Protective Role of NS1-Specific Antibodies in the Immune Response to Dengue Virus through Antibody-Dependent Cellular Cytotoxicity.

BACKGROUND: Dengue virus (DENV) non-structural protein 1 (NS1) has multiple functions within infected cells, on the cell surface, and in secreted form, and is highly immunogenic. Immunity from previous DENV infections is known to exert both positive and negative effects on subsequent DENV infections, but the contribution of NS1-specific antibodies to these effects is incompletely understood. METHODS: We investigated the functions of NS1-specific antibodies and their significance in DENV infection. We analyzed plasma samples collected in a prospective cohort study prior to symptomatic or subclinical secondary DENV infection. We measured binding to purified recombinant NS1 protein and to NS1-expressing CEM cells, antibody-mediated NK cell activation by plate-bound NS1 protein, and antibody-dependent cellular cytotoxicity (ADCC) of NS1-expressing target cells. RESULTS: We found that antibody responses to NS1 were highly serotype-cross-reactive and that subjects who experienced subclinical DENV infection had significantly higher antibody responses to NS1 in pre-infection plasma than subjects who experienced symptomatic infection. We observed strong positive correlations between antibody binding and NK activation. CONCLUSIONS: These findings demonstrate the involvement of NS1-specific antibodies in ADCC and provide evidence for a protective effect of NS1-specific antibodies in secondary DENV infection.

Return to play after rotator cuff tear in National Football League athletes.

Background: Rotator cuff tears are rare injuries in National Football League (NFL) athletes and there are limited data to help guide players and team physicians. The purpose of this study was to assess return to play (RTP) rates, performance levels, and career length following a rotator cuff tear during their playing career. Methods: Using publicly available data, we identified players who sustained a rotator cuff tear between 2000 and 2019. Demographic information, treatment (operative vs. nonoperative), RTP rate, preinjury and postinjury performance score, position, and career length were entered into the analysis. Results: Twenty-nine athletes with a mean age of 27.4 years (±3.1) at the time of injury were included in this study. Forty-eight percent were offensive and 52% defensive players. 79.3% (23/29) were able to RTP at the same professional level for an average of 2.8 ± 3.4 years. The average time to RTP after injury was 198.4 ± 125.3 days. The average age of players who RTP was 26.7 ± 2.5 years compared to those who did not (30.3 ± 3.7, P = .02). Similarly, the preinjury NFL career length was 4.0 ± 2.2 in players who RTP compared to those who did not (7.5 ± 2.7, P = .01). Most injuries (82.2%) were treated surgically; however, there was no significant difference (P > .05) in RTP rates, performance score, or career longevity between operative and nonoperative cohorts. Conclusion: Overall RTP rates for NFL athletes following a rotator cuff injury are promising with approximately 80% returning at the same performance level regardless of treatment type. Older, veteran players particularly those over the age of 30 were significantly less likely to RTP and should be counseled accordingly.

Celiac disease seroprevalence in patients with infertility. A case-control study.

BACKGROUND: Although most patients with celiac disease (CD) have digestive manifestations, in some of them they may be of extraintestinal (atypical) nature, such as chronic anemia, ataxia, and fertility disorders. OBJECTIVE: To determine the prevalence of CD-related antibodies in Mexican women with fertility disorders. MATERIAL AND METHODS: Case-control study of women who attended evaluation for fertility disorders in a specialized center. h-tTG-IgA, gliadin IgA II and gliadin IgG II were quantified; titers > 30 IU were considered positive. RESULTS: One-hundred and seventy-one cases and 171 controls were included; 137 patients (80.1%) had infertility, and 34 (19.9%), sterility. Eight patients (4.6%, 95% CI = 2.3-8.9) had at least one positive marker for CD in comparison with one woman in the control group (0.5%, 95% CI = 0.01-3, p = 0.04, odds ratio = 8.3). Six of the eight patients had unexplained infertility. CONCLUSIONS: Up to 4.6% of women with infertility had at least one positive marker for CD. As in other parts of the world, screening for CD could be recommended in women with infertility, especially in those with unexplained infertility.

