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In persons living with HIV-1 (PLWH) who start antiretroviral therapy (ART), plasma virus decays in a biphasic fashion to below the detection limit. The first phase reflects the short half-life (<1 d) of cells that produce most of the plasma virus. The second phase represents the slower turnover (t1/2 = 14 d) of another infected cell population, whose identity is unclear. Using the intact proviral DNA assay (IPDA) to distinguish intact and defective proviruses, we analyzed viral decay in 17 PLWH initiating ART. Circulating CD4+ T cells with intact proviruses include few of the rapidly decaying first-phase cells. Instead, this population initially decays more slowly (t1/2 = 12.9 d) in a process that largely represents death or exit from the circulation rather than transition to latency. This more protracted decay potentially allows for immune selection. After â¼3 mo, the decay slope changes, and CD4+ T cells with intact proviruses decay with a half-life of 19 mo, which is still shorter than that of the latently infected cells that persist on long-term ART. Two-long-terminal repeat (2LTR) circles decay with fast and slow phases paralleling intact proviruses, a finding that precludes their use as a simple marker of ongoing viral replication. Proviruses with defects at the 5' or 3' end of the genome show equivalent monophasic decay at rates that vary among individuals. Understanding these complex early decay processes is important for correct use of reservoir assays and may provide insights into properties of surviving cells that can constitute the stable latent reservoir.
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Antirretrovirais/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Provírus/efeitos dos fármacos , Vírion/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , DNA Viral/efeitos dos fármacos , Humanos , Estudos Longitudinais , Carga Viral/efeitos dos fármacos , Latência Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Antiretroviral therapy (ART) effectively inhibits HIV-1 replication but is not curative due to the persistence of a latent viral reservoir in resting CD4+ T cells. This reservoir is a major barrier to cure. Sequencing studies have revealed that the population of proviruses persisting in ART-treated individuals is dominated by defective proviruses that cannot give rise to viral rebound due to fatal defects including large deletions and APOBEC3-mediated hypermutation. Near full genome sequencing (nFGS) of individual proviruses is used in reservoir assays to provide an estimate of the fraction of proviruses that are intact. nFGS methods rely on a long-distance outer PCR capturing most (~9 kb) of the genome, followed by nested inner PCRs. The outer PCR is carried out at limit dilution, and interpretation of the results is based on the assumption that all proviruses are quantitatively captured. Here, we evaluate nFGS methods using the intact proviral DNA assay (IPDA), a multiplex digital droplet PCR assay that quantitates intact and defective proviruses with single molecule sensitivity using only short, highly efficient amplicons. We analyzed proviral templates of known sequence to avoid the additional complication of sequence polymorphism. With the IPDA, we quantitated molecular yields at each step of nFGS methods. We demonstrate that nFGS methods are inefficient and miss ~70% of full-length proviruses due to amplification failure at the initial outer PCR step. In contrast, proviruses with large internal deletions encompassing 70% of the genome can be quantitatively amplified under the same conditions. Accurate measurement of the latent reservoir of HIV-1 is essential for evaluating the efficacy of cure strategies, and the bias against full length proviruses in nFGS methods must be considered.
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Infecções por HIV , Soropositividade para HIV , HIV-1 , Linfócitos T CD4-Positivos , DNA Viral/genética , HIV-1/genética , Humanos , Provírus/genética , Carga ViralRESUMO
All vitamins play essential roles in various aspects of body function and systems. Patients with chronic kidney disease (CKD), including those receiving dialysis, may be at increased risk of developing vitamin deficiencies due to anorexia, poor dietary intake, protein energy wasting, restricted diet, dialysis loss, or inadequate sun exposure for vitamin D. However, clinical manifestations of most vitamin deficiencies are usually subtle or undetected in this population. Testing for circulating levels is not undertaken for most vitamins except folate, B12, and 25-hydroxyvitamin D because assays may not be available or may be costly to perform and do not always correlate with body stores. The last systematic review through 2016 was performed for the Kidney Disease Outcome Quality Initiative (KDOQI) 2020 Nutrition Guideline update, so this article summarizes the more recent evidence. We review the use of vitamins supplementation in the CKD population. To date there have been no randomized trials to support the benefits of any vitamin supplementation for kidney, cardiovascular, or patient-centered outcomes. The decision to supplement water-soluble vitamins should be individualized, taking account the patient's dietary intake, nutritional status, risk of vitamins deficiency/insufficiency, CKD stage, comorbid status, and dialysis loss. Nutritional vitamin D deficiency should be corrected, but the supplementation dose and formulation need to be personalized, taking into consideration the degree of 25-hydroxyvitamin D deficiency, parathyroid hormone levels, CKD stage, and local formulation. Routine supplementation of vitamins A and E is not supported due to potential toxicity. Although more trial data are required to elucidate the roles of vitamin supplementation, all patients with CKD should undergo periodic assessment of dietary intake and aim to receive various vitamins through natural food sources and a healthy eating pattern that includes vitamin-dense foods.
