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1.
Genes (Basel) ; 11(1)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952359

RESUMO

Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically "dirty" DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation.

2.
Contemp Clin Trials ; 87: 105859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31669450

RESUMO

BACKGROUND: Although people who inject drugs (PWID) having the highest incidence and prevalence of hepatitis C virus (HCV) in the US, HCV treatment is rarely provided to PWID due to assumptions about poor adherence and reinfection risk. As direct-acting antiviral agents (DAAs) have achieved sustained virologic response (SVR) rates of 95% or more, evidence-based strategies are urgently needed to demonstrate real-world effectiveness in marginalized patient populations such as PWID. The objectives of this study are: 1) to determine whether either of two patient-centered treatment models - patient navigation (PN) or modified directly observed therapy (mDOT) - results in more forward movement along the HCV care cascade including treatment initiation, adherence, and SVR; 2) using quantitative and qualitative methods, to understand factors associated with lack of treatment uptake, poor adherence (<80%), failure to achieve SVR, DAA resistance, and HCV reinfection. METHODS: The HERO study is a multi-site, pragmatic randomized clinical trial conducted in eight states where 754 HCV-infected PWID were randomly assigned to either PN or mDOT. CONCLUSIONS: This study addresses an urgent need for timely and accurate information on optimal models of care to promote HCV treatment initiation, adherence, treatment completion and SVR among PWID, as well as rates and factors associated with reinfection and resistance after treatment. This clinical trial has the potential to provide valuable information on how to reduce the burden of the HCV epidemic in PWID.

3.
Reg Anesth Pain Med ; 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31563880

RESUMO

BACKGROUND: No studies have examined the long-term benefits of regional anesthesia (RA) for pain management after combat-related injury. The objective of this prospective cohort study was to examine the relationship between RA administration and patient-reported pain-related outcomes among Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) service members sustaining a combat-related extremity injury. METHODS: Between 2007 and 2013, n=358 American military personnel injured in OEF/OIF were enrolled at two military treatment facilities. Individuals were followed for up to 2 years after injury. Cohorts were defined based on whether participants were administered RA within 7 days after sustaining a combat-related injury, or not. Linear mixed effects models examined the association between RA and average pain intensity. Secondary outcomes included pain relief, pain interference, neuropathic pain symptoms, treatment outcomes related to pain management, and mental health symptoms. RESULTS: Receiving early RA was associated with improved average pain over the first 6 months after injury (ß=-0.57; p=0.012) adjusting for injury severity and length of stay at the primary treatment facility. This difference was observed up to 24 months after injury (ß=-0.36; p=0.046). Individuals receiving early RA reported greater pain relief, improved neuropathic pain intensity, and higher satisfaction with pain outcomes; however, by 24 months, mean scores did not significantly differ between cohorts. CONCLUSION: Findings indicate that when administered soon after traumatic injury, RA is a valuable pain management intervention. Future longitudinal studies investigating the timely delivery of RA for optimal pain management in civilian trauma settings are needed. TRIAL REGISTRATION NUMBER: NCT00431847.

5.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975860

RESUMO

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.


Assuntos
Adaptação Fisiológica , Astronautas , Voo Espacial , Imunidade Adaptativa , Peso Corporal , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dano ao DNA , Metilação de DNA , Microbioma Gastrointestinal , Instabilidade Genômica , Humanos , Masculino , Homeostase do Telômero , Fatores de Tempo , Estados Unidos , United States National Aeronautics and Space Administration
6.
Radiat Res ; 191(4): 311-322, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30714852

