminatum (64.43%), molluscum contagiosum (8.13%), syphilis (7.34%), urethritis (7.02%) and genital herpes (3.67%). The prevalent counter-referral diagnoses were: condylomas (51.20%), syphilis (10.85%), molluscum contagiosum (10.37%), urethritis (6.86%), and genital herpes (3.51%). The study's overall diagnostic concordance was moderate (54%). PHC physicians achieved a substantial concordance (62%) and midwives had a moderate concordance (49.19%) to the diagnoses made by the specialist. Conclusions: There is a moderate diagnostic concordance between the PHC professionals and the specialists' doctors of UNACESS. It is crucial to reinforce STI training and develop training strategies for general physicians and PHC midwives.

Linfoma cutáneo primario de células B centrofolicular: un desafío diagnóstico / Primary cutaneous follicular B-cell lymphoma: a diagnostic challenge

El linfoma cutáneo primario de células B (LCPCB) centrofolicular corresponde a una proliferación neoplásica infrecuente e indolente de células del centro germinal confinadas a la piel. Se reporta y revisa un caso de LCPCB centrofolicular. Paciente femenino de 76 años, con antecedentes de hipertensión arterial y resistencia a la insulina. Consultó por aumento de volumen frontal de dos años de evolución. Al examen físico destacaba un nódulo único en región frontal derecha. La ecografía de partes blandas fue compatible con quiste epidérmico. La histopatología demostró en dermis profunda, tejido adiposo subcutáneo y tejido muscular estriado una proliferación linfoide sólida dispuesta en patrón nodular y difuso. A la inmunohistoquímica (IHQ), los linfocitos fueron CD20 y BCL-6 positivo, con un Ki-67 de 60% y BCL-2, CD3, CD5 y CD10 negativo. El estudio de diseminación tumoral resultó negativo. El LCPCB centrofolicular concentra el 60% de todos los LCPCB. Se presenta en promedio a los 51 años. Se ha descrito asociación con Borrelia burgdorferi, VIH, virus hepatitis C y virus Epstein-Barr. Clínicamente corresponde a un nódulo eritematoso y asintomático, localizado preferentemente en cabeza, cuello y tronco. La IHQ es fundamental para diferenciarlo de otros tipos de LCPCB. Habitualmente, el tratamiento es con radioterapia o cirugía escisional. La supervivencia es de un 95% a 5 años. Se presenta este caso dado que el LCPCB centrofolicular corresponde a un tumor cutáneo infrecuente, con múltiples diagnósticos diferenciales, que requiere de un alto índice de sospecha para lograr un diagnóstico y tratamiento oportuno.

The primary cutaneous follicle center lymphoma (PCFCL) corresponds to an infrequent and indolent neoplastic proliferation of germinal center cells confined to the skin. A case of PCFCL is reported and revised. Results: A female patient, 76 years old, with arterial hypertension and insulin resistance. Sough attention for an increase in size of the frontal region over the course of two years. Upon physical examination, a single nodule was noted in the right frontal region. A soft tissue ultrasound identified results indicative of an epidermal cyst. The histopathology revealed a proliferation of solid lymphoid arrayed in a diffuse and nodular pattern in the deep dermis, subcutaneous adipose tissue, and striated muscular tissue. Immunohistochemistry (IHQ) revealed CD20 and BCL-6 positive lymphocytes, with 60% of Ki-67 and BCL-2, CD3, CD5, and CD10 negative. A study of tumor dissemination resulted negative. The PCFCL concentrates 60% of all primary cutaneous B cell lymphomas (PCBCL). It presents at an average of 51 years of age. It has been described association with Borrelia burgdorferi, HIV, hepatitis C virus and Epstein-Barr virus. Clinically it corresponds to an erythematous and asymptomatic nodule, found frequently on the head, neck and trunk. The IHQ is essential to differentiate it from other types of PCBCL. It is usually treated with radiotherapy or excisional surgery. Survival is 95% over 5 years. This case is presented because the PCFCL corresponds to an infrequent cutaneous tumor, with multiple differential diagnoses, requiring a high index of suspicion to achieve an opportune diagnostic and treatment.

Xantogranuloma juvenil múltiple: variante inusual en un lactante / Multiple juvenile xanthogranuloma: unusual variant in an infant

El Xantogranuloma Juvenil (XJ) es un tumor benigno de la infancia, constituido por histiocitos progresivamente lipidizados, en ausencia de anomalías metabólicas. Se reporta un caso de XJ múltiple en un lactante. Paciente masculino de 1 año y 11 meses de edad, sin antecedentes mórbidos. Consultó por lesiones de 15 meses de evolución en cuero cabelludo. Al examen físico destacaban dos pápulas amarillentas y tres máculas anaranjadas en cuero cabelludo. A la dermatoscopía se apreciaba un color amarillonaranja homogéneo. La biopsia incisional demostró infiltrado de histiocitos en dermis y células de Touton. A la inmunohistoquímica, los histiocitos fueron CD68 positivo, S100 negativo y CD1a negativo. Los exámenes de laboratorio y la evaluación por oftalmología no evidenciaron anormalidades. El XJ es un tumor benigno, siendo la forma más común de Histiocitosis no Langerhans. El 90% de las veces ocurre en etapas tempranas de la vida. Se caracteriza por una pápula o nódulo asintomático, amarillo-anaranjado, que compromete cabeza, cuello y/o tronco superior. Hasta el 82% de los casos se manifiesta de manera única. El ojo es el sitio extracutáneo más frecuentemente comprometido. La dermatoscopía describe un patrón de "puesta de sol". Su pronóstico es bueno y tiende a involucionar a los 3-6 años desde su aparición. Se presenta este caso dado que el XJ múltiple es menos frecuente de observar que su forma única y para recordar que su asociación con neurofibromatosis tipo 1 predispone a un mayor riesgo de desarrollar una leucemia mieloide crónica infantil.