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Deficiência de Vitaminas , Insuficiência Renal Crônica , Deficiência de Vitamina D , Humanos , Vitaminas/uso terapêutico , Vitamina D , Suplementos Nutricionais , Insuficiência Renal Crônica/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/etiologia , Vitamina A , Deficiência de Vitaminas/epidemiologia , Deficiência de Vitaminas/complicações , Vitamina KRESUMO
Chronic graft-versus-host disease (GvHD) treatment response is assessed using National Institutes of Health (NIH) Consensus Criteria in clinical trials, and by clinician assessment in routine practice. Patient-reported treatment response is central to the experience of chronic GvHD manifestations as well as treatment benefit and toxicity, but how they correlate with clinician- or NIH-responses has not been well-studied. We aimed to characterize 6-month patientreported response, determine associated chronic GvHD baseline organ features and changes, and evaluate which patientreported quality of life and chronic GvHD symptom burden measures correlated with patient-reported response. From two nationally representative Chronic GVHD Consortium prospective observational studies, 382 subjects were included in this analysis. Patient and clinician responses were categorized as improved (completely gone, very much better, moderately better, a little better) versus not improved (about the same, a little worse, moderately worse, very much worse). At six months, 270 (71%) patients perceived chronic GvHD improvement, while 112 (29%) perceived no improvement. Patient-reported response had limited correlation with either clinician-reported (kappa 0.37) or NIH chronic GvHD response criteria (kappa 0.18). Notably, patient-reported response at six months was significantly associated with subsequent failure-free survival. In multivariate analysis, NIH responses in eye, mouth, and lung had significant association with 6-month patient-reported response, as well as a change in Short Form 36 general health and role physical domains and Lee Symptom Score skin and eye changes. Based on these findings, patient-reported responses should be considered as an important complementary endpoint in chronic GvHD clinical trials and drug development.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Qualidade de Vida , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/terapia , Doença Crônica , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: Allogeneic hematopoietic stem cell transplant (alloHSCT) is a mainstay of treatment for hematologic malignancies such as acute leukemias and aggressive lymphomas. Historically, fresh hematopoietic progenitor cell (HPC) products have been preferred to cryopreserved products (cryo-HPC) due to concerns of loss of stem cell viability and number with the cryopreservation procedure. OBJECTIVE: We aimed to analyze the outcomes of patients who received cryo-HPCs during the COVID-19 pandemic and compare this against historical cohorts that received fresh HPC. STUDY DESIGN: A retrospective chart review was conducted on all adult patients who received a peripheral blood alloHSCT in British Columbia, Canada between June 2017 and November 2021. Baseline characteristics, Kaplan-Meier (KM) overall survival (OS), engraftment, and incidences of acute and chronic graft versus host disease were compared between patients who received cryo-HPCs and fresh HPCs. Univariable analysis followed by multivariable analysis was performed using a backward stepwise selection procedure to generate predictors of OS, cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and primary and secondary graft failure. RESULTS: Three hundred eighty-three patients were included in the analysis, with cryo-HPC representing 40%. Median viability was higher in the fresh-HPC group at 99.2% (IQR 98.3-99.5) versus cryo-HPCs at 97.0% (96.0, 98.6) (P < 0.01). The 12-month actuarial survivals were 77% in the fresh HPC and 75% in the cryo-HPC groups (P = 0.21). There were no differences between cryo-HPCs and fresh HPCs on univariable analysis of OS, CIR, or NRM. There was a shorter median time to platelet engraftment in patients receiving fresh HPC at 17 days (IQR 16, 20) versus cryo-HPC at 21 days (IQR 18, 29), P < 0.001. There was a shorter median time to neutrophil engraftment in the fresh HPC group at 17 days (IQR 14, 20) versus 20 days (17, 23), P < 0.001. Cryo-HPC accounted for 5 out of 6 cases of primary graft failure (P = 0.04), and 3 out of five cases of secondary graft failure (P = 0.39). There were no significant differences in acute GVHD between the fresh HPC and cryo-HPC groups (P = 0.34). The incidence of moderate or severe chronic GVHD was 32% in the fresh-HPC group and 17% in the cryo-HPC group (P < 0.001). In multivariable analysis, cryopreservation did not emerge as an independent predictor of