RESUMO

It has now been over 60 years since U.S. nuclear testing was conducted in the Pacific islands and Nevada, exposing military personnel to varying levels of ionizing radiation. Actual doses are not well-established, as film badges in the 1950s had many limitations. We sought a means of independently assessing dose for comparison with historical film badge records and dose reconstruction conducted in parallel. For the purpose of quantitative retrospective biodosimetry, peripheral blood samples from 12 exposed veterans and 12 age-matched (>80 years) veteran controls were collected and evaluated for radiation-induced chromosome damage utilizing directional genomic hybridization (dGH), a cytogenomics-based methodology that facilitates simultaneous detection of translocations and inversions. Standard calibration curves were constructed from six male volunteers in their mid-20s to reflect the age range of the veterans at time of exposure. Doses were estimated for each veteran using translocation and inversion rates independently; however, combining them by a weighted-average generally improved the accuracy of dose estimations. Various confounding factors were also evaluated for potential effects on chromosome aberration frequencies. Perhaps not surprisingly, smoking and age-associated increases in background frequencies of inversions were observed. Telomere length was also measured, and inverse relationships with both age and combined weighted dose estimates were observed. Interestingly, smokers in the non-exposed control veteran cohort displayed similar telomere lengths as those in the never-smoker exposed veteran group, suggesting that chronic smoking had as much effect on telomere length as a single exposure to radioactive fallout. Taken together, we find that our approach of combined chromosome aberration-based retrospective biodosimetry provided reliable dose estimation capability, particularly on a group average basis, for exposures above statistical detection limits.


Assuntos
Inversão Cromossômica/efeitos da radiação , Armas Nucleares , Radiometria/métodos , Telômero/genética , Translocação Genética/efeitos da radiação , Veteranos , Adulto , Idoso de 80 Anos ou mais , Calibragem , Humanos , Masculino , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Estudos Retrospectivos
7.
J Adolesc Health ; 62(1): 114-117, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102250

RESUMO

PURPOSE: Examine the prevalence of hepatitis C virus (HCV) screening, confirmatory testing, and care experiences among young adult nonmedical prescription opioid (NMPO) users. METHODS: We examined self-reported HCV screening history in a sample of 18- to 29-year-olds reporting past-month NMPO use, and we used modified Poisson regression to identify associated sociodemographic and drug use patterns. RESULTS: Among 196 participants, 154 (78.6%) reported prior HCV screening, among whom 18 (11.7%) reported positive results. Of these, 13 (72.2%) reported receiving a confirmatory test; 12 (66.7%) were referred for specialty HCV care. Screening was associated with injection drug use (adjusted prevalence ratio [APR] = 1.19; 95% confidence interval [CI] = 1.05-1.33) and history of hospitalization for psychiatric illness (APR = 1.23; 95% CI = 1.09-1.39). Younger participants (18-23 years) were less likely to have been screened (APR = .69; 95% CI = .57-.85). CONCLUSION: Among young adult NMPO users, post-HCV screening support and referral to care were inadequate.


Assuntos
Analgésicos Opioides/administração & dosagem , Hepatite C/epidemiologia , Programas de Rastreamento , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Abuso de Substâncias por Via Intravenosa/epidemiologia , Adulto , Feminino , Hepatite C/diagnóstico , Humanos , Masculino , Prevalência , Rhode Island/epidemiologia , Adulto Jovem
8.
BMC Nurs ; 16: 31, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28615990

RESUMO

BACKGROUND: Immunisation coverage rates vary considerably at the local level across New Zealand and challenges remain with effectively translating best available research evidence into public health practice. This study aimed to translate best practices from high performing general practices into strategies to improve childhood immunisation coverage among low performing practices. METHODS: An intervention study was undertaken of general practices with low immunisation coverage rates and a high percentage of the enrolled population being of Maori ethnicity. Intervention groups received customised action plans and support for a 12 month period while control groups received 'business as usual' support. Structured interviews were conducted with key informants from all participating practices to understand current aspects related to childhood immunisation delivery and surveys were conducted to understand how the intervention worked. Collected data were thematically analysed. RESULTS: Ten sites were randomised to either intervention (n = 6) or control group (n = 4). Positive aspects of childhood immunisation delivery included high prioritisation at the practice and staff being pro-immunisation and knowledgeable. Key challenges experienced included inaccurate family contact information and discrepancies with referral processes to other providers. Other challenges noted were building rapport with families and vaccine hesitancy. The action plans included various strategies aimed to improve processes at the practice, contact and engagement with parents, and partnership development with local service providers. CONCLUSIONS: Creating customised action plans and providing support to providers were considered as helpful approaches when attempting to improve childhood immunisation coverage rates. Our study supports the notion that one strategy will not solely by itself improve childhood immunisation rates and highlights the importance of having a toolkit of strategies from which to draw from.

