RESUMO
Alloreactive memory T cells have been implicated as central drivers of transplant rejection. Perplexingly, innate cytokines, such as IL-6, IL-1ß, and IL-12, are also associated with rejection of organ transplants. However, the pathways of innate immune activation in allogeneic transplantation are unclear. While the role of microbial and cell death products has been previously described, we identified alloreactive memory CD4 T cells as the primary triggers of innate inflammation. Memory CD4 T cells engaged MHC II-mismatched dendritic cells (DCs), leading to the production of innate inflammatory cytokines. This innate inflammation was independent of several pattern recognition receptors and was primarily driven by TNF superfamily ligands expressed by alloreactive memory CD4 T cells. Blocking of CD40L and TNFα resulted in dampened inflammation, and mice genetically deficient in these molecules exhibited prolonged survival of cardiac allografts. Furthermore, myeloid cell and CD8 T cell infiltration into cardiac transplants was compromised in both CD40L- and TNFα-deficient recipients. Strikingly, we found that priming of naive alloreactive CD8 T cells was dependent on licensing of DCs by memory CD4 T cells. This study unravels the key mechanisms by which alloreactive memory CD4 T cells contribute to destructive pathology and transplant rejection.
Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Células Dendríticas , Rejeição de Enxerto , Transplante de Coração , Imunidade Inata , Inflamação , Animais , Rejeição de Enxerto/imunologia , Camundongos , Células Dendríticas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Inflamação/imunologia , Imunidade Inata/imunologia , Camundongos Endogâmicos C57BL , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Células T de Memória/imunologia , Camundongos Knockout , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Citocinas/metabolismo , Citocinas/imunologiaRESUMO
Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined. Here, we find that the reparative macrophage transition is dictated by B-cell adapter for PI3K (BCAP). Mice harboring a macrophage-specific deletion of BCAP fail to recover from and succumb to dextran sulfate sodium-induced colitis due to prolonged intestinal inflammation and impaired tissue repair. Following microbial stimulation, gene expression in WT macrophages switches from an early inflammatory signature to a late reparative signature, a process that is hampered in BCAP-deficient macrophages. We find that absence of BCAP hinders inactivation of FOXO1 and GSK3ß, which contributes to their enhanced inflammatory state. BCAP deficiency also results in defective aerobic glycolysis and reduced lactate production. This translates into reduced histone lactylation and decreased expression of reparative macrophage genes. Thus, our results reveal BCAP to be a critical cell-intrinsic switch that regulates transition of inflammatory macrophages to reparative macrophages by imprinting epigenetic changes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Histonas/metabolismo , Macrófagos/metabolismo , Transdução de Sinais , Receptores Toll-Like/metabolismo , Animais , Camundongos , Processamento de Proteína Pós-TraducionalRESUMO
It is important to focus on common pediatric fractures seen in community emergency rooms, including supracondylar humerus, elbow, forearm, distal radius, and femoral shaft fractures, along with periarticular fractures around the knee and ankle in children. The principles of surgical and nonsurgical management of these fractures are based on the fracture type and age of the patient. The orthopaedic surgeon should be aware of important tips and tricks to help manage these injuries and be familiar with common complications that may occur when these injuries are encountered during trauma call.
Assuntos
Fraturas do Úmero , Ortopedia , Criança , Humanos , Antebraço , Fraturas do Úmero/complicações , Fraturas do Úmero/cirurgia , ÚmeroRESUMO
BACKGROUND: The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance imaging at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly. OBJECTIVE: This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging-determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis. STUDY DESIGN: This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks' gestational age with acute moderate to severe histologic chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic chorioamnionitis and brain abnormality score using mediation analysis. RESULTS: Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (ß=2.84; 1.51-4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities after the significant indirect effects of preterm birth were accounted for. CONCLUSION: Acute histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.