OS, CIR, NRM, primary GF or secondary GF. However, viability <90% on arrival at our center was a significant predictor of OS (HR 5.3, 2.3-12.3, P < 0.01), primary graft failure (OR 36.3, 5.4-210.2, P < 0.01), and secondary graft failure (OR 18.4, 1.7-121.1, P < 0.01). CONCLUSIONS: Patients who received cryo-HPCs had similar OS and relapse rates to those who received fresh-HPCs but typically took 2-3 days longer to achieve engraftment of platelets or neutrophils and were associated increased primary graft failure. However, after accounting for multiple variables, cryopreservation was no longer a significant predictor of survival or engraftment while viability <90% emerged as an important predictor of OS, primary graft failure, and secondary graft failure. If confirmed, this suggests that viability on arrival at the infusion center may be a good quality control indicator used to identify HPC products that may warrant recollection if the risk of graft failure is sufficiently increased.
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BACKGROUND: The uptake of the health assessment for persons aged 75 years and older (75 + HA) remains low. Repeat assessments provide an opportunity to identify areas of change in cognitive function which may mark the onset of dementia. We aimed to explore general practitioner (GP) and practice nurse experiences of implementing the 75 + HA with a focus on clinical considerations for dementia care. METHODS: An interpretative qualitative study involving interviews with 15 GPs (female = 11, male = 4) and 5 practice nurses (all female). Data were analysed using an inductive thematic approach. RESULTS: The majority of GPs (n = 11) worked in metropolitan settings and four GPs worked in regional settings across NSW. All participants worked in separate clinics, except for two GPs and one practice nurse who worked within the same metropolitan clinic. Distinct themes emerged regarding participants experiences of implementing the 75 + HA for patients with dementia: (1) negotiating aged care is complex and facilitated by a comprehensive assessment; (2) implementing work practices that support the 75 + HA in patients with cognitive decline; and (3) variations in follow up of findings and implications for care. DISCUSSION: The 75 + HA provides an opportunity for monitoring and acting on emergent physical and cognitive health changes. Increased engagement and support towards implementing the 75 + HA, particularly in the context of dementia, may facilitate the instigation of interventions. While some participants in this study were confident with identifying and managing cognitive decline, the majority relied on geriatricians to confirm dementia diagnosis and refer to community support services. We suggest the need for greater initiatives and clinical guidelines to assist GPs in the identification and management of cognitive decline. IMPLICATIONS FOR THE PROFESSION: From a nursing perspective, this study highlights the valuable role of nurses towards assessment and management of issues raised in the health assessment for persons aged 75 years and older. However, more resources are needed to enable nurse time for adequate follow-up care.
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AIMS: To explore the emotional wellbeing of dementia carers in the lead up to and during transition of a person living with dementia to a residential aged care facility. DESIGN: An interpretative qualitative study. METHODS: Semi-structured interviews were conducted with informal carers of person living with dementia between February and June 2023. Data were analysed using an inductive thematic approach and resulted in three themes. RESULTS: The majority of carers were adult children (n = 19) and six were wives. Carers lived across metropolitan (n = 20) and regional settings (n = 5) in the most populous state of Australia. Three themes were identified which were attributed to different aspects of the carer role: (1) Carer emotional journey as dementia progresses - impacted by knowledge and lack of support; (2) Questioning decision making-underpinned by knowledge and confidence; and (3) Challenges in re-establishing identity - impacted by ongoing concerns. CONCLUSION: As dementia progresses carers of person living with dementia consistently reported gaps in knowledge including how to access support. Specifically, this study identified the need for more to be done to help carers to develop the skills needed for their role, including participation in care planning and identifying care preferences for the future. Nurses can play a key role in promoting referral to services that support carers. Findings offer practical solutions to ameliorate carer stress and promote shared decision making. REPORTING METHOD: This research was guided by the Consolidated Criteria for Reporting Qualitative Research.