9.
J Med Virol ; 89(11): 1904-1911, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28460153

RESUMO

A beneficial impact of the Human Pegivirus (HPgV)-formerly called GB virus C (GBV-C)-on HIV disease progression has been reported previously. One possible mechanism by which HPgV inhibits HIV replication is an alteration of the cytokine/chemokine milieu. Their expression has not been specifically evaluated in women despite their influence on disease progression and the possibility of gender-based differences in expression. Moreover, the impact of HPgV genotype on cytokine/chemokine expression is unknown. Sera levels of IL-2, IL-4, IL-7, IL-8, IL-10, IL-12p70, IL-13, IFNγ, TNFα, IP-10, MIP-1α, MIP-1ß, and TGF-ß1 were quantified in 150 HIV-positive women based on HPgV RNA status. Cytokines/chemokines with detection rates of at least 50% included IL-2, IL-4, IL-8, IL-10, IL-12p70, IFNγ, TNFα, IP-10, MIP-1α, MIP-1ß, and TGF-ß1 . Absolute values were significantly higher for HPgV positive compared to HPgV negative women for IL-7, IL-13, IL-12p70, and IFNγ. Absolute values were significantly lower for HPgV positive women for IL-4, IL-8, TGF-ß1 , and IP-10. IFNγ values were higher for HPgV genotype 2 than for genotype 1 (P = 0.036). Further study of cytokine/chemokine regulation by HPgV may ultimately lead to the development of novel therapeutic agents to treat HIV infection and/or the design of vaccine strategies that mimic the "protective" effects of HPgV replication.


Assuntos
Quimiocinas/sangue , Citocinas/sangue , Infecções por Flaviviridae/complicações , Infecções por Flaviviridae/imunologia , Vírus GB C/imunologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , Adulto , Quimiocinas/genética , Quimiocinas/imunologia , Citocinas/genética , Citocinas/imunologia , Progressão da Doença , Feminino , Vírus GB C/isolamento & purificação , Genótipo , Humanos , Interleucina-12/sangue , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-2/sangue , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-4/sangue , Interleucina-4/genética , Interleucina-4/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/genética , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/imunologia , Estados Unidos
10.
J Prim Health Care ; 9(1): 62-68, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29530189

RESUMO

INTRODUCTION Outreach Immunisation Services (OIS) enable children who have not been immunised on time at general practice to be immunised in the community, thereby improving immunisation coverage and reducing equity gaps. AIM To identify the most effective service delivery models and make recommendations for more effective and cost-efficient OIS delivery in New Zealand. METHODS Data collection and thematic analysis through a detailed review of OIS contracts and service specifications, an online survey and in-depth interviews with stakeholders and providers, and an analysis of cost data was conducted. RESULTS In total, 28 OIS providers completed survey questionnaires, 28 OIS staff were interviewed, and cost effectiveness data were obtained from 11 providers. The surveys and interviews identified key themes around identifying clients with the highest needs, effective engagement strategies, staffing requirements, and service challenges. On average, each OIS referral costs NZ$361 (median NZ$257), and each vaccination event costs NZ$636, ranging from NZ$145 to NZ$2403. Characteristics for two separate models of service delivery were identified based on provider size. CONCLUSION There is considerable range in costs and style of OIS delivery, and efficiencies can be gained. Models need to fit with locality needs and include adequate resourcing, staff with good local knowledge, close relationships with other key child health services and preferably co-location, sustainable funding, and regular service reviews. OIS are part of an effective integrated service that relies on accurate data, positive relationships and a rapid response when children fail to present for vaccination in a timely fashion.


