RESUMO
Since prion diseases result from infection and neurodegeneration of the central nervous system (CNS), experimental characterizations of prion strain properties customarily rely on the outcomes of intracerebral challenges. However, natural transmission of certain prions, including those causing chronic wasting disease (CWD) in elk and deer, depends on propagation in peripheral host compartments prior to CNS infection. Using gene-targeted GtE and GtQ mice, which accurately control cellular elk or deer PrP expression, we assessed the impact that peripheral or intracerebral exposures play on CWD prion strain propagation and resulting CNS abnormalities. Whereas oral and intraperitoneal transmissions produced identical neuropathological outcomes in GtE and GtQ mice and preserved the naturally convergent conformations of elk and deer CWD prions, intracerebral transmissions generated CNS prion strains with divergent biochemical properties in GtE and GtQ mice that were changed compared to their native counterparts. While CWD replication kinetics remained constant during iterative peripheral transmissions and brain titers reflected those found in native hosts, serial intracerebral transmissions produced 10-fold higher prion titers and accelerated incubation times. Our demonstration that peripherally and intracerebrally challenged Gt mice develop dissimilar CNS diseases which result from the propagation of distinct CWD prion strains points to the involvement of tissue-specific cofactors during strain selection in different host compartments. Since peripheral transmissions preserved the natural features of elk and deer prions, whereas intracerebral propagation produced divergent strains, our findings illustrate the importance of experimental characterizations using hosts that not only abrogate species barriers but also accurately recapitulate natural transmission routes of native strains.
Assuntos
Encéfalo , Cervos , Príons , Doença de Emaciação Crônica , Animais , Doença de Emaciação Crônica/transmissão , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Príons/metabolismo , Príons/genética , Príons/patogenicidade , Camundongos TransgênicosRESUMO
An observational cross-sectional study was conducted to examine multidimensional frailty and its potential impact on quality of life (QOL) in aging Hispanic people living with HIV (PLWH) and assess the extent to which HIV self-management moderates this association. The sample included 120 Hispanic PLWH aged 50 years and older (M = 59.11; SD = 7.04). The structural equation modeling analyses demonstrated that multidimensional frailty was significantly related to QOL in its two dimensions, physical and mental (p < .001). The relationship between multidimensional frailty and mental and physical QOL remained significant even after controlling for confounders (age and gender). The moderator analyses indicated no statistically significant moderator effect of HIV self-management on multidimensional frailty and mental or physical QOL. These study results have practical implications that highlight the need for early screening for frailty with a multidimensional focus. Age-appropriate and culturally tailored interventions to prevent or mitigate multidimensional frailty may improve QOL.
Assuntos
Fragilidade , Infecções por HIV , Hispânico ou Latino , Qualidade de Vida , Autogestão , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Envelhecimento/psicologia , Estudos Transversais , Idoso Fragilizado/psicologia , Fragilidade/etnologia , Hispânico ou Latino/psicologia , Infecções por HIV/etnologia , Infecções por HIV/psicologia , Infecções por HIV/terapiaRESUMO
Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5' untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias , Humanos , Processamento Alternativo , RNA Mensageiro/genética , Regiões 5' não Traduzidas , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Antígenos CD20/genética , Isoformas de Proteínas/genética , Imunoterapia , Biossíntese de Proteínas , Neoplasias/genéticaRESUMO
While consonant acquisition clearly requires mastery of different articulatory configurations (segments), sub-segmental features and suprasegmental contexts influence both order of acquisition and mismatch (error) patterns (Bérubé, Bernhardt, Stemberger & Ciocca, 2020). Constraints-based nonlinear phonology provides a comprehensive framework for investigating the impact of sub- and suprasegmental impacts on acquisition (Bernhardt & Stemberger, 1998). The current study adopted such a framework in order to investigate these questions for Granada Spanish. Single-word samples of monolingual preschoolers in Granada (29 typically developing; 30 with protracted phonological development) were transcribed by native Spanish speakers in consultation with an international team. Beta regression analyses showed significant effects of age, developmental group, and word structure variables (word length, stress, position of consonants and syllables within the word); salience, markedness and/or frequency across the phonological hierarchy accounted for many patterns. The study further demonstrates the impacts of sub- and suprasegmental constraints of the phonological system on consonant acquisition.
