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Documentación , Comunicación , Documentación/métodos , Documentación/normas , Humanos , Registros Médicos/normasRESUMEN
Hemolysis and consequent hemoglobinuria is a well-known cause of acute kidney injury (AKI). Hemolysis has been associated with malpositioned prosthetic valves, but other prosthetic devices may rarely be associated with red cell shear stress. We report a case of a 56-year-old man who presented with hemolysis, AKI, and anemia. During workup, he was found to have anti-phospholipid antibodies, leading to a presumptive diagnosis of catastrophic anti-phospholipid antibody syndrome. However, further investigation revealed the cause of hemolysis to be from aortic root graft dysfunction. Following replacement of the prosthesis, there was complete resolution of his hemolysis and recovery of renal function. This case underscores the need to consider cardiac prosthetic devices in patients presenting with hemoglobinuric AKI.
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Lesión Renal Aguda/etiología , Aneurisma de la Aorta/cirugía , Disección Aórtica/cirugía , Implantación de Prótesis Vascular/efectos adversos , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Hemoglobinuria/etiología , Falla de Prótesis , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/fisiopatología , Anemia Hemolítica/etiología , Disección Aórtica/diagnóstico , Aneurisma de la Aorta/diagnóstico , Remoción de Dispositivos , Ecocardiografía Doppler en Color , Ecocardiografía Transesofágica , Hemoglobinuria/diagnóstico , Hemoglobinuria/fisiopatología , Hemólisis , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Recuperación de la Función , Reoperación , Resultado del TratamientoRESUMEN
Human immunodeficiency virus type 1 (HIV-1) controllers maintain viremia at <2,000 RNA copies/ml without antiretroviral therapy. Viruses from controllers with chronic infection were shown to exhibit impaired replication capacities, in part associated with escape mutations from cytotoxic-T-lymphocyte (CTL) responses. In contrast, little is known about viruses during acute/early infection in individuals who subsequently become HIV controllers. Here, we examine the viral replication capacities, HLA types, and virus sequences from 18 HIV-1 controllers identified during primary infection. gag-protease chimeric viruses constructed using the earliest postinfection samples displayed significantly lower replication capacities than isolates from persons who failed to control viremia (P = 0.0003). Protective HLA class I alleles were not enriched in these early HIV controllers, but viral sequencing revealed a significantly higher prevalence of drug resistance mutations associated with impaired viral fitness in controllers than in noncontrollers (6/15 [40.0%] versus 10/80 [12.5%], P = 0.018). Moreover, of two HLA-B57-positive (B57(+)) controllers identified, both harbored, at the earliest time point tested, signature escape mutations within Gag that likewise impair viral replication capacity. Only five controllers did not express "protective" alleles or harbor viruses with drug resistance mutations; intriguingly, two of them displayed typical B57 signature mutations (T242N), suggesting the acquisition of attenuated viruses from B57(+) donors. These data indicate that acute/early stage viruses from persons who become controllers have evidence of reduced replication capacity during the initial stages of infection which is likely associated with transmitted or acquired CTL escape mutations or transmitted drug resistance mutations. These data suggest that viral dynamics during acute infection have a major impact on HIV disease outcome.
