RESUMO
BACKGROUND: Older adults commonly face challenges in understanding, obtaining, administering, and monitoring medication regimens after hospitalization. These difficulties can lead to avoidable morbidity, mortality, and hospital readmissions. Pharmacist-led peri-discharge interventions can reduce adverse drug events, but few large randomized trials have examined their effectiveness in reducing readmissions. Demonstrating reductions in 30-day readmissions can make a financial case for implementing pharmacist-led programs across hospitals. METHODS/DESIGN: The PHARMacist Discharge Care, or the PHARM-DC intervention, includes medication reconciliation at admission and discharge, medication review, increased communication with caregivers, providers, and retail pharmacies, and patient education and counseling during and after discharge. The intervention is being implemented in two large hospitals: Cedars-Sinai Medical Center and the Brigham and Women's Hospital. To evaluate the intervention, we are using a pragmatic, randomized clinical trial design with randomization at the patient level. The primary outcome is utilization within 30 days of hospital discharge, including unforeseen emergency department visits, observation stays, and readmissions. Randomizing 9776 patients will achieve 80% power to detect an absolute reduction of 2.5% from an estimated baseline rate of 27.5%. Qualitative analysis will use interviews with key stakeholders to study barriers to and facilitators of implementing PHARM-DC. A cost-effectiveness analysis using a time-and-motion study to estimate time spent on the intervention will highlight the potential cost savings per readmission. DISCUSSION: If this trial demonstrates a business case for the PHARM-DC intervention, with few barriers to implementation, hospitals may be much more likely to adopt pharmacist-led peri-discharge medication management programs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04071951.
Assuntos
Farmacêuticos , Cuidado Transicional , Idoso , Feminino , Hospitalização , Humanos , Reconciliação de Medicamentos , Alta do Paciente , Readmissão do PacienteRESUMO
OBJECTIVES: Though progressive multifocal leucencephalopathy (PML) may manifest with visual impairment, including bilateral visual loss as the presenting manifestation, in single patients, it has not been described in association with left ventricular hypertrabeculation/noncompaction (LVHT). CASE REPORT: A 37 years old HIV-positive Caucasian male developed visual impairment, which continuously progressed to near blindness within two weeks. He could differentiate bright and dark but was unable to count fingers, and there was bradydiadochokinesia. Ophthalmologic investigations exclusively revealed severe visual field defects bilaterally. Visually-evoked-potentials were absent bilaterally. MRI of the cerebrum revealed bilateral occipital, non-enhancing T2-hyperintensities, which extended towards the temporal lobe. On diffusion weighted imaging hyperintense areas were intermingled with hypointense areas. H-MR-spectroscopy disclosed an increased lactate peak, but reduced creatine, cholin, and N-acetyl-aspartate peaks. CSF-protein was slightly elevated, oligoclonal bands were positive, and PCR positive for the JC-virus. T-helper cells were markedly reduced. Cardiologic investigations revealed right bundle-branch-block, left ventricular wall thickening and LVHT in the left ventricular apex and the lateral wall. During follow-up visual acuity transiently improved but lastly deteriorated again despite a highly-active anti-retroviral therapy. CONCLUSIONS: This case shows that cortical blindness may be the initial clinical manifestation of PML and that isolated LVHT is not causally related to a HIV-infection but rather to a subclinical neuromuscular disorder.