ANTECEDENTES: Aunque los pacientes con enfermedad celiaca (EC) tienen en su mayoría manifestaciones digestivas, algunos pueden presentarlas de índole extraintestinal (atípicas), como anemia crónica, ataxia y trastornos de la fertilidad. OBJETIVO: Determinar la prevalencia de anticuerpos relacionados con EC en mujeres mexicanas con trastornos de la fertilidad. MATERIAL Y MÉTODOS: Estudio de casos y controles de mujeres que acudieron a valoración por trastornos de la fertilidad en un centro especializado. Se cuantificó h-tTG IgA, gliadina IgA II y gliadina IgG II; los títulos > 30 UI fueron considerados como positivos. RESULTADOS: Se incluyeron 171 casos y 171 controles; 137 pacientes (80.1 %) tuvieron infertilidad y 34 (19.9 %), esterilidad. Ocho pacientes (4.6 %, IC 95 % = 2.3-8.9) tuvieron al menos un marcador positivo para EC comparadas con una mujer del grupo control (0.5 %, IC 95 % = 0.01-3, p = 0.04, razón de momios = 8.3). Seis de las ocho pacientes presentaron infertilidad inexplicable. CONCLUSIONES: Hasta 4.6 % de las mujeres con infertilidad presentó al menos un marcador positivo para EC. Al igual que en otras partes del mundo, podría recomendarse el escrutinio para EC en mujeres con infertilidad, en especial en quienes padecen infertilidad inexplicable.

Seroprevalencia de enfermedad celiaca en pacientes con infertilidad. Un estudio de casos y controles / Celiac disease seroprevalence in patients with infertility. A case-control study

Resumen Antecedentes: Aunque los pacientes con enfermedad celiaca (EC) tienen en su mayoría manifestaciones digestivas, algunos pueden presentarlas de índole extraintestinal (atípicas), como anemia crónica, ataxia y trastornos de la fertilidad. Objetivo: Determinar la prevalencia de anticuerpos relacionados con EC en mujeres mexicanas con trastornos de la fertilidad. Material y métodos: Estudio de casos y controles de mujeres que acudieron a valoración por trastornos de la fertilidad en un centro especializado. Se cuantificó h-tTG IgA, gliadina IgA II y gliadina IgG II; los títulos > 30 UI fueron considerados como positivos. Resultados: Se incluyeron 171 casos y 171 controles; 137 pacientes (80.1 %) tuvieron infertilidad y 34 (19.9 %), esterilidad. Ocho pacientes (4.6 %, IC 95 % = 2.3-8.9) tuvieron al menos un marcador positivo para EC comparadas con una mujer del grupo control (0.5 %, IC 95 % = 0.01-3, p = 0.04, razón de momios = 8.3). Seis de las ocho pacientes presentaron infertilidad inexplicable. Conclusiones: Hasta 4.6 % de las mujeres con infertilidad presentó al menos un marcador positivo para EC. Al igual que en otras partes del mundo, podría recomendarse el escrutinio para EC en mujeres con infertilidad, en especial en quienes padecen infertilidad inexplicable.

Abstract Background: Although most patients with celiac disease (CD) have digestive manifestations, in some of them they may be of extraintestinal (atypical) nature, such as chronic anemia, ataxia, and fertility disorders. Objective: To determine the prevalence of CD-related antibodies in Mexican women with fertility disorders. Material and methods: Case-control study of women who attended evaluation for fertility disorders in a specialized center. h-tTG-IgA, gliadin IgA II and gliadin IgG II were quantified; titers > 30 IU were considered positive. Results: One-hundred and seventy-one cases and 171 controls were included; 137 patients (80.1%) had infertility, and 34 (19.9%), sterility. Eight patients (4.6%, 95% CI = 2.3-8.9) had at least one positive marker for CD in comparison with one woman in the control group (0.5%, 95% CI = 0.01-3, p = 0.04, odds ratio = 8.3). Six of the eight patients had unexplained infertility. Conclusions: Up to 4.6% of women with infertility had at least one positive marker for CD. As in other parts of the world, screening for CD could be recommended in women with infertility, especially in those with unexplained infertility.