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Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , VIH-1/fisiología , Replicación Viral , Farmacorresistencia Viral , Infecciones por VIH/inmunología , VIH-1/crecimiento & desarrollo , VIH-1/inmunología , VIH-1/patogenicidad , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Datos de Secuencia Molecular , Mutación Missense , ARN Viral/genética , Análisis de Secuencia de ADN , Linfocitos T Citotóxicos/inmunología , Carga Viral , ViremiaRESUMEN
BACKGROUND: The immune system behaves like a complex, dynamic network with interacting elements including leukocytes, cytokines, and chemokines. While the immune system is broadly distributed, leukocytes must communicate effectively to respond to a pathological challenge. The Basic Immune Simulator 2010 contains agents representing leukocytes and tissue cells, signals representing cytokines, chemokines, and pathogens, and virtual spaces representing organ tissue, lymphoid tissue, and blood. Agents interact dynamically in the compartments in response to infection of the virtual tissue. Agent behavior is imposed by logical rules derived from the scientific literature. The model captured the agent-to-agent contact history, and from this the network topology and the interactions resulting in successful versus failed viral clearance were identified. This model served to integrate existing knowledge and allowed us to examine the immune response from a novel perspective directed at exploiting complex dynamics, ultimately for the design of therapeutic interventions. RESULTS: Analyzing the evolution of agent-agent interactions at incremental time points from identical initial conditions revealed novel features of immune communication associated with successful and failed outcomes. There were fewer contacts between agents for simulations ending in viral elimination (win) versus persistent infection (loss), due to the removal of infected agents. However, early cellular interactions preceded successful clearance of infection. Specifically, more Dendritic Agent interactions with TCell and BCell Agents, and more BCell Agent interactions with TCell Agents early in the simulation were associated with the immune win outcome. The Dendritic Agents greatly influenced the outcome, confirming them as hub agents of the immune network. In addition, unexpectedly high frequencies of Dendritic Agent-self interactions occurred in the lymphoid compartment late in the loss outcomes. CONCLUSIONS: An agent-based model capturing several key aspects of complex system dynamics was used to study the emergent properties of the immune response to viral infection. Specific patterns of interactions between leukocyte agents occurring early in the response significantly improved outcome. More interactions at later stages correlated with persistent inflammation and infection. These simulation experiments highlight the importance of commonly overlooked aspects of the immune response and provide insight into these processes at a resolution level exceeding the capabilities of current laboratory technologies.
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Simulación por Computador , Sistema Inmunológico/fisiología , Programas InformáticosRESUMEN
Introduction: Vertically integrating physiology into patient care has the potential to improve clinical reasoning. Clinical Physiology Grand Rounds (CPGR) is a case-based teaching method that brings together students from all years of medical school to focus on linking clinical presentations to core basic science concepts including anatomy, physiology, and pathophysiology. In this study, we describe the implementation of CPGR at two different institutions in the United States and assess student-reported outcomes.Methods: We survey students who participated in CPGR at Columbia University College of Physicians & Surgeons (P&S) and Medical University of South Carolina (MUSC). Subjects were queried across three domains: the benefits of attending, the impact of concept maps, and the impact of the mixed-learner environment.Results: Despite differences in session leadership and the underlying medical school curricula, conference attendees reported similar benefits at the two schools included in this study. Students overwhelmingly (92.9%) reported that remembering clinical presentations was easier when they understood the underlying physiology. They also reported gaining a true understanding of concepts that were previously memorized (87.5%). Both clinical (92.5%) and preclinical students (93.1%) valued the mixed-learner environment as a component of the conference.Discussion: By assuring a mixed-learner environment with near-peer interactions, using concept maps as a teaching tool, and rigorously linking clinical presentation and management to physiological concepts, we found that the key benefits of CPGR were replicable across different institutions, despite several local differences in how CPGR was implemented, led, and conducted.
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Fisiología/educación , Facultades de Medicina/organización & administración , Ciencia/educación , Rondas de Enseñanza/organización & administración , Curriculum , Humanos , Evaluación de Programas y Proyectos de Salud , Estados UnidosRESUMEN
Survivors of COVID-19 are a vulnerable population, with complex needs because of lingering symptoms and complications across multiple organ systems. Those who required hospitalization or intensive care are also at risk for post-hospital syndrome and post-ICU syndromes, with attendant cognitive, psychological, and physical impairments, and high levels of health care utilization. Effective ambulatory care for COVID-19 survivors requires coordination across multiple subspecialties, which can be burdensome if not well coordinated. With growing recognition of these needs, post-COVID-19 clinics are being created across the country. We describe the design and implementation of multidisciplinary post-COVID-19 clinics at two academic health systems, Johns Hopkins and the University of California-San Francisco. We highlight components of the model which should be replicated across sites, while acknowledging opportunities to tailor offerings to the local institutional context. Our goal is to provide a replicable framework for others to create these much-needed care delivery models for survivors of COVID-19.