Assuntos
Cegueira Cortical/etiologia , Infecções por HIV/complicações , Miocárdio Ventricular não Compactado Isolado/complicações , Leucoencefalopatia Multifocal Progressiva/complicações , Adulto , Cegueira Cortical/patologia , Humanos , Miocárdio Ventricular não Compactado Isolado/diagnóstico por imagem , Leucoencefalopatia Multifocal Progressiva/patologia , Masculino , UltrassonografiaRESUMO
BACKGROUND: Pulmonary tumorlets are usually an incidental pathologic curiosity of no clinical importance, but may be mistaken for epithelial and nonepithelial neoplasms. Fine needle aspiration (FNA) of this cell proliferation has rarely been reported. We describe a pulmonary tumorlet associated with bronchocentric granulomatosis presenting as a tumorous consolidation on chest radiograph. CASE: In a hitherto healthy 70-year-old man admitted for acute respiratory infection, a solid consolidation was found on chest radiograph. Medical history was uneventful except right-sided pleurisy in 1949. Computed tomography-guided FNA sample was composed of loose clusters of small columnar cells with cyanophilic cytoplasm and centrally located round to oval nuclei. With a tentative diagnosis of well-differentiated adenocarcinoma, lumpectomy was performed. Intraoperative cytology demonstrated lymphocytes, epithelioid cells, giant cells of Langerhans type and clusters of columnar cells. Definitive histologic examination confirmed the intraoperative diagnosis of necrotizing granulomatosis and tumorlet. Neuroendocrine origin of the cells was confirmed by immunocytochemical and immunohistochemical studies resulting in strong reactivity of the cells to synaptophysin, NSE, chromogranin A and N-Cam. CONCLUSION: Knowledge of the cytomorphologic presentation of tumorlets in FNA and consideration of the appropriate differential diagnoses combined with ancillary studies might have prevented lung resection.
Assuntos
Adenocarcinoma/patologia , Broncopatias/patologia , Erros de Diagnóstico/prevenção & controle , Granuloma do Sistema Respiratório/patologia , Pneumopatias/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/cirurgia , Idoso , Biópsia por Agulha Fina , Broncopatias/diagnóstico por imagem , Broncopatias/cirurgia , Granuloma do Sistema Respiratório/diagnóstico por imagem , Granuloma do Sistema Respiratório/cirurgia , Humanos , Hiperplasia , Imuno-Histoquímica , Pneumopatias/diagnóstico por imagem , Pneumopatias/cirurgia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/cirurgia , Masculino , Necrose , Pneumonectomia , Radiografia , Procedimentos DesnecessáriosRESUMO
INTRODUCTION: In adults, peripheral primitive neuroectodermal tumors (pPNETs) represent a rare and heterogeneous group of neoplasms exhibiting neuronal and glial differentiation. PATIENTS AND METHODS: We present the clinicopathologic features of four examples of the Ewing's sarcoma (EWS)/pPNET group in adults. Hematoxylin and eosin staining, immunohistochemical and molecular studies were reviewed in every case. Immunohistochemical stains were performed on formalin-fixed, paraffin-embedded sections, molecular studies were done using fluorescence in situ hybridization (FISH). RESULTS: Three patients presented with tumors of the thoracopulmonary region, one patient showed EWS of the soft tissue. Microscopically, tumor tissue was composed of round, small, blue cells with fine granular chromatin texture and inconspicuous nucleoli. Mitotic figures and rosettes were present. Tumor cells strongly coexpressed CD99 and vimentin, but due to technical reasons t(22q12) translocation studies proved the presumptive diagnosis of EWS/pPNET in one case only. Despite similar multimodality treatment survival time ranged from 6 to 42 months, two patients were alive at the time of reporting. CONCLUSIONS: As tumors of the EWS/pPNET family behave aggressively, rapid diagnosis is warranted. Since diagnosis of EWS/pPNET requires ancillary studies, it is necessary to consider it even in adult patients.
