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BACKGROUND: Fetoscopic spina bifida repair is increasingly being practiced, but limited skill acquisition poses a barrier to widespread adoption. Extensive training in relevant models, including both ex vivo and in vivo models may help. To address this, a synthetic training model that is affordable, realistic, and that allows skill analysis would be useful. OBJECTIVE: This study aimed to create a high-fidelity model for training in the essential neurosurgical steps of fetoscopic spina bifida repair using synthetic materials. In addition, we aimed to obtain a cheap and easily reproducible model. STUDY DESIGN: We developed a 3-layered, silicon-based model that resemble the anatomic layers of a typical myelomeningocele lesion. It allows for filling of the cyst with fluid and conducting a water tightness test after repair. A compliant silicon ball mimics the uterine cavity and is fixed to a solid 3-dimensional printed base. The fetal back with the lesion (single-use) is placed inside the uterine ball, which is reusable and repairable to allow for practicing port insertion and fixation multiple times. Following cannula insertion, the uterus is insufflated and a clinical fetoscopic or robotic or prototype instruments can be used. Three skilled endoscopic surgeons each did 6 simulated fetoscopic repairs using the surgical steps of an open repair. The primary outcome was surgical success, which was determined by water tightness of the repair, operation time <180 minutes and an Objective Structured Assessment of Technical Skills score of ≥18 of 25. Skill retention was measured using a competence cumulative sum analysis of a composite binary outcome of surgical success. Secondary outcomes were cost and fabrication time of the model. RESULTS: We made a model that can be used to simulate the neurosurgical steps of spina bifida repair, including anatomic details, port insertion, placode release and descent, undermining of skin and muscular layer, and endoscopic suturing. The model was made using reusable 3-dimensional printed molds and easily accessible materials. The 1-time startup cost was 211, and each single-use, simulated myelomeningocele lesion cost 9.5 in materials and 50 minutes of working time. Two skilled endoscopic surgeons performed 6 simulated, 3-port fetoscopic repairs, whereas a third used a Da Vinci surgical robot. Operation times decreased by more than 30% from the first to the last trial. Six experiments per surgeon did not show an obvious Objective Structured Assessment of Technical Skills score improvement. Competence cumulative sum analysis confirmed competency for each surgeon. CONCLUSION: This high-fidelity, low-cost spina bifida model allows simulated dissection and closure of a myelomeningocele lesion. VIDEO ABSTRACT.
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Meningomielocele , Disrafia Espinal , Embarazo , Femenino , Humanos , Meningomielocele/diagnóstico , Meningomielocele/cirugía , Silicio , Disrafia Espinal/diagnóstico , Disrafia Espinal/cirugía , Fetoscopía/métodos , AguaRESUMEN
Congenital diaphragmatic hernia (CDH) is a congenital malformation characterized by pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction. Pulmonary hypertension represents the major cause of neonatal mortality and morbidity. Prenatal diagnosis allows assessment of severity and selection of foetal surgery candidates. We have shown that treprostinil, a prostacyclin analogue with an anti-remodelling effect, attenuates the relative hypermuscularization of the pulmonary vasculature in rats with nitrofen-induced CDH. Here we confirm these observations in a large animal model of surgically-created CDH. In the rabbit model, subcutaneous maternal administration of treprostinil at 150 ng/kg/min consistently reached target foetal concentrations without demonstrable detrimental foetal or maternal adverse effects. In pups with CDH, prenatal treprostinil reduced pulmonary arteriolar proportional medial wall thickness and downregulated inflammation and myogenesis pathways. No effect on alveolar morphometry or lung mechanics was observed. These findings provide further support towards clinical translation of prenatal treprostinil for CDH.