RESUMO
Hispanic men who have sex with men (HMSM) experience HIV risk-related and mental health disparities. The relationship of mental health (i.e., depressive symptoms and anxiety) on sexual risk behaviors of HMSM has been reported. However, little is known about the influence of impulsivity and compulsivity on sexual risk behaviors. A cross-sectional study explored these factors among 150 HMSM in the El Paso, Texas area utilizing standardized measures, in a cross-sectional study. Regression analysis determined the influence of sexual impulsivity and compulsivity, and demographic variables on sexual risk behaviors, indicating interventions should target these behaviors to mitigate sexual risk among HMSM.
Assuntos
Hispânico ou Latino , Homossexualidade Masculina , Assunção de Riscos , Comportamento Sexual , Minorias Sexuais e de Gênero , Humanos , Masculino , Estudos Transversais , Hispânico ou Latino/psicologia , Hispânico ou Latino/estatística & dados numéricos , Infecções por HIV/etnologia , Homossexualidade Masculina/etnologia , Homossexualidade Masculina/psicologia , Comportamento Impulsivo , México , Minorias Sexuais e de Gênero/psicologia , Minorias Sexuais e de Gênero/estatística & dados numéricos , Comportamento Sexual/etnologia , Comportamento Sexual/psicologia , Transtornos Mentais/etnologia , Texas , Disparidades nos Níveis de Saúde , Análise de RegressãoRESUMO
BACKGROUND: Panic-like reactions elicited by electrical stimulation of the dorsal periaqueductal grey matter (ES-dPAG) seem to be regulated by dopamine (DA). We showed that DA applied intranasally (IN) increased escape-behaviour thresholds induced by ES-dPAG of rats, indicating a panicolytic-like effect. AIMS: We investigated whether IN-DA increases escape-response thresholds induced by ES-dPAG by acting on D2-like receptors, and whether IN-DA affects escape responses elicited by the presence of a potential predator and by open space and height of the elevated T-maze (ETM) as well as motor performance in the open field (OF) test. METHODS: Wistar rats exposed to ES-dPAG were treated with Sulpiride (SUL, 40 mg/kg, D2-like receptor antagonist) previously IN-DA (2 mg/kg). Independent groups of rats treated with IN-DA were submitted to prey versus snake paradigm (PSP), ETM and OF. RESULTS: Anti-aversive effects of the IN-DA were reduced by SUL pretreatment in the ES-dPAG test. IN-DA did not affect the escape number in the PSP nor the escape latencies in the ETM as well as motor performance in the OF. CONCLUSIONS/INTERPRETATION: The IN-DA effects in reducing unconditioned fear responses elicited by ES-dPAG seem to be mediated by D2-like receptors. The lack of effects on panic-related responses in the ETM and PSP may be related to the possibility of avoiding the danger inherent to these models, a defence strategy not available during ES-dPAG. These findings cannot be attributed to motor performance. The decision-making responses to avoid dangerous situations can be orchestrated by supra-mesencephalic structures connected by non-dopaminergic inputs.
Assuntos
Crotalinae , Substância Cinzenta Periaquedutal , Ratos , Animais , Dopamina/farmacologia , Ratos Wistar , Medo , Estimulação Elétrica , Reação de FugaRESUMO
Following Hurricanes Irma and Maria in September 2017, there were elevated rates of depression and suicide in Puerto Rico. This study evaluates mental health in older and elderly Puerto Ricans 6 months after the hurricanes and suggests strategies for improving future psychosocial responses. Patients attending clinics were evaluated for depression (Patient Health Questionnaire [PHQ-9]) and suicide risk (Ask Suicide-Screening Questions [ASQ]) and were surveyed about their perceived safety, designated as a proxy for anxiety. Used in conjunction, PHQ-9 and ASQ were found to identify a greater proportion of individuals experiencing adverse mental health effects than if each instrument was used in isolation. Patients were also surveyed about time to water and electricity restoration, and it was found that prolonged time to water restoration was associated with increased prevalence and severity of depression and decreased perceived safety. Based on collected patient data (n = 523), using multiple mental health screening tools for diagnosis, improving perceptions of home safety or anxiety, and prioritizing water restoration may reduce mental health sequelae in the elderly and enhance the effect of psychosocial responses following disasters.
