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The designability of orthogonal coiled coil (CC) dimers, which draw on well-established design rules, plays a pivotal role in fueling the development of CCs as synthetically versatile assembly-directing motifs for the fabrication of bionanomaterials. Here, we aim to expand the synthetic CC toolkit through establishing a "minimalistic" set of orthogonal, de novo CC peptides that comprise 3.5 heptads in length and a single buried Asn to prescribe dimer formation. The designed sequences display excellent partner fidelity, confirmed via circular dichroism (CD) spectroscopy and Ni-NTA binding assays, and are corroborated in silico using molecular dynamics (MD) simulation. Detailed analysis of the MD conformational data highlights the importance of interhelical E@g-N@a interactions in coordinating an extensive 6-residue hydrogen bonding network that "locks" the interchain Asn-Asn' contact in place. The enhanced stability imparted to the Asn-Asn' bond elicits an increase in thermal stability of CCs up to ~15°C and accounts for significant differences in stability within the collection of similarly designed orthogonal CC pairs. The presented work underlines the utility of MD simulation as a tool for constructing de novo, orthogonal CCs, and presents an alternative handle for modulating the stability of orthogonal CCs via tuning the number of interhelical E@g-N@a contacts. Expansion of CC design rules is a key ingredient for guiding the design and assembly of more complex, intricate CC-based architectures for tackling a variety of challenges within the fields of nanomedicine and bionanotechnology.
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Simulação de Dinâmica Molecular , Peptídeos , Sequência de Aminoácidos , Estrutura Secundária de Proteína , Peptídeos/química , Domínios Proteicos , Dicroísmo CircularRESUMO
Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.
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Leucemia , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Bexaroteno/farmacologia , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/farmacologia , Receptores X do Fígado , Retinoides/farmacologia , TriglicerídeosRESUMO
Intrinsically disordered proteins and protein regions (IDPs) are prevalent in all proteomes and are essential to cellular function. Unlike folded proteins, IDPs exist in an ensemble of dissimilar conformations. Despite this structural plasticity, intramolecular interactions create sequence-specific structural biases that determine an IDP ensemble's three-dimensional shape. Such structural biases can be key to IDP function and are often measured in vitro, but whether those biases are preserved inside the cell is unclear. Here we show that structural biases in IDP ensembles found in vitro are recapitulated inside human-derived cells. We further reveal that structural biases can change in a sequence-dependent manner due to changes in the intracellular milieu, subcellular localization, and intramolecular interactions with tethered well-folded domains. We propose that the structural sensitivity of IDP ensembles can be leveraged for biological function, can be the underlying cause of IDP-driven pathology or can be used to design disorder-based biosensors and actuators.
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Proteínas Intrinsicamente Desordenadas , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteoma , Viés , Conformação ProteicaRESUMO
An adaptive steady state constrained autoregressive with extra input (SSARX) model is developed and embedded into a model predictive control (MPC) framework to regulate a nonlinear process for setpoint tracking. The resulting linear MPC can minimize the deviation of output from the setpoint along the entire prediction horizon and finally achieve zero-offset control even with model mismatch. Our contributions lie in three aspects: First, we develop a steady state constrained ARX model identification method. Second, we design an information matrix based index for model re-identification using online closed-loop data. Third, when steady state input values are unknown, our algorithm can adaptively adjust parameters in the objective function and model to track the setpoint crossing a wide range of operating conditions. A fermenter control problem is studied to demonstrate the effectiveness of the proposed approach.