Assuntos
Corioamnionite , Doenças do Prematuro , Malformações do Sistema Nervoso , Complicações na Gravidez , Nascimento Prematuro , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Corioamnionite/diagnóstico , Estudos de Coortes , Feminino , Retardo do Crescimento Fetal/patologia , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico por imagem , Doenças do Prematuro/epidemiologia , Imageamento por Ressonância Magnética , Gravidez , Complicações na Gravidez/patologia , Nascimento Prematuro/epidemiologia , Estudos ProspectivosRESUMO
Chorioamnionitis or intrauterine inflammation is a frequent cause of preterm birth. Chorioamnionitis can affect almost every organ of the developing fetus. Multiple microbes have been implicated to cause chorioamnionitis, but "sterile" inflammation appears to be more common. Eradication of microorganisms has not been shown to prevent the morbidity and mortality associated with chorioamnionitis as inflammatory mediators account for continued fetal and maternal injury. Mounting evidence now supports the concept that the ensuing neonatal immune dysfunction reflects the effects of inflammation on immune programming during critical developmental windows, leading to chronic inflammatory disorders as well as vulnerability to infection after birth. A better understanding of microbiome alterations and inflammatory dysregulation may help develop better treatment strategies for infants born to mothers with chorioamnionitis.
Assuntos
Corioamnionite/fisiopatologia , Corioamnionite/imunologia , Corioamnionite/microbiologia , Corioamnionite/terapia , Citocinas/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Resultado da Gravidez , Nascimento PrematuroRESUMO
Preterm birth (PTB) is a major cause of neonatal mortality and morbidity, often triggered by chorioamnionitis or intrauterine inflammation (IUI) with or without infection. Recently, there has been a strong association of IL-1 with PTB. We hypothesized that IL-1R-associated kinase 1 (IRAK1), a key signaling mediator in the TLR/IL-1 pathway, plays a critical role in PTB. In human fetal membranes (FM) collected immediately after birth from women delivering preterm, p-IRAK1 was significantly increased in all the layers of FM with chorioamnionitis, compared with no-chorioamnionitis subjects. In a preterm rhesus macaque model of IUI given intra-amniotic LPS, induction of p-IRAK1 and downstream proinflammatory signaling mediators were seen in the FM. In a C57BL/6J wild-type PTB mouse model of IUI given intrauterine LPS, an IRAK1 inhibitor significantly decreased PTB and increased live birth in a dose-dependent manner. Furthermore, IRAK1 knockout mice were protected from LPS-induced PTB, which was seen in wild-type controls. Activation of IRAK1 was maintained by K63-mediated ubiquitination in preterm FM of humans with chorioamnionitis and rhesus and mouse IUI models. Mechanistically, IRAK1 induced PTB in the mouse model of IUI by upregulating expression of COX-2. Thus, our data from human, rhesus, and mouse demonstrates a critical role IRAK1 in IUI and inflammation-associated PTB and suggest it as potential therapeutic target in IUI-induced PTB.
Assuntos
Membranas Extraembrionárias/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Nascimento Prematuro/metabolismo , Útero/imunologia , Adulto , Animais , Corioamnionite , Modelos Animais de Doenças , Membranas Extraembrionárias/patologia , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Lipopolissacarídeos/imunologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Nascimento Prematuro/imunologia , Adulto JovemRESUMO
OBJECTIVE: To assess whether a citywide structured book-sharing program (NICU Bookworms) designed to promote reading to infants while admitted in the neonatal intensive care unit (NICU) would increase parental reading behaviors (≥3-4 days/week) in the NICU and after discharge home, including high-risk parents who do not themselves enjoy reading. STUDY DESIGN: The NICU Bookworms program comprised staff training, parent education, and building a literacy-rich environment. In this quasi-experimental intervention study, parents of medically high-risk NICU graduates <6 months of age were administered a questionnaire at their first NICU follow-up clinic visit. The survey incorporated questions from the StimQ-I READ subscale to assess home reading environment and shared reading practices. RESULTS: A total of 317 infants were enrolled, 187 in an unexposed comparison group and 130 in the intervention group. Parents exposed to Bookworms were significantly more likely to read ≥3-4 days per week while in the NICU (34.5% vs 51.5%; P = .002; aOR, 2.2; 95% CI, 1.2-4.0), but reading at home did not differ (67.9% vs 73.1%; P = .28; aOR, 0.99; 95% CI, 0.5-1.8). However, among parents who did not themselves enjoy reading, frequency was significantly higher both in the NICU (18.4% vs 46.1%; P = .009; aOR, 5.0; 95% CI, 1.2-21.5) and at home (36.9% vs 70%; P = .003; aOR, 3.7; 95% CI, 1.1-12.9). A qualitative thematic analysis found that Bookworms decreased parental stress, enhanced bonding, and supported positive parent-infant interactions. CONCLUSIONS: A book-sharing intervention in the NICU increased parent-reported reading aloud during hospitalization and among parents disinclined to read for pleasure, both in the NICU and following discharge. This change may have been mediated by enhancement of parent-infant interactions.
