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OBJECTIVE: Given incarcerated women's lack of access to contraception prior to, during, and post-incarceration and concerns of potential reproductive coercion in correctional settings, the objective was to explore incarcerated women's perspective of making provider-controlled methods of long-acting reversible contraception (LARC) available in an U.S. urban jail. STUDY DESIGN: Using a concurrent mixed-methods approach, we explored contraceptive use and method choice prior to and after incarceration among women detained in a U.S. urban jail. Focus group discussions primarily focused on incarcerated women's perceptions of LARC. RESULTS: In the 30 days prior to arrest, 28 of 116 women (24%) were using a non-barrier contraceptive method. Methods of LARC were used the least, and the majority (n = 74, 64%) were not interested in initiating LARC in jail. Concern about the potential side effects of LARC was the main reason for disinterest followed by distrust in correctional health care staffs' qualifications. Study participants did not reference coercion as a concern. CONCLUSIONS: Apprehension about the training of health care providers and cleanliness of the detention facility outweighed participants' concerns regarding autonomy restrictions associated with provider-controlled methods of LARC. Despite limited interest in initiating LARC use while incarcerated, participants supported making all forms of contraception more accessible in jail settings. IMPLICATIONS: Understanding incarcerated women's reproductive and contraceptive desires, including their perceptions of LARC, will help improve the provision of equitable reproductive health care in correctional settings. Our findings highlight the importance of contextual factors in determining women's willingness to access contraceptive care in carceral settings, if available.
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Anticoncepción Reversible de Larga Duración , Anticoncepción , Conducta Anticonceptiva , Femenino , Humanos , Cárceles Locales , PercepciónAsunto(s)
Servicio de Urgencia en Hospital/organización & administración , Trastornos Relacionados con Opioides , Salud Poblacional , Baltimore , Socorristas , Humanos , Liderazgo , Antagonistas de Narcóticos/provisión & distribución , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/prevención & control , Trastornos Relacionados con Opioides/terapia , FarmacéuticosRESUMEN
BACKGROUND: Previous models of support for premature sheep fetuses have consisted of cesarean delivery followed by catheterization of umbilical or central vessels and support with extracorporeal membrane oxygenation (ECMO). The limitations of these models have been insufficient blood flow, significant fetal edema, and hemorrhage related to anticoagulation. METHODS: We performed a gravid hysterectomy on 13 ewes between 135 and 145days gestational age. The uterine vessels were cannulated bilaterally and circulatory support was provided via ECMO. Successful transition was defined as maintenance of fetal heart rate for 30minutes after establishing full extracorporeal support. Circuit flow was titrated to maintain mixed venous oxygen saturation (SvO2) of 70-75%. RESULTS: Seven experiments were successfully transitioned to ECMO, with an average survival time of 2hours 9minutes. The longest recorded time from cannulation to death was 6hours 14minutes. By delivering a circuit flow of up to 2120ml/min, all but one of the transitioned uteri were maintained within the desired SvO2 range. CONCLUSION: We report a novel animal model of fetal ECMO support that preserves the placenta, mitigates the effects of heparin, and allows for increased circuit flow compared to prior techniques. This approach may provide insight into a technique for future studies of fetal physiology.
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Órganos Artificiales , Oxigenación por Membrana Extracorpórea , Feto/irrigación sanguínea , Modelos Animales , Placenta/irrigación sanguínea , Útero/irrigación sanguínea , Animales , Femenino , Feto/fisiología , Preservación de Órganos/métodos , Placenta/fisiología , Embarazo , Ovinos , Útero/cirugíaRESUMEN
Nonoperative management of focal nodular hyperplasia (FNH) is an accepted paradigm in adults, but current management strategies for children vary substantially between institutions. We reviewed medical records at Johns Hopkins Hospital between January 1, 1998, and December 31, 2008, to investigate the diagnosis, treatment, and outcome of pediatric patients with a pathologic diagnosis of FNH to provide additional data to help formulate management guidelines for this disease. Ten pediatric patients were identified as having a pathologic diagnosis of FNH, either by biopsy sample (n = 5) or hepatic resection (n = 5). The mean age of the patients was 12.1 years, and most were female (n = 7). Mean tumor size was 5.7 cm (range, 0.8-13 cm). Four of 5 patients whose FNH was diagnosed by biopsy alone developed no sequelae, and 1 patient eventually required surgery for mass effect. Patients with either large lesions (≥5 cm) or symptoms were referred for resection. Observational management of small lesions that can be confidently diagnosed as FNH appears to be safe and appropriate. Surgical resection should be reserved for large or symptomatic lesions amenable to resection.