Assuntos
Acesso aos Serviços de Saúde , Programas de Imunização/organização & administração , Modelos Organizacionais , Pré-Escolar , Análise Custo-Benefício , Bases de Dados Factuais , Medicina de Família e Comunidade , Pesquisas sobre Serviços de Saúde , Humanos , Lactente , Entrevistas como Assunto , Nova Zelândia , Atenção Primária à Saúde
11.
J Prim Health Care ; 9(1): 69-77, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29530190

RESUMO

INTRODUCTION The role of healthcare providers and their use of systems is one of the most important factors in vaccination uptake. AIM To identify reasons and find patterns behind why immunisation providers code the word 'decline' in their system for childhood immunisation events. METHODS A qualitative study involving face-to-face semi-structured interviews with staff members involved in immunisation delivery. General practices were purposively selected for having either high or low rates of registered children coded on the electronic practice management system as having declined immunisation events. Thematic analysis was undertaken using an inductive approach to link themes to the data. RESULTS A total of 35 interviews were conducted with practice nurses; 21 were from practices with high rates of registered children recorded as having declining immunisation events, and 14 practices with low rates of declining. Common themes were: effective use of systems, early and ongoing engagement, adequate health care practitioner time and practitioner experience. Practices with low rates of coded decliners had stronger approaches for early and ongoing engagement, and were less likely to use formalised decline forms. As practice immunisation coverage rates improved over time, there was perceived to be less expressed vaccine hesitancy from families. CONCLUSIONS The reasons for coding individuals as 'decliners' are a complex mixture of individual, community, practitioner and practice systems. Front-line providers need adequate tools, time and resourcing to support effective and ongoing engagement with families. Community factors have influence but can change over time.


Assuntos
Medicina Geral , Programas de Imunização , Terminologia como Assunto , Recusa do Paciente ao Tratamento , Pessoal de Saúde , Humanos , Entrevistas como Assunto , Nova Zelândia , Pais , Pesquisa Qualitativa
12.
CMAJ Open ; 4(4): E605-E614, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28018873

RESUMO

BACKGROUND: In Canada, interferon-free, direct-acting antiviral hepatitis C virus (HCV) regimens are costly. This presents challenges for universal drug coverage of the estimated 220 000 people with chronic HCV infection nationwide. The study objective was to appraise criteria for reimbursement of 4 HCV direct-acting antivirals in Canada. METHODS: We reviewed the reimbursement criteria for simeprevir, sofosbuvir, ledipasvir-sofosbuvir and paritaprevir-ritonavir-ombitasvir plus dasabuvir in the 10 provinces and 3 territories. Data were extracted from April 2015 to June 2016. The primary outcomes extracted from health ministerial websites were: 1) minimum fibrosis stage required, 2) drug and alcohol use restrictions, 3) HIV coinfection restrictions and 4) prescriber type restrictions. RESULTS: Overall, 85%-92% of provinces/territories limited access to patients with moderate fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis stage F2 or greater, or equivalent). There were no drug and alcohol use restrictions; however, several criteria (e.g., active injection drug use) were left to the discretion of the physician. Quebec did not reimburse simeprevir and sofosbuvir for people coinfected with HIV; no restrictions were found in the remaining jurisdictions. Prescriber type was restricted to specialists in up to 42% of provinces/territories. INTERPRETATION: This review of criteria of reimbursement of HCV direct-acting antivirals in Canada showed substantial interjurisdictional heterogeneity. The findings could inform health policy and support the development and adoption of a national HCV strategy.

13.
Nutr Cancer ; 68(8): 1269-1280, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27689688

RESUMO

Consumption of navy beans (NB) and rice bran (RB) have been shown to inhibit colon carcinogenesis. Given the overall poor diet quality in colorectal cancer (CRC) survivors and low reported intake of whole grains and legumes, practical strategies to increase consumption merit attention. This study determined feasibility of increasing NB or RB intake in CRC survivors to increase dietary fiber and examined serum inflammatory biomarkers and telomere lengths. Twenty-nine subjects completed a randomized controlled trial with foods that included cooked NB powder (35 g/day), heat-stabilized RB (30 g/day), or no additional ingredient. Fasting blood, food logs, and gastrointestinal health questionnaires were collected. The amount of NB or RB consumed equated to 4-9% of subjects' daily caloric intake and no major gastrointestinal issues were reported with increased consumption. Dietary fiber amounts increased in NB and RB groups at Weeks 2 and 4 compared to baseline and to control (P ≤ 0.01). Telomere length correlated with age and HDL cholesterol at baseline, and with improved serum amyloid A (SAA) levels at Week 4 (P ≤ 0.05). This study concludes feasibility of increased dietary NB and RB consumption to levels associated with CRC chemoprevention and warrants longer-term investigations with both foods in high-risk populations that include cancer prevention and control outcomes.