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The Lancet Commission on Global Surgery (LCoGS) launched Global Surgery 2030 to address the surgical services inequities with a bias toward low-income and middle-income countries like the Philippines. The same inequity is observed particularly when it comes to the urban-rural divide. With more than half of the population living in rural areas, access to surgery becomes a major challenge that further impedes the much-needed health of an economically productive workforce. The Universal Health Care [UHC] Act (RA 11332) of 2019 ensures that all Filipinos have access to quality, cost-effective, promotive, preventive, curative, rehabilitative, and palliative health services without causing a financial burden. Recognizing the provision of essential surgery, in the context of primary healthcare is important. It should be accessible, continuous, comprehensive, and coordinated at the time of need - parallel to the principle of primary health care. Driven by this concept and experiences, the authors conceptualized and presented the Philippine Rural Surgery model for future development and implementation. This is envisioned to provide essential surgery among local rural primary health care settings that is universal, accessible, cost-effective and safe. As this is still new in the Philippines, we proposed tenets and recommendations based on WHO Health System Strengthening building blocks to guide stakeholders in creating formal plans towards institutionalization under the principles of UHC. Such access to surgical service in the context of a unique socio-demography of the Philippines would be essential in attaining the parameters and provisions set by the UHC Act.
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INTRODUCTION: Caustic agents, also called corrosive agents, could be acids or alkali in nature. If ingested, these agents can injure any part of the aerodigestive tree. Extent of injury depends on the type, concentration, duration of exposure and volume of caustic agent ingested. Serious complications after caustic agent ingestion can occur both in the short term such as hollow viscus perforation and death and in the long term such as stricture formation causing obstruction and lifetime risk of development of carcinoma. PRESENTATION OF A CASE: This is a case of a 25-year-old female who ingested an unknown substance resulting to a severe stricture of the larynx, hypopharynx, esophagus and pyloroantral region of the stomach. Six months after her tracheostomy and tube jejunostomy, she sought further medical attention in our institution due to inability to swallow food and saliva. She underwent pharyngolaryngectomy (PL) with the strictured esophagus and stomach left in-situ due to extensive adhesions. The subcutaneous colonic interposition reestablished the alimentary continuity by providing enough length for tension-free anastomosis and a more direct route for cervical anastomosis. DISCUSSION: Stricture formation is one of the most challenging late complication of corrosive injury. It results from scar formation in response to inflammation of the aerodigestive tract. Key factors in managing caustic strictures include safety of strictured segment resection, choice of replacement organ for reconstruction and route of conduit. CONCLUSION: Timing of surgery and proper selection the surgical procedure for complications of caustic ingestion can result in excellent long term outcomes.
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INTRODUCTION: Gallbladder duplication is a rare congenital anomaly of the biliary tree. Although a double gallbladder by itself is not clinically significant, complications of gallstone disease increases the complexity of the management. Preoperative recognition decreases the risk of complications during laparoscopic cholecystectomy. PRESENTATION OF CASE: Presented herein is the case of a 52 year old who presented with abdominal pain. A transabdominal ultrasound was suggestive of a gallbladder duplication with the larger gallbladder filled with cholelithiasis. Subsequent imaging studies, including an endoluminal ultrasound, confirmed the diagnosis and documented a choledocholithiasis. Endoscopic extraction of the biliary stone with subsequent laparoscopic cholecystectomy of both gallbladders was successfully performed. DISCUSSION: This case is being presented not only for the rarity of the condition but also of the challenges in management it poses. In gallbladder duplication, pathologic involvement of one gallbladder requires removal of both gallbladders. A high index of suspicion on initial scanning warrants further delineation of the important anatomic structures of the biliary tree to avoid perioperative complications. CONCLUSION: Laparoscopic cholecystectomy may be safely performed in patients with gallbladder duplication. Preoperative recognition with appropriate imaging modalities, including ultrasound and MRCP may avoid surgical complications. In cases where the anomaly is detected intraoperatively during cholecystectomy, meticulous dissection and intraoperative cholangiography will avoid iatrogenic injuries and lead to successful outcomes.