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Anaplasmosis, caused by the tickborne bacterium Anaplasma phagocytophilum, is an emerging public health threat in the United States. In the northeastern United States, the blacklegged tick (Ixodes scapularis) transmits the human pathogenic genetic variant of A. phagocytophilum (Ap-ha) and a nonpathogenic variant (Ap-V1). New York has recently experienced a rapid and geographically focused increase in cases of anaplasmosis. We analyzed A. phagocytophilum-infected I. scapularis ticks collected across New York during 2008-2020 to differentiate between variants and calculate an entomological risk index (ERI) for each. Ap-ha ERI varied between regions and increased in all regions during the final years of the study. Space-time scan analyses detected expanding clusters of Ap-ha located within documented anaplasmosis hotspots. Ap-ha ERI was more positively correlated with anaplasmosis incidence than non-genotyped A. phagocytophilum ERI. Our findings help elucidate the relationship between the spatial ecology of A. phagocytophilum variants and anaplasmosis.
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Anaplasma phagocytophilum , Anaplasmose , Ixodes , Animais , Humanos , Ixodes/microbiologia , Anaplasma phagocytophilum/genética , Anaplasmose/microbiologia , New York , New EnglandRESUMO
We conducted a longitudinal study of cryptosporidiosis from birth to three years of age in an urban slum of Dhaka Bangladesh. Fecal DNA was extracted from monthly surveillance samples and diarrheal stool samples collected from 392 infants from birth to three years. A pan-Cryptosporidium qPCR assay was used to identify sub-clinical and symptomatic cryptosporidiosis. Anthropometric measurements were collected quarterly to assess child nutritional status. 31% (121/392) of children experienced a single and 57% (222/392) multiple infections with Cryptosporidium. Repeat infections had a lower burden of parasites in the stool (Cq slope = -1.85; p<0.0001) and were more likely to be sub-clinical (Chi square test for trend; p = 0.01). Repeat infections were associated with the development of growth faltering (Pearson correlation = -0.18; p = 0.0004). High levels of fecal IgA antibodies against the Cryptosporidium Cp23 sporozoite protein at one year of life were associated with a delay in reinfection and amelioration of growth faltering through three years of life (HAZ IgA high responders -1.323 ± 0.932 versus HAZ -1.731 ± 0.984 p = 0.0001). We concluded that nonsterile immunity to cryptosporidiosis in young children was associated with high levels of mucosal IgA anti-Cp23 and protection from diarrhea and growth faltering. Trial Registration: NCT02764918.
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Transtornos da Nutrição Infantil/imunologia , Transtornos da Nutrição Infantil/parasitologia , Criptosporidiose/imunologia , Imunidade nas Mucosas/imunologia , Imunoglobulina A/imunologia , Bangladesh , Pré-Escolar , Criptosporidiose/complicações , Diarreia/parasitologia , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Proteínas de Protozoários/imunologia , Esporozoítos/imunologiaRESUMO
BACKGROUND: The Avoidant Restrictive Food Intake Disorder - Genes and Environment (ARFID-GEN) study is a study of genetic and environmental factors that contribute to risk for developing ARFID in children and adults. METHODS: A total of 3,000 children and adults with ARFID from the United States will be included. Parents/guardians and their children with ARFID (ages 7 to 17) and adults with ARFID (ages 18 +) will complete comprehensive online consent, parent verification of child assent (when applicable), and phenotyping. Enrolled participants with ARFID will submit a saliva sample for genotyping. A genome-wide association study of ARFID will be conducted. DISCUSSION: ARFID-GEN, a large-scale genetic study of ARFID, is designed to rapidly advance the study of the genetics of eating disorders. We will explicate the genetic architecture of ARFID relative to other eating disorders and to other psychiatric, neurodevelopmental, and metabolic disorders and traits. Our goal is for ARFID to deliver "actionable" findings that can be transformed into clinically meaningful insights. TRIAL REGISTRATION: ARFID-GEN is a registered clinical trial: clinicaltrials.gov NCT05605067.