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Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Embarazo , Femenino , Conejos , Ratas , Animales , Hernias Diafragmáticas Congénitas/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Ratas Sprague-Dawley , Pulmón/metabolismo , Éteres Fenílicos/efectos adversos , Éteres Fenílicos/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Prenatal spina bifida aperta repair improves neurologic outcomes yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce such complications, different fetoscopic techniques, for example, with varying numbers of ports, are being explored. This has an effect on the duration of the procedure, potentially affecting central nervous system development. Both the condition and anesthesia can affect the central nervous system, particularly the hippocampus, a region crucial for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area. OBJECTIVE: This study aimed to compare the effects of 2- vs 3-port fetoscopic spina bifida aperta repair in the fetal lamb model using neuron count of the hippocampus as the primary outcome. STUDY DESIGN: Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required 5 animals per group to achieve a statistical power of ≥ 80%. A spina bifida aperta defect was developed in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean delivery, anesthetized, and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine magnetic resonance imaging after which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on magnetic resonance images and volumes of relevant brain and medulla areas were segmented. RESULTS: Both treatment groups included 5 fetuses and 9 unoperated littermates served as normal controls. The durations for both skin-to-skin (341±31 vs 287±40 minutes; P=.04) and fetal surgery (183±30 vs 128±22; P=.01) were longer for the 2-port approach than for the 3-port approach. There was no significant difference in neuron density in the hippocampus, frontal cortex, and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965±156 vs 767±92 neurons/mm2; P=.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in animals undergoing the 2-port approach than in animals undergoing the 3-port approach (-0.72±0.67 vs -2.47±0.91 mm; P=.009). There was no significant difference in the ratio of the hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no difference was noted in spine volume-to-body weight ratio for the lower (L1-L2), middle (L3-L4), and higher (L5-L6) levels. Compared with controls, in repaired animals, the cerebellar vermis tip laid closer to the foramen magnum, parietal ventricles were enlarged, and medulla volumes were reduced. CONCLUSION: In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. However, there was no indication of any relevant morphologic differences in the fetal brain.
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Espina Bífida Quística , Disrafia Espinal , Embarazo , Femenino , Ovinos , Animales , Humanos , Espina Bífida Quística/cirugía , Estudios Prospectivos , Disrafia Espinal/cirugía , Feto , Sistema Nervioso Central , Peso CorporalRESUMEN
The so called "Artificial Placenta" and "Artificial Womb" (EXTEND) technologies share a common goal of improving outcomes for extreme premature infants. Beyond that goal, they are very dissimilar and, in our view, differ sufficiently in their technology, intervention strategy, demonstrated physiology, and risk profiles that bundling them together for consideration of the ethical challenges in designing first in human trials is misguided. In this response to the commentary by Kukora and colleagues, we will provide our perspective on these differences, and how they impact ethical clinical study design for first-in-human trials of safety/feasibility, and subsequently efficacy of the two technologies.
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Recien Nacido Prematuro , Placenta , Embarazo , Recién Nacido , Lactante , Femenino , Humanos , Útero , TecnologíaRESUMEN
Maternal-fetal surgical interventions have become a more common part of prenatal care. This third option, beside termination or post-natal interventions, complicates prenatal decision-making: while interventions may be lifesaving, survivors may face a life with disability. Pediatric palliative care (PPC) is more than end of life or hospice care, it aims at helping patients with complex medical conditions live well. In this paper, we briefly discuss maternal-fetal surgery, challenges regarding counseling and benefit-risk evaluation, argue that PPC should be a routine part of prenatal consultation, discuss the pivotal role of the maternal-fetal surgeon in the PCC-team, and finally discuss some of the ethical considerations of maternal-fetal surgery. We illustrate this with a case example of an infant diagnosed with congenital diaphragmatic hernia (CDH).
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Terapias Fetales , Hernias Diafragmáticas Congénitas , Lactante , Embarazo , Femenino , Humanos , Niño , Cuidados Paliativos , Hernias Diafragmáticas Congénitas/cirugía , Familia , Diagnóstico PrenatalRESUMEN
OBJECTIVE: To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH). STUDY DESIGN: A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores. RESULTS: Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded. CONCLUSIONS: In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.
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Antihipertensivos , Epoprostenol , Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Humanos , Antihipertensivos/uso terapéutico , Epoprostenol/uso terapéutico , Masculino , Femenino , Hernias Diafragmáticas Congénitas/tratamiento farmacológico , Hipertensión Pulmonar/tratamiento farmacológico , Estudios Retrospectivos , Recién Nacido , Péptido Natriurético Encefálico/sangre , Resultado del TratamientoRESUMEN
This Viewpoint discusses ethical issues surrounding the use of artificial womb technology for extremely premature infants.
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Recien Nacido Prematuro , Sistemas de Manutención de la Vida , Humanos , Recién NacidoRESUMEN
Since the early 1980's, with the clinical advent of in vitro fertilization resulting in so-called "test tube babies," a wide array of ethical considerations and concerns regarding artificial womb technology (AWT) have been described. Recent breakthroughs in the development of extracorporeal neonatal life support by means of AWT have reinitiated ethical interest about this topic with a sense of urgency. Most of the recent ethical literature on the topic, however, pertains not to the more imminent scenario of a physiologically improved method of neonatal care through AWT, but instead to the remote scenario of "complete ectogenesis" that imagines human gestation occurring entirely outside of the womb. This scoping review of the ethical literature on AWT spans from more abstract concerns about complete ectogenesis to more immediate concerns about the soon-to-be-expected clinical life support of what we term the fetal neonate or fetonate. Within an organizing framework of different stages of human gestational development, from conception to the viable premature infant, we discuss both already identified and newly emerging ethical considerations and concerns regarding AWT and the care of the fetonate.
