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1.
Pediatr Crit Care Med ; 25(7): 643-675, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38959353

RESUMO

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.


Assuntos
Anticoagulantes , Estado Terminal , Oxigenação por Membrana Extracorpórea , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Anticoagulantes/uso terapêutico , Anticoagulantes/administração & dosagem , Criança , Estado Terminal/terapia , Recém-Nascido , Lactente , Pré-Escolar
2.
Pediatr Crit Care Med ; 25(7 Suppl 1): e7-e13, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38959355

RESUMO

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the medications used for anticoagulation for pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE (PEACE). DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Included studies assessed anticoagulation used in pediatric ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third reviewer adjudicating any conflicts. Eighteen references were used for data extraction as well as for creation of recommendations. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-informed recommendations and, when evidence was lacking, expert-based consensus statements, or good practice statements for anticoagulation during pediatric ECMO. A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was based on a modified Delphi process with agreement defined as greater than 80%. Two recommendations, two consensus statements, and one good practice statement were developed, and, in all, agreement greater than 80% was reached. CONCLUSIONS: There is insufficient evidence to formulate optimal anticoagulation therapy during pediatric ECMO. Additional high-quality research is needed to inform evidence-based practice for anticoagulation during pediatric ECMO.


Assuntos
Anticoagulantes , Técnica Delphi , Oxigenação por Membrana Extracorpórea , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Criança , Consenso
3.
Pediatr Crit Care Med ; 25(7 Suppl 1): e44-e52, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38959359

RESUMO

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding antifibrinolytic and adjunct hemostatic agents in neonates and children supported with extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE consensus conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Use of antifibrinolytics (epsilon-aminocaproic acid [EACA] or tranexamic acid), recombinant factor VII activated (rFVIIa), or topical hemostatic agents (THAs). DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Eleven references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. MEASUREMENTS AND MAIN RESULTS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for the management of bleeding and thrombotic complications in pediatric ECMO patients. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One weak recommendation and three consensus statements are presented. CONCLUSIONS: Evidence supporting recommendations for administration of antifibrinolytics (EACA or tranexamic acid), rFVIIa, and THAs were sparse and inconclusive. Much work remains to determine effective and safe usage strategies.


Assuntos
Antifibrinolíticos , Técnica Delphi , Oxigenação por Membrana Extracorpórea , Hemostáticos , Ácido Tranexâmico , Humanos , Antifibrinolíticos/uso terapêutico , Antifibrinolíticos/administração & dosagem , Oxigenação por Membrana Extracorpórea/métodos , Criança , Hemostáticos/uso terapêutico , Hemostáticos/administração & dosagem , Ácido Tranexâmico/uso terapêutico , Ácido Tranexâmico/administração & dosagem , Fator VIIa/uso terapêutico , Fator VIIa/administração & dosagem , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Recém-Nascido , Ácido Aminocaproico/uso terapêutico , Ácido Aminocaproico/administração & dosagem , Hemorragia/prevenção & controle , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Lactente , Consenso
4.
Curr Protoc ; 4(6): e1067, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38857108

RESUMO

The blood-brain barrier (BBB) constitutes a crucial protective anatomical layer with a microenvironment that tightly controls material transit. Constructing an in vitro BBB model to replicate in vivo features requires the sequential layering of constituent cell types. Maintaining heightened integrity in the observed tight junctions during both the establishment and post-experiment phases is crucial to the success of these models. We have developed an in vitro BBB model that replicates the cellular composition and spatial orientation of in vivo BBB observed in humans. The experiment includes comprehensive procedures and steps aimed at enhancing the integration of the four-cell model. Departing from conventional in vitro BBB models, our methodology eliminates the necessity for pre-coated plates to facilitate cell adhesion, thereby improving cell visualization throughout the procedure. An in-house coating strategy and a simple yet effective approach significantly reduce costs and provides superior imaging of cells and corresponding tight junction protein expression. Also, our BBB model includes all four primary cell types that are structural parts of the human BBB. With its innovative and user-friendly features, our in-house optimized in vitro four-cell-based BBB model showcases novel methodology and provides a promising experimental platform for drug screening processes. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Coating and culture system Basic Protocol 2: Cell seeding and Transwell insert handling Basic Protocol 3: Assessment of model functionality.