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INTRODUCTION: Melioidosis is a rare infectious tropical disease caused by Burkholderia pseudomallei (B. pseudomallei), an environmental saprophyte usually habitating on soils of Southeast Asian fields. Most of the reported cases present with pneumonia and intra-abdominal abscess. Diagnosis is established by culture studies from the blood, sputum or abscess drainage. Management relies on culture-guided antibiotic treatment, with good prognosis. Surgical intervention is required in cases not responsive to medical management. PRESENTATION OF CASE: We are presenting a case of Melioidosis in a 72 year old Filipino who presented with Pneumonia, Femoral and Sacral Osteomyelitis, Splenic Abscess and High Rectal Fistula. He was successfully managed with systemic antibiotic treatment and surgery. The splenic abscess was managed by splenectomy and a transverse loop colostomy was used for fecal diversion to address the rectal fistula. DISCUSSION: Melioidosis varies in its presentation and thus management should be individualized, depending on the organs involved. Our patient presented with multiple foci of infection which rendered the treatment more complicated as compared to those reported previously in published literature. The pneumonia and the osteomyelitis were managed with aggressive systemic antibiotics but the other sites of infection required drainage and surgery. CONCLUSION: Melioidosis is a rare infection caused by an environmental saprophyte Burkholderia pseudomallei. An accurate diagnosis using culture studies is essential to institute appropriate treatment. Antibiotic treatment complemented by surgery for specific organ involvement is essential for cure.
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INTRODUCTION: Solid Pseudopapillary Neoplasm (SPN) is a rare pancreatic neoplasm with low malignant potential and a relative indolent course. Complete resection of the SPN is curative for most cases and has a high survival rate. Recurrences, though rare, can still occur despite adequate resection. Pancreaticoduodenectomy is commonly performed to treat pancreatic head SPNs. In recent years, duodenum-preserving pancreatic head resection (DPPHR) has been reported as a less radical and acceptable alternative. CASE PRESENTATION: We are reporting a case of 26-year old female who presented with a 7 month history of epigastric pain and increasing abdominal girth. She was diagnosed by MRI to have a huge but resectable pancreatic head mass and subsequently underwent duodenum-preserving pancreatic head resection (DPPHR) with pancreaticojejunostomy. Histopathologic examination revealed a solid pseudopapillary tumor (SPN) with lymphovascular invasion and negative margins of resection. The patient underwent hepaticojejunostomy 5 months after resection for biliary stricture. Surveillance imaging revealed tumor recurrence warranting re-exploration for recurrence 3 years after the initial surgery. Intraoperative findings revealed the mass at the distal pancreatic remnant, requiring distal pancreatectomy and splenectomy. DISCUSSION: Solid pseudopapillary neoplasms are rare pancreatic neoplasms. Surgical resection of SPNs affords long term cure with good 5-year survival rates for localized tumors Despite the low malignant potential of SPNs, relapse after resection can still occur. CONCLUSION: Complete local resection of the tumor is the treatment of choice in SPNs. DPPHR should be considered as an alternative in young patients with a localized SPN in the pancreatic head.
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INTRODUCTION AND IMPORTANCE: Colouterine fistulas related to diverticulitis are very rare due to the thickness of the uterine myometrium. Other causes related to colouterine fistula formation particularly malignancy, have to be considered. Diagnosis by imaging or endoscopy may be inconclusive. CASE PRESENTATION: We are presenting a case of a 70-year-old female who presented with malodorous vaginal discharge and painful labial lesions. No previous history of surgery, gynecologic malignancy or other possible causes of the fistula was elicited. CT scan imaging suggested a colouterine fistula. The patient was admitted and underwent Exploratory laparotomy, Hartmann's procedure and total hysterectomy with bilateral salpingo oophorectomy. The patient was discharged without perioperative complications. CLINICAL DISCUSSION: Colouterine fistulas are extremely rare complications of diverticular disease. Diagnosis entails clinical astuteness and judicious use of imaging and endoscopic modalities. Accurate diagnosis is essential to select the appropriate surgical approach, along with intraoperative findings patient status and prevailing conditions. CONCLUSION: This case is being presented not only for the rarity of the case but also for the complexity of the management and decision making during the period of the pandemic.