Mucosal Vaccination: A Promising Alternative Against Flaviviruses.

The Flaviviridae are a family of positive-sense, single-stranded RNA enveloped viruses, and their members belong to a single genus, Flavivirus. Flaviviruses are found in mosquitoes and ticks; they are etiological agents of: dengue fever, Japanese encephalitis, West Nile virus infection, Zika virus infection, tick-borne encephalitis, and yellow fever, among others. Only a few flavivirus vaccines have been licensed for use in humans: yellow fever, dengue fever, Japanese encephalitis, tick-borne encephalitis, and Kyasanur forest disease. However, improvement is necessary in vaccination strategies and in understanding of the immunological mechanisms involved either in the infection or after vaccination. This is especially important in dengue, due to the immunological complexity of its four serotypes, cross-reactive responses, antibody-dependent enhancement, and immunological interference. In this context, mucosal vaccines represent a promising alternative against flaviviruses. Mucosal vaccination has several advantages, as inducing long-term protective immunity in both mucosal and parenteral tissues. It constitutes a friendly route of antigen administration because it is needle-free and allows for a variety of antigen delivery systems. This has promoted the development of several ways to stimulate immunity through the direct administration of antigens (e.g., inactivated virus, attenuated virus, subunits, and DNA), non-replicating vectors (e.g., nanoparticles, liposomes, bacterial ghosts, and defective-replication viral vectors), and replicating vectors (e.g., Salmonella enterica, Lactococcus lactis, Saccharomyces cerevisiae, and viral vectors). Because of these characteristics, mucosal vaccination has been explored for immunoprophylaxis against pathogens that enter the host through mucosae or parenteral areas. It is suitable against flaviviruses because this type of immunization can stimulate the parenteral responses required after bites from flavivirus-infected insects. This review focuses on the advantages of mucosal vaccine candidates against the most relevant flaviviruses in either humans or animals, providing supporting data on the feasibility of this administration route for future clinical trials.

Inlay total shoulder arthroplasty for primary glenohumeral arthritis.

BACKGROUND: Anatomic total shoulder arthroplasty with a nonspherical humeral head and inlay glenoid replacement has been introduced in the past; however, clinical evidence remains limited. We hypothesized that patients with advanced glenohumeral arthritis demonstrate significant improvements in pain and function. METHODS: Prospective patient-reported outcomes (PROs) included the American Shoulder and Elbow Surgeons score, a pain visual analog scale, and satisfaction. Range of motion was compared to the preoperative status. A sensitivity analysis examined responder rates and compared them to literature thresholds using the minimal clinically important difference and substantial clinical benefit. The preoperative glenoid morphology was determined using the Walsh classification. Zone-specific periprosthetic radiolucent lines were quantified at the last follow-up. RESULTS: Thirty-nine shoulders in 36 patients (3 bilateral) with a mean age of 65.9 years (26 males, 13 females) and a mean follow-up of 41.0 months were included. Ninety-three percent had grade III osteoarthritis, and 7% grade II. The glenoid Walsh classification included A1 (25%), A2 (25%), B1 (22%), B2 (25%), and C (3%). All PROs improved significantly (P < .001) with a mean American Shoulder and Elbow Surgeons score from 30.4 to 77.1, a pain visual analog scale from 8.1 to 1.5, and excellent (9.1/10) patient satisfaction. PRO-related responder rates for minimal clinically important difference and substantial clinical benefit were ≥85%. Forward elevation improved from 107° to 155°, and external rotation from 22° to 51°. One intraoperative glenoid rim fracture led to advanced radiolucency; no other clinically relevant lucency was observed. CONCLUSION: Treatment with inlay total shoulder arthroplasty demonstrated significant functional improvement, excellent pain relief, and patient satisfaction in patients with advanced shoulder arthritis and various glenoid morphology types. Our initial results provide further support for this new option in primary shoulder replacement.

Non-structural protein 1-specific antibodies directed against Zika virus in humans mediate antibody-dependent cellular cytotoxicity.

