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Hydrogen peroxide (H2O2) is a prime member of the reactive oxygen species (ROS) family of molecules produced during normal cell function and in response to various stimuli, but if left unchecked, it can inflict oxidative damage on all types of biological macromolecules and lead to cell death. In this context, a major source of H2O2 for redox signaling purposes is the NADPH oxidase (Nox) family of enzymes, which were classically studied for their roles in phagocytic immune response but have now been found to exist in virtually all mammalian cell types in various isoforms with distinct tissue and subcellular localizations. Downstream of this tightly regulated ROS generation, site-specific, reversible covalent modification of proteins, particularly oxidation of cysteine thiols to sulfenic acids, represents a prominent posttranslational modification akin to phosphorylation as an emerging molecular mechanism for transforming an oxidant signal into a dynamic biological response. We review two complementary types of chemical tools that enable (a) specific detection of H2O2 generated at its sources and (b) mapping of sulfenic acid posttranslational modification targets that mediate its signaling functions, which can be used to study this important chemical signal in biological systems.
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Peróxido de Hidrogênio/metabolismo , NADPH Oxidases/metabolismo , Transdução de Sinais , Animais , Humanos , Oxirredução , Ácidos Sulfênicos/metabolismoRESUMO
Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.
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Diferenciação Celular/efeitos dos fármacos , Reprogramação Celular/genética , Anemia de Fanconi/genética , Formaldeído/toxicidade , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Anemia de Fanconi/sangue , Anemia de Fanconi/patologia , Formaldeído/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/genética , Instabilidade Genômica/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Células K562 , Transcrição GênicaRESUMO
Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)-heteroatom bonds from strong C-H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp3)-H bonds via substrate-directed transition-metal C-H insertion8, undirected C-H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)-C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.
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Carbono/química , Ligação de Hidrogênio , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Níquel/química , Compostos de Tungstênio/químicaRESUMO
The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.
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Carbono/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Formaldeído/química , Formaldeído/metabolismo , Redes e Vias Metabólicas , Mutagênicos/química , Mutagênicos/metabolismo , Álcool Desidrogenase/metabolismo , Animais , Carbono/deficiência , Linhagem Celular , Galinhas , Coenzimas/metabolismo , Reagentes de Ligações Cruzadas/metabolismo , Dano ao DNA , Reparo do DNA , Humanos , Inativação Metabólica , Camundongos , Nucleotídeos/biossíntese , Oxirredução , Serina/química , Serina/metabolismo , Tetra-Hidrofolatos/metabolismoRESUMO
This corrects the article DOI: 10.1038/nature23481.
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Carbon monoxide (CO) is an emerging gasotransmitter and reactive carbon species with broad anti-inflammatory, cytoprotective, and neurotransmitter functions along with therapeutic potential for the treatment of cardiovascular diseases. The study of CO chemistry in biology and medicine relative to other prominent gasotransmitters such as NO and H2S remains challenging, in large part due to limitations in available tools for the direct visualization of this transient and freely diffusing small molecule in complex living systems. Here we report a ligand-directed activity-based sensing (ABS) approach to CO detection through palladium-mediated carbonylation chemistry. Specifically, the design and synthesis of a series of ABS probes with systematic alterations in the palladium-ligand environment (e.g., sp3-S, sp3-N, sp2-N) establish structure-activity relationships for palladacycles to confer selective reactivity with CO under physiological conditions. These fundamental studies led to the development of an optimized probe, termed Carbon Monoxide Probe-3 Ester Pyridine (COP-3E-Py), which enables imaging of CO release in live cell and brain settings, including monitoring of endogenous CO production that triggers presynaptic dopamine release in fly brains. This work provides a unique tool for studying CO in living systems and establishes the utility of a synthetic methods approach to activity-based sensing using principles of organometallic chemistry.
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Monóxido de Carbono/análise , Complexos de Coordenação/química , Corantes Fluorescentes/química , Paládio/química , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Células HEK293 , Humanos , Ligantes , Estrutura MolecularRESUMO
Cyclic dinucleotides are an expanding class of signaling molecules that control many aspects of bacterial physiology. A synthase for cyclic AMP-GMP (cAG, also referenced as 3'-5', 3'-5' cGAMP) called DncV is associated with hyperinfectivity of Vibrio cholerae but has not been found in many bacteria, raising questions about the prevalence and function of cAG signaling. We have discovered that the environmental bacterium Geobacter sulfurreducens produces cAG and uses a subset of GEMM-I class riboswitches (GEMM-Ib, Genes for the Environment, Membranes, and Motility) as specific receptors for cAG. GEMM-Ib riboswitches regulate genes associated with extracellular electron transfer; thus cAG signaling may control aspects of bacterial electrophysiology. These findings expand the role of cAG beyond organisms that harbor DncV and beyond pathogenesis to microbial geochemistry, which is important to environmental remediation and microbial fuel cell development. Finally, we have developed an RNA-based fluorescent biosensor for live-cell imaging of cAG. This selective, genetically encodable biosensor will be useful to probe the biochemistry and cell biology of cAG signaling in diverse bacteria.