Assuntos
Barreira Hematoencefálica , Humanos , Barreira Hematoencefálica/metabolismo , Junções Íntimas/metabolismo , Técnicas de Cultura de Células/métodos , Modelos Biológicos , Encéfalo/citologia , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/metabolismo
5.
Pediatr Infect Dis J ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38900075

RESUMO

BACKGROUND: In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. METHODS: This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. RESULTS: Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. CONCLUSIONS: Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

6.
Addict Behav ; 155: 108025, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38593596

RESUMO

BACKGROUND: People in substance use disorder (SUD) treatment have a smoking prevalence that is five times higher than the national average. California funded the Tobacco Free for Recovery Initiative, designed to support programs in implementing tobacco-free grounds and increasing smoking cessation services. In the first cohort of the initiative (2018-2020) client smoking prevalence decreased from 54.2% to 26.6%. The current study examined whether similar findings would be replicated with a later cohort of programs (2020-2022). METHOD: Cross-sectional survey data were collected from clients in 11 residential SUD treatment programs at baseline (n = 185) and at post intervention (n = 227). Multivariate logistic regression assessed change over time in smoking prevalence, tobacco use behaviors, and receipt of cessation services across the two timepoints. RESULTS: Client smoking prevalence decreased from 60.3 % to 40.5 % (Adjusted Odds Ratio [AOR] = 0.46, 95 % CI = 0.27, 0.78; p = 0.004). Current smokers and those who quit while in treatment reported an increase in nicotine replacement therapy (NRT)/pharmacotherapy from baseline to post intervention (31.9 % vs 45.6 %; AOR = 2.22, 95 % CI = 1.08, 4.58; p = 0.031). CONCLUSIONS: Like the first cohort, the Tobacco Free for Recovery initiative was associated with decreased client smoking prevalence and an increase in NRT/pharmacotherapy. These findings strengthen the evidence that similar initiatives may be effective in reducing smoking prevalence among people in SUD treatment.


Assuntos
Abandono do Hábito de Fumar , Transtornos Relacionados ao Uso de Substâncias , Humanos , California/epidemiologia , Masculino , Feminino , Adulto , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/estatística & dados numéricos , Estudos Transversais , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Prevalência , Dispositivos para o Abandono do Uso de Tabaco/estatística & dados numéricos , Tratamento Domiciliar
7.
ACS Omega ; 9(2): 3017-3027, 2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38250344

RESUMO

This study examines the role of water in binding equilibria with a special focus on secondary solutes (cosolutes) that influence the equilibrium but are not constituents of the final product. Using a thermodynamic framework that includes an explicit term for the release of water molecules upon binding, this investigation reveals how solutes may alter equilibria by changing the activity of the reactants, reflected in ΔG°(obs), and by changing the chemical potential of the solvent, reflected in ΔGS. The framework is applied to four experimental binding systems that differ in the degree of electrostatic contributions. The model systems include the chelation of Ca2+ by EDTA and three host-guest reactions; the pairings of p-sulfonatocalix[4]arene with tetramethylammonium ion, cucurbit[7]uril with N-acetyl-phenylalanine-amide, and ß-cyclodextrin with adamantane carboxylate are tested. Each reaction pair is examined by isothermal titration calorimetry at 25 °C in the presence of a common osmolyte, sucrose, and a common chaotrope, urea. Molar solutions of trehalose and phosphate were also tested with selected models. In general, cosolutes that enhance binding tend to reduce the solvation free energy penalty and cosolutes that weaken binding tend to increase the solvation free energy penalty. Notably, the nonpolar-nonpolar interaction between adamantane carboxylate and ß-cyclodextrin is characterized by a ΔGS value near zero. The results with ß-cyclodextrin, in particular, prompt further discussions of the hydrophobic effect and the biocompatible properties of trehalose. Other investigators are encouraged to test and refine the approach taken here to further our understanding of solvent effects on molecular recognition.

8.
Cancer Med ; 12(23): 21075-21096, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37997517

RESUMO

BACKGROUND: Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT. METHODS: We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software. FOCUS: We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers. FINDING: Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.