There is growing interest in understanding antibody (Ab) function beyond neutralization. The non-structural protein 1 (NS1) of Zika virus (ZIKV) is an attractive candidate for an effective vaccine as Abs against NS1, unlike the envelope or premembrane, do not carry the risk of mediating antibody-dependent enhancement. Our aim was to evaluate whether ZIKV NS1 Abs elicited following natural infection in humans can mediate antibody-dependent cellular cytotoxicity (ADCC). We evaluated the isotype specificity of ZIKV-specific Abs in immune sera and supernatants from stimulated immune PBMC and found that Abs against ZIKV NS1 and virus-like particles were predominantly of the IgG1 isotype. Using a recently developed FluoroSpot assay, we found robust frequencies of NS1-specific Ab-secreting cells in PBMC of individuals who were naturally infected with ZIKV. We developed assays to measure both natural killer cell activation by flow cytometry and target cell lysis of ZIKV NS1-expressing cells using an image cytometry assay in the presence of ZIKV NS1 Abs. Our data indicate efficient opsonization of ZIKV NS1-expressing CEM-NKR cell lines using ZIKV-immune but not ZIKV-naïve sera, a prerequisite of ADCC. Furthermore, sera from immune donors were able to induce both NK cell degranulation and lysis of ZIKV NS1 CEM-NKR cells in vitro. Our data suggest that ADCC is a possible mechanism for ZIKV NS1 Abs to eliminate virally infected target cells.

Outcomes of Arthroscopic Fixation of Unstable Distal Clavicle Fractures: A Systematic Review.

BACKGROUND: Surgical management of unstable distal clavicle fractures (DCFs) remains controversial. Traditional open techniques result in acceptable union rates but are fraught with complications. In response to these limitations, arthroscopic techniques have been developed; however, clinical outcome data are limited. PURPOSE: The primary purpose was to systematically evaluate the clinical and radiographic outcomes of arthroscopic fixation of unstable DCFs. The secondary purpose was to characterize the overall complication rate, focusing on major complications and subsequent reoperations. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review of the literature was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and included a search of the PubMed, Web of Science, Cochrane Register of Controlled Trials, EMBASE, and Scopus databases. English-language studies between 2008 and 2019 that reported on outcomes of patients with DCFs who underwent operative fixation using an arthroscopic or arthroscopically assisted surgical technique were included. Data consisted of patient characteristics, fracture type, surgical technique, concomitant injuries, union rates, functional outcomes, and complications. RESULTS: A total of 15 studies consisting of 226 DCFs treated using an arthroscopically based technique were included in the systematic review. The majority of fractures were classified as Neer type II. Most (97%) of the fractures underwent arthroscopic fixation using a cortical button coracoclavicular stabilization surgical technique. Bony union was reported in 94.1% of the fractures. Good to excellent outcomes were recorded in most patients at the final follow-up. The Constant-Murley score was the most widely used functional outcome score; the pooled mean Constant score was 93.06 (95% CI, 91.48-94.64). Complications were reported in 14 of the 15 studies, and the overall complication rate was 27.4%. However, only 12% of these were considered major complications, and only 6% required a reoperation for hardware-related complications. CONCLUSION: Arthroscopic fixation of DCFs resulted in good functional outcomes with union rates comparable to those of traditional open techniques. While the overall complication profile was similar to that of other described techniques, there was a much lower incidence of major complications, including hardware-related complications and reoperations.

Longitudinal Analysis of Memory B and T Cell Responses to Dengue Virus in a 5-Year Prospective Cohort Study in Thailand.

Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.

Peripheral follicular helper T cells in acute viral diseases: a perspective on dengue.

Follicular helper T cells (TFH) are a predominant subset of CD4+ T cells specialized in providing help to B cells in germinal centers and necessary to generate T cell-dependent antibody responses. Peripheral TFH (pTFH) are the counterpart of TFH found in the circulation, which resemble TFH in many aspects of their phenotype and function. The CD4+ pTFH subset has received a lot of interest recently because they are easy to access and have the potential to serve as a biomarker for long-lasting humoral immunity. This review will discuss recent findings of pTFH in human acute viral diseases with a focus on dengue infection.