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Recien Nacido Prematuro , Útero , Recién Nacido , Femenino , Lactante , Humanos , Feto , TecnologíaRESUMEN
BACKGROUND: Thoracoscopic bilateral T3 sympathectomy for primary focal palmar hyperhidrosis in children has excellent short-term outcomes. However, data in the literature, on the long-term outcomes of the operation are scarce. METHODS: We conducted a retrospective institutional review of all children and adolescents undergoing T3 bilateral thoracoscopic sympathectomy for primary focal palmar hyperhidrosis between June 2013 and October 2020. We composed a quality of life (QoL) questionnaire evaluating the patient's perception of how much the hyperhidrosis affected their daily life in multiple domains. The questionnaire was completed before the operation and at every postoperative follow-up visit. RESULTS: We operated on 58 patients with a median age of 15 (6-25) years. There were no intraoperative or postoperative complications, and all patients had immediate complete postoperative resolution of their palmar hyperhidrosis. Fifty-three patients (91.4%) had long-term follow-up data available with a median of 2.5 (range 0.1-7.5) years. Two patients (3.4%) experienced recurrence of their palmar hyperhidrosis. Nine patients (15.5%) experienced compensatory hyperhidrosis and required occasional medical management with oral anticholinergics. Two patients reported regretting having undergone the operation. Overall, the mean QoL score improved remarkably, from 42/100 before the operation to 92/100 at 1 month, 89/100 at six months to a year, 97/100 between two and four years, and 80/100 ≥ 5 years after the operation. CONCLUSION: Thoracoscopic bilateral T3 sympathectomy has a high success rate for primary palmar hyperhidrosis in children in the mid- to long-term. Compensatory sweating and recurrence can occur years after the operation, so long-term follow up is mandatory. LEVEL OF EVIDENCE: IV.
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Hiperhidrosis , Calidad de Vida , Adolescente , Humanos , Niño , Adulto Joven , Adulto , Resultado del Tratamiento , Toracoscopía/efectos adversos , Estudios Retrospectivos , Mano/cirugía , Simpatectomía/efectos adversos , Hiperhidrosis/cirugía , Satisfacción del PacienteRESUMEN
Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.
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Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Preeclampsia , Femenino , Retardo del Crecimiento Fetal , Hernias Diafragmáticas Congénitas/inducido químicamente , Hernias Diafragmáticas Congénitas/tratamiento farmacológico , Humanos , Inhibidores de Fosfodiesterasa 5/farmacología , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Preeclampsia/inducido químicamente , Embarazo , Citrato de Sildenafil/farmacología , Citrato de Sildenafil/uso terapéuticoRESUMEN
BACKGROUND: Persistent pulmonary hypertension (PH) causes significant mortality and morbidity in infants with congenital diaphragmatic hernia (CDH). Since pulmonary vascular abnormalities in CDH develop early during foetal development, we hypothesized that prenatal maternal administration of treprostinil, through its anti-remodelling effect, would improve the PH-phenotype in the nitrofen rat model of CDH. METHODS: In a dose-finding study in normal, healthy pregnant rats, we demonstrated target-range foetal plasma treprostinil concentrations without signs of toxicity. Next, an efficacy study was performed assessing the effects of treprostinil administration at 900 and 1500ng/kg/min from gestational day (GD) 16 until term (GD 21) in CDH and control pups. Pulmonary vascular and airway morphometry, lung mechanics, and expression patterns of genes implicated in the prostaglandin vasoactive pathway were studied. FINDINGS: In rats maternal administration of 1500ng/kg/min treprostinil reached target foetal concentrations, with no detrimental maternal or foetal side-effects. Prenatal exposure to 900 and 1500 ng/kg/min treprostinil reduced the medial wall thickness (%MWT) (CDH·900, 38.5± 8·4%; CDH.1500, 40·2±9·7%; CDH, 46·6±8·2%; both p < 0·0001) in rat pups with CDH, however increased the %MWT in normal foetuses (C.T.900, 36·6±11·1%; C.T.1500, 36·9±9·3%; C.P., 26·9±6·2%; both p < 0·001). Pulmonary airway development, lung hypoplasia and pulmonary function were unaffected by drug exposure. INTERPRETATION: In pregnant rats maternally administered treprostinil crosses the placenta, attains foetal target concentrations, and is well tolerated by both mother and foetuses. This report shows a significant reduction of pulmonary arteriole muscularization with prenatal treprostinil in a nitrofen rat model, supporting the promise of this treatment approach for PH of CDH. FUNDING: United Therapeutics Corporation provided treprostinil and financial support (ISS-2020-10879).