Assuntos
Antineoplásicos , Neoplasias Encefálicas , Criança , Humanos , Barreira Hematoencefálica , Qualidade de Vida , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Antineoplásicos/uso terapêutico
9.
Drugs Aging ; 40(9): 785-813, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37596380

RESUMO

One-third of older adults with depression meet criteria for treatment resistance, typically defined as a lack of response to two or more adequate trials of an antidepressant. Treatment resistance contributes to an unfavorable prognosis, compromised medical outcomes, heightened disability, accelerated cognitive decline, and an elevated risk of developing dementia. Despite this significant morbidity, evidence is sparse for how to proceed with treatment in this population. Non-pharmacologic therapy (e.g., diet, psychotherapy) can be utilized as adjunctive therapy, despite little published evidence of benefit, given that the risks are low. Pharmacotherapy trials in the treatment-resistant late-life depression population lack strong methods and external validity; however, the use of venlafaxine as monotherapy and add-on therapy, as well as lithium, bupropion, or aripiprazole as add-on therapy to standard antidepressant therapy, have enough evidence that a trial with appropriate monitoring is a prudent strategy. Electroconvulsive therapy remains a well-studied safe therapy, especially when used as maintenance treatment once an initial cycle is completed but is traditionally underutilized in the treatment-resistant late-life depression population. Ensuring non-pharmacologic and pharmacologic strategies are optimized and given a sufficient trial in those with treatment-resistant late-life depression is the best we can do for this vulnerable population.


Assuntos
Disfunção Cognitiva , Depressão , Humanos , Idoso , Bupropiona
11.
DNA Repair (Amst) ; 126: 103501, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37075541

RESUMO

Saccharomyces cerevisiae apurinic/apyrimidinic (AP) endonuclease 1 (yApn1) is a key player of the base excision repair pathway. This multifunctional enzyme is an AP endonuclease, 3'-5' exonuclease, 3'-phosphodiesterase, and participates in nucleotide incision repair. To the best of our knowledge, the known substrates of yApn1 are small DNA lesions such as AP sites and 3'-phospho-α,ß-unsaturated aldehyde (3'-PUA). Here, we wish to report in vitro findings that yApn1 repairs bulky DNA-peptide cross-links (DpCs) and DNA-protein cross-links (DPCs) arising from AP sites and 3'-PUA. We chemically synthesized stable and linkage-defined DpCs and DPCs by oxime ligation and reductive amination, respectively. Our steady-state kinetic data showed that yApn1 repairs a 10-mer peptide-conjugated AP site and 3'-PUA with comparable efficiencies to that of processing the unconjugated lesions. We demonstrated that yApn1 is the predominant enzyme that incises AP-DpC in yeast cell extracts. We also demonstrated that yApn1 incises AP-DPCs in a DPC size-dependent manner, and prior DPC proteolysis by trypsin facilitates the repair. We further found that yApn1 removes 3'-PUA-histone DPCs with moderate efficiencies. Together, our results uncovered a novel role of yApn1 in DPC repair, and support the emerging model that proteolysis is required for efficient DPC repair.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos) , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Reparo do DNA , DNA/metabolismo , Dano ao DNA , Endonucleases/metabolismo , Peptídeos
12.
J Biomol Struct Dyn ; 41(23): 13535-13562, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36890638

RESUMO

Xeroderma pigmentosum C (XPC) is a key initiator in the global genome nucleotide excision repair pathway in mammalian cells. Inherited mutations in the XPC gene can cause xeroderma pigmentosum (XP) cancer predisposition syndrome that dramatically increases the susceptibility to sunlight-induced cancers. Various genetic variants and mutations of the protein have been reported in cancer databases and literature. The current lack of a high-resolution 3-D structure of human XPC makes it difficult to assess the structural impact of the mutations/genetic variations. Using the available high-resolution crystal structure of its yeast ortholog, Rad4, we built a homology model of human XPC protein and compared it with a model generated by AlphaFold. The two models are largely consistent with each other in the structured domains. We have also assessed the degree of conservation for each residue using 966 sequences of XPC orthologs. Our structure- and sequence conservation-based assessments largely agree with the variant's impact on the protein's structural stability, computed by FoldX and SDM. Known XP missense mutations such as Y585C, W690S, and C771Y are consistently predicted to destabilize the protein's structure. Our analyses also reveal several highly conserved hydrophobic regions that are surface-exposed, which may indicate novel intermolecular interfaces that are yet to be characterized.Communicated by Ramaswamy H. Sarma.