Assuntos
Unidades de Terapia Intensiva Neonatal , Pais , Leitura , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Apego ao Objeto , Relações Pais-Filho , Estresse Psicológico/prevenção & controle , Inquéritos e QuestionáriosRESUMO
PURPOSE: While posterior-alone techniques have been successful for most pediatric spinal deformities, anterior spinal release may be useful for severe rigid deformities. Traditional lateral-positioned video-assisted thoracoscopic surgical release (VATSR) followed by prone posterior spinal fusion (PSF) has been criticized for adding extensive operative morbidity. We aimed to reduce its disadvantages by performing prone VATSR and PSF simultaneously and evaluate its long-term outcomes. METHODS: All consecutive patients from 1991 to 2012 undergoing VATSR and PSF at one institution were retrospectively reviewed. The inclusion criteria comprised severe rigid thoracic scoliosis (> 70°, bending correction > 45°) or kyphosis (> 75°, bolster correction > 45°), and a minimum 2 year follow-up. Demographics, operative data, hospital stay, and radiographic correction data were compared between patients who had undergone sequential VATSR followed by PSF and those who had undergone these procedures simultaneously. RESULTS: Of 153 patients who had undergone VATSR and PSF, 53 met the inclusion criteria (31 sequential, 22 simultaneous; average follow-up, 50 [range, 24-86] months). Age, preoperative measurements and flexibility, and perioperative complications did not differ significantly. The simultaneous group showed significantly lower operative time (449 vs. 618 min), blood loss (1039 vs. 1906 cc), and hospital stay (6.3 vs. 8.5 days) (all, p < 0.05). Postoperative radiographic correction and maintenance at the final follow-up showed a non-significant trend favoring the simultaneous group. CONCLUSION: Our simultaneous prone VATSR and PSF technique showed significantly lower operative time, blood loss, and hospital stay compared with the traditional sequential VATSR and PSF method, suggesting its value in treating rigid deformities.
Assuntos
Escoliose , Fusão Vertebral , Criança , Humanos , Estudos Retrospectivos , Cirurgia Torácica Vídeoassistida , Vértebras Torácicas , Resultado do TratamentoRESUMO
PURPOSE: To investigate the risk and predictive factors of junctional issues after conversion from Traditional growing rod (TGR) to definitive spinal fusion in Early-onset scoliosis (EOS). METHODS: Retrospective review of a multicenter EOS database. TGR patients who received final fusion with at least two-year follow-up were included. Proximal (PJA) and Distal junctional angles (DJA) on pre-final fusion, post-final fusion (within one year of surgery), and at latest follow-up were measured on lateral upright spinal radiographs. Differences in values among designated time points and predictive factors of junctional issues were evaluated statistically. RESULTS: Forty-six of 251 patients (28 females, 18 males and mean age at final fusion: 12 ± 2 [9-17] years) met the inclusion criteria. Mean follow-up between first postoperative measurement and latest follow-up was 49 ± 22 (24-112) months. No statistical differences in PJA and DJA values were available at pre-fusion, first post-fusion, or latest follow-up (p = 0.827, p = 0.076). Fifty percent of patients had extension of TGR instrumentation at fusion, either proximal or distal. No factor including sex and etiology, lumbar lordosis, thoracic kyphosis, major curve magnitude, PJA, and DJA at pre-fusion was found to be a predictive issue for extension of index TGR instrumentation, except the history of at least one implant-related complication during the period from index surgery to the definitive fusion. CONCLUSION: PJA and DJA remained stable when transitioning from TGR to final posterior spinal fusion. But 50% of patients had extension of construction at fusion, either proximal or distal.
Assuntos
Cifose , Escoliose , Fusão Vertebral , Feminino , Seguimentos , Humanos , Cifose/diagnóstico por imagem , Cifose/epidemiologia , Cifose/cirurgia , Masculino , Prevalência , Estudos Retrospectivos , Escoliose/diagnóstico por imagem , Escoliose/epidemiologia , Escoliose/cirurgia , Fusão Vertebral/efeitos adversosRESUMO
Congenital tibial pseudarthrosis is a rare condition seen in neurofibromatosis type 1 (NF1), and treatment is complex. A randomized, placebo-controlled trial of bone morphogenetic protein (rhBMP-2; INFUSE bone graft) at time of tibial surgery was developed by the Neurofibromatosis Clinical Trials Consortium. Patients were randomized to receive rhBMP-2 that would, or would not, be added to the standard surgical procedure consisting of resection of pseudarthrosis tissue, insertion of a rigid intramedullary rod, and placement of autogenous iliac crest bone graft. Despite involvement of 16 centers with wide experience with NF1 orthopaedic management, only 5 patients (of 54 required) were able to be enrolled in the study during a 3-year time period. Because of the inability to recruit sufficient patients, this study was closed in June 2019, with plans to terminate. The obstacles that were encountered during the study are summarized. The authors question whether a randomized, placebo-controlled trial of a rare pediatric orthopaedic condition is possible to accomplish. Recommendations are provided to guide future studies of orthopaedic manifestations of NF1.Level of Evidence: Level V.