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Transtorno Alimentar Restritivo Evitativo , Transtornos da Alimentação e da Ingestão de Alimentos , Adulto , Criança , Humanos , Estudo de Associação Genômica Ampla , Motivação , Estudos RetrospectivosRESUMO
OBJECTIVE: This study describes a novel transfer model implemented between an academic, level 1 trauma center (Hospital A) and a nearby affiliate community hospital (Hospital B). Primary outcome is change in boarding hours and percentage of boarders in the Hospital A emergency department. Secondary objectives of this study include how improved flow in the emergency department to reduce boarding improves length of stay, prevents patients from escalating to more acute acuity levels of care, reduces patient morbidity and mortality and therefore improves health care costs as well. METHODS: A retrospective chart review was conducted over a consecutive 14-months period of all patients that presented to main hospital emergency department who were transferred to the Hospital B for inpatient admission. This included analysis of patient cohort characteristics, hospital LOS, return rate to the Hospital A (boomerang), rates of against medical advice (AMA) dispositions, post-discharge recidivism, in addition to enterprise data on total number of boarders, percent of boarders, and total boarding hours. RESULTS: There was a total of 718 transfer encounters during the study period. Percent boarding decreased from 70.6% in the pre-period to 63.8% in the post-period (p < 0.001). Total boarding hours decreased at both the main hospital and the sister hospital with this transfer process. The median length of stay at the sister hospital was 74 h, with 9 upgrades to ICU admissions. Five patients were dispositioned back to the hospital A after admission to hospital B. CONCLUSION: A distributive model was useful in transferring admissions within a healthcare system, reducing number of boarders, percent of boarders, and boarding hours in Hospital A emergency department. Furthermore, the Hospital B was an appropriate location for transfers, based on the low number of ICU transfers and dispositions back to the main hospital.
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Assistência ao Convalescente , Admissão do Paciente , Humanos , Tempo de Internação , Estudos Retrospectivos , Alta do Paciente , Serviço Hospitalar de EmergênciaRESUMO
In untreated HIV-1 infection, rapid viral evolution allows escape from immune responses. Viral replication can be blocked by antiretroviral therapy. However, HIV-1 persists in a latent reservoir in resting CD4+ T cells, and rebound viremia occurs following treatment interruption. The reservoir, which is maintained in part by clonal expansion, can be measured using quantitative viral outgrowth assays (QVOAs) in which latency is reversed with T cell activation to allow viral outgrowth. Recent studies have shown that viruses detected in QVOAs prior to treatment interruption often differ from rebound viruses. We hypothesized that autologous neutralizing antibodies directed at the HIV-1 envelope (Env) protein might block outgrowth of some reservoir viruses. We modified the QVOA to reflect pressure from low concentrations of autologous antibodies and showed that outgrowth of a substantial but variable fraction of reservoir viruses is blocked by autologous contemporaneous immunoglobulin G (IgG). A reduction in outgrowth of >80% was seen in 6 of 15 individuals. This effect was due to direct neutralization. We established a phylogenetic relationship between rebound viruses and viruses growing out in vitro in the presence of autologous antibodies. Some large infected cell clones detected by QVOA carried neutralization-sensitive viruses, providing a cogent explanation for differences between rebound virus and viruses detected in standard QVOAs. Measurement of the frequency of reservoir viruses capable of outgrowth in the presence of autologous IgG might allow more accurate prediction of time to viral rebound. Ultimately, therapeutic immunization targeting the subset of variants resistant to autologous IgG might contribute to a functional cure.