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Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/cirugía , Adolescente , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Femenino , Hiperplasia Nodular Focal/complicaciones , Hepatectomía , Humanos , Lactante , Masculino , Selección de Paciente , Resultado del Tratamiento , Espera Vigilante , Adulto JovenRESUMEN
BACKGROUND: Most quality improvement (QI) activities in developing countries, established with funds from external donors, are focused on specific diseases or outreach programs, such as family planning or child survival. District hospitals in developing countries serve as the primary entry point for patients with surgical problems in developing countries, yet little is known about the extent to which formal QI activities for surgical services are present in these settings or the perceptions of hospital staff about the barriers to improving quality in this setting. This study aimed to document surgical QI efforts at district hospitals and perceived barriers to improving quality in a developing country-Ghana. It also provides a summary of the existing published scientific literature concerning surgical QI in developing countries. METHODS: A survey team visited 10 government district hospitals in Ghana, one in each of Ghana's 10 regions. The number and type of QI activities (surgical and nonsurgical) at these district hospitals and the perspectives of hospital staff regarding the steps required to improve the quality of surgical services in their facility were recorded. RESULTS: Of the 10 hospitals assessed, nine reported having some type of QI activity, ranging from satisfaction surveys to assessing quality of infection prevention. Only one hospital reported having QI activity addressing surgical care. To improve the quality of surgical care, seven hospitals reported the need for trained specialists in surgery, obstetrics, and gynecology. Six cited the need for an appropriately equipped operating theater and recovery ward. The primary barrier to achieving these recommendations, cited by 70 % of the hospitals, was the inability to recruit and retain qualified specialists with surgical skills. CONCLUSIONS: For Ghana to improve significantly the quality of surgical care provided in its district hospitals, greater emphasis is needed for continuous, systematic QI monitoring and for solving the problems identified. Increasing the number of appropriately trained surgical care providers is essential to strengthen the quality of surgical services in district hospitals. These findings likely apply to other resource-limited countries as well. Increased attention to improving the quality of surgical services at district hospitals in developing countries is urgently needed.
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Cirugía General/normas , Mejoramiento de la Calidad , Países en Desarrollo , Ghana , Necesidades y Demandas de Servicios de Salud , Hospitales de Distrito , Humanos , Entrevistas como AsuntoRESUMEN
Surgical mortality is considered a benchmark for measuring quality of care. This study quantifies the incidence of death on the day of elective pediatric surgery, which generally is considered preventable and might be considered a "never" event. The authors conducted a retrospective analysis of national state inpatient databases from 1988 to 2007 that included elective pediatric surgical patients. A descriptive analysis of same-day mortality by demographics, surgical specialties, and age was performed. Of 835 880 elective pediatric surgical cases identified, 174 patients died on the day of surgery-that is, 2.1 deaths/10 000 cases. Surgical specialty mortality rates ranged from 0.06 (otolaryngology) to 17.4 (cardiothoracic surgery) deaths per 10 000 cases. Death on the day of elective pediatric surgery is rare, limiting its utility to compare performance in pediatric surgery. However, this metric may be useful at individual institutions as a case-finding tool for root-cause analysis in quality improvement efforts.
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Procedimientos Quirúrgicos Electivos/mortalidad , Mortalidad Hospitalaria , Seguridad del Paciente/estadística & datos numéricos , Especialidades Quirúrgicas/estadística & datos numéricos , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Femenino , Humanos , Incidencia , Lactante , Masculino , Estudios Retrospectivos , Factores de Riesgo , Estados UnidosAsunto(s)
Enfermedades de la Aorta/diagnóstico , Enfermedades Duodenales/diagnóstico , Endofuga/diagnóstico , Fístula Intestinal/diagnóstico , Anciano de 80 o más Años , Aneurisma de la Aorta Abdominal/cirugía , Enfermedades de la Aorta/etiología , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/métodos , Enfermedades Duodenales/etiología , Endofuga/etiología , Endofuga/terapia , Endoscopía del Sistema Digestivo , Procedimientos Endovasculares/efectos adversos , Femenino , Humanos , Fístula Intestinal/etiología , Peritonitis/etiología , Peritonitis/terapiaRESUMEN
Esophageal schwannoma is a rare diagnosis and historically has been a tumor of middle-aged females. We report a case of a 22-year-old male presenting initially with dyspnea secondary to tracheal compression from an 8 × 6 × 3.0 cm esophageal schwannoma. The tumor was surgically resected, and diagnosis was confirmed with immunohistochemical and pathological studies. We report the youngest case of esophageal schwannoma in an otherwise healthy individual.