Assuntos
Tempestades Ciclônicas , Idoso , Hispânico ou Latino , Humanos , Saúde Mental , Porto Rico/epidemiologia , Fatores de Risco , ÁguaRESUMO
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Alanina Transaminase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida/uso terapêutico , Etoposídeo , Humanos , Inibidores de MTOR , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Fosfoproteínas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TORRESUMO
OBJECTIVE: The objective of this study was 2-fold: (1) to describe the rabbit temporomandibular joint (TMJ) anatomy and (2) to provide a detailed, step-by-step description of a minimally invasive approach to perform a standard osteochondral TMJ defect that can be used to investigate the regenerative potential of biomaterials. STUDY DESIGN: This study was performed in 2 steps. In the first, a total of 8 rabbit carcasses (n = 16 joints) were used to study the normal TMJ anatomy and histology to develop a minimally invasive approach to access the articulating surface of the condyle to perform a standard osteochondral defect. In the second, the surgical procedure was performed in 10 live animals to evaluate the feasibility of the model and to evaluate the regenerative potential of a biodegradable light-cured hydrogel seeded with stem cells (results not shown). RESULTS: The cartilage of the mandibular condyle showed 4 layers: fibrous, proliferative, hypertrophic, and a zone of calcified cartilage. Positive safranin O staining was observed in the cartilage. The mean duration of the procedure (from incision to last stitch) was 35.5 (±9.21) minutes. All animals survived the procedures without any major complications. CONCLUSIONS: This animal model represents an easy and nonmorbid surgical approach to rabbit TMJ.
Assuntos
Cartilagem Articular , Transtornos da Articulação Temporomandibular , Animais , Materiais Biocompatíveis , Cartilagem Articular/cirurgia , Humanos , Côndilo Mandibular/patologia , Coelhos , Regeneração , Articulação Temporomandibular/patologia , Articulação Temporomandibular/cirurgia , Transtornos da Articulação Temporomandibular/patologia , Alicerces TeciduaisRESUMO
Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.
Assuntos
Condicionamento Psicológico/fisiologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dopamina/farmacologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Receptores de Dopamina D2/fisiologia , Sulpirida/farmacologia , Administração Intranasal , Animais , Condicionamento Psicológico/efeitos dos fármacos , Dopaminérgicos/farmacologia , Extinção Psicológica/efeitos dos fármacos , Masculino , Ratos , Sulpirida/antagonistas & inibidoresRESUMO
Following the Deepwater Horizon oil spill of 2010, large amounts of biodegraded oil (petrocarbon) sank to the seafloor. Our objectives were to 1) determine post-spill isotopic values as the sediments approached a new baseline and 2) track the recovery of affected sediments. Sediment organic carbon δ13C and Δ14C reached a post-spill baseline averaging -21.2 ± 0.9 (n = 129) and -220 ± 66 (n = 95). Spatial variations in seafloor organic carbon baseline isotopic values, 13C and 14C, were influenced by river discharge and hydrocarbon seepage, respectively. Inverse Distance Weighting of surface sediment Δ14C values away from seep sites showed a 50% decrease in the total mass of petrocarbon, from 2010 to 2014. We estimated a rate of loss of -2 × 109 g of petrocarbon-C/year, 2-11% of the degradation rates in surface slicks. Despite the observed recovery in sediments, lingering residual material in the surface sediments was evident seven years following the blowout.