Assuntos
Neoplasias , Xeroderma Pigmentoso , Animais , Humanos , Xeroderma Pigmentoso/metabolismo , Reparo por Excisão , Proteínas de Ligação a DNA/química , Reparo do DNA/genética , Mutação , Nucleotídeos , Mamíferos/metabolismo
13.
J Atten Disord ; 27(4): 437-446, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36635886

RESUMO

OBJECTIVE: We aimed to assess the degree to which the American Academy of Pediatrics' (AAP) clinical guidelines were followed when treating attention deficit/hyperactivity disorder (ADHD) in preschoolers. METHOD: Using Medicaid claims for children 4 to 5 years of age receiving their first dose of stimulants/alpha-2 agonists in 2017 (n = 836), we determined if BH was received prior to initiation of medication. We examined predictors after controlling for confounders. RESULTS: More than half the sample did not receive first-line BH, which did not differ by demographics. Those receiving BH prior to medication had a higher rate of receiving an ADHD diagnosis. Only three diagnoses were significant in multivariate (OR 13.8, 95% CI [1.7-115.1]) analyses. CONCLUSION: More than half the sample did not, conservatively, meet the AAP clinical recommendations. Further research is needed to identify targets for intervention. Limitations are noted.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Criança , Humanos , Estados Unidos , Medicaid , Kentucky , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Estimulantes do Sistema Nervoso Central/uso terapêutico
14.
Mol Cell Neurosci ; 124: 103804, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36592800

RESUMO

Cardiolipin is a mitochondrial phospholipid that is also detected in serum inferring its extracellular release; however, this process has not been directly demonstrated for any of the brain cell types. Nevertheless, extracellular cardiolipin has been shown to modulate several neuroimmune functions of microglia and astrocytes, including upregulation of their endocytic activity. Low cardiolipin levels are associated with brain aging, and may thus hinder uptake of amyloid-ß (Αß) in Alzheimer's disease. We hypothesized that glial cells are one of the sources of extracellular cardiolipin in the brain parenchyma where this phospholipid interacts with neighboring cells to upregulate the endocytosis of Αß. Liquid chromatography-mass spectrophotometry identified 31 different species of cardiolipin released from murine BV-2 microglial cells and revealed this process was accelerated by exposure to Aß42. Extracellular cardiolipin upregulated internalization of fluorescently-labeled Aß42 by primary murine astrocytes, human U118 MG astrocytic cells, and murine BV-2 microglia. Increased endocytic activity in the presence of extracellular cardiolipin was also demonstrated by studying uptake of Aß42 and pHrodo™ Bioparticles™ by human induced pluripotent stem cells (iPSCs)-derived microglia, as well as iPSC-derived human brain organoids containing microglia, astrocytes, oligodendrocytes and neurons. Our observations indicate that Aß42 augments the release of cardiolipin from microglia into the extracellular space, where it can act on microglia and astrocytes to enhance their endocytosis of Aß42. Our observations suggest that the reduced glial uptake of Aß due to the decreased levels of cardiolipin could be at least partially responsible for the extracellular accumulation of Aß in aging and Alzheimer's disease.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Humanos , Animais , Camundongos , Microglia/metabolismo , Cardiolipinas/metabolismo , Doença de Alzheimer/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neuroglia/metabolismo , Peptídeos beta-Amiloides/metabolismo , Astrócitos/metabolismo
15.
J Neurochem ; 164(5): 560-582, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36517959

RESUMO

Brain organoids have the potential to improve clinical translation, with the added benefit of reducing any extraneous use of experimental animals. As brain organoids are three-dimensional in vitro constructs that emulate the human brain, they bridge in vitro and in vivo studies more appropriately than monocultures. Although many factors contribute to the failure of extrapolating monoculture-based information to animal-based experiments and clinical trials, for the purpose of this review, we will focus on glia (non-neuronal brain cells), whose functions and transcriptome are particularly abnormal in monocultures. As discussed herein, glia require signals from-and contact with-other cell types to exist in their homeostatic state, which likely contributes to some of the differences between data derived from monocultures and data derived from brain organoids and even two-dimensional co-cultures. Furthermore, we highlight transcriptomic differences between humans and mice in regard to aging and Alzheimer's disease, emphasizing need for a model using the human genome-again, a benefit of brain organoids-to complement data derived from animals. We also identify an urgency for guidelines to improve the reporting and transparency of research using organoids. The lack of reporting standards creates challenges for the comparison and discussion of data from different articles. Importantly, brain organoids mark the first human model enabling the study of brain cytoarchitecture and development.