Assuntos
Proteína Morfogenética Óssea 2/farmacologia , Neurofibromatose 1/cirurgia , Procedimentos Ortopédicos/métodos , Seleção de Pacientes , Pseudoartrose , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Fator de Crescimento Transformador beta/farmacologia , Proteínas Morfogenéticas Ósseas/farmacologia , Humanos , Neurofibromatose 1/complicações , Pseudoartrose/congênito , Pseudoartrose/cirurgia , Doenças Raras , Proteínas Recombinantes/farmacologia , Tamanho da Amostra , Tíbia/anormalidades , Tíbia/cirurgiaRESUMO
BACKGROUND: Most neonatal outcomes in neonates are related to normal adrenal gland function. Assessment of adrenal function in a sick preterm neonate remains a challenge, thus we hypothesized that adrenal steroid precursors to their product ratios have a direct relationship with neonatal outcomes. METHODS: We studied demographics of pregnancy and neonatal outcomes in 99 mother-infant pairs (24-41 weeks) and assayed 7 glucocorticoid precursors in the cortisol biosynthesis/degradation pathway. We correlated antenatal factors and short-term neonatal outcomes with these precursors and their ratios to assess maturity of individual enzymes. RESULTS: We found no correlation between cortisol levels with antenatal factors and outcomes. Antenatal steroid use impacted several cortisol precursors. 17-OH pregnenolone-to-cortisol ratio at birth was the best predictor of short-term neonatal outcomes, such as hypotension, RDS, IVH and PDA. A cord blood 17-OH pregnenolone:cortisol ratio of <0.21 predicts which neonate will have a normal outcome with a high sensitivity and specificity. CONCLUSIONS: Maternal factors and antenatal steroids impact neonatal adrenal function and leads to maturation of adrenal function. 17-OH pregnenolone:cortisol ratio and not cortisol is the best predictor of adrenal function. Adrenal function can be assessed by evaluating the profile of adrenal steroids.
Assuntos
17-alfa-Hidroxipregnenolona/sangue , Testes de Função do Córtex Suprarrenal , Glândulas Suprarrenais/metabolismo , Hidrocortisona/sangue , Glândulas Suprarrenais/crescimento & desenvolvimento , Fatores Etários , Biomarcadores/sangue , Desenvolvimento Infantil , Feminino , Humanos , Recém-Nascido , Valor Preditivo dos Testes , Gravidez , Prognóstico , Estudos Prospectivos , Fatores de TempoRESUMO
Inflammatory responses are controlled by signaling mediators that are regulated by various posttranslational modifications. Recently, transcription-independent functions for glucocorticoids (GC) in restraining inflammation have emerged, but the underlying mechanisms are unknown. In this study, we report that GC receptor (GR)-mediated actions of GC acutely suppress TLR9-induced inflammation via inhibition of IL-1R-associated kinase 1 (IRAK1) ubiquitination. ß-TrCP-IRAK1 interaction is required for K48-linked ubiquitination of IRAK1 at Lys134 and subsequent membrane-to-cytoplasm trafficking of IRAK1 interacting partners TNFR-associated factor 6 and TAK1 that facilitates NF-κB and MAPK activation. Upon costimulation of macrophages with GC and TLR9-engaging ligand, GR physically interacts with IRAK1 and interferes with protein-protein interactions between ß-TrCP and IRAK1. Ablation of GR in macrophages prevents GC-dependent suppression of ß-TrCP-IRAK1 interactions. This GC-mediated suppression of IRAK1 activation is unique to TLR9, as GC treatment impairs TLR9 but not TLR4 ligand-induced K48-linked IRAK1 ubiquitination and trafficking of IRAK1 interacting partners. Furthermore, mutations in IRAK1 at Lys134 prevent TLR9 ligand-induced activation of inflammatory signaling mediators and synthesis of proinflammatory cytokines to an extent comparable to GC-mediated inhibition. Collectively, these findings identify a transcription-independent, rapid, and nongenomic GC suppression of TLR9 ligand-mediated IRAK1 ubiquitination as a novel mechanism for restraining acute inflammatory reactions.