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Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Enfermedades Pulmonares , Animales , Modelos Animales de Enfermedad , Epoprostenol/análogos & derivados , Femenino , Hernias Diafragmáticas Congénitas/etiología , Hernias Diafragmáticas Congénitas/genética , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Enfermedades Pulmonares/metabolismo , Fenotipo , Embarazo , RatasRESUMEN
Despite advances in clinical care and modest improvement in mortality rates for extreme prematurity, morbidity remains a significant challenge. The ideal environment to support prematurity would be fluidic and rely on natural fetal circulation to mimic the natural fetal amniotic environment, yet such an environment has been unsuccessful in long-term support until recently. Our group has succeeded in developing such a support system to foster fetal growth in the premature lamb model that shows promise for clinical translation. Here, we describe the EXTrauterine Environment for Neonatal Development (EXTEND) from its conception onwards, review published literature on fetal development and support of the premature lamb model in EXTEND, and discuss future applications.
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Nacimiento Prematuro , Amnios , Animales , Femenino , Desarrollo Fetal , Feto , Humanos , Pulmón , OvinosRESUMEN
OBJECTIVE: To assess the safety of Partial-Amniotic-Insufflation-of-heated-humidified-CO2 (hPACI) during fetoscopic spina bifida repair (fSB-repair). METHOD: A simulated fSB-repair through an exteriorized uterus under hPACI was performed in 100-day fetal lambs (term = 145 days) under a laboratory anesthesia protocol (n = 5; group 1) which is known to induce maternal-fetal acidosis and hypercapnia. Since these may not occur clinically, we applied a clinical anesthesia protocol (n = 5; group 2), keeping maternal parameters within physiological conditions, that is, controlled maternal arterial carbon dioxide (CO2) pressure (pCO2 = 30 mmHg), blood pressure (≥67 mmHg), and temperature (37.1-39.8°C). Our superiority study used fetal pH as the primary outcome. RESULTS: Compared to group 1, controlled anesthesia normalized fetal pH (7.23 ± 0.02 vs. 7.36 ± 0.02, p < 0.001), pCO2 (70.0 ± 9.1 vs. 43.0 ± 1.0 mmHg, p = 0.011) and bicarbonate (27.8 ± 1.1 vs. 24.0 ± 0.9 mmol/L, p = 0.071) at baseline. It kept them within clinically acceptable limits (pH ≥ 7.23, pCO2 ≤ 70 mmHg, bicarbonate ≤ 30 mm/L) for ≥120 min of hPACI as opposed to ≤30 min in group one. Fetal pO2 and lactate were comparable between groups and generally within normal range. Fetal brain histology demonstrated fewer apoptotic cells and higher neuronal density in the prefrontal cortex in group two. There was no difference in fetal membrane inflammation, which was mild. CONCLUSION: Fetoscopic insufflation of heated-humidified CO2 during simulated fSB-repair through an exteriorized uterus can be done safely under controlled anesthesia.
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Anestesia/métodos , Dióxido de Carbono/administración & dosificación , Fetoscopía/métodos , Insuflación/métodos , Disrafia Espinal/cirugía , Animales , Femenino , Calor , Humedad , Embarazo , OvinosRESUMEN
PURPOSE: The significance and management of pediatric pneumatosis intestinalis (PI) remains poorly defined. We sought to add clarity in children beyond the neonatal period. METHODS: Pediatric patients 3 months-18 years admitted to a quaternary children's hospital with a diagnosis of PI were included in this retrospective study. Pathologic PI was defined as irreversible, transmural intestinal ischemia. RESULTS: 167 children were identified with PI. Of these children, 155 (92.8%) had benign PI and 12 (7.2%) developed pathologic PI. The most common underlying diagnosis for pathologic PI was global developmental delay (75%), although we identified a spectrum of underlying diagnoses at risk for PI. Physical exam notable for abdominal distension (p = 0.023) or guarding (p = 0.028), and imaging with portal venous gas (p < 0.001) or bowel distension (p = 0.001) were significantly associated with pathologic PI. Only 6.6% of all children underwent an operation. For those undergoing non-surgical management of benign PI, 75% of children received antibiotics and average duration of bowel rest was 6.8 days. CONCLUSIONS: PI in children is primarily a benign phenomenon and often does not warrant surgical intervention. Bowel rest and antibiotics are therapeutic strategies frequently used in the treatment of this finding.