Assuntos
Doença de Alzheimer , Neuroquímica , Humanos , Animais , Camundongos , Microglia , Encéfalo/fisiologia , Organoides/metabolismo , Doença de Alzheimer/metabolismo
16.
J Emerg Manag ; 20(6): 487-498, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36523193

RESUMO

How do people think they should prepare for tornadoes? To answer this question, we surveyed 340 people in six states in tornado alley and presented eight severe weather preparation choice sets that varied short and long-term benefits and costs with benefits or to the individual or to the community. Fifty-six percent of respondents preferred tornado preparations for the long-term that benefit individuals rather than the community. Correlations between personal characteristics, future expectations, and an individual's preferred preparation strategy show that being married, expecting stronger tornados, and having an individualistic worldview significantly increased the choice of individual preparation options. Past tornado experience and one's current protection level were not significantly related to individual-minded preparation choices. Out of 18 independent variables analyzed, individual worldview was the best predictor of a person's preferences. Individual worldview by itself had better predictive power than a regression model that included an individual's socioeconomic status, past severe weather experience, expectations about future tornados, and current protective measures for severe weather by itself. These findings can inform elected officials considering public policies for natural disaster preparedness and deciding between tradeoffs for keeping government costs low or providing benefits for everyone in the community. Our results are useful for planners and emergency managers who develop strategies to encourage tornado preparation by citizens in the community. For example, emergency managers can replicate the study with options specific to their community to determine what government communications or actions could prompt individuals to put protective measures in place.


Assuntos
Tornados , Humanos , Tempo (Meteorologia) , Comunicação , Inquéritos e Questionários
17.
Pharmacotherapy ; 2022 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-36571459

RESUMO

BACKGROUND: Parenteral penicillin G (PENG) and oral amoxicillin (AMOX) are recommended as treatment for pediatric community-acquired pneumonia (CAP). With recent epidemiologic penicillin susceptibility data for Streptococcus pneumoniae, the most common etiology of CAP, the objective of this study was to evaluate optimal dosing regimens of PENG and AMOX based on population pharmacokinetics linked to current susceptibility data. METHODS: Using NONMEM v7.3, Monte Carlo simulations (N = 10,000) were conducted for AMOX 15 mg/kg/dose PO every 8 h (standard-dose), AMOX 45 mg/kg/dose PO every 12 h (high-dose), and PENG 62,500 units/kg/day IV every 6 h using six virtual subjects with ages spanning 3 months to 15 years old. The probability of target attainment (PTA) was determined for both serum and epithelial lining fluid (ELF) to achieve free drug concentrations above the minimum inhibitory concentration (%fT>MIC) across the population of pneumococci for 30%-50% of the dosing interval. RESULTS: In 2018, all 21 (100%) pneumococcal isolates were susceptible to both PENG and AMOX based on Clinical and Laboratory Standards Institute (CLSI; MIC at 2 mg/L) breakpoints, and 15 of 21 (71%) were susceptible based on EUCAST (MIC at 0.5 mg/L) breakpoints. As compared to CLSI, EUCAST breakpoints consistently achieved higher PTA for all antibiotic regimens. At 50% fT>MIC in the serum at the susceptible MICs, standard-dose AMOX achieved >4% PTA (CLSI) and >86% PTA (EUCAST); high-dose AMOX achieved >73% PTA (CLSI) and >99% PTA (EUCAST); and PENG achieved 0% PTA (using CLSI) and 100% PTA (using EUCAST). Standard-dose AMOX, high-dose AMOX, and PENG achieved >71%, >93%, and 100% PTA, respectively, in the serum at 30%-50% fT>MIC when each patient was stochastically linked to an MIC based on the frequency distribution of national susceptibility data. The PTA was consistently lower in ELF as compared with serum for all regimens. CONCLUSION: Based on the recent rates of resistance, antibiotic doses evaluated provide appropriate exposure for pediatric CAP based on the serum and ELF data associated with predicted clinical and microbiologic success for pneumococcus. High-dose AMOX may still be required to treat pediatric CAP, especially if using CLSI breakpoints. Ongoing surveillance for resistance is essential.

