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2.
Value Health ; 23(4): 481-486, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32327165

RESUMO

OBJECTIVES: To examine the uptake of filgrastim-sndz (Zarxio), the first biosimilar to launch in the United States, in the Medicare Part B fee-for-service program from its launch in September 2015 to December 2017 and compare characteristics of patients and facilities that used filgrastim-sndz or originator filgrastim (Neupogen). METHODS: The 20% sample of Medicare Part B fee-for-service administrative claims data was used to extract information on claims for any filgrastim product between January 1, 2015 and December 31, 2017. RESULTS: The utilization of filgrastim-sndz in Medicare Part B increased sharply between January and August 2016, surpassing filgrastim by November 2017, contributing to a 30% decrease in overall spending on this drug since 2015. Uptake was faster and larger in physician practices compared with hospital outpatient departments. About 77% of patients receiving filgrastim-sndz were new users. Utilization patterns indicated that product selection occurred at the facility level, rather than being at the discretion of the prescribing physician or driven by patient characteristics. CONCLUSION: Uptake of biosimilar filgrastim in the Medicare Part B program occurred despite multiple challenges to the adoption of biosimilars in the US market, suggesting that substantial potential savings could be generated by improving biosimilar uptake. Our findings indicated that physician practices and hospital outpatient departments have distinctive biosimilar uptake patterns. Thus policy makers aiming to contain Medicare Part B spending might consider focusing on incentivizing biosimilar uptake among hospital outpatient departments.

3.
J Peripher Nerv Syst ; 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32319184

RESUMO

Mutations in MCM3AP have recently been reported to cause autosomal recessive Charcot-Marie-Tooth disease (CMT). However, only nine CMT families with MCM3AP mutations have been reported and genotype-phenotype correlation remains unclear. This study aimed to investigate the genetic spectrum of MCM3AP and its relationship with phenotype of CMT. Whole-exome sequencing (WES) was performed in the family and variants were validated by Sanger sequencing. Reverse transcription-PCR (RT-PCR) were performed in splicing analysis. We reported a novel splicing variant (c.5634-1G>T) and a known missense variant (c.2633G>A, p.Arg878His). Functional studies showed that c.5634-1G>T led to splicing defect and aberrant transcript eliminated by nonsense-mediated mRNA decay. The symptom of the patient was less severe and slowly progressed with axonal peripheral neuropathy compared to the reported CMT patients. Genotype-phenotype correlation analysis indicated that affected individuals with null mutations presented with delayed independent walking. The percentage of intellectual disability and loss of ambulation in the null group tended to be greater, although this failed to reach statistical significance. Our findings expand the genetic spectrum of MCM3AP and suggest that genotype-phenotype correlation would help genetic counseling of MCM3AP in CMT patients.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32120925

RESUMO

BACKGROUND: Although China began implementing medical reforms in 2009 aimed at fair allocation of the regional distribution of doctors, little is known of their impact. This study analyzed the geographic distribution of doctors from 2002 to 2017. METHODS: This study calculated the Gini coefficient and Theil index among doctors in the eastern, central, and western regions (Category 1) of China, and in urban and rural areas (Category 2). The statistical significance of fairness changes was analyzed using the Mann-Whitney U test. RESULTS: The annual growth rates of the number of doctors for the periods from 2002 to 2009 and 2010 to 2017 were 2.38% and 4.44%. The Gini coefficients among Category 1 were lower than those in Category 2, and statistically decreased after the medical reforms (P < 0.01) but continued to increase in Category 2 (P = 0.463). In 2017, the Theil decomposition result of Category 1 was 74.33% for the between-group, and in Category 2, it was 95.22% for the within-group. CONCLUSIONS: The fairness among the regional distribution of doctors in Category 1 is now at a high level and is better than that before the reforms. While the fairness in Category 2 is worse than that before the reforms, it causes moderate inequality and is continually decreasing. Overall unfairness was found to be derived from the between-group.

5.
7.
Xenotransplantation ; 27(1): e12550, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31435990

RESUMO

BACKGROUND: In vivo pig liver xenotransplantation preclinical trials appear to have poor efficiency compared to heart or kidney xenotransplantation because of xenogeneic rejection, including coagulopathy, and particularly thrombocytopenia. In contrast, ex vivo pig liver (wild type) perfusion systems have been proven to be effective in "bridging" liver failure patients until subsequent liver allotransplantation, and transgenic (human CD55/CD59) modifications have even prolonged the duration of pig liver perfusion. Despite the fact that hepatocyte cell lines have also been proposed for extracorporeal blood circulation in conditions of acute liver failure, porcine hepatocyte cell lines, and the GalT-KO background in particular, have not been developed and applied in this field. Herein, we established immortalized wild-type and GalT-KO porcine hepatocyte cell lines, which can be used for artificial liver support systems, cell transplantation, and even in vitro studies of xenotransplantation. METHODS: Primary hepatocytes extracted from GalT-KO and wild-type pigs were transfected with SV40 LT lentivirus to establish immortalized GalT-KO porcine hepatocytes (GalT-KO-hep) and wild-type porcine hepatocytes (WT). Hepatocyte biomarkers and function-related genes were assessed by immunofluorescence, periodic acid-Schiff staining, indocyanine green (ICG) uptake, biochemical analysis, ELISA, and RT-PCR. Furthermore, the tumorigenicity of immortalized cells was detected. In addition, a complement-dependent cytotoxicity (CDC) assay was performed with GalT-KO-hep and WT cells. Cell death and viability rates were assessed by flow cytometry and CCK-8 assay. RESULTS: GalT-KO and wild-type porcine hepatocytes were successfully immortalized and maintained the characteristics of primary porcine hepatocytes, including albumin secretion, ICG uptake, urea and glycogen production, and expression of hepatocyte marker proteins and specific metabolic enzymes. GalT-KO-hep and WT cells were confirmed as having no tumorigenicity. In addition, GalT-KO-hep cells showed less apoptosis and more viability than WT cells when exposed to complement and xenogeneic serum. CONCLUSIONS: Two types of immortalized cell lines of porcine hepatocytes with GalT-KO and wild-type backgrounds were successfully established. GalT-KO-hep cells exhibited higher viability and injury resistance against a xenogeneic immune response.