The Juvenile Xanthogranuloma (JX) is a benign tumor of childhood, composed of progressively lipidized histiocytes in the absence of metabolic abnormalities. A case of multiple JX is reported in an infant. Male patient of 1 year and 11 months, without morbid history. Checking injuries in scalp of 15 months of evolution. At physical examination highlights two yellow papules and three orange macules in the scalp. Dermatoscopy shown a homogeneous yellow-orange color. The incisional biopsy showed infiltration of histiocytes in the dermis and Touton cells. At immunohistochemistry, histiocytes were CD68 positive, S100 negative and CD1a negative. Laboratory tests and evaluation by Ophthalmology showed no abnormalities. The JX is a benign tumor, been the most common form non- Langerhans histiocytosis. This taking place 90% of the time in early life, and characterized by yellow-orange asymptomatic papule or nodule, which undertake head, neck and / or upper body. Up to 82% of cases appears uniquely. The eye is the most frequently committed extracutaneous site. The dermoscopy describes a pattern of "setting sun". His prognosis is good and tends to return to the 3-6 years since their appearance. We present this case because the multiple JX is less common to observe that this singular form, and to remember that their association with neurofibromatosis type 1 predisposes to increased risk of developing childhood chronic myeloid leukemia.

Asociación entre la terapia hormonal y el desarrollo craneofacial en personas con deficiencia hormonal entre los 10 y 18 años de edad. Revisión sistemática / Association between hormonal therapy and craniofacial development in subjects between 10 and 18 years of age. Systematic review

Introducción: Las deficiencias hormonales pueden afectar el complejo craneofacial durante el crecimiento y desarrollo esque- lético. Objetivo: Determinar si existía evidencia científica acerca de la asociación entre el tratamiento hormonal y el crecimiento craneofacial en personas con deficiencia hormonal entre los 10 y 18 años de edad evaluados cefalométricamente. Materiales y método: Revisión sistemática de la literatura en Pubmed, Google acadé - mico, Lilacs, Embase, ScienceDirect, sin límite de año de publicación. Se incluye - ron ensayos clínicos, estudios de casos y controles, cohorte, revisiones sistemáticas y meta-análisis. Se hizo lectura ciega e in - dependiente por parte de 2 investigadores, de los resúmenes y los artículos completos. Resultados: De 1085 artículos encontra - dos se excluyeron 1074 por no cumplir criterios de inclusión. Luego de la lectura completa se excluyeron 5 por ser estudios transversales y uno porque no se tuvo ac- ceso a él, quedando un total de 6 artículos incluidos. Estas investigaciones reportaron que los pacientes tratados con terapias de sustitución hormonal presentaron cambios favorables en las estructuras craneofaciales, especialmente la longitud total mandibular, longitud de la rama y cuerpo mandibular; también presentaron mejoría del perfil fa - cial, relaciones intermaxilares y estructuras óseas corporales. Conclusiones: A pesar de la heteroge - neidad de los estudios,se encontró queel tratamiento temprano de sustitución hor - monal, independientemente de la dosis y siempre y cuando sea a largo plazo, acelera el desarrollo de estructuras craneofaciales, principalmente de la mandíbula, hasta lo - grar los patrones esqueléticos establecidos genéticamente. Se requieren estudios que evalúen el efecto de la terapia de sustitución hormonal en pacientes sin compromisos sistémicos adicionales.

Background: Hormone deficiency could affect craniofacial complex during esque- letal growth and development. Objective: Determine whether there is scientific evidence of the association bet - ween hormonal treatment and craniofacial growth measured by cephalometry films, in subjects of 10 to 18 years with hormonal treatment. Materials and Methods: A systematic re- view. For the articles published in PubMed, Google Scholar, Lilacs, Embase and Scien - ce Direct databases, without restriction of publication year was performed. Clinical trials, case control studies, cohort, syste - matic reviews and meta analysis studies were included. Reading of the abstracts and the complete articles were made by two researchers. Results: Among 1085 articles found, 1074 were excluded because did not meet the inclusion criteria. After complete reading of the articles, five were excluded because they were cross-sectional studies and one was not recovered in the full text. In total, 6 articles were included. These studies report that patients who were treated with hormo - ne substitution therapy showed favorable changes in their craniofacial structures, especially in mandibular total length, ramus length and mandibular body length. These positive changes led to an improvement in profile, inter-maxillary relations, and other osseous body structures. Conclusions: Despite the heterogeneity of the studies it was found that early replace - ment with hormone treatment, regardless of the dose and long-term treatment, ac - celerates the development of craniofacial structures, mainly the mandible, to reach the skeletal patterns genetically established. Studies are required to evaluate replace hormone treatment in patients without additional systemic compromises.