Assuntos
Neoplasias Ósseas/patologia , Neoplasias Encefálicas/patologia , Tumores Neuroectodérmicos Primitivos/patologia , Sarcoma de Ewing/patologia , Adulto , Neoplasias Ósseas/terapia , Neoplasias Encefálicas/terapia , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos/terapia , Doenças Raras , Sarcoma de Ewing/terapiaRESUMO
BACKGROUND: The broadly neutralizing recombinant human HIV-1 antibodies 4E10, 2F5 and Igh1b12 are reported to have autoreactive potential, which is significant for HIV-1 vaccine development and passive immunotherapy using these antibodies. OBJECTIVE: To investigate the clinical relevance of these findings in subjects receiving passive immunotherapy with these antibodies. METHODS: Four types of investigations were performed: (1) Investigation of clotting parameters in an ongoing clinical study with 4E10, 2F5 and 2G12. (2) Mixing experiments of pooled plasma with the same antibodies. (3) Retrospective analysis of serum from patients who received passive immunotherapy with 4E10, 2F5 and 2G12 either alone or in combination. (4) Assessment of clinical safety data obtained after 418 infusions with these antibodies. RESULTS: Standard clinical assays confirmed that 4E10 showed low-level cross-reactivity with cardiolipin, while previously reported cardiolipin cross-reactivity for 2F5 could not be confirmed. High serum titers of 4E10 induced mild prolongation of the activated partial thromboplastin time, which resolved with the wash out of 4E10. Neither 2F5 nor 2G12 affected coagulation. Repeated high-dose infusions of the monoclonal antibody combination were well tolerated with no incidence for thrombotic complications after 418 infusions in 39 subjects. CONCLUSIONS: Monoclonal antibody 4E10 but not 2F5 or 2G12 showed autoreactive binding specificities. Infusion of 4E10 resulted in transient low anticardiolipin titers. Although an increased thromboembolic risk cannot definitely be excluded, this risk appears to be low and likely depend on underlying disorders.
Assuntos
Anticorpos Anti-HIV/administração & dosagem , Imunização Passiva/efeitos adversos , Fatores Imunológicos/administração & dosagem , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Testes de Coagulação Sanguínea , Cardiolipinas/imunologia , Ensaios Clínicos como Assunto , Reações Cruzadas , Relação Dose-Resposta Imunológica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Ensaio de Imunoadsorção Enzimática , Feminino , Anticorpos Anti-HIV/imunologia , Humanos , Imunização Passiva/métodos , Fatores Imunológicos/imunologia , Recém-Nascido , Masculino , Fosfatidilserinas/imunologia , Protrombina/imunologiaRESUMO
Myocardial tissue engineering aims to repair, replace, and regenerate damaged cardiac tissue using tissue constructs created ex vivo. This approach may one day provide a full treatment for several cardiac disorders, including congenital diseases or ventricular dysfunction after myocardial infarction. Although the ex vivo construction of a myocardium-like tissue is faced with many challenges, it is nevertheless a pressing objective for cardiac reparative medicine. Multidisciplinary efforts have already led to the development of promising viable muscle constructs. In this article, we review the various concepts of cardiac tissue engineering and their specific challenges. We also review the different types of existing biografts and their physiological relevance. Although many investigators have favored cardiomyocytes, we discuss the potential of other clinically relevant cells, as well as the various hypotheses proposed to explain the functional benefit of cell transplantation.
Assuntos
Cardiopatias/terapia , Miocárdio , Engenharia Tecidual/métodos , Engenharia Tecidual/tendências , Animais , Humanos , Mioblastos , Miócitos CardíacosRESUMO
Neurosarcoidosis is often a diagnostic dilemma, especially in the absence of other organ involvement. We report a 64-year-old patient who had suffered from paraplegia due to an intramedullar process since 1995. The presumptive diagnosis based on computed tomography was spinal cord infarction. Six years later, he complained about increasing paresthesia. Magnetic resonance imaging of the spinal cord showed nodular meningeal enhancement. Computed tomography of the thorax revealed mediastinal and hilar lymphadenopathy. Bronchoscopy under generalized anesthesia was performed. The differential cell count in bronchoalveolar lavage fluid showed 39% lymphocytes and a CD4(+)/CD8(+) ratio of 17.7. Histological examination of biopsy specimens from the hilar lymph nodes revealed non-necrotizing granulomas with epitheloid cells and Langerhans-type giant cells, consistent with the diagnosis of sarcoidosis. As a result of these findings, lumbar puncture was undertaken and a raised protein concentration and pleocytosis were found in the cerebrospinal fluid. The number of lymphocytes (9,250 lymphocytes/l) and a CD4(+)/CD8(+) ratio of 10.78 led to the diagnosis of neurosarcoidosis. Paralysis might have been prevented if the correct diagnosis of neurosarcoidosis had been established earlier in this patient.