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Fenômenos Eletrofisiológicos , Geobacter/metabolismo , Nucleotídeos Cíclicos/metabolismo , RNA Bacteriano/metabolismo , Riboswitch/fisiologia , Sistemas do Segundo Mensageiro/fisiologia , Geobacter/genética , Nucleotídeos Cíclicos/genética , RNA Bacteriano/genética , Vibrio cholerae/genética , Vibrio cholerae/metabolismoRESUMO
Formaldehyde (FA) is a reactive signaling molecule that is continuously produced through a number of central biological pathways spanning epigenetics to one-carbon metabolism. On the other hand, aberrant, elevated levels of FA are implicated in disease states ranging from asthma to neurodegenerative disorders. In this context, fluorescence-based probes for FA imaging are emerging as potentially powerful chemical tools to help disentangle the complexities of FA homeostasis and its physiological and pathological contributions. Currently available FA indicators require direct modification of the fluorophore backbone through complex synthetic considerations to enable FA detection, often limiting the generalization of designs to other fluorophore classes. To address this challenge, we now present the rational, iterative development of a general reaction-based trigger utilizing 2-aza-Cope reactivity for selective and sensitive detection of FA in living systems. Specifically, we developed a homoallylamine functionality that can undergo a subsequent self-immolative ß-elimination, creating a FA-responsive trigger that is capable of masking a phenol on a fluorophore or any other potential chemical scaffold for related imaging and/or therapeutic applications. We demonstrate the utility of this trigger by creating a series of fluorescent probes for FA with excitation and emission wavelengths that span the UV to visible spectral regions through caging of a variety of dye units. In particular, Formaldehyde Probe 573 (FAP573), based on a resorufin scaffold, is the most red-shifted and FA sensitive in this series in terms of signal-to-noise responses and enables identification of alcohol dehydrogenase 5 (ADH5) as an enzyme that regulates FA metabolism in living cells. The results provide a starting point for the broader use of 2-aza-Cope reactivity for probing and manipulating FA biology.
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Compostos Aza/química , Formaldeído/análise , Formaldeído/química , Imagem Óptica , Sobrevivência Celular , Células HEK293 , Humanos , Estrutura MolecularRESUMO
Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces. We describe the design, synthesis, biochemical, and in vivo evaluation of a small-molecule scaffold that captures the topography of α-helices. We designed mimics of a key α-helical domain at the interface of hypoxia-inducible factor 1α and p300 to develop inhibitors of hypoxia-inducible signaling. The hypoxia-inducible factor/p300 interaction regulates the transcription of key genes, whose expression contributes to angiogenesis, metastasis, and altered energy metabolism in cancer. The designed compounds target the desired protein with high affinity and in a predetermined manner, with the optimal ligand providing effective reduction of tumor burden in experimental animal models.
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Biomimética/métodos , Descoberta de Drogas/métodos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sequência de Aminoácidos , Anaerobiose , Animais , Western Blotting , Clonagem Molecular , Perfilação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Luciferases , Camundongos , Dados de Sequência Molecular , Estrutura Molecular , Mutagênese , Piperazina , Piperazinas/química , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismoRESUMO
It has been suggested that clinical screening for suicide, along with firearm assessment and safety counseling, are important in service provision to older adults. It is unclear, however, how geriatric case managers respond to these issues. This study surveyed geriatric case managers (n=161) from Area Agencies on Aging in Ohio on their knowledge, attitudes, and behaviors related to suicide, firearm assessment, and safety counseling. Results indicated that the majority of respondents (70%) agree their clients are at risk for suicide. However, few (30%) in this study reported that they assess for firearms and less than half (48%) discuss firearms with their clients/family members when specifically assessing for suicide. Analyses identified barriers that contribute to the decreased likelihood that routine firearm assessment and safety counseling would occur, such as lack of training and time. Implications include the need for training with geriatric case managers that addresses barriers to suicide, firearm assessment and safety counseling as a means to decrease these population risks.