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Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/terapia , HIV-1/imunologia , Replicação Viral/imunologia , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/uso terapêutico , Transfusão de Sangue Autóloga/métodos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Células Cultivadas , Terapia Combinada/métodos , Feminino , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/isolamento & purificação , Anticorpos Anti-HIV/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina G/isolamento & purificação , Imunoglobulina G/uso terapêutico , Leucaférese , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
A scalable approach for quantifying intact HIV-1 proviruses is critical for basic research and clinical trials directed at HIV-1 cure. The intact proviral DNA assay (IPDA) is a novel approach to characterizing the HIV-1 reservoir, focusing on the genetic integrity of individual proviruses independent of transcriptional status. It uses multiplex digital droplet PCR to distinguish and separately quantify intact proviruses, defined by a lack of overt fatal defects such as large deletions and APOBEC3G-mediated hypermutation, from the majority of proviruses that have such defects. This distinction is important because only intact proviruses cause viral rebound on ART interruption. To evaluate IPDA performance and provide benchmark data to support its implementation, we analyzed peripheral blood samples from 400 HIV-1+ adults on ART from several diverse cohorts, representing a robust sample of treated HIV-1 infection in the United States. We provide direct quantitative evidence that defective proviruses greatly outnumber intact proviruses (by >12.5 fold). However, intact proviruses are present at substantially higher frequencies (median, 54/106 CD4+ T cells) than proviruses detected by the quantitative viral outgrowth assay, which requires induction and in vitro growth (â¼1/106 CD4+ T cells). IPDA amplicon signal issues resulting from sequence polymorphisms were observed in only 6.3% of individuals and were readily apparent and easily distinguished from low proviral frequency, an advantage of the IPDA over standard PCR assays which generate false-negative results in such situations. The large IPDA dataset provided here gives the clearest quantitative picture to date of HIV-1 proviral persistence on ART.
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DNA Viral/sangue , Infecções por HIV , Provírus/genética , Latência Viral/genética , Adulto , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodosRESUMO
INTRODUCTION: Del Nido cardioplegia (DN) is gaining acceptance in adult cardiac surgery but there is paucity of experimental data regarding its efficacy. We set out to assess the safety and efficacy of single-dose DN with and without topical cooling (TC) versus multi-dose blood cardioplegia (BC). METHODS: Thirty-two healthy adult sheep had pressure-volume (PV) catheters placed in the left (LV) and right (RV) ventricle. Animals were assigned to receive cold (4°C) antegrade solution for a 60-min arrest using: (1) multi-dose (every 20 min) BC with TC (n = 11), (2) single-dose DN with TC (DN-C, n = 10), or (3) single-dose DN without TC (DN-H, n = 11). LV and RV PV-derived indexes, epicardial echocardiographic strains, and blood samples were acquired before CPB and at 1, 2, and 3 h of reperfusion. Dobutamine bolus (2.5 µg) was given after 3 h to test for myocardial reserve. RESULTS: Time to rhythm restoration was shortest (54 ± 29 s, 118 ± 167 s, and 172 ± 170 s for DN-H, DN-C, and BC, respectively; p = 0.024) and number of shocks lowest (1.7 ± 1.8, 3.6 ± 2.8, and 5.6 ± 4.6 for DN-H, DN-C, and BC, respectively; p = 0.020) in DN-H group. Hemodynamic, load-independent myocardial function, echocardiographic, and metabolic data revealed only slight differences between groups. Troponin I levels did not differ between groups. With dobutamine, preload-recruitable stroke work of both LV (136 ± 50%, 131 ± 31%, 142 ± 58% for BC, DN-C and DN-H, respectively; p = 0.993) and RV (161 ± 67%, 185 ± 45%, 166 ± 75% for BC, DN-C and DN-H respectively; p = 0.580) increased similarly. CONCLUSIONS: Single-dose DN cardioplegia with or without topical cooling offered comparable biventricular myocardial protection to multi-dose BC for a 60-min arrest in sheep.
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West Nile virus (WNV) is the most common domestic arbovirus in the United States. During 2018, WNV was transmitted through solid organ transplantation to 2 recipients who had neuroinvasive disease develop. Because of increased illness and death in transplant recipients, organ procurement organizations should consider screening during region-specific WNV transmission months.