Assuntos
Sarcoidose/diagnóstico , Doenças da Medula Espinal/diagnóstico , Proteínas do Líquido Cefalorraquidiano/análise , Diagnóstico Diferencial , Humanos , Leucocitose/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paraplegia/etiologia , Radiografia Torácica , Sarcoidose/líquido cefalorraquidiano , Sarcoidose/complicações , Doenças da Medula Espinal/líquido cefalorraquidiano , Doenças da Medula Espinal/complicações , Punção Espinal , Tomografia Computadorizada por Raios XRESUMO
While certain antibodies directed against the human immunodeficiency virus (HIV) envelope have the potential to suppress virus replication in vitro, the impact of neutralizing antibodies in vivo remains unclear. In a recent proof-of-concept study, the broadly neutralizing monoclonal antibodies 2G12, 4E10, and 2F5 exhibited inhibitory activities in vivo, as exemplified by a delay of the viral rebound following the interruption of antiretroviral therapy. Unexpectedly, the antiviral effect seen was most prominently due to 2G12 activity. To further investigate whether differential HIV-inhibitory activity was due to different pharmacokinetic properties of the antibodies, we performed a formal pharmacokinetic analysis with 14 patients. Repeated infusions at high dose levels were well tolerated by the patients and did not elicit an endogenous immune response against the monoclonal antibodies. The pharmacokinetic parameters of all three antibodies correlated with each other. Mean estimates were 0.047, 0.035, and 0.044 liter/kg for the central volume of distribution of 2G12, 4E10, and 2F5, respectively, and 0.0018, 0.0058, and 0.0077 liter/kg . day for the systemic clearance of 2G12, 4E10, and 2F5, respectively. Monoclonal antibody 2G12 had a significantly longer elimination half-life (21.8 +/- 7.2 days [P < 0.0001]) than monoclonal antibodies 4E10 (5.5 +/- 2.2 days) and 2F5 (4.3 +/- 1.1 days). The comprehensive pharmacokinetic data from this long-term multiple-dose phase II study were coherent with those from previous short-term phase I studies, as assessed by compartmental and noncompartmental techniques. The anti-HIV type 1 antibodies studied showed distribution and elimination kinetics similar to those seen for other human-like antibodies. Further studies examining tissue concentrations to explain the differential in vivo activity of the anti-gp120 antibody compared with those of the two anti-gp41 antibodies are warranted.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacocinética , Proteína gp120 do Envelope de HIV/imunologia , Proteína gp41 do Envelope de HIV/imunologia , HIV-1/imunologia , Adulto , Anticorpos Monoclonais/análise , Anticorpos Monoclonais/imunologia , Relação Dose-Resposta Imunológica , Feminino , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To study the safety, immunogenicity and pharmacokinetics of the human monoclonal antibody (hMAb) 4E10 alone and in combination with the hMAbs 2F5 and 2G12 in HIV-1-infected persons. MATERIALS AND METHODS: Eight healthy volunteers with > or =350 CD4 cells/mm3 and < or =100 000 HIV-1 RNA copies/mL were enrolled, seven finished the study. A single 4E10 infusion was administered on day 0, followed by three doses of the hMAb combination 4E10/2F5/2G12 on days 7, 14 and 21 (total amount 8.5 g). Safety was assessed by physical examination, blood chemistry, complete blood cell count and recording of adverse events. 4E10, 2F5 and 2G12 plasma levels were determined before and at the end of each infusion and during the 7 week follow-up. RESULTS: No drug-related adverse events were observed throughout the study. The median plasma concentrations immediately after the first infusion were 371, 253 and 139 microg/mL for 4E10, 2F5 and 2G12. Multiple infusions resulted in maximum plasma concentrations of 407, 294 and 210 microg/mL for 4E10, 2F5, and 2G12, respectively. The median elimination half-lives (t1/2beta) were 6.6, 3.2 and 14.1 days for 4E10, 2F5 and 2G12. A low level antibody response against 2G12 was found in two patients. CONCLUSION: This Phase I trial showed that the hMAb 4E10 can be safely administered, both alone and in combination with 2F5 and 2G12 to HIV-1-infected patients.