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Cuidados Posteriores/organización & administración , COVID-19 , Servicio Ambulatorio en Hospital/organización & administración , Sobrevivientes , COVID-19/terapia , Arquitectura y Construcción de Hospitales , Humanos , Factores de TiempoRESUMEN
Some hospitals have faced a surge of patients with COVID-19, while others have not. We assessed whether COVID-19 burden (number of patients with COVID-19 admitted during April 2020 divided by hospital certified bed count) was associated with mortality in a large sample of US hospitals. Our study population included 14,226 patients with COVID-19 (median age 66 years, 45.2% women) at 117 hospitals, of whom 20.9% had died at 5 weeks of follow-up. At the hospital level, the observed mortality ranged from 0% to 44.4%. After adjustment for age, sex, and comorbidities, the adjusted odds ratio for in-hospital death in the highest quintile of burden was 1.46 (95% CI, 1.07-2.00) compared to all other quintiles. Still, there was large variability in outcomes, even among hospitals with a similar level of COVID-19 burden and after adjusting for age, sex, and comorbidities.
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COVID-19/mortalidad , Capacidad de Camas en Hospitales/estadística & datos numéricos , Mortalidad Hospitalaria/tendencias , Anciano , Comorbilidad/tendencias , Femenino , Hospitalización , Humanos , Masculino , Estados UnidosRESUMEN
Elite controllers (EC) of human immunodeficiency virus type 1 (HIV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8(+) T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag, pol, and nef sequences from HLA-diverse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC, compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HIV-1 infection.
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Infecciones por VIH/inmunología , Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , VIH-1/genética , VIH-1/inmunología , Mutación Missense/inmunología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Humanos , Plasma/virología , Polimorfismo Genético , Selección Genética , Carga Viral , Viremia/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Human immunodeficiency virus type 1 (HIV-1)-infected persons who maintain plasma viral loads of <50 copies RNA/ml without treatment have been termed elite controllers (EC). Factors contributing to durable control of HIV in EC are unknown, but an HLA-dependent mechanism is suggested by overrepresentation of "protective" class I alleles, such as B*27, B*51, and B*57. Here we investigated the relative replication capacity of viruses (VRC) obtained from EC (n = 54) compared to those from chronic progressors (CP; n = 41) by constructing chimeric viruses using patient-derived gag-protease sequences amplified from plasma HIV RNA and inserted into an NL4-3 backbone. The chimeric viruses generated from EC displayed lower VRC than did viruses from CP (P < 0.0001). HLA-B*57 was associated with lower VRC (P = 0.0002) than were other alleles in both EC and CP groups. Chimeric viruses from B*57(+) EC (n = 18) demonstrated lower VRC than did viruses from B*57(+) CP (n = 8, P = 0.0245). Differences in VRC between EC and CP were also observed for viruses obtained from individuals expressing no described "protective" alleles (P = 0.0065). Intriguingly, two common HLA alleles, A*02 and B*07, were associated with higher VRC (P = 0.0140 and 0.0097, respectively), and there was no difference in VRC between EC and CP sharing these common HLA alleles. These findings indicate that cytotoxic T-lymphocyte (CTL) selection pressure on gag-protease alters VRC, and HIV-specific CTLs inducing escape mutations with fitness costs in this region may be important for strict viremia control in EC of HIV.
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VIH-1/fisiología , Antígenos HLA/genética , Replicación Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , VIH-1/inmunología , Antígenos HLA/metabolismo , Humanos , Datos de Secuencia Molecular , Mutación , Filogenia , ARN Viral/genética , Recombinación Genética , Selección Genética , Análisis de Secuencia de ADN , Homología de Secuencia , Linfocitos T Citotóxicos/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-gamma) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-gamma ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.