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INTRODUCTION: Interventional internal drainage of the biliary tract has become an established procedure for the temporary and definitive treatment of biliary obstruction due to malignant or benign disease. The complication rate is reported to be so low that when feasible, this technique is preferred over a surgical drainage procedure. PRESENTATION OF A CASE: A 26-year old woman was referred to the hepatopancreaticobiliary surgery service due to severe abdominal pain for 3 days after undergoing endoscopic retrograde cholangiopancreatography (ERCP). She underwent biliary dilatation and stent insertion for obstructive jaundice secondary to biliary stricture from hepatobiliary tuberculosis. The patient underwent exploratory laparotomy, peritoneal lavage, duodenorrhaphy and tube jejunostomy for bilious peritonitis and duodenal perforation from biliary stent migration. The patient died one day post-operation due to septic shock from secondary bacterial peritonitis. DISCUSSION: ERCP and other interventional endoscopic biliary interventions are increasingly being used for biliary obstruction. Despite the various complications which arise from these diagnostic and therapeutic modalities, complications are relatively uncommon. Duodenal perforation from biliary stent migration is a rare complication after undergoing ERCP and stenting. However, in patients presenting with severe pain and physical signs of acute abdomen after the procedure, it should always be a consideration. CONCLUSIONS: Despite the relative safety of interventional techniques for biliary obstruction, complications like pancreatitis, hemorrhage and perforation may occur. Early recognition and high index of suspicion allows for early intervention with good outcomes. Duodenal perforation from stent migration can occur and when intervention is delayed may lead to morbidity and mortality.
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INTRODUCTION: Primary thyroid lymphomas are rare. They constitute only 2% of all thyroid malignancies. It is important to distinguish it from other tumors of the thyroid due to the marked difference in approach to management. Preoperative diagnostic confirmation is ideal to allow for appropriate therapeutic management, which consists of chemotherapy with or without radiotherapy and to avoid unnecessary surgery. In a select group of patients, surgery may be of benefit to relieve obstructive symptoms and establish diagnosis. CASE PRESENTATION: Presented herein is a 48 year old female with a progressively enlarging neck mass previously being treated for Hashimoto's thyroiditis. Obstructive symptoms and a preoperative diagnosis of anaplastic carcinoma prompted surgical intervention. The patient underwent resection of the tumor with a total thyroidectomy and bilateral neck dissection. Post -operative diagnosis of non Hodgkins diffuse large B cell type of lymphoma was made. DISCUSSION: Primary thyroid lymphomas are rare tumors that may present similarly with some types of thyroid malignancies. An accurate diagnosis is important because non-surgical treatment options like combination chemotherapy and radiotherapy may be effective while sparing the patient from unnecessary radical surgery. CONCLUSION: Primary thyroid lymphoma must be a differential diagnosis in patients presenting with large thyroid tumors in the background of Hashimoto's thyroiditis. Although chemoradiotherapy is the preferred treatment approach, there is a role for surgery in cases of tumor obstruction and uncertain diagnosis.
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INTRODUCTION: Splenic disease are uncommon and primary tumors of the spleen are very rare. These are classified as splenic cyst, benign and malignant tumors. Splenic lymphangioma is a rare, slow-growing benign tumor of the spleen. More often seen in children, it is a congenital malformation of the lymphatic system and is rarely seen in adulthood. When present in adults, it is usually asymptomatic and would be incidentally detected through imaging studies. Infrequently, some patients would present with abdominal pain, distension, nausea, and may have palpable abdominal mass. It may be solitary or may have multiple splenic lesions. PRESENTATION OF CASE: We present of a case of splenic mass in a 56-year old female, which remained undetected until incidentally discovered on work-up for chronic back pain. Laparoscopic splenectomy was eventually performed with eventual resolution of the chronic back pain. Histopathologic examination revealed splenic lymphangioma. DISCUSSION: Splenic tumors are uncommon. Splenic lymphangiomas presenting in adulthood are extremely rare, and preoperative diagnosis may be difficult in asymptomatic patients. CONCLUSION: Surgical removal of splenic lymphangiomas may be necessary to relieve symptoms, prevent complications and confirm diagnosis.