Assuntos
Síndrome da Imunodeficiência Adquirida/terapia , Anticorpos Monoclonais/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Imunização Passiva , Síndrome da Imunodeficiência Adquirida/prevenção & controle , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Feminino , Humanos , Imunização Passiva/efeitos adversos , Masculino , Pessoa de Meia-IdadeRESUMO
This study was designed to test the hypothesis that impaired neutrophil function might contribute to the development of bacterial pneumonia in patients with HIV-infection. Numbers of inflammatory cells and immunoglobulin G Fcgamma receptor (IgG FcgammaR) I, II, III levels were investigated in bronchoalveolar lavage (BAL) fluid of HIV-seronegative and HIV-infected patients with bacterial pneumonia. The 99 patients were classified into three groups: I: HIV-seronegative and pneumonia (n = 40); II: HIV-infected and pneumonia (n = 19); III: HIV-seronegative with other pulmonary diseases than pneumonia (n = 40). The results of groups I and II, II and III, and I and III were compared. The percentage of alveolar macrophages was significantly lower (group II vs. III: p = 0.005, group I vs. III: p = 0.001), that of neutrophils increased significantly in patients with pneumonia (group II vs. III: p = 0.02, group I vs. III: p = 0.01). Lymphocytes differed only between groups I and III (p = 0.04). Although only the expression of FcgammaRI was significantly higher in HIV-seronegative pneumonia patients compared to those without pneumonia (p = 0.01), the mean expression of all three receptors was lower in the HIV-infected group, with that of FcgammaRI approaching statistical significance. This report provides first evidence that altered FcgammaR expression on BAL neutrophils might contribute to the increased susceptibility of HIV-infected patients to bacterial pneumonia.
Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por HIV/imunologia , Soronegatividade para HIV/imunologia , Neutrófilos/imunologia , Pneumonia Bacteriana/imunologia , Receptores de IgG/biossíntese , Adulto , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de IgG/imunologiaRESUMO
BACKGROUND: The human monoclonal antibodies (MAbs) 2F5 and 2G12 were identified to be two of the most potent neutralizing antibodies against HIV-1. In a first human study they have been shown to be safe after repeated intravenous infusions to asymptomatic HIV-1-infected individuals. However, the antiviral effects of antibody treatment have not been fully analyzed in this first clinical trial. METHODS: The aim of the present study was to gain a preliminary insight into the antiviral effects of 2F5 and 2G12 in humans. For this purpose, plasma samples obtained from the previous phase I study were studied for RNA copy numbers by reverse transcriptase-polymerase chain reaction. As a measure for activation of complement levels of the major complement factor C3 were measured by enzyme-linked immunosorbent assay. Flow cytometry was used to study T-lymphocyte counts and the amount of infected peripheral blood mononuclear cells (PBMC) was determined by co-culture with uninfected donor PBMC. Virus escape from antibody neutralization was determined in vitro in a PBMC neutralization assay. RESULTS: Transient reduction in viral loads was observed in five of seven patients. Vigorous complement activation was observed directly after HIV-specific antibody infusions. The number of infective peripheral blood mononuclear cells was reduced in some patients whereas CD4+ T-lymphocyte counts and CD4+/CD8+ ratios were transiently increased in all patients. Virus escape occurred only against 2G12. CONCLUSIONS: Analysis of disease progression markers indicate that antibody therapy may have antiviral effects. These findings suggest that neutralizing antibodies should be further evaluated as an alternative therapeutic approach in HIV-1 disease.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/terapia , Imunização Passiva , Carga Viral , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Contagem de Linfócito CD4 , Ativação do Complemento , Feminino , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , HIV-1/fisiologia , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , RNA Viral/sangueRESUMO