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Envelhecimento/psicologia , Gerentes de Casos , Aconselhamento , Serviços de Saúde para Idosos/normas , Prevenção do Suicídio , Suicídio , Idoso , Atitude do Pessoal de Saúde , Gerentes de Casos/educação , Gerentes de Casos/psicologia , Barreiras de Comunicação , Aconselhamento/educação , Aconselhamento/métodos , Aconselhamento/normas , Estudos Transversais , Feminino , Armas de Fogo , Avaliação Geriátrica/métodos , Humanos , Vida Independente/psicologia , Masculino , Avaliação das Necessidades , Ohio , Papel Profissional , Suicídio/psicologia , Suicídio/estatística & dados numéricosRESUMO
Formaldehyde (FA) is a reactive carbonyl species (RCS) produced in living systems that has been implicated in epigenetics as well as in the pathologies of various cancers, diabetes, and heart, liver, and neurodegenerative diseases. Traditional methods for biological FA detection rely on sample destruction and/or extensive processing, resulting in a loss of spatiotemporal information. To help address this technological gap, we present the design, synthesis, and biological evaluation of a fluorescent probe for live-cell FA imaging that relies on a FA-induced aza-Cope rearrangement. Formaldehyde probe-1 (FAP-1) is capable of detecting physiologically relevant concentrations of FA in aqueous buffer and in live cells with high selectivity over potentially competing biological analytes. Moreover, FAP-1 can visualize endogenous FA produced by lysine-specific demethylase 1 in a breast cancer cell model, presaging the potential utility of this chemical approach to probe RCS biology.
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Compostos Aza/química , Corantes Fluorescentes/química , Formaldeído/análise , Compostos Aza/análise , Compostos Aza/síntese química , Sobrevivência Celular , Corantes Fluorescentes/análise , Corantes Fluorescentes/síntese química , Células HEK293 , Humanos , Células MCF-7 , Estrutura MolecularRESUMO
Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.
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Transtornos da Nutrição Infantil , Enteropatias , Desnutrição , Biomarcadores , Criança , Pré-Escolar , Países em Desenvolvimento , Humanos , Síndromes de MalabsorçãoRESUMO
Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.
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Proteínas/química , Aminoácidos/química , Biologia Computacional , Desenho de Fármacos , Proteína p300 Associada a E1A/antagonistas & inibidores , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Modelos Moleculares , Mimetismo Molecular , Ligação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Proteína Supressora de Tumor p53/antagonistas & inibidoresRESUMO
Formaldehyde (FA) is both a highly reactive environmental genotoxin and an endogenously produced metabolite that functions as a signaling molecule and one-carbon (1C) store to regulate 1C metabolism and epigenetics in the cell. Owing to its signal-stress duality, cells have evolved multiple clearance mechanisms to maintain FA homeostasis, acting to avoid the established genotoxicity of FA while also redirecting FA-derived carbon units into the biosynthesis of essential nucleobases and amino acids. The highly compartmentalized nature of FA exposure, production, and regulation motivates the development of chemical tools that enable monitoring of transient FA fluxes with subcellular resolution. Here we report a mitochondrial-targeted, activity-based sensing probe for ratiometric FA detection, MitoRFAP-2, and apply this reagent to monitor endogenous mitochondrial sources and sinks of this 1C unit. We establish the utility of subcellular localization by showing that MitoRFAP-2 is sensitive enough to detect changes in mitochondrial FA pools with genetic and pharmacological modulation of enzymes involved in 1C and amino acid metabolism, including the pervasive, less active genetic mutant aldehyde dehydrogenase 2*2 (ALDH2*2), where previous, non-targeted versions of FA sensors are not. Finally, we used MitoRFAP-2 to comparatively profile basal levels of FA across a panel of breast cancer cell lines, finding that FA-dependent fluorescence correlates with expression levels of enzymes involved in 1C metabolism. By showcasing the ability of MitoRFAP-2 to identify new information on mitochondrial FA homeostasis, this work provides a starting point for the design of a broader range of chemical probes for detecting physiologically important aldehydes with subcellular resolution and a useful reagent for further studies of 1C biology.