Elevated circulating levels of IL-21 and IL-22 define a cytokine signature profile in type 2 autoimmune hepatitis patients.

UNLABELLED:  Background and aims. Autoimmune hepatitis (AIH) is a chronic inflammatory condition of the liver in which the immunological mechanisms involved in tissue destruction and/or repair are still unclear. Different pro-inflammatory cytokines have been shown to play a determinant role in AIH pathogenesis. Here, we aim to compare the circulating levels of pro- and anti-inflammatory cytokines such as IL-6, TNF-?, IL-17A/F, IL-21, IL-22, IL-23, and IL-10 in patients with type 2 AIH compared to patients with type 1 AIH and healthy controls (HC). Fourty-six Mexican patients with AIH were recruited in our study. Patients were classified as type 1 or 2 AIH based on immune serological markers. Fourty-four serum samples from healthy individuals were included as controls. Serum cytokine levels were determined by ELISA technique. RESULTS: Compared to healthy controls, serum levels of IL-17F, IL-21, IL-23, IL-10, IL-6, and TNF-?, but not IL-17A and IL-22, were significantly increased in AIH patients. When patients were grouped by aminotransferase activity, a biomarker of active disease, a positive correlation between serum IL-17F and alanine transaminase (rs: 0.4739; P = 0.0009) and aspartate transaminase (rs: 0.4984; P = 0.0004) levels was found. A cytokine signature profile associated with type 2 AIH was characterized by high serum IL-21 (type 1 AIH: 0.66 pg/mL; type 2 AIH: 331.1 pg/mL; P = 0.0042) and IL-22 (type 1 AIH: 0.1 pg/mL; type 2 AIH: 55.26 pg/mL; P = 0.0028) levels. CONCLUSIONS: We show for the first time, differential regulation of certain pro-inflammatory cytokines associated with disease progression and AIH type in Mexican patients.

Whey protein isolate improves acid and bile tolerances of Streptococcus thermophilus ST-M5 and Lactobacillus delbrueckii ssp. bulgaricus LB-12.

Acid tolerance and bile tolerance are important probiotic characteristics. Whey proteins contain branched-chain amino acids, which play a role in muscle building and are popular among athletes. Increasing emphasis is being placed on diets containing less carbohydrate, less fat, and more protein. The effect of incremental additions of whey protein isolate (WPI) on probiotic characteristics of pure cultures is not known. The objective of this study was to determine the influence of added WPI on acid tolerance and bile tolerance of pure cultures of Streptococcus thermophilus ST-M5 and Lactobacillus bulgaricus LB-12. The WPI was used at 0 (control), 1, 2 and 3% (wt/vol). Assessment of acid tolerance was conducted on pure cultures at 30-min intervals for 2h of acid exposure and bile tolerance at 1-h intervals for 5h of bile exposure. Use of 1, 2, and 3% WPI improved acid tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12. The highest counts for acid tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12 were obtained when 3% WPI was used. Use of 2 and 3% WPI improved bile tolerance of Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12 over 5h of bile exposure. The use of WPI is recommended to improve acid and bile tolerance of the yogurt culture bacteria Strep. thermophilus ST-M5 and Lb. bulgaricus LB-12.

Evaluation of the SD BIOLINE Dengue Duo rapid test in the course of acute and convalescent dengue infections in a Mexican endemic region.

In this study, we evaluated the performance of a rapid test, the SD BIOLINE Dengue Duo (SD BDD) kit, with a panel of serum samples from 310 Mexican patients with diagnosis of dengue infection previously confirmed by reference enzyme-linked immunosorbent assay tests. Eighty-seven negative samples from other febrile illnesses were included as controls. The SD BDD showed an overall sensitivity of 90.65% and specificity of 89.66%. No statistically significant differences were found in the sensitivity of the SD BDD kit compared between primary or secondary infections (87.05% versus 93.57%, respectively, P = 0.0761) and dengue fever or dengue hemorrhagic fever cases (90.77% versus 89.74%, respectively, P = 0.7716). However, a higher sensitivity in the acute phase of dengue infection was found compared with the convalescent phase (93.03% versus 81.82%, respectively, P = 0.0089). These results indicate that the SD BDD kit is a useful tool to diagnose dengue infections, both in primary or secondary infections and mainly during the acute phase.