Assuntos
Poluição por Petróleo , Poluentes Químicos da Água , Monitoramento Ambiental , Sedimentos Geológicos , Golfo do México , Hidrocarbonetos/análise , Poluição por Petróleo/análise , Poluentes Químicos da Água/análiseRESUMO
BACKGROUND: Cervical cancer is the leading cause of cancer and related deaths among women in Mozambique. There is limited access to screening and few trained personnel to manage women with abnormal results. Our objective was to implement cervical cancer screening with human papillomavirus (HPV) testing, with navigation of women with abnormal results to appropriate diagnostic and treatment services. METHODS: We prospectively enrolled women aged 30-49 years living in Maputo, Mozambique, from April 2018 to September 2019. All participants underwent a pelvic examination by a nurse, and a cervical sample was collected and tested for HPV using the careHPV test (Qiagen, Gaithersburg, Maryland, USA). HPV positive women were referred for cryotherapy or, if ineligible for cryotherapy, a loop electrosurgical excision procedure. Women with findings concerning for cancer were referred to the gynecologic oncology service. RESULTS: Participants (n=898) had a median age of 38 years and 20.3% were women living with the human immunodeficiency virus. HPV positivity was 23.7% (95% confidence interval 21.0% to 26.6%); women living with human immunodeficiency virus were twice as likely to test positive for HPV as human immunodeficiency virus negative women (39.2% vs 19.9%, p<0.001). Most HPV positive women (194 of 213, 91.1%) completed all steps of their diagnostic work-up and treatment. Treatment included cryotherapy (n=158, 77.5%), loop electrosurgical excision procedure (n=30, 14.7%), or referral to a gynecologist or gynecologic oncologist (n=5, 2.5%). Of eight invasive cervical cancers, 5 (2.8%) were diagnosed in women living with human immunodeficiency virus and 3 (0.4%) in human immunodeficiency virus negative women (p=0.01). CONCLUSION: Cervical cancer screening with HPV testing, including appropriate follow-up and treatment, was feasible in our study cohort in Mozambique. Women living with human immunodeficiency virus appear to be at a significantly higher risk for HPV infection and the development of invasive cervical cancer than human immunodeficiency virus negative women.
Assuntos
Papillomaviridae/patogenicidade , Neoplasias do Colo do Útero/diagnóstico , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Moçambique , Estudos Prospectivos , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: To our knowledge, no previous study has prospectively documented the incidence of common diseases and related mortality in high-income countries (HICs), middle-income countries (MICs), and low-income countries (LICs) with standardised approaches. Such information is key to developing global and context-specific health strategies. In our analysis of the Prospective Urban Rural Epidemiology (PURE) study, we aimed to evaluate differences in the incidence of common diseases, related hospital admissions, and related mortality in a large contemporary cohort of adults from 21 HICs, MICs, and LICs across five continents by use of standardised approaches. METHODS: The PURE study is a prospective, population-based cohort study of individuals aged 35-70 years who have been enrolled from 21 countries across five continents. The key outcomes were the incidence of fatal and non-fatal cardiovascular diseases, cancers, injuries, respiratory diseases, and hospital admissions, and we calculated the age-standardised and sex-standardised incidence of these events per 1000 person-years. FINDINGS: This analysis assesses the incidence of events in 162â534 participants who were enrolled in the first two phases of the PURE core study, between Jan 6, 2005, and Dec 4, 2016, and who were assessed for a median of 9·5 years (IQR 8·5-10·9). During follow-up, 11â307 (7·0%) participants died, 9329 (5·7%) participants had cardiovascular disease, 5151 (3·2%) participants had a cancer, 4386 (2·7%) participants had injuries requiring hospital admission, 2911 (1·8%) participants had pneumonia, and 1830 (1·1%) participants had chronic obstructive pulmonary disease (COPD). Cardiovascular disease occurred more often in LICs (7·1 cases per 1000 person-years) and in MICs (6·8 cases per 1000 person-years) than in HICs (4·3 cases per 1000 person-years). However, incident cancers, injuries, COPD, and pneumonia were most common in HICs and least common in LICs. Overall mortality rates in LICs (13·3 deaths per 1000 person-years) were double those in MICs (6·9 deaths per 1000 person-years) and