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Transplante de Órgãos , Febre do Nilo Ocidental , Vírus do Nilo Ocidental , Seleção do Doador , Humanos , Transplante de Órgãos/efeitos adversos , Doadores de Tecidos , Estados Unidos/epidemiologia , Febre do Nilo Ocidental/diagnóstico , Febre do Nilo Ocidental/epidemiologiaRESUMO
Approximately 476,000 cases of Lyme disease are diagnosed in the United States annually, yet comprehensive economic evaluations are lacking. In a prospective study among reported cases in Lyme disease-endemic states, we estimated the total patient cost and total societal cost of the disease. In addition, we evaluated disease and demographic factors associated with total societal cost. Participants had a mean patient cost of ≈$1,200 (median $240) and a mean societal cost of ≈$2,000 (median $700). Patients with confirmed disseminated disease or probable disease had approximately double the societal cost of those with confirmed localized disease. The annual, aggregate cost of diagnosed Lyme disease could be $345-968 million (2016 US dollars) to US society. Our findings emphasize the importance of effective prevention and early diagnosis to reduce illness and associated costs. These results can be used in cost-effectiveness analyses of current and future prevention methods, such as a vaccine.
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Borrelia burgdorferi , Ixodes , Doença de Lyme , Animais , Estresse Financeiro , Humanos , Incidência , Doença de Lyme/diagnóstico , Doença de Lyme/epidemiologia , Estudos Prospectivos , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Herbicides are environmental contaminants that have gained much attention due to the potential hazards they pose to human health. Glyphosate, the active ingredient in many commercial herbicides, is the most heavily applied herbicide worldwide. The recent rise in glyphosate application to corn and soy crops correlates positively with increased death rates due to Alzheimer's disease and other neurodegenerative disorders. Glyphosate has been shown to cross the blood-brain barrier in in vitro models, but has yet to be verified in vivo. Additionally, reports have shown that glyphosate exposure increases pro-inflammatory cytokines in blood plasma, particularly TNFα. METHODS: Here, we examined whether glyphosate infiltrates the brain and elevates TNFα levels in 4-month-old C57BL/6J mice. Mice received either 125, 250, or 500 mg/kg/day of glyphosate, or a vehicle via oral gavage for 14 days. Urine, plasma, and brain samples were collected on the final day of dosing for analysis via UPLC-MS and ELISAs. Primary cortical neurons were derived from amyloidogenic APP/PS1 pups to evaluate in vitro changes in Aß40-42 burden and cytotoxicity. RNA sequencing was performed on C57BL/6J brain samples to determine changes in the transcriptome. RESULTS: Our analysis revealed that glyphosate infiltrated the brain in a dose-dependent manner and upregulated TNFα in both plasma and brain tissue post-exposure. Notably, glyphosate measures correlated positively with TNFα levels. Glyphosate exposure in APP/PS1 primary cortical neurons increases levels of soluble Aß40-42 and cytotoxicity. RNAseq revealed over 200 differentially expressed genes in a dose-dependent manner and cell-type-specific deconvolution analysis showed enrichment of key biological processes in oligodendrocytes including myelination, axon ensheathment, glial cell development, and oligodendrocyte development. CONCLUSIONS: Collectively, these results show for the first time that glyphosate infiltrates the brain, elevates both the expression of TNFα and soluble Aß, and disrupts the transcriptome in a dose-dependent manner, suggesting that exposure to this herbicide may have detrimental outcomes regarding the health of the general population.