[Tuberculosis surveillance in the Balearic Islands and characteristics of unreported cases from 2005 to 2007]. / Vigilancia de la tuberculosis en las Islas Baleares y caracterización de los casos infradeclarados entre los años 2005 y 2007.

We performed a descriptive study of tuberculosis cases detected by the Epidemiological Surveillance System in the Balearic Islands in the triennium 2005-2007. Our goal was to characterize underreported cases in sociodemographic terms and their contact with primary care. Overall, underreporting of tuberculosis was approximately 20%. Significant factors in multivariate analysis were social marginality (consisting of alcoholism, intravenous drug use or indigence) (aOR: 2.6 [1.2 to 5.3]), contact with primary care (aOR: 3.2 [1.4 to 7.1]), and extrapulmonary tuberculosis (aOR: 5.5[3.2-9.6]). We recommend strengthening notification by hospital specialists through the use of hospital electronic records. Our findings show that the information obtained from the primary care computerized history is helpful in improving the epidemiological surveillance of tuberculosis.

Vigilancia de la tuberculosis en las Islas Balearesy caracterización de los casos infradeclarados entre los a˜nos 2005 y 2007 / Tuberculosis surveillance in the Balearic Islands and characteristics of unreported cases from 2005 to 2007

Estudio descriptivo de los casos de tuberculosis detectados por el Sistema de Vigilancia Epidemiológicaen Baleares, en el trienio de 2005 a 2007. El objetivo fue caracterizar los casos infradeclarados en términossociodemográficos y de su contacto con la atención primaria de salud. Globalmente, la infradeclaraciónde la tuberculosis se sitúa en torno al 20%. Las características que resultan significativas en el análisismultivariado son la marginalidad social (alcoholismo, usuarios de drogas por vía parenteral o indigencia)(odds ratio ajustada [ORa] : 2,6 [1,2-5,3]), el contacto con la atención primaria (ORa : 3,2 [1,4-7,1]) y latuberculosis extrapulmonar (ORa : 5,5 [3,2-9,6]). Se recomienda reforzar la notificación de los especialistashospitalarios mediante la adecuación informática de la historia clínica hospitalaria, y se observa quela información obtenida desde la informatización de la historia en atención primaria resulta de utilidadpara mejorar la vigilancia epidemiológica de la tuberculosis (AU)

Weperformed a descriptive study of tuberculosis cases detected by the Epidemiological Surveillance Systemin the Balearic Islands in the triennium 2005-2007. Our goal was to characterize underreported casesin sociodemographic terms and their contact with primary care. Overall, underreporting of tuberculosiswas approximately 20%. Significant factors in multivariate analysis were social marginality (consistingof alcoholism, intravenous drug use or indigence) (aOR: 2.6 [1.2 to 5.3]), contact with primary care (aOR:3.2 [1.4 to 7.1]), and extrapulmonary tuberculosis (aOR: 5.5[3.2-9.6]). We recommend strengtheningnotification by hospital specialists through the use of hospital electronic records. Our findings showthat the information obtained from the primary care computerized history is helpful in improving theepidemiological surveillance of tuberculosis (AU)

A meta-systems approach to evidence-based practice for children and adolescents.

Improving outcomes for children and adolescents with mental health needs demands a broad meta-systemic orientation to overcome persistent problems in current service systems. Improving outcomes necessitates inclusion of current and emerging evidence about effective practices for the diverse population of youth and their families. Key components of the meta-system for children with emotional or behavioral needs include families, cultural norms and values, and service sectors such as schools, pediatric health centers, specialty mental health systems, juvenile justice systems, child protection services, and substance use treatment systems. We describe each component of the meta-system, noting challenges to the provision of evidence-based practice (EBP) and highlighting ways to optimize outcomes. Our focus is on the inclusion of evidence-based assessment and interventions, including prevention, within a developmentally driven and culturally responsive contextual model. Recommendations for addressing disparities in research funding and essential steps to foster communication and coordination of EBP across settings are provided.