Assuntos
Glucocorticoides/metabolismo , Inflamação/imunologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Macrófagos/imunologia , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Ligação Proteica , Transporte Proteico , Receptor Toll-Like 9/metabolismo , UbiquitinaçãoRESUMO
BACKGROUND: Extensor pollicis longus (EPL) tendon injury following the dorsal approach to elastic stable intramedullary nailing (ESIN) of the radius has been reported in a growing number of cases in the literature. This study includes 5 new cases from our institution as well as a comprehensive review of previously reported cases from the literature. METHODS: We conducted a retrospective chart review of all patients undergoing ESIN between January 1, 2004 and December 31, 2013 at our institution. Those patients with an EPL injury or rupture were identified and clinical data collected included operative technique, diagnosis, treatment, and outcomes data. In addition, we performed a systematic review of the literature using Pubmed MEDLINE database, the Chochrane database, Scopus, Web of Science, and Embase. A total of 28 cases of EPL injury following ESIN of the radius were identified in the literature and the relevant data were extracted from those studies. RESULTS: All 33 pediatric cases of EPL tendon injury occurred after entry to the radial canal was obtained by the dorsal approach to ESIN. EPL injury was diagnosed an average of 10 weeks following the index procedure. Extensor indicis pollicis to EPL transfer was performed in 13 patients, tendon release/lysis of adhesions in 5, EPL repair in 2, EPL graft reconstruction from palmaris longus tendon in 1, 3 patients refused further intervention, and treatment was unreported in 7 cases. By 12-month follow-up, all operatively treated patients had a good functional outcome with near anatomic extension at the thumb interphalangeal joint, no pain, and no further complication. CONCLUSIONS: EPL tendon injury was found to be a complication unique to the dorsal entry approach for ESIN of the radius. The lateral approach appears to offer a safer alternative with regard to the EPL tendon. We suggest that physicians consider the risk of EPL tendon injury when planning for ESIN of the radius, and make an effort to avoid direct injury when using a dorsal approach. LEVEL OF EVIDENCE: Level III-therapeutic.
Assuntos
Pinos Ortopédicos/efeitos adversos , Fixação Intramedular de Fraturas/efeitos adversos , Fraturas do Rádio/cirurgia , Traumatismos dos Tendões/etiologia , Transferência Tendinosa/métodos , Adolescente , Criança , Feminino , Humanos , Masculino , Fraturas do Rádio/diagnóstico , Estudos Retrospectivos , Traumatismos dos Tendões/diagnóstico , Traumatismos dos Tendões/cirurgiaAssuntos
Hérnias Diafragmáticas Congênitas , Humanos , NF-kappa B , Organogênese , Transdução de Sinais , PulmãoRESUMO
STUDY QUESTION: Does cord blood androgen level obtained at birth affect the AGD in human newborns? SUMMARY ANSWER: In human newborns, though males have a significantly longer AGD compared to females (as early as 22 weeks of gestation) the AGD is not affected by androgen levels at birth in both the sexes. WHAT IS KNOWN ALREADY: Animal studies have reported a critical time period in early fetal life, termed the masculinization programming window (MPW) during which AGD is fixed by in utero androgen action and is unaffected by testosterone levels later during gestation. Thus, AGD may serve as a lifelong biomarker of androgen exposure during this window. This MPW is hypothesized to occur in humans at 8-14 weeks of gestation during which AGD is fixed. The effect of androgens (testosterone) on AGD after the MPW in humans is not known. Furthermore, altered AGD has been associated with various human reproductive health disorders in both males and females. STUDY DESIGN, SIZE, DURATION: A prospective descriptive cohort study was performed using data from randomly selected neonates (n = 205) born at a single center over a period of 1 year (August 2015 to August 2016). PARTICIPANTS/MATERIALS, SETTING, METHODS: AGDs in male (n = 117) and female infants (n = 88) together with penile width, glans girth and stretched penile length were measured by trained caregivers. Gestation ranged from 22 to 41 weeks and infants were examined within 24 h of birth (within 48-72 h in very sick preterm infants after clinical stabilization). AGD-1 was measured from the center of the anus to the posterior base of scrotum in males or to the posterior fourchette in females. AGD-2 was measured from the center of the