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PURPOSE: Necrotizing enterocolitis (NEC) is a common acquired gastrointestinal disease of infancy that is strongly correlated with prematurity. Both percutaneous abdominal drainage and laparotomy with resection of diseased bowel are surgical options for treatment of NEC. The objective of the present study is to compare outcomes of patients who were treated either with bowel resection/ostomy (BR/O), percutaneous drainage (PD) or Both procedures for NEC in a retrospective analysis. METHODS: A retrospective analysis was performed using data from the Agency for Healthcare Research and Quality, extracted from a combination of the Nationwide Inpatient Sample (NIS) and Kids' Inpatient Database (KID) from 1988 to 2005. Multiple logistic regression analyses were performed for in-hospital mortality associated with PD, BR/O or Both procedures for management of NEC. In addition, linear regression was performed for length of stay and total hospital charges. Odds ratios were calculated using the BR/O category as the reference group. RESULTS: There were 4,238 patients identified who underwent BR/O, 286 for PD, and 133 for Both procedures for NEC. Patients undergoing PD had a 5.7 times higher odds of death compared to patients treated with BR/O (p < 0.05) alone; patients receiving Both procedures did not have significantly higher odds of death compared to the BR/O group. Patients who underwent PD had a shorter length of stay (43 days; p < 0.05) and lower total hospital charges ($173,850; p < 0.05) in comparison to patients treated with BR/O. Length of stay and total hospital charges were greater in patients who received Both procedures, compared to those receiving BR/O alone, but this was not statistically significant. CONCLUSION: In this nationwide sample of infants with NEC, outcomes for peritoneal drainage alone were poorer than those for bowel resection and enterostomy and for Both procedures. Increased overall mortality and shorter length of stay and hospital charges suggest higher early mortality associated with peritoneal drainage alone. Risk stratifying these groups using prematurity, birth weight, and number of concurrent diagnoses yielded equivocal results. A more detailed study will be needed to determine whether the patient populations that underwent initial laparotomy and bowel resection are substantially different from those that receive peritoneal drainage, or whether differences in outcome may be directly attributable to the type of procedure performed.
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Drenaje/métodos , Enterocolitis Necrotizante/cirugía , Laparotomía/métodos , Preescolar , Enterocolitis Necrotizante/mortalidad , Femenino , Estudios de Seguimiento , Mortalidad Hospitalaria/tendencias , Humanos , Masculino , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: To document the quality of training and experience of those who care for patients undergoing surgery and emergency obstetrical procedures at 10 government district hospitals in Ghana. METHOD: A study team composed of Ghanaian and U.S. surgeons visited 10 district hospitals in 10 different regions of Ghana in August 2009. On-site interviews were conducted documenting the formal and informal training and the experience of the medical officers (MOs) performing in surgical facilities in these hospitals. RESULTS: Fourteen of the 17 MOs working at these facilities were available for interviews. All 14 had completed two years of housemanship, which is similar to a rotating internship. Only one had obtained any formal surgical training beyond the housemanship, although all were responsible for performing major surgical procedures. The formal training under qualified supervision during the housemanship was limited; the mean number of the most common major surgical procedures performed during training ranged from four to eight, depending on the procedure. CONCLUSIONS: Even though formal general surgical residency training in Ghana is well developed, graduates of these programs are not working in the district hospitals surveyed. The majority of surgical services provided at the district hospital are provided by MOs, who would benefit from more comprehensive training and ongoing supervision. To help meet the challenge of a shortage of physicians working at district hospitals, the authors present alternative approaches to care described in the literature that involve nonphysician midlevel health providers.