four times higher than in HICs (3·4 deaths per 1000 person-years). This pattern of the highest mortality in LICs and the lowest in HICs was observed for all causes of death except cancer, where mortality was similar across country income levels. Cardiovascular disease was the most common cause of deaths overall (40%) but accounted for only 23% of deaths in HICs (vs 41% in MICs and 43% in LICs), despite more cardiovascular disease risk factors (as judged by INTERHEART risk scores) in HICs and the fewest such risk factors in LICs. The ratio of deaths from cardiovascular disease to those from cancer was 0·4 in HICs, 1·3 in MICs, and 3·0 in LICs, and four upper-MICs (Argentina, Chile, Turkey, and Poland) showed ratios similar to the HICs. Rates of first hospital admission and cardiovascular disease medication use were lowest in LICs and highest in HICs. INTERPRETATION: Among adults aged 35-70 years, cardiovascular disease is the major cause of mortality globally. However, in HICs and some upper-MICs, deaths from cancer are now more common than those from cardiovascular disease, indicating a transition in the predominant causes of deaths in middle-age. As cardiovascular disease decreases in many countries, mortality from cancer will probably become the leading cause of death. The high mortality in poorer countries is not related to risk factors, but it might be related to poorer access to health care. (AU)
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doenças Cardiovasculares , Neoplasias/mortalidadeRESUMO
PURPOSE: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/biossíntese , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor ErbB-2/genética , Fatores de Risco , Trastuzumab/administração & dosagemRESUMO
OBJECTIVES: Tailoring hypothermia duration to ischemia duration may improve outcome from out-of-hospital cardiac arrest. We investigated the association between the hypothermia/ischemia ratio and functional outcome in a secondary analysis of data from the Resuscitation Outcomes Consortium Amiodarone, Lidocaine, or Placebo Study trial. DESIGN: Cohort study of out-of-hospital cardiac arrest patients screened for Resuscitation Outcomes Consortium-Amiodarone, Lidocaine, or Placebo Study. SETTING: Multicenter study across North America. PATIENTS: Adult, nontraumatic, out-of-hospital cardiac arrest patients screened for Resuscitation Outcomes Consortium-Amiodarone, Lidocaine, or Placebo Study who survived to hospital admission and received targeted temperature management between May 2012 and October 2015. INTERVENTIONS: Targeted temperature management in comatose survivors of out-of-hospital cardiac arrest. We defined hypothermia/ischemia ratio as total targeted temperature management time (initiation through rewarming) divided by calculated total ischemia time (approximate time of arrest [9-1-1 call or emergency medical services-witnessed] to return of spontaneous circulation). MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital survival with good functional status (modified Rankin Score, 0-3) at hospital discharge. We fitted logistic regression models to estimate the association between hypothermia/ischemia ratio and the primary outcome, adjusting for demographics, arrest characteristics, and Resuscitation Outcomes Consortium enrolling site. A total of 3,429 patients were eligible for inclusion, of whom 36.2% were discharged with good functional outcome. Patients had a mean age of 62.0 years (SD, 15.8), with 69.7% male, and 58.0% receiving lay-rescuer cardiopulmonary resuscitation. Median time to return of spontaneous circulation was 21.1 minutes (interquartile range, 16.1-26.9), and median duration of targeted temperature management was 32.9 hours (interquartile range, 23.7-37.8). A total of 2,579 had complete data and were included in adjusted regression analyses. After adjustment for patient characteristics and Resuscitation Outcomes Consortium site, a greater hypothermia/ischemia ratio was associated with increased survival with good functional outcome (odds ratio, 2.01; 95% CI, 1.82-2.23). This relationship, however, appears to be primarily driven by time to return of spontaneous circulation in this patient cohort. CONCLUSIONS: Although a larger hypothermia/ischemia ratio was associated with good functional outcome after out-of-hospital cardiac arrest in this cohort, this association is primarily driven by duration of time to return of spontaneous circulation. Tailoring duration of targeted temperature management based on duration of time to return of spontaneous circulation or patient characteristics requires prospective study.