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Accurate and comprehensive measurements of economic well-being are fundamental inputs into both research and policy, but such measures are unavailable at a local level in many parts of the world. Here we train deep learning models to predict survey-based estimates of asset wealth across ~ 20,000 African villages from publicly-available multispectral satellite imagery. Models can explain 70% of the variation in ground-measured village wealth in countries where the model was not trained, outperforming previous benchmarks from high-resolution imagery, and comparison with independent wealth measurements from censuses suggests that errors in satellite estimates are comparable to errors in existing ground data. Satellite-based estimates can also explain up to 50% of the variation in district-aggregated changes in wealth over time, with daytime imagery particularly useful in this task. We demonstrate the utility of satellite-based estimates for research and policy, and demonstrate their scalability by creating a wealth map for Africa's most populous country.
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A hypothesis in prebiotic chemistry argues that organics were delivered to the early Earth in abundance by meteoritic sources. This study tests that hypothesis by measuring how the transfer of organic matter to the surface of Earth is affected by energy-dissipation processes such as ablation and airbursts. Exogenous delivery has been relied upon as a source of primordial material, but it must stand to reason that other avenues (i.e., hydrothermal vents, electric discharge) played a bigger role in the formation of life as we know it on Earth if exogenous material was unable to deliver significant quantities of organics. For this study, we look at various properties of meteors such as initial velocity and mass of the object, and atmospheric composition to see how meteors with different initial velocities and masses ablate. We find that large meteors do not slow down fast enough and thus impact the surface, vaporizing their components; fast meteors with low masses are vaporized during entry; and meteors with low velocities and high initial masses reach the surface. For those objects that survive to reach the surface, about 60 to >99% of the mass is lost by ablation. Large meteors that fragment are also shown to spread out over increasingly larger areas with increasing mass, and small meteors (~1 mm) are subjected to intense thermal heating, potentially degrading intrinsic organics. These findings are generally true across most atmospheric compositions. These findings provide several caveats to extraterrestrial delivery models that—while a viable point source of organics—likely did not supply as much prebiotic material as an effective endogenous production route.
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Labor migration offers an important mechanism to reallocate workers when there are regional differences in employment conditions. Whereas conventional wisdom suggests migration rates should increase during recessions as workers move out of areas that are hit hardest, initial evidence suggested that overall migration rates declined during the Great Recession, despite large regional differences in unemployment and growth rates. In this paper, we use data from the American Community Survey to analyze internal migration trends before and during the economic downturn. First, we find only a modest decline in the odds of adults leaving distressed labor market areas during the recession, which may result in part from challenges related to the housing price crash. Second, we estimate conditional logit models of destination choice for individuals who migrate across labor market areas and find a substantial effect of economic factors such as labor demand, unemployment, and housing values. We also estimate latent class conditional logit models that test whether there is heterogeneity in preferences for destination characteristics among migrants. Over all, the latent class models suggest that roughly equal percentages of migrants were motivated by economic factors before and during the recession. We conclude that fears of dramatic declines in labor migration seem to be unsubstantiated.
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Five percent of typical oral contraceptive users experience an unintended pregnancy every year. Inconsistent use of oral contraception may be a leading contributor to the high rate of unintended pregnancy among oral contraceptive users. Previous medical research also suggests that anxiety may play a role in medication compliance, yet no known studies have examined the relationship between anxiety and oral contraceptive use. To test this relationship, the authors analyze data from the National Survey of Family Growth Cycle V (NSFG-V), restricting their sample to sexually active women currently taking oral contraceptives. They find that women who report multiple episodes of anxiety lasting at least 6 months have a greater probability of inconsistent use. The authors suggest goals for future research and discuss the role of health care professionals in addressing oral contraception compliance in light of their findings.