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Cirugía General/educación , Hospitales de Distrito/organización & administración , Calidad de la Atención de Salud , Femenino , Ghana , Humanos , Intercambio Educacional Internacional , Masculino , Procedimientos Quirúrgicos Obstétricos/educación , Encuestas y CuestionariosRESUMEN
BACKGROUND: Significant barriers limit the safe and timely provision of surgical and anaesthetic care in low- and middle-income countries. Nearly one-half of Mongolia's population resides in rural areas where the austere geography makes travel for adequate surgical care very difficult. Our goal was to characterize the availability of surgical and anaesthetic services, in terms of infrastructure capability, physical resources (supplies and equipment), and human resources for health at primary level health facilities in Mongolia. METHODS: A situational analysis of the capacity to deliver emergency and essential surgical care (EESC) was performed in a nonrandom sample of 44 primary health facilities throughout Mongolia. RESULTS: Significant shortfalls were noted in the capacity to deliver surgical and anesthetic services. Deficiencies in infrastructure and supplies were common, and there were no trained surgeons or anaesthesiologists at any of the health facilities sampled. Most procedures were performed by general doctors and paraprofessionals, and occasionally visiting surgeons from higher levels of the health system. While basic interventions such as suturing or abscess drainage were commonly performed, the availability of many essential interventions was absent at a significant number of facilities. CONCLUSIONS: This situational analysis of the availability of essential surgical and anesthetic services identified significant deficiencies in infrastructure, supplies, and equipment, as well as a lack of human resources at the primary referral level facilities in Mongolia. Given the significant travel distances to secondary level facilities for the majority of the rural population, there is an urgent need to strengthen the delivery of essential surgical and anaesthetic services at the primary referral level (soum and intersoum). This will require a multidisciplinary, multi-sectoral effort aimed to improve infrastructure, procure and maintain essential equipment and supplies, and train appropriate health professionals.
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Anestesia/estadística & datos numéricos , Instituciones de Salud/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Atención Primaria de Salud/estadística & datos numéricos , Procedimientos Quirúrgicos Operativos/estadística & datos numéricos , Humanos , Mongolia , Recursos HumanosRESUMEN
BACKGROUND: For most of the population in Africa, district hospitals represent the first level of access for emergency and essential surgical services. The present study documents the number and availability of surgical and obstetrical care providers as well as the types of surgical and obstetrical procedures being performed at 10 first-referral district hospitals in Ghana. MATERIALS AND METHODS: After institutional review board and governmental approval, a study team composed of Ghanaian and American surgeons performed on-site surveys at 10 district hospitals in 10 different regions of Ghana in August 2009. Face-to-face interviews were conducted documenting the numbers and availability of surgical and obstetrical personnel as well as gathering data relating to the number and types of procedures being performed at the facilities. RESULTS: A total of 68 surgical and obstetrical providers were interviewed. Surgical and obstetrical care providers consisted of Medical Officers (8.5%), nurse anesthetists (6%), theatre nurses (33%), midwives (50.7%), and others (4.5%). Major surgical cases represented 37% of overall case volumes with cesarean section as the most common type of major surgical procedure performed. The most common minor surgical procedures performed were suturing of lacerations or episiotomies. CONCLUSIONS: The present study demonstrates that there is a substantial shortage of adequately trained surgeons who can perform surgical and obstetrical procedures at first-referral facilities. Addressing human resource needs and further defining practice constraints at the district hospital level are important facets of future planning and policy implementation.
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Cirugía General/estadística & datos numéricos , Hospitales de Distrito/estadística & datos numéricos , Obstetricia/estadística & datos numéricos , Servicios Médicos de Urgencia/provisión & distribución , Femenino , Ghana/epidemiología , Encuestas de Atención de la Salud , Hospitales de Distrito/provisión & distribución , Humanos , Cuerpo Médico de Hospitales/provisión & distribución , Partería , Enfermeras Anestesistas/provisión & distribución , Personal de Enfermería en Hospital/provisión & distribución , Enfermería de Quirófano , Embarazo , Recursos HumanosRESUMEN
BACKGROUND: The World Health Organization (WHO) Tool for Situational Analysis to Assess Emergency and Essential Surgical Care (hereafter called the WHO Tool) has been used in more than 25 countries and is the largest effort to assess surgical care in the world. However, it has not yet been independently validated. Test-retest reliability is one way to validate the degree to which tests instruments are free from random error. The aim of the present field study was to determine the test-retest reliability of the WHO Tool. METHODS: The WHO Tool was mailed to 10 district hospitals in Ghana. Written instructions were provided along with a letter from the Ghana Health Services requesting the hospital administrator to complete the survey tool. After ensuring delivery and completion of the forms, the study team readministered the WHO Tool at the time of an on-site visit less than 1 month later. The results of the two tests were compared to calculate kappa statistics for each of the 152 questions in the WHO Tool. The kappa statistic is a statistical measure of the degree of agreement above what would be expected based on chance alone. RESULTS: Ten hospitals were surveyed twice over a short interval (i.e., less than 1 month). Weighted and unweighted kappa statistics were calculated for 152 questions. The median unweighted kappa for the entire survey was 0.43 (interquartile range 0-0.84). The infrastructure section (24 questions) had a median kappa of 0.81; the human resources section (13 questions) had a median kappa of 0.77; the surgical procedures section (67 questions) had a median kappa of 0.00; and the emergency surgical equipment section (48 questions) had a median kappa of 0.81. CONCLUSIONS: Hospital capacity survey questions related to infrastructure characteristics had high reliability. However, questions related to process of care had poor reliability and may benefit from supplemental data gathered by direct observation. Limitations to the study include the small sample size: 10 district hospitals in a single country. Consistent and high correlations calculated from the field testing within the present analysis suggest that the WHO Tool for Situational Analysis is a reliable tool where it measures structure and setting, but it should be revised for measuring process of care.