Assuntos
Coma/etiologia , Coma/terapia , Hipotermia Induzida/métodos , Isquemia Miocárdica/fisiopatologia , Parada Cardíaca Extra-Hospitalar/complicações , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Temperatura Corporal , Coma/mortalidade , Serviços Médicos de Emergência , Feminino , Mortalidade Hospitalar/tendências , Humanos , Hipotermia Induzida/mortalidade , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , América do Norte , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Avaliação de Processos e Resultados em Cuidados de Saúde , Alta do Paciente , Estudos Prospectivos , Estudos Retrospectivos , Fatores Socioeconômicos , Fatores de Tempo , Centros de Traumatologia/estatística & dados numéricosRESUMO
Commercial producers of containerized ornamental plants almost exclusively use soilless media as the substrate for growing the plants. Soilless media are composed primarily of organic materials as opposed to mineral soils. Significant amounts of pesticides can leach from pots containing soilless media to which pesticides have been added as drenches or top-dressings. One of the goals of this project was to identify whether individual components comprising soilless media have differing affinities for the pesticides acephate, imidacloprid, metalaxyl, and plant growth regulator paclobutrazol. One-point 24 h equilibrium sorption assays were conducted to characterize sorption of the pesticides to sand, perlite, vermiculite, coir, peat, pine bark, and aluminum-water treatment residuals (Al-WTRs). Five-point isotherms were then constructed for the more sorptive peat and pine bark substrate components, and for the Al-WTRs. Results indicated significant differences in pesticide behavior with each substrate. Sorption of acephate to most of the substrate components was relatively low, comprising 21-31% of the initial amounts for soilless media components and 63% in Al-WTRs. Al-WTRs were highly sorptive for imidacloprid as evidenced by a partition coefficient of K F = 3275.4 L kg-1. Pine bark was the most sorptive for metalaxyl-M with a measured K F = 195.0 L kg-1. Peat had the highest affinity for paclobutrazol (K F = 398.4 L kg-1). These results indicate that none of component of soilless media has a universally high attraction for all of the pesticides studied.
RESUMO
OBJECTIVE: Patient safety is challenging for health systems around the world, particularly in low-and middleincome countries such as Guatemala. The goal of this report is to summarize a strategic planning process for a national patient safety plan in Guatemala. METHODS: This strategic planning process involved multiple stakeholders, including representatives of the Guatemala Ministry of Health and Social Assistance, medical leadership from across the public health system, and academic experts from Guatemala and the United States of America. We used mixed methods (quantitative and qualitative surveys) and a nominal group technique at a national symposium to prioritize patient safety challenges across Guatemala, and subsequent meetings to develop a national patient safety plan. RESULTS: This national patient safety plan outlines four domains to advance patient safety across the public hospital system over a five-year period in Guatemala: leadership and governance, training and awareness, safety culture, and outcome metrics. For each domain, we developed a set of goals, activities, outputs, and benchmarks to be overseen by the Ministry of Health. CONCLUSIONS: With this national patient safety plan, Guatemala has made a long-term commitment to improving patient safety across the public hospital system of Guatemala. Future efforts will require its extension to all levels of the Guatemalan health system.
RESUMO
PURPOSE: Intranasally applied dopamine (IN-DA), which likely reaches the brain via nasal-brain pathways and bypasses the blood-brain barrier, has been found to increase extracellular DA and bind to the DA2 transporter in the striatum. Recent studies suggest that DA plays a significant role in the processing of signaled and unconditioned aversive stimulation, including evidence that may attenuate responses to painful input. The purpose of this study was to examine the effects of IN-DA on fear-related behaviors induced by electric shock to the foot or by electrical stimulation of the dorsal periaqueductal gray matter (dPAG). METHODS: DA hydrochloride suspended in a viscous castor oil gel (1 or 2 mg/kg) was applied (IN-DA) in a volume of 5 µL into the nostrils of adult Wistar male rats in order to evaluate its effects on (a) freezing induced by electric shock to the foot and (b) thresholds of freezing and escape and duration of post-stimulation freezing induced by electrical stimulation of the dPAG. RESULTS: IN-DA attenuated freezing induced by electric shock to the foot in the three test trials, indicating that it reduced long-term fear responses. IN-DA also increased the threshold of dPAG stimulation-induced escape responses and reduced post-stimulation freezing. CONCLUSIONS: IN-DA, which has previously been shown to facilitate learning and to have antidepressive-like effects, attenuated unconditioned fear responses elicited by peripheral and intramesencephalic (dPAG) stimulation and reduced long-term conditioned fear responses.