anus to the anterior base of the penis in males or to the clitoris in females. Sex steroid hormones (testosterone, 17-OH progesterone (17-OHP) and androstenedione) were measured in serum prepared from umbilical cord blood samples taken at birth, using liquid chromatography-tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: Males had a significantly lower gestational age (mean ± SD; 34.6 ± 4.9 versus 36.1 ± 4.1 weeks, P = 0.04), and a significantly longer AGD-1 (mean ± SD; 21.6 ± 6.0 versus 12.7 ± 3.8 mm, P < 0.001) and AGD-2 (41.9 ± 8.7 versus 33.9 ± 7.1 mm, P = 0.004) compared to female infants, respectively. The cord serum testosterone levels were significantly higher for male than female infants [median, interquartile range; 13.0 (7.3, 20.5) versus 4.1 (2.5, 5.9), ng/dl, P < 0.001]. There was no difference in levels of 17-OHP (P = 0.697) or androstenedione (P = 0.601) between the two sexes. On multiple regression analysis after adjusting for potential confounders, none of the AGD's in both males and females correlated with any sex steroid hormonal levels. We also provide normative charts for penile length, penile width and glans girth in preterm and term infants. LIMITATIONS, REASONS FOR CAUTION: No data were collected on family history of genital malformation, infertility or hormonal disorders, parental endocrine-disrupting chemical exposure or diet pattern, any of which might have influenced the AGD and/or sex steroid hormone levels in the offspring. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that AGD in humans, like animals, is fixed in early gestation (likely during the hypothesized MPW) and is unaffected by androgen levels thereafter. Thus, AGD can serve as a biomarker of in utero androgen action during early gestation (likely 8-14 weeks) in humans. As such, causes of human newborn and adult reproductive health disorders, such as endocrine disruptors, should be explored during early gestation. However, further larger studies are needed to help corroborate these findings. STUDY FUNDING/COMPETING INTERESTS: No specific funding was obtained for this study, and all authors have no conflict of interest to declare.
Assuntos
Canal Anal/anatomia & histologia , Clitóris/anatomia & histologia , Pênis/anatomia & histologia , Escroto/anatomia & histologia , Vulva/anatomia & histologia , Androstenodiona/sangue , Feminino , Sangue Fetal , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Progesterona/sangue , Estudos Prospectivos , Fatores Sexuais , Espectrometria de Massas em Tandem , Testosterona/sangueRESUMO
BACKGROUND: Enhanced recovery after surgery protocols increasingly use multimodal analgesia after major surgeries with intravenous acetaminophen and ketorolac, despite no documented cost-effectiveness of these strategies. AIMS: The goal of this prospective cohort study was to model cost-effectiveness of adding acetaminophen or acetaminophen + ketorolac to opioids for postoperative outcomes in children having scoliosis surgery. METHODS: Of 106 postsurgical children, 36 received only opioids, 26 received intravenous acetaminophen, and 44 received acetaminophen + ketorolac as analgesia adjuncts. Costs were calculated in 2015 US $. Decision analytic model was constructed with Decision Maker® software. Base-case and sensitivity analyses were performed with effectiveness defined as avoidance of opioid adverse effects. RESULTS: The groups were comparable demographically. Compared with opioids-only strategy, subjects in the intravenous acetaminophen + ketorolac strategy consumed less opioids (P = .002; difference in mean morphine consumption on postoperative days 1 and 2 was -0.44 mg/kg (95% CI -0.72 to -0.16); tolerated meals earlier (P < .001; RR 0.250 (0.112-0.556)) and had less constipation (P < .001; RR 0.226 (0.094-0.546)). Base-case analysis showed that of the 3 strategies, use of opioids alone is both most costly and least effective, opioids + intravenous acetaminophen is intermediate in both cost and effectiveness; and opioids + intravenous acetaminophen and ketorolac is the least expensive and most effective strategy. The addition of intravenous acetaminophen with or without ketorolac to an opioid-only strategy saves $510-$947 per patient undergoing spine surgery and decreases opioid side effects. CONCLUSION: Intravenous acetaminophen with or without ketorolac reduced opioid consumption, opioid-related adverse effects, length of stay, and thereby cost of care following idiopathic scoliosis in adolescents compared with opioids-alone postoperative analgesia strategy.