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Atención a la Salud/organización & administración , Tratamiento de Urgencia/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hospitales de Distrito/normas , Organización Mundial de la Salud , Países en Desarrollo , Cirugía General/normas , Cirugía General/tendencias , Ghana , Necesidades y Demandas de Servicios de Salud , Encuestas Epidemiológicas , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
OBJECTIVES: To survey infrastructure characteristics, personnel, equipment and procedures of surgical, obstetric and anaesthesia care in 17 hospitals in Ghana. METHODS: The assessment was completed by WHO country offices using the World Health Organization Tool for Situational Analysis to Assess Emergency and Essential Surgical Care, which surveyed infrastructure, human resources, types of surgical interventions and equipment in each facility. RESULTS: Overall, hospitals were well equipped with general patient care and surgical supplies. The majority of hospitals had a basic laboratory (100%), running water (94%) and electricity (82%). More than 75% had the basic supplies needed for general patient care and basic intra-operative care, including sterilization. Almost all hospitals were able to perform major surgical procedures such as caesarean sections (88%), herniorrhaphy (100%) and appendectomy (94%), but formal training of providers was limited: a few hospitals had a fully qualified surgeon (29%) or obstetrician (36%) available. CONCLUSIONS: The greatest barrier to improving surgical care at district hospitals in Ghana is the shortage of adequately trained medical personnel for emergency and essential surgical procedures. Important future steps include strengthening their number and qualifications.
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Anestesia/normas , Recursos en Salud/provisión & distribución , Accesibilidad a los Servicios de Salud/normas , Hospitales/normas , Obstetricia/normas , Procedimientos Quirúrgicos Operativos/normas , Países en Desarrollo , Ghana , Encuestas de Atención de la Salud , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Fuerza Laboral en Salud , Humanos , Quirófanos/normas , Organización Mundial de la SaludRESUMEN
BACKGROUND: The aim of this study is to assess skin strength in MWL patients relative to control cosmetic abdominoplasty patients biophysically, biochemically, and histologically. Growing success of weight loss programs has brought about an increase in the MWL population. Skin quality is thought to be impaired by MWL, but there are no compelling studies that have fully addressed the structural mechanisms involved. METHODS: Skin from the medial and lateral abdomen was harvested fresh from patients undergoing cosmetic abdominoplasty (n = 6) or abdominal panniculectomy for MWL (n = 35), and burst strength was tested in the horizontal and vertical directions. Collagen content was measured, and histological studies were performed to assess epidermal and dermal thickness, vascularity as well as the morphology and density of the collagen fibers. RESULTS: In all groups, skin stretched horizontally was stronger than skin stretched vertically (p < 0.001). The skin of MWL patients was stronger medially compared to the skin of cosmetic patients. (p = 0.047) Newly formed collagen was diminished in MWL than that in the control group, but the results were not statistically significant. Epidermal thickness was significantly higher medially in MWL (p = 0.049). Elastin fibers were decreased in the MWL group, while dermal vascularity was higher in the MWL group. CONCLUSIONS: The skin of MWL patients demonstrated stronger mechanical parameters than that of cosmetic patients in the medial part of the abdomen; however, the decrease in elastic fibers associated with a decrease in newly formed collagen seemingly provides a contradiction. Skin changes with MWL merits further study to understand it more completely.