18.
J Perinatol ; 42(11): 1465-1472, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36209233

RESUMO

OBJECTIVE: Identify practices associated with breastfeeding maintenance, examine breastfeeding-related hospital practices by hospital designation level (Baby Friendly vs. Gift vs. none), and assess racial disparities in hospital practices and breastfeeding maintenance. STUDY DESIGN: The Pregnancy Risk Assessment Monitoring System is a population-based survey of mothers who have recently given birth. Non-Hispanic Black (NHB) and non-Hispanic White (NHW) participants who gave birth from 2016-2019 and initiated breastfeeding were included (n = 2200). Associations between twelve breastfeeding-related hospital and breastfeeding at 2-6 months postpartum were assessed. Baby Friendly hospital designation is based on a set of criteria related to hospital practices that promote breastfeeding. The Gift is a Louisiana program that offers a lower level designation and quality improvement support designed to help hospitals transition to and achieve Baby Friendly designation. RESULT: Breastfeeding in the hospital, infant only receiving breast milk, and breastfeeding within one hour after birth were positively associated and receiving a gift pack with formula was negatively associated with breastfeeding maintenance in both NHW and NHB women. Associations were stronger in NHW compared to NHB mothers. CONCLUSION: We identified several practices significantly associated with breastfeeding maintenance. However, racial disparities indicate a need for population-specific supportive practices.


Assuntos
Aleitamento Materno , Mães , Lactente , Gravidez , Feminino , Humanos , Hospitais , Medição de Risco , Grupos Raciais , Promoção da Saúde
19.
Curr Pharm Teach Learn ; 14(9): 1091-1097, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36154953

RESUMO

INTRODUCTION: The objectives of this study were to develop and evaluate a curriculum that integrated biostatistics and research design content with core sciences content within a pharmacy course. METHODS: An inquiry curriculum was developed in 2019 and included lectures on biostatistics and research design with small group discussions of clinical research papers directly related to the core sciences content. Students' perceptions and pass rates between students who did (2019 cohort) and did not (2018 cohort) undergo the curriculum were compared. Test scores taken approximately one year after completion of each cohort's course were also compared. RESULTS: Of 127 students in the 2019 cohort, 120 (94%) responded. Over 90% agreed or strongly agreed that inquiry and core sciences contents were integrated well. The 2019 cohort had a significantly higher pass rate than the 2018 cohort on two of three assessment questions evaluated: one multiple choice question (P = .037) and one short answer question (P = .013). After adjustments for baseline characteristics, retention study volunteers from the 2019 cohort had a significantly higher percent test score than those from the 2018 cohort (parameter estimate = 8.48%; P = .026). CONCLUSIONS: An inquiry curriculum consisting of select biostatistics and research design topics can be integrated with a core sciences curriculum in a large integrated pharmacy course. Inclusion of this content increased student academic performance and retention of knowledge and skills.


Assuntos
Bioestatística , Avaliação Educacional , Estudos de Coortes , Currículo , Humanos , Projetos de Pesquisa
20.
Mar Environ Res ; 181: 105740, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36155343

RESUMO

Deep-sea images are routinely collected during at-sea expeditions and represent a repository of under-utilized knowledge. We leveraged dive videos collected by the remotely-operated vehicle Hercules (deployed from E/V Nautilus, operated by the Ocean Exploration Trust), and adapted biological trait analysis, to develop an approach that characterizes ecosystem services. Specifically, fisheries and climate-regulating services related to carbon are assessed for three southern California methane seeps: Point Dume (∼725 m), Palos Verdes (∼506 m), and Del Mar (∼1023 m). Our results enable qualitative intra-site comparisons that suggest seep activity influences ecosystem services differentially among sites, and site-to-site comparisons that suggest the Del Mar site provides the highest relative contributions to fisheries and carbon services. This study represents a first step towards ecosystem services characterization and quantification using deep-sea images. The results presented herein are foundational, and continued development should help guide research and management priorities by identifying potential sources of ecosystem services.


Assuntos
Ecossistema , Metano , Clima , Carbono
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