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Doença de Alzheimer , Glicina , Herbicidas , Fator de Necrose Tumoral alfa , Animais , Encéfalo , Cromatografia Líquida , Citocinas/genética , Glicina/análogos & derivados , Glicina/toxicidade , Herbicidas/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , GlifosatoRESUMO
BACKGROUND: Cryoprecipitated antihemophiliac factor (CryoAHF) manufacturing in the US has not kept pace with the increasing demand for hospital transfusion services. Association for Advancement of Blood and Biologics (AABB) and Food and Drug Administration (FDA) require that CryoAHF be manufactured from fresh frozen plasma within 8 h (FFP). We evaluated whether CryoAHF manufactured from plasma frozen within 24 h (PF24) met regulatory quality control (QC) requirements to increase available plasma for CryoAHF. STUDY DESIGN AND METHODS: In a "worst-case scenario" feasibility study, we produced 21 single units of CryoAHF from type-O whole blood-derived PF24 frozen between 20 and 24 h after collection. A follow-up QC validation was conducted wherein 69 PF24 units across three sites were manufactured into CryoAHF. Factor VIII (FVIII) and fibrinogen levels were measured. RESULTS: CryoAHF manufactured in our feasibility study from PF24 contained FVIII levels of 208 ± 61 IU (mean ± SD) and 509 ± 152 mg of fibrinogen levels per unit. CryoAHF manufactured in our QC validation from PF24 yielded FVIII levels of 214 ± 58 IU and 607 ± 176 mg of fibrinogen levels per unit. The coagulation factor levels from each of the individual CryoAHF units exceeded the minimum AABB and FDA requirement of ≥80 IU of FVIII per unit and ≥150 mg of fibrinogen per unit. There was no decrease in FVIII or fibrinogen levels in CryoAHF produced from PF24 as compared to historic QC results of CryoAHF produced from FFP. CONCLUSION: These studies demonstrated that CryoAHF produced from PF24 meets AABB and FDA QC requirements. FDA approved the American Red Cross request to manufacture CryoAHF singles and pools from PF24 as source material.
Assuntos
Preservação de Sangue , Flebotomia , Fatores de Coagulação Sanguínea , Preservação de Sangue/métodos , Fator VIII/uso terapêutico , Fibrinogênio , Humanos , PlasmaRESUMO
OBJECTIVES: Acute myeloid leukaemia (AML) is a disease of older adults, who are vulnerable to socio-economic factors. We determined AML incidence in older adults and the impact of socio-economic factors on outcomes. METHODS: We included 3024 AML patients (1996-2016) identified from a population-based registry. RESULTS: AML incidence in patients ≥60 years increased from 11.01 (2001-2005) to 12.76 (2011-2016) per 100 000 population. Among 879 patients ≥60 years in recent eras (2010-2016), rural residents (<100 000 population) were less likely to be assessed by a leukaemia specialist (39% rural, 47% urban, p = .032); no difference was seen for lower (43%, quintile 1-3) vs. higher (47%, quintile 4-5) incomes (p = .235). Similar numbers received induction chemotherapy between residence (16% rural, 18% urban, p = .578) and incomes (17% lower, 17% high, p = 1.0). Differences between incomes were seen for hypomethylating agent treatment (14% low, 20% high, p = .041); this was not seen for residence (13% rural, 18% urban, p = .092). Among non-adverse karyotype patients ≥70 years, 2-year overall survival was worse for rural (5% rural, 12% urban, p = .006) and lower income (6% low, 15% high, p = .017) patients. CONCLUSIONS: AML incidence in older adults is increasing, and outcomes are worse for older rural and low-income residents; these patients face treatment barriers.
Assuntos
Leucemia Mieloide Aguda , Idoso , Estudos de Coortes , Humanos , Incidência , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , População Rural , Fatores SocioeconômicosRESUMO
BACKGROUND: The HI-Light Trial demonstrated that for active, limited vitiligo, combination treatment with potent topical corticosteroid (TCS) and handheld narrowband ultraviolet B offers a better treatment response than potent TCS alone. However, it is unclear how to implement these findings. AIM: We sought to answer three questions: (i) Can combination treatment be used safely and effectively by people with vitiligo?; (ii) Should combination treatment be made available as routine clinical care?; and (iii) Can combination treatment be integrated within current healthcare provision? METHODS: This was a mixed-methods process evaluation, including semi-structured interviews with a purposive sample of trial participants, structured interviews with commissioners, and an online survey and focus groups with trial staff. Transcripts were coded by framework analysis, with thematic development by multiple researchers. RESULTS: Participants found individual treatments easy to use, but the combination treatment was complicated and required nurse support. Both participants and site investigators felt that combination treatment should be made available, although commissioners were less certain. There was support for the development of services offering combination treatment, although this might not be prioritized above treatment for other conditions. A 'mixed economy' model was suggested, involving patients purchasing their own devices, although concerns regarding the safe use of treatments mean that training, monitoring and ongoing support are essential. The need for medical physics support may mean that a regional service is more practical. CONCLUSION: Combination treatment should be made available for people seeking treatment for vitiligo, but services require partnership with medical physics and ongoing training and support for patients.