Assuntos
Acetaminofen/economia , Acetaminofen/uso terapêutico , Analgésicos não Narcóticos/economia , Analgésicos não Narcóticos/uso terapêutico , Anti-Inflamatórios não Esteroides/economia , Anti-Inflamatórios não Esteroides/uso terapêutico , Cetorolaco de Trometamina/economia , Cetorolaco de Trometamina/uso terapêutico , Escoliose/cirurgia , Acetaminofen/administração & dosagem , Adolescente , Analgésicos não Narcóticos/administração & dosagem , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/administração & dosagem , Criança , Estudos de Coortes , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Quimioterapia Combinada/economia , Feminino , Humanos , Injeções Intravenosas , Cetorolaco de Trometamina/administração & dosagem , Masculino , Dor Pós-Operatória/tratamento farmacológico , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Magnetically controlled growing rods (MCGRs) are increasingly used in the treatment of early onset scoliosis (EOS). Few studies have reported whether desired lengthening can reliably be achieved, or if prior spine instrumentation and large tissue depths affect lengthening. In this clinical study of EOS patients, it was hypothesized that increases in rod length would equal programmed increases, patients with prior spine instrumentation would lengthen less than patients without prior surgery, and larger tissue depths would decrease lengthening success. METHODS: A retrospective chart review was conducted on EOS patients with single and dual MCGRs placed between April 2014 to September 2015 and distracted at a single institution. Rod distraction was measured at each visit using ultrasound. Differences between programmed and actual distraction for each patient, and between groups with and without prior spine instrumentation, were determined by 2-tailed t tests. Regression and correlation were used to determine the relationship between tissue depth and length increases. RESULTS: Thirty-one patients were included, 18 males, 13 females, age 8.1 (±2.5) years, with major curves measuring 60 (±14.6) degrees at time of MCGR insertion. In the 12 patients with prior instrumentation, time from initial growing rod placement to MCGR insertion was 23.1 (±10.6) months. The number of surgical procedures before MCGR insertion was 2.8 (±2.0). Total length increase relative to the programmed distraction was 86% (±21) (P<0.001). Length increases for patients with and without prior surgery were 87% (±23) and 86% (±19), respectively (P>0.9). Total lengthening was inversely proportional to tissue depth (r=0.38, P<0.01); the decrease in lengthening achieved was 2.1%/mm of tissue depth. CONCLUSIONS: Increases in rod length were 14% lower than the programmed distraction. Prior instrumentation did not impact the amount of rod distraction. Greater distance between the rod and the skin surface negatively affected the magnitude of distraction.
Assuntos
Fixadores Internos , Próteses e Implantes , Escoliose/cirurgia , Criança , Feminino , Humanos , Imãs , Masculino , Estudos Retrospectivos , Escoliose/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/crescimento & desenvolvimento , UltrassonografiaRESUMO
BACKGROUND: Spinal deformities associated with neurofibromatosis type 1 (NF1) often have an early onset. These curves frequently develop dysplastic features. Rapid progression is common, and is often difficult to control with casting or bracing. Spinal fusion at a young age can potentially interfere with chest and trunk growth. Growing rods (GRs) have been used in early-onset scoliosis (EOS) effectively. The purpose of this study was to evaluate GR use in NF1. METHODS: Retrospective data collection was performed from a multicenter EOS database with additional patients from our own institute. Each patient had a genetic diagnosis of NF1 and was treated with GR. Results were compared with reported results of GR in EOS in the literature. RESULTS: Fourteen patients from 5 centers underwent a total of 71 procedures with an average follow-up of 54 months. Mean age at surgery was 6.8 years. Means of initial and final curves were 74 and 36 degrees, respectively (51% correction). Spine grew at an average of 39 mm (11.2 mm per year). Implant-related complications were the most common (8/14, 57%), including failure of proximal construct (5/14), rod breakage (2/14), and prominent implants (1/14). There was no significant difference between screws and hooks as proximal anchors (Fischer test). Two patients had deep infection that needed debridement. CONCLUSIONS: This retrospective pooled data study is the first report on the treatment of early-onset NF1 scoliosis with GRs. The use of GRs in these patients effectively controls the spinal deformity and facilitates growth of the spine. The complications were no greater than those seen in other conditions causing EOS. Failure of proximal anchors was found to be the most common complication. LEVEL OF EVIDENCE: Level IV-retrospective case series.