Assuntos
Fibras na Dieta/farmacologia , Inflamação/dietoterapia , Oryza , Phaseolus , Idoso , Biomarcadores/sangue , Sobreviventes de Câncer , HDL-Colesterol/sangue , Neoplasias Colorretais/complicações , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Amiloide A Sérica/análise , Homeostase do Telômero
14.
Artigo em Inglês | MEDLINE | ID: mdl-27022409

RESUMO

A growing multitude of known genetic diagnoses can result in presentation to child psychiatry. For numerous reasons, it is important to identify a genetic etiology in child psychiatry patients when it is present. Genetic diagnoses can guide treatment and enable access to specialized clinics and appropriate screening measures. They can also allow for genetic counseling for the patient and family. A better understanding of etiology with a named diagnosis can itself be of great value to many patients and families; prognostic information can be empowering. Since patients with genetic conditions may present to psychiatric care in diverse ways, child psychiatrists must decide who to refer for genetic evaluation. Here we create a table to provide a framework of concerning/notable history and exam features that a practicing child psychiatrist may encounter that should prompt one to consider whether a larger, unifying genetic diagnosis is at hand. We hope this framework will facilitate referral of child psychiatry patients to genetics so that more patients can benefit from an appropriate diagnosis.

16.
J Correct Health Care ; 22(1): 41-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26672118

RESUMO

Although hepatitis C (HCV) infection is common among prisoners, relatively few undergo evaluation for treatment. This study reports the prevalence of chronic infection and the genotype distribution among an incarcerated population. HCV antibody testing was provided to adults entering Pennsylvania prisons; confirmatory and genotype testing were offered to those eligible for treatment. Antibody prevalence among 101,727 individuals was 18.1%. Among 7,633 individuals who underwent confirmatory testing, 69.3% had detectable RNA. Among 3,247 individuals who underwent genotype testing, genotype 1 was the most common (76.6%). The rate of chronic infection after HCV exposure is similar to that reported in the community, as is genotype distribution. Correctional facilities provide access to a population with a high disease burden, creating a public health opportunity for evaluation and treatment.


Assuntos
Hepatite C Crônica/epidemiologia , Hepatite C/epidemiologia , Programas de Rastreamento/estatística & dados numéricos , Adulto , Feminino , Genótipo , Anticorpos Anti-Hepatite B/sangue , Hepatite C/genética , Hepatite C Crônica/genética , Humanos , Masculino , Pennsylvania , Reação em Cadeia da Polimerase , Prevalência , Prisões , Fatores de Risco
17.
Int J Drug Policy ; 26(10): 1028-38, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26282715

RESUMO

In high income countries, the majority of new and existing hepatitis C virus (HCV) infections occur among people who inject drugs (PWID). In many low and middle income countries large HCV epidemics have also emerged among PWID populations. The burden of HCV-related liver disease among PWID is increasing, but treatment uptake remains extremely low. There are a number of barriers to care which should be considered and systematically addressed, but should not exclude PWID from HCV treatment. The rapid development of interferon-free direct-acting antiviral (DAA) therapy for HCV infection has brought considerable optimism to the HCV sector, with the realistic hope that therapeutic intervention will soon provide near optimal efficacy with well-tolerated, short duration, all oral regimens. Further, it has been clearly demonstrated that HCV treatment is safe and effective across a broad range of multidisciplinary healthcare settings. Given the burden of HCV-related disease among PWID, strategies to enhance HCV assessment and treatment in this group are urgently needed. These recommendations demonstrate that treatment among PWID is feasible and provide a framework for HCV assessment and care. Further research is needed to evaluate strategies to enhance testing, linkage to care, treatment, adherence, viral cure, and prevent HCV reinfection among PWID, particularly as new interferon-free DAA treatments for HCV infection become available.