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Linfocitos T CD4-Positivos/virología , VIH/inmunología , Linfocitos T Citotóxicos/inmunología , Alelos , Células Cultivadas , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Epítopos de Linfocito T/inmunología , Antígenos HLA/genética , Humanos , Activación de LinfocitosRESUMEN
Human immunodeficiency virus type 1 (HIV-1) elite controllers (EC) maintain viremia below the limit of commercial assay detection (<50 RNA copies/ml) in the absence of antiviral therapy, but the mechanisms of control remain unclear. HLA-B57 and the closely related allele B*5801 are particularly associated with enhanced control and recognize the same Gag(240-249) TW10 epitope. The typical escape mutation (T242N) within this epitope diminishes viral replication capacity in chronically infected persons; however, little is known about TW10 epitope sequences in residual replicating viruses in B57/B*5801 EC and the extent to which mutations within this epitope may influence steady-state viremia. Here we analyzed TW10 in a total of 50 B57/B*5801-positive subjects (23 EC and 27 viremic subjects). Autologous plasma viral sequences from both EC and viremic subjects frequently harbored the typical cytotoxic T-lymphocyte (CTL)-selected mutation T242N (15/23 sequences [65.2%] versus 23/27 sequences [85.1%], respectively; P = 0.18). However, other unique mutants were identified in HIV controllers, both within and flanking TW10, that were associated with an even greater reduction in viral replication capacity in vitro. In addition, strong CTL responses to many of these unique TW10 variants were detected by gamma interferon-specific enzyme-linked immunospot assay. These data suggest a dual mechanism for durable control of HIV replication, consisting of viral fitness loss resulting from CTL escape mutations together with strong CD8 T-cell immune responses to the arising variant epitopes.
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Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos HLA-B/inmunología , Replicación Viral/genética , Replicación Viral/inmunología , Sustitución de Aminoácidos/genética , Epítopos de Linfocito T/genética , Infecciones por VIH/virología , VIH-1/genética , VIH-1/fisiología , Humanos , Datos de Secuencia Molecular , Mutación Missense , Filogenia , Análisis de Secuencia de ADNRESUMEN
Despite reports of viral genetic defects in persons who control human immunodeficiency virus type 1 (HIV-1) in the absence of antiviral therapy, the extent to which such defects contribute to the long-term containment of viremia is not known. Most previous studies examining for such defects have involved small numbers of subjects, primarily focused on subjects expressing HLA-B57, or have examined single viral genes, and they have focused on cellular proviral DNA rather than plasma viral RNA sequences. Here, we attempted viral sequencing from 95 HIV-1 elite controllers (EC) who maintained plasma viral loads of <50 RNA copies/ml in the absence of therapy, the majority of whom did not express HLA-B57. HIV-1 gene fragments were obtained from 94% (89/95) of the EC, and plasma viral sequences were obtained from 78% (61/78), the latter indicating the presence of replicating virus in the majority of EC. Of 63 persons for whom nef was sequenced, only three cases of nef deletions were identified, and gross genetic defects were rarely observed in other HIV-1 coding genes. In a codon-by-codon comparison between EC and persons with progressive infection, correcting for HLA bias and coevolving secondary mutations, a significant difference was observed at only three codons in Gag, all three of which represented the historic population consensus amino acid at the time of infection. These results indicate that the spontaneous control of HIV replication is not attributable to shared viral genetic defects or shared viral polymorphisms.
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VIH-1/genética , Secuencia de Aminoácidos , Secuencia de Bases , Codón , Estudios de Cohortes , Productos del Gen gag/metabolismo , Productos del Gen nef/química , Productos del Gen nef/genética , Genoma Viral , VIH-1/fisiología , Humanos , Filogenia , ARN Viral/genética , ARN Viral/metabolismo , Análisis de Secuencia de ADN , Análisis de Secuencia de Proteína , Análisis de Secuencia de ARN , Eliminación de Secuencia , Carga Viral , Replicación ViralRESUMEN
During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in approximately 80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
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Epítopos de Linfocito T/genética , Infecciones por VIH/inmunología , VIH-1/genética , Proteínas del Virus de la Inmunodeficiencia Humana/genética , Mutación , Linfocitos T Citotóxicos/inmunología , Enfermedad Aguda , Alelos , Secuencia de Aminoácidos , Evolución Molecular , Genes gag/genética , Genes nef/genética , Genes pol/genética , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/inmunología , Antígenos HLA-B/metabolismo , Humanos , Datos de Secuencia MolecularRESUMEN