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Ansiedade/psicologia , Anticoncepcionais Orais/uso terapêutico , Cooperação do Paciente/psicologia , Adolescente , Adulto , Fatores Etários , Ansiedade/etnologia , Coito , Feminino , Inquéritos Epidemiológicos , Humanos , Menarca , Modelos Estatísticos , Motivação , Cooperação do Paciente/etnologia , Cooperação do Paciente/estatística & dados numéricos , Gravidez , Gravidez não Planejada/psicologia , Fatores de Risco , Estados UnidosRESUMO
BACKGROUND: In recent years, use of prosthetic material for inguinal hernia repair has increased dramatically. Tension-free repairs have gained popularity not only for recurrent or complicated hernias, but for primary hernia repairs as well. Although routine use of prophylactic antibiotics is not recommended in the Philippines for open nonimplant herniorrhaphy, there is little direct clinical evidence on which to base recommendations when implantable mesh is used. STUDY DESIGN: We conducted a prospective, randomized, double-blind, placebo-controlled trial comparing wound infection rates in 360 patients (180 received prophylactic antibiotics, 180 received a placebo) undergoing primary inguinal hernia repair electively using polypropylene mesh. Age, gender, American Society of Anesthesiologists class, type of hernia, type of anesthesia, and duration of operation were recorded. Infections were evaluated 1 week, 2 weeks, and 1 month after operation by an independent surgeon. All complications were recorded. Results were assessed using chi-square, Fisher's exact test, and Student's t-tests as appropriate. RESULTS: Groups were well matched for all preoperative variables studied, including comorbid conditions. Six patients from the antibiotic group and four from the placebo group failed to followup after the second week. Superficial surgical site infection developed in 3 patients (1.7%) from the antibiotic group and 6 (3.3%) from the placebo group (p = 0.50). One from each group developed deep surgical site infection. Both patients were readmitted and underwent repeated debridement, which eventually resulted in graft loss. CONCLUSIONS: Preoperative administration of single-dose antibiotic for tension-free inguinal mesh herniorrhaphy did not markedly decrease risk of wound infection in this patient population. Our results do not support use of antibiotic prophylaxis for tension-free mesh herniorrhaphy.
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Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Cefazolina/administração & dosagem , Hérnia Inguinal/cirurgia , Infecções por Pseudomonas/prevenção & controle , Telas Cirúrgicas , Infecção da Ferida Cirúrgica/prevenção & controle , Adolescente , Adulto , Idoso , Distribuição de Qui-Quadrado , Procedimentos Cirúrgicos do Sistema Digestório/instrumentação , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pseudomonas/isolamento & purificação , Infecções por Pseudomonas/microbiologia , Infecção da Ferida Cirúrgica/microbiologia , Resultado do TratamentoRESUMO
This paper presents a residual methods approach to identifying social mobility across race/ethnic categories. In traditional demographic accounting models, population growth is limited to changes in natural increase and migration. Other sources of growth are absorbed by the model residual and can only be estimated indirectly. While these residual estimates have been used to illuminate a number of elusive demographic processes, there has been little effort to incorporate shifts in racial identification into formal accounts of population change. In light of growing evidence that a number of Americans view race/ethnic identities as a personal choice, and not a fixed characteristic, mobility across racial categories may play important roles in the growth of race/ethnic sub-populations and changes to the composition of the U.S. To examine this potential, we derive a reduced-form population balancing equation that treats fertility and international migration as given and estimates survival from period life table data. After subtracting out national increase and migration and adjusting the balance of observed growth for changes in racial measurement and census coverage, we argue that the remaining error of closure provides a reasonable estimate of net interracial mobility among the native born. Using recent Census and ACS microdata, we illustrate the impact that identity shifts may have had on the growth of race/ethnic sub-populations in the past quarter century. Findings suggest a small drift from the non-Hispanic white population into race/ethnic minority groups, though the pattern varies by age and between time periods.