Assuntos
Antivirais/uso terapêutico , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Abuso de Substâncias por Via Intravenosa/complicações , Humanos
19.
Ann Intern Med ; 163(3): 215-23, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26120969

RESUMO

The aim of this study was to systematically evaluate state Medicaid policies for the treatment of hepatitis C virus (HCV) infection with sofosbuvir in the United States. Medicaid reimbursement criteria for sofosbuvir were evaluated in all 50 states and the District of Columbia. The authors searched state Medicaid Web sites between 23 June and 7 December 2014 and extracted data in duplicate. Any differences were resolved by consensus. Data were extracted on whether sofosbuvir was covered and the criteria for coverage based on the following categories: liver disease stage, HIV co-infection, prescriber type, and drug or alcohol use. Of the 42 states with known Medicaid reimbursement criteria for sofosbuvir, 74% limit sofosbuvir access to persons with advanced fibrosis (Meta-Analysis of Histologic Data in Viral Hepatitis [METAVIR] fibrosis stage F3) or cirrhosis (F4). One quarter of states require persons co-infected with HCV and HIV to be receiving antiretroviral therapy or to have suppressed HIV RNA levels. Two thirds of states have restrictions based on prescriber type, and 88% include drug or alcohol use in their sofosbuvir eligibility criteria, with 50% requiring a period of abstinence and 64% requiring urine drug screening. Heterogeneity is present in Medicaid reimbursement criteria for sofosbuvir with respect to liver disease staging, HIV co-infection, prescriber type, and drug or alcohol use across the United States. Restrictions do not seem to conform with recommendations from professional organizations, such as the Infectious Diseases Society of America and the American Association for the Study of Liver Diseases. Current restrictions seem to violate federal Medicaid law, which requires states to cover drugs consistent with their U.S. Food and Drug Administration labels.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Reembolso de Seguro de Saúde , Medicaid/economia , Uridina Monofosfato/análogos & derivados , Antivirais/economia , Custos de Medicamentos , Definição da Elegibilidade , Política de Saúde , Humanos , Sofosbuvir , Estados Unidos , Uridina Monofosfato/economia , Uridina Monofosfato/uso terapêutico
20.
Neurochem Int ; 88: 10-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25510640

RESUMO

The GLS1 gene encodes a mitochondrial glutaminase that is highly expressed in brain, kidney, small intestine and many transformed cells. Recent studies have identified multiple lysine residues in glutaminase that are sites of N-acetylation. Interestingly, these sites are located within either a loop segment that regulates access of glutamine to the active site or the dimer:dimer interface that participates in the phosphate-dependent oligomerization and activation of the enzyme. These two segments also contain the binding sites for bis-2[5-phenylacetamido-1,2,4-thiadiazol-2-yl]ethylsulfide (BPTES), a highly specific and potent uncompetitive inhibitor of this glutaminase. BPTES is also the lead compound for development of novel cancer chemotherapeutic agents. To provide a preliminary assessment of the potential effects of N-acetylation, the corresponding lysine to alanine mutations were constructed in the hGACΔ1 plasmid. The wild type and mutated proteins were purified by Ni(+)-affinity chromatography and their phosphate activation and BPTES inhibition profiles were analyzed. Two of the alanine substitutions in the loop segment (K311A and K328A) and the one in the dimer:dimer interface (K396A) form enzymes that require greater concentrations of phosphate to produce half-maximal activation and exhibit greater sensitivity to BPTES inhibition. By contrast, the K320A mutation results in a glutaminase that exhibits near maximal activity in the absence of phosphate and is not inhibited by BPTES. Thus, lysine N-acetylation may contribute to the acute regulation of glutaminase activity in various tissues and alter the efficacy of BPTES-type inhibitors.


Assuntos
Alanina/genética , Glutaminase/genética , Lisina/genética , Mutação/genética , Fosfatos/farmacologia , Sulfetos/farmacologia , Tiadiazóis/farmacologia , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Glutaminase/antagonistas & inibidores , Glutaminase/metabolismo , Humanos
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