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Importance: Patients with kidney failure have an increased risk of diabetes-related foot complications. The benefit of regular foot and ankle care in this at-risk population is unknown. Objective: To investigate foot and ankle care by podiatrists and the outcomes of diabetic foot ulcers (DFUs) in patients with kidney failure. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries with type 2 diabetes receiving dialysis who had a new DFU diagnosis. The analysis of the calendar year 2016 to 2019 data from the United States Renal Data System was performed on June 15, 2023, with subsequent updates on December 11, 2023. Exposures: Foot and ankle care by podiatrists during 3 months prior to DFU diagnosis. Main Outcomes and Measures: The outcomes were a composite of death and/or major amputation, as well as major amputation alone. Kaplan-Meier analysis was used to estimate 2 to 3 years of amputation-free survival. Foot and ankle care by podiatrists and the composite outcome was examined using inverse probability-weighted Cox regression, while competing risk regression models were used for the analysis of amputation alone. Results: Among the 14â¯935 adult patients with kidney failure and a new DFU (mean [SD] age, 59.3 [12.7] years; 35.4% aged ≥65 years; 8284 men [55.4%]; Asian, 2.7%; Black/African American, 35.0%; Hispanic, 17.7%; White, 58.5%), 18.4% (n = 2736) received care by podiatrists in the 3 months before index DFU diagnosis. These patients were older, more likely to be male, and have more comorbidities than those without prior podiatrist visits. Over a mean (SD) 13.5 (12.0)-month follow-up, 70% of those with podiatric care experienced death and/or major amputation, compared with 74% in the nonpodiatric group. Survival probabilities at 36 months were 26.3% vs 22.8% (P < .001, unadjusted Kaplan-Meier survival analysis). In multivariate regression analysis, foot and ankle care was associated with an 11% lower likelihood of death and/or amputation (hazard ratio [HR], 0.89 95% CI, 0.84-0.93) and a 9% lower likelihood of major amputation (above or below knee) (HR, 0.91; 95% CI, 0.84-0.99) than those who did not. Conclusions and Relevance: The findings of this study suggest that patients with kidney failure at risk for DFUs who receive foot and ankle care from podiatrists may be associated with a reduced likelihood of diabetes-related amputations.
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Diabetes Mellitus Tipo 2 , Pé Diabético , Insuficiência Renal , Adulto , Humanos , Masculino , Idoso , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Tornozelo , Estudos Retrospectivos , Medicare , Pé Diabético/epidemiologia , Pé Diabético/cirurgia , Fatores de Risco , Amputação Cirúrgica , Insuficiência Renal/epidemiologiaRESUMO
Changes in small bowel function early in infancy in developing countries are increasingly being demonstrated, probably accompanied by altered mucosal architecture in most individuals, including reduced enterocyte mass and evidence of immune activation and inflammation in the mucosa. These alterations appear to be the result of factors of uncertain nature in the environment, and may be a cause of growth faltering and stunting in young children. For these reasons, this constellation of findings is being referred to as environmental enteropathy, or as we propose herein, environmental enteric dysfunction. If the causes were known and effective interventions were available, strategies and policies to intervene at--or possibly before--birth could be developed and promoted in order to prevent subsequent malnutrition and recurrent infection, which are known to interact in a cyclical and synergistic manner in a downward clinical course often ending in death. Resources would be mobilized and applied differently, and the emphasis would change from treatment to prevention. In order to move in this highly desired direction, investments in research will be required to establish the criteria to assess environmental enteric dysfunction, determine its predictive value for growth faltering and stunting, identify the causes, and propose and test potential interventions. The concepts and tools are available. What is required is the decision to move forward along this pathway to better health for infants and children in low-income countries.
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Países em Desenvolvimento , Exposição Ambiental , Transtornos do Crescimento/epidemiologia , Enteropatias/epidemiologia , Pobreza , Causalidade , Humanos , LactenteRESUMO
BACKGROUND: Despite national and international guidelines supporting podiatric services as a means of prevention for lower-extremity complications, especially in at-risk individuals, current coverage for these services under the US Medicaid program is not universal. The vast differences between state Medicaid programs regarding reimbursable foot care services is confusing and potentially serves as a barrier for the most vulnerable populations to receive preventative services. This article provides a brief discussion of "routine" podiatric services from a clinical perspective and provides a review of state Medicaid programs including optional services (eg, podiatric coverage). METHODS: Using data from a national survey of state Medicaid programs, we present and discuss common Medicaid coverage schemes for routine foot care provided by podiatric physicians. RESULTS: Analysis demonstrated that states vary dramatically in basic descriptions of preventive foot care, levels of coverage, eligibility, and methods of documenting coverage details. CONCLUSIONS: The authors recommend bringing Medicaid in line with other federal health programs and including podiatric physicians in the definition of "physician" for coverage purposes. States should move away from describing preventative services as "routine" and choose language that more accurately reflects the true nature and purpose of the care.