Assuntos
Dopamina/farmacologia , Estimulação Elétrica , Medo/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Administração Intranasal , Animais , Comportamento Animal/efeitos dos fármacos , Dopamina/administração & dosagem , Eletrochoque , Reação de Fuga/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Fatores de TempoRESUMO
[ABSTRACT]. Objective. Patient safety is challenging for health systems around the world, particularly in low- and middleincome countries such as Guatemala. The goal of this report is to summarize a strategic planning process for a national patient safety plan in Guatemala. Methods. This strategic planning process involved multiple stakeholders, including representatives of the Guatemala Ministry of Health and Social Assistance, medical leadership from across the public health system, and academic experts from Guatemala and the United States of America. We used mixed methods (quantitative and qualitative surveys) and a nominal group technique at a national symposium to prioritize patient safety challenges across Guatemala, and subsequent meetings to develop a national patient safety plan. Results. This national patient safety plan outlines four domains to advance patient safety across the public hospital system over a five-year period in Guatemala: leadership and governance, training and awareness, safety culture, and outcome metrics. For each domain, we developed a set of goals, activities, outputs, and benchmarks to be overseen by the Ministry of Health. Conclusions. With this national patient safety plan, Guatemala has made a long-term commitment to improving patient safety across the public hospital system of Guatemala. Future efforts will require its extension to all levels of the Guatemalan health system.
[RESUMEN]. Objetivo. La seguridad del paciente constituye un reto para los sistemas de salud de todo el mundo, particularmente en los países de ingresos medianos y bajos como Guatemala. El objetivo del presente informe es resumir el proceso de planificación estratégica para elaborar un plan nacional sobre seguridad del paciente en Guatemala. Métodos. En el proceso de planificación estratégica participaron varios interesados directos, entre los cuales se encontraron representantes del Ministerio de Salud Pública y Asistencia Social de Guatemala, autoridades médicas de todo el sistema de salud pública, así como expertos académicos de Guatemala y Estados Unidos de América. Para establecer las prioridades en cuanto a los retos que deben abordarse en Guatemala en materia de seguridad del paciente se utilizó un método mixto (encuestas cuantitativas y cualitativas) y la técnica de grupo nominal en un simposio nacional, y posteriormente se realizaron reuniones para elaborar un plan nacional sobre la seguridad del paciente. Resultados. En el plan nacional sobre la seguridad del paciente se presentan cuatro ámbitos en los cuales se puede impulsar la seguridad del paciente en todos los hospitales públicos de Guatemala en un período de cinco años: liderazgo y gobernanza, capacitación y concientización, cultura de seguridad y métodos para medir los resultados. Se creó un conjunto de metas, actividades, resultados y puntos de referencia para cada ámbito, que estarán bajo la supervisión del Ministerio de Salud. Conclusiones. Con este plan nacional sobre la seguridad del paciente, Guatemala ha adquirido el compromiso a largo plazo de mejorar la seguridad del paciente en los hospitales públicos del país. Las iniciativas que se emprendan en el futuro requerirán que se extienda a todos los niveles del sistema de salud guatemalteco.
[RESUMO]. Objetivo. A segurança do paciente representa um desafio aos sistemas de saúde em todo o mundo, sobretudo nos países de baixa e média renda como a Guatemala. O presente tem o objetivo de descrever sucintamente o processo de planejamento estratégico para um plano nacional de segurança do paciente na Guatemala. Métodos. Este processo de planejamento estratégico contou com a participação de diversos interessados diretos, como representantes do Ministério da Saúde e Assistência Social da Guatemala, autoridades médicas da área de saúde pública e especialistas acadêmicos da Guatemala e dos Estados Unidos. Métodos combinados (pesquisas quantitativas e qualitativas) e técnica de grupo nominal foram usados em um simpósio nacional para priorizar os desafios em segurança do paciente na Guatemala e reuniões subsequentes foram realizadas para elaborar o plano nacional de segurança do paciente. Resultados. No plano nacional de segurança do paciente, são definidos quatro domínios para fazer avançar o processo de segurança do paciente no sistema hospitalar público em um período de cinco anos: liderança e governança; capacitação e conscientização; cultura de segurança e métricas para mensuração dos resultados. Um conjunto de metas, atividades, resultados e parâmetros de referência foi elaborado para cada domínio, a ser supervisado pelo Ministério da Saúde. Conclusões. Com este plano nacional de segurança do paciente, a Guatemala assumiu um compromisso de longo prazo de melhorar a segurança do paciente no sistema hospitalar público. Esforços devem ser empreendidos para expandir o plano a todos os níveis do sistema de saúde da Guatemala.