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Neumatosis Cistoide Intestinal , Niño , Humanos , Recién Nacido , Intestinos , Neumatosis Cistoide Intestinal/diagnóstico por imagen , Neumatosis Cistoide Intestinal/terapia , Vena Porta , Estudios RetrospectivosRESUMEN
Congenital diaphragmatic hernia (CDH) is a complex malformation characterised by a triad of pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. Much of the mortality and morbidity in CDH is largely accounted for by PH, especially when persistent beyond the neonatal period and refractory to available treatment. Gentle ventilation, haemodynamic optimisation and pulmonary vasodilation constitute the foundations of neonatal treatment of CDH-related PH (CDH-PH). Moreover, early prenatal diagnosis, the ability to assess severity and the developmental nature of the condition generate the perfect rationale for fetal therapy. Shortcomings of currently available clinical therapies in combination with increased understanding of CDH pathophysiology have spurred experimental drug trials, exploring new therapeutic mechanisms to tackle CDH-PH. We herein discuss clinically available neonatal and fetal therapies specifically targeting CDH-PH and review the most promising experimental treatments and future research avenues.
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Terapias Fetales , Hernias Diafragmáticas Congénitas , Hipertensión Pulmonar , Femenino , Hernias Diafragmáticas Congénitas/complicaciones , Hernias Diafragmáticas Congénitas/diagnóstico por imagen , Hernias Diafragmáticas Congénitas/terapia , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Recién Nacido , Pulmón , Embarazo , Diagnóstico PrenatalRESUMEN
BACKGROUND: There is a steady decline in the general surgery workforce in rural areas of the United States. In response, some surgery residency programs have developed rural tracks to encourage rural practice and adequately prepare trainees for this setting. OBJECTIVE: To compare the practice type and location of graduates from general surgery residency programs with and without a dedicated rural track between 2011-2020. METHODS: General surgery residency programs with and without a rural track were identified using the American Medical Association Residency and Fellowship Electronic Interactive Database and the Rural Surgery Program list from the American College of Surgeons. Graduates of these programs who entered general surgery practice between 2011-2020 were subsequently identified from individual residency program websites and tracked to their current practice setting using a Google search of first and last name and residency affiliation. Practice location was identified by zip code or county name and coded by Rural-Urban Continuum Codes (RUCC, Economic Research Service, USDA). RESULTS: We identified 2,582 general surgery residency graduates from 2011 to 2020 across 66 residency programs. Of these graduates from programs without a rural track, 23.6% entered general surgery practice without additional fellowship training, compared to 34.0% from residency programs with a rural track (pâ¯=â¯0.019). Community or University-based program designation was not associated with decision to enter general surgery practice over fellowship training (pâ¯=â¯0.420). Proportion of graduates entering rural practice as defined by RUCC groups 7-9 was not associated with having a rural program track or with community or university-based program status. CONCLUSION: Residency programs with a rural track produce a higher proportion of graduates entering general surgery compared to fellowship, though they are no more likely than programs without a rural track to produce graduates who ultimately practice in rural areas.
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Cirugía General , Internado y Residencia , Becas , Cirugía General/educación , Humanos , Población Rural , Estados Unidos , Universidades , Recursos HumanosRESUMEN
BACKGROUND: Maternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil. METHODS: Five fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3-0.5-0.7â¯mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response. FINDINGS: The target concentration range (47-500â¯ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose. INTERPRETATION: Immediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5â¯mg/kg/24â¯h dose balancing rapid attainment of target concentrations with short-lived systemic effects. RESEARCH IN CONTEXT: None. SEARCH STRATEGY BEFORE UNDERTAKING THE STUDY: A literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work. EVIDENCE BEFORE THIS STUDY: Prenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model. ADDED VALUE OF THIS STUDY: We therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference. IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE: We demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5â¯mg/kg/24â¯h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.
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Aorta/efectos de los fármacos , Circulación Extracorporea , Terapias Fetales , Arteria Pulmonar/efectos de los fármacos , Citrato de Sildenafil/farmacocinética , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacocinética , Animales , Aorta/diagnóstico por imagen , Aorta/fisiopatología , Presión Arterial/efectos de los fármacos , Edad Gestacional , Infusiones Intravenosas , Modelos Biológicos , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Oveja Doméstica , Citrato de Sildenafil/administración & dosificación , Citrato de Sildenafil/sangre , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/administración & dosificación , Vasodilatadores/sangreRESUMEN
In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua GâA (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA GâA (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.