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Cobertura do Seguro , Medicaid , Estados Unidos , HumanosRESUMO
OBJECTIVES: Medicaid provides health insurance for low-income people meeting specific eligibility requirements. It is funded and administered by both the federal and state governments; this decentralization leads to vastly different programs across the country. The objective of this legal surveillance project was to describe state-by-state differences in podiatric care coverage for nonelderly adults across Medicaid programs. METHODS: We used policy surveillance, a form of advanced legal mapping. It is the systematic collection and analysis of written policies across jurisdictions. Policy surveillance captures the important features of law through a rigorous scientific process to turn these policies into structured, quantitative legal data that are suitable for further evaluation or modeling. Data for the 51 jurisdictions were current as of September 1, 2020. RESULTS: The vast majority of jurisdictions (82%) covered podiatric services for all classes of Medicaid beneficiaries, but the rules, restrictions, and limitations around coverage differed. Twenty-five jurisdictions had no limits on the number of podiatric visits during a specified period; 26 jurisdictions indicated a cap. Ten jurisdictions had no explicit limitations on coverage of routine foot care, whereas 33 jurisdictions covered routine foot care only when medically necessary or with a triggering condition. Eight jurisdictions did not cover routine foot care at all, and 28 jurisdictions required prior authorizations. CONCLUSIONS: Podiatric care coverage, which is often preventive, varies greatly by state. This variability in coverage, which has not been previously tracked at the level of detail provided in our study, has implications for cost and health outcomes. The value of podiatric care is especially apparent in Medicaid populations. The compilation of these data can serve as a valuable resource for clinicians, researchers, and policy makers.
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Seguro Saúde , Medicaid , Adulto , Estados Unidos , Humanos , Pobreza , Políticas , Pessoal Administrativo , Cobertura do Seguro , Acessibilidade aos Serviços de SaúdeRESUMO
As of 2016, Medicaid accounted for nearly 20% of state general fund budgets. Optional Medicaid services such as podiatry are often subject to cost-cutting measures in periods of economic downturn, as was the case in the wake of the 2007 financial crisis. Although the cuts were intended as a cost-saving measure, research indicates that they had the opposite effect. The restriction and limitation of these services during the Great Recession resulted in both poorer health outcomes for beneficiaries, and poorer financial outcomes for state Medicaid programs. With states citing record levels of unemployment as of April of 2020 and projecting significant declines in annual revenue in 2021, the economic conditions resulting from the coronavirus disease of 2019 pandemic are likely to rival those of the Great Recession. Given the historical precedent for restricting or eliminating optional Medicaid services as a cost-saving measure, it is likely that podiatric services will once again come under scrutiny. Previous efforts by state-level podiatric societies have proven successful in lobbying for the reinstatement of coverage under Medicaid by conveying evidence of the negative outcomes associated with elimination to stakeholders. The specialty must once again engage policymakers by drawing on evidence gleaned and lessons learned from past cuts of optional Medicaid services to avert counterproductive coverage restrictions intended to mitigate the financial impact of the coronavirus disease of 2019 pandemic.
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COVID-19 , Podiatria , Estados Unidos , Humanos , Medicaid , COVID-19/epidemiologia , Orçamentos , Cobertura do SeguroRESUMO
Many countries have adopted targets to increase marine protected areas (MPAs) to limit the degradation of water bodies. Although there is evidence that MPAs can conserve marine life and promote biodiversity, there are limited data on the human health implications of MPAs. Using panel data from 1990, 2000, and 2014, we estimated the country-level associations between MPAs (i.e., percentage of territorial waters designated as marine reserves) and age-standardized mortality (i.e., age-standardized probability of dying between 15 and 60 years from all-causes among ages 15-60/100,000 population) by sex, among 110 countries. We fit mixed-effects linear regression models of mortality as a function of current MPA coverage, gross domestic product growth, year, the prior extent of MPA, electricity coverage, governance, and country-level random effects. We observed a significant inverse association between current MPA coverage and adult mortality. For each 5-percentage-point increase in current MPA coverage, a country had 0.982 times the geometric means of female and male mortality [geometric mean ratio: 0.982 (95% CI 0·976, 0·988)] conditional on past %MPA coverage and other modeled variables. The model showed no significant residual association of mortality with past %MPA conditional on current %MPA and other modeled variables. This is one of the first studies to show a positive association between increasing marine conservation and human health. This macro-level study suggests there may be important co-benefits for human health from expanding MPAs that merit further investigation.