Recurrent respiratory papillomatosis is a rare but often severe disease. Although benign in histology, epithelial proliferations may result in progressive hoarseness, stridor, obstruction of the airway and respiratory distress. The current standard of care is surgical therapy with a goal of complete removal or debulking of papillomas and preservation of normal structures. Frequent recurrences and the need for repeated surgical interventions make this treatment a frustrating experience for both the patient and the physician. Many adjuvant therapies have been investigated but no single treatment modality proved to be effective in eradicating recurrent respiratory papillomatosis. In contrast to HIV, cytomegalovirus and hepatitis B pharmaceutical research has been less successful with human papilloma virus vaccines for a variety of reasons. This review focuses on the current status of recurrent respiratory papillomatosis and on future directions of prevention and therapy.
Assuntos
Antivirais/uso terapêutico , Recidiva Local de Neoplasia/prevenção & controle , Papiloma/tratamento farmacológico , Papillomaviridae/efeitos dos fármacos , Neoplasias do Sistema Respiratório/tratamento farmacológico , Humanos , Terapia a Laser , Papiloma/cirurgia , Papiloma/virologia , Infecções por Papillomavirus/tratamento farmacológico , Infecções por Papillomavirus/cirurgia , Infecções por Papillomavirus/virologia , Neoplasias do Sistema Respiratório/cirurgia , Neoplasias do Sistema Respiratório/virologia , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/cirurgia , Infecções Tumorais por Vírus/virologiaRESUMO
OBJECTIVE: To study the safety, immunogenicity and pharmacokinetics of two intravenously administered human monoclonal antibodies (hMAb 2F5, 2G12) against HIV-1 in humans. DESIGN: Open label clinical phase I trial. SETTING: Primary institutional care. PATIENTS: Seven HIV-1-infected healthy volunteers with > or = 500 x 10(6)CD4 cells/l and < or = 10,000 HIV-1 RNA copies/ml, not treated with highly active antiretroviral therapy (HAART), entered and finished the study. INTERVENTIONS: and main outcome measures: Eight separate infusions of the hMAb were administered over a 4-week period (total dose 14 g). The safety was assessed by physical examination, blood chemistry, complete blood cell count and recording adverse events. 2F5 and 2G12 plasma levels were determined prior to and at the end of each infusion and during the follow-up period of 22 weeks. RESULTS: No clinical or laboratory abnormalities were observed throughout the study. The median distribution half-life (t(1/2 alpha)) of 2F5 and 2G12 was 1.02 (range, 0.77-1.47) days and 2.49 (range, 0.92-4.59) days, respectively. The elimination half-life (t(1/2 beta)) was calculated to be 7.94 (range, 3.46-8.31) days for 2F5 and 16.48 (range, 12.84-24.85) days for 2G12. The median plasma concentration immediately after the first infusion was 216 microg/ml (range, 158-409 microg/ml) for 2F5 and 238 microg/ml (range, 197-402 microg/ml) for 2G12. Multiple infusions resulted in maximum plasma concentrations of 374 microg/ml (range, 304-700 microg/ml) and 605 microg/ml (range, 479-897 microg/ml) for 2F5 and 2G12, respectively. CONCLUSIONS: This study showed that the hMAb 2F5 and 2G12 are safe and well tolerated by HIV-1-infected subjects.