BACKGROUND: Expanded HIV screening efforts in the United States have increased the use of rapid HIV tests in emergency departments. The reported sensitivity and specificity of rapid HIV tests exceed 99%. OBJECTIVE: To assess whether a reactive rapid oral HIV test result correctly identifies adults with HIV infection in the emergency department. DESIGN: Diagnostic test performance assessment within the framework of a randomized, clinical trial. SETTING: Brigham and Women's Hospital emergency department (Boston, Massachusetts) from 7 February to 1 October 2007. PATIENTS: 849 adults with valid rapid oral HIV test results. INTERVENTION: Rapid HIV testing with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania). Patients with reactive rapid test results were offered enzyme-linked immunoassay, Western blot, and plasma HIV-1 RNA testing for confirmation. MEASUREMENTS: Specificity and positive likelihood ratio. RESULTS: 39 patients had reactive results (4.6% [95% CI, 3.2% to 6.0%]). On confirmation, 5 patients were HIV-infected (prevalence, 0.6% [CI, 0.1% to 1.1%]) and 26 were non-HIV-infected (8 patients declined confirmation). The estimated rapid test specificity was 96.9% (CI, 95.7% to 98.1%). Sensitivity analyses of the true HIV status of unconfirmed cases and test sensitivity resulted in a positive likelihood ratio of 8 to 32. Western blot alone as a confirmation test provided conclusive HIV status in only 50.0% (CI, 30.8% to 69.2%) of patients at first follow-up. The addition of HIV-1 RNA testing to the confirmation protocol improved this rate to 96.2% (CI, 88.8% to 100.0%). LIMITATION: Test sensitivity cannot be assessed because nonreactive OraQuick test results were not confirmed. CONCLUSION: Although patients with a reactive oral OraQuick HIV screening test in the emergency department had an 8- to 32-fold increased odds of HIV infection compared with the pretest odds, the specificity of the test was lower than anticipated.
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Servicio de Urgencia en Hospital , Infecciones por VIH/diagnóstico , Juego de Reactivos para Diagnóstico/normas , Adulto , Femenino , VIH-1 , VIH-2 , Humanos , Masculino , Massachusetts , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
This Viewpoint examines how artificial intelligence could support surrogate decision-makers while addressing some of the attendant epistemic and moral challenges.
RESUMEN
Persistent postmastectomy pain is quite common and has been classified into several distinct types. Few studies, however, have investigated either the predictors or functional impact of multiple types of post mastectomy pain. In this investigation, 278 women, who were, on average, several years post mastectomy, completed questionnaires assessing pain, pain-related physical function, and psychosocial distress. We assessed three distinct categories of postmastectomy pain: phantom breast pain, scar pain, and other mastectomy-related pain. Each of the three types of postmastectomy pain was strongly related to one another (i.e., women reporting one type of pain were more likely to report the other types as well). In general, the more types of postmastectomy pain a woman reported, the greater the degree of disability and distress. Collectively, the presence of "other mastectomy-related pain" was a stronger unique predictor of disability and distress than were the other two categories of pain. Interestingly, demographic and surgical factors, including time since surgery, were not consistent predictors of pain or function. The findings suggest that the assessment of postmastectomy pain should include formal evaluation of multiple types of pain, with additional attention paid to the category of "other mastectomy-related pains," and that the number of types of pain reported by women after surgery may be important in predicting functional outcomes.
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Neoplasias de la Mama/cirugía , Mastectomía , Dolor Postoperatorio/diagnóstico , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Encuestas y CuestionariosRESUMEN
Pneumocystis jirovecii pneumonia (PCP) typically presents as an interstitial and alveolar process with ground glass opacities on chest computed tomography (CT). The absence of ground glass opacities on chest CT is thought to have a high negative predictive value for PCP in individuals with AIDS. Here, we report a case of PCP in a man with AIDS who presented to our hospital with subacute shortness of breath and a nonproductive cough. While his chest CT revealed diffuse nodular rather than ground glass opacities, bronchoscopy with bronchoalveolar lavage and transbronchial biopsies confirmed the diagnosis of PCP and did not identify additional pathogens. PCP was not the expected diagnosis based on chest CT, but it otherwise fit well with the patient's clinical and laboratory presentation. In the era of combination antiretroviral therapy, routine prophylaxis for PCP, and increased use of computed tomography, it may be that PCP will increasingly present with nonclassical chest radiographic patterns. Clinicians should be aware of this presentation when selecting diagnostic and management strategies.