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Obesidad Mórbida/fisiopatología , Piel , Pérdida de Peso/fisiología , Abdomen , Fenómenos Biomecánicos , Colágeno/metabolismo , Tejido Elástico/patología , Elasticidad , Derivación Gástrica , Humanos , Inmunohistoquímica , Obesidad Mórbida/patología , Obesidad Mórbida/cirugía , Piel/metabolismo , Piel/patologíaRESUMEN
BACKGROUND: The nationwide mortality of neonates with gastroschisis was compared to determine whether significant variations in outcome occurred at the hospital level. METHODS: Utilizing a previously developed risk-stratification index, low-risk neonates with gastroschisis were identified by a score of < or = 2. Only hospitals that had a record of treating >25 low-risk neonates were included in the analysis. Hospital performance in treating infants with gastroschisis was categorized into moderate and extreme outliers. RESULTS: A total of 4,344 neonates with gastroschisis were identified at 506 individual hospitals. Low-risk neonates had an overall mortality of 2.9% compared with high-risk neonates whose overall mortality was 24.4%. Forty hospitals treated >25 low-risk neonates in the years studied for a total of 1,775 low-risk patients. The mean, in-hospital mortality of this cohort was 3.1% (range, 0-14.3). Eight hospitals were moderate outliers with mortality rates between 3.8% and 8.0%. Two hospitals were extreme outliers with mortality rates of 8.6% and 14.3%. CONCLUSION: A substantial variation exists in the mortality of neonates with low-risk gastroschisis across hospitals. Further improvements in survival may, thus, depend on targeting quality improvement initiatives to standardization of operative approaches as well improvements in nonoperative factors such as neonatal intensive care unit practices, nurse-to-patient ratios, and levels of intensivist staffing.
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Benchmarking/normas , Gastrosquisis/cirugía , Procedimientos Quirúrgicos Operativos/normas , Comorbilidad , Femenino , Gastrosquisis/complicaciones , Gastrosquisis/mortalidad , Mortalidad Hospitalaria , Humanos , Recién Nacido , Masculino , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Grupos Raciales , Medición de RiesgoRESUMEN
Charcot-Marie-Tooth disease type 2C (CMT2C) is an autosomal dominant neuropathy characterized by limb, diaphragm and laryngeal muscle weakness. Two unrelated families with CMT2C showed significant linkage to chromosome 12q24.11. We sequenced all genes in this region and identified two heterozygous missense mutations in the TRPV4 gene, C805T and G806A, resulting in the amino acid substitutions R269C and R269H. TRPV4 is a well-known member of the TRP superfamily of cation channels. In TRPV4-transfected cells, the CMT2C mutations caused marked cellular toxicity and increased constitutive and activated channel currents. Mutations in TRPV4 were previously associated with skeletal dysplasias. Our findings indicate that TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. The CMT2C-associated mutations lie in a distinct region of the TRPV4 ankyrin repeats, suggesting that this phenotypic variability may be due to differential effects on regulatory protein-protein interactions.
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Enfermedad de Charcot-Marie-Tooth/genética , Mutación/genética , Canales Catiónicos TRPV/genética , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Repetición de Anquirina , Secuencia de Bases , Membrana Celular/metabolismo , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Análisis Mutacional de ADN , Femenino , Humanos , Activación del Canal Iónico , Masculino , Persona de Mediana Edad , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Mutantes/metabolismo , Neurotoxinas , Linaje , Fenotipo , Canales Catiónicos TRPV/química , Adulto JovenRESUMEN
Transient receptor potential vanilloid (TRPV) channels, which include the thermosensitive TRPV1-V4, have large cytoplasmic regions flanking the transmembrane domain, including an N-terminal ankyrin repeat domain. We show that a multiligand binding site for ATP and calmodulin previously identified in the TRPV1 ankyrin repeat domain is conserved in TRPV3 and TRPV4, but not TRPV2. Accordingly, TRPV2 is insensitive to intracellular ATP, while, as previously observed with TRPV1, a sensitizing effect of ATP on TRPV4 required an intact binding site. In contrast, ATP reduced TRPV3 sensitivity and potentiation by repeated agonist stimulations. Thus, ATP and calmodulin, acting through this conserved binding site, are key players in generating the different sensitivity and adaptation profiles of TRPV1, TRPV3, and TRPV4. Our results suggest that competing interactions of ATP and calmodulin influence channel sensitivity to fluctuations in calcium concentration and perhaps even metabolic state. Different feedback mechanisms likely arose because of the different physiological stimuli or temperature thresholds of these channels.