8.
Genetics ; 214(1): 163-178, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31776169

RESUMO

Members of the superfamily of solute carrier (SLC) transmembrane proteins transport diverse substrates across distinct cellular membranes. Three SLC protein families transport distinct neurotransmitters into synaptic vesicles to enable synaptic transmission in the nervous system. Among them is the SLC17A6/7/8 family of vesicular glutamate transporters, which endows specific neuronal cell types with the ability to use glutamate as a neurotransmitter. The genome of the nematode Caenorhabditis elegans encodes three SLC17A6/7/8 family members, one of which, eat-4 /VGLUT, has been shown to be involved in glutamatergic neurotransmission. Here, we describe our analysis of the two remaining, previously uncharacterized SLC17A6/7/8 family members, vglu-2 and vglu-3 These two genes directly neighbor one another and are the result of a recent gene duplication event in C. elegans, but not in other Caenorhabditis species. Compared to EAT-4, the VGLU-2 and VGLU-3 protein sequences display a more distant similarity to canonical, vertebrate VGLUT proteins. We tagged both genomic loci with gfp and detected no expression of vglu-3 at any stage of development in any cell type of both C. elegans sexes. In contrast, vglu-2::gfp is dynamically expressed in a restricted set of distinct cell types. Within the nervous system, vglu-2::gfp is exclusively expressed in a single interneuron class, AIA, where it localizes to vesicular structures in the soma, but not along the axon, suggesting that VGLU-2 may not be involved in synaptic transport of glutamate. Nevertheless, vglu-2 mutants are partly defective in the function of the AIA neuron in olfactory behavior. Outside the nervous system, VGLU-2 is expressed in collagen secreting skin cells where VGLU-2 most prominently localizes to early endosomes, and to a lesser degree to apical clathrin-coated pits, the trans-Golgi network, and late endosomes. On early endosomes, VGLU-2 colocalizes most strongly with the recycling promoting factor SNX-1, a retromer component. Loss of vglu-2 affects the permeability of the collagen-containing cuticle of the worm, and based on the function of a vertebrate VGLUT1 protein in osteoclasts, we speculate that vglu-2 may have a role in collagen trafficking in the skin. We conclude that C. elegans SLC17A6/7/8 family members have diverse functions within and outside the nervous system.

9.
Annu Rev Public Health ; 41: 499-512, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-31874070

RESUMO

The United States relies primarily on market forces to determine prices for drugs, whereas most other industrialized countries use a variety of approaches to determine drug prices. Branded drug companies have patents and market exclusivity periods in most industrialized countries. During this period, pharmaceutical companies are allowed to set their list price as high as they prefer in the United States owing to the absence of government price control mechanisms that exist in other countries. Insured patients often pay a percentage of the list price, and cost sharing creates some pressure to lower the list price. Pharmacy benefit managers negotiate with drug companies for lower prices by offering the drug company favorable formulary placement and fewer utilization controls. However, these approaches appear to be less effective, compared with other countries' approaches to containing branded drug prices, because prices are substantially higher in the United States. Other industrialized countries employ various forms of rate setting and price regulation, such as external reference pricing, therapeutic valuation, and health technology assessment to determine the appropriate price.

10.
CNS Neurosci Ther ; 26(5): 567-575, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31885218

RESUMO

AIM: Leukodystrophies are a group of inherited white matter disorders with clinical, genetic, and imaging heterogeneity, which usually pose a diagnostic challenge for physicians. We aimed to identify new clinical characteristics and novel pathogenic variants of hereditary leukodystrophies in this study. METHODS: Whole exome sequencing (WES) was performed in 28 unrelated patients clinically suspected with leukodystrophies. Leukocytes enzyme activity test, electroencephalogram (EEG), electromyography (EMG), and brain MRI were conducted. Functional analysis was performed, and the pathogenicity of variants was classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: We made definite diagnosis in 8 probands with 12 pathogenic variants and reported new clinical characteristics and imaging features of these patients. Three novel pathogenic variants were identified, including a microdeletion variant c.2654_2654+3del within CSF1R, a nonsense variant c.1321C>T, and a missense variant c.166G>C within GALC. CONCLUSION: Our results have deepened the understanding of clinical, genetic, and imaging heterogeneity of hereditary leukodystrophies, and expanded the spectrum of pathogenic variants and clinical features.

11.
Environ Sci Technol ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31790214

RESUMO

Partial nitritation providing a suitable effluent for subsequent anammox is a critical step in a two-stage autotrophic nitrogen removal system. This study demonstrates an innovative approach for attaining partial nitritation in an acidic bioreactor operating at a slightly low pH (i.e., 5-6). This approach is based on our hypothesis in this study that acid-tolerant ammonia-oxidizing bacteria (AOB) can produce nitrite and protons to self-sustain free nitrous acid (FNA, NO2- + H+ ↔ HNO2) at a parts per million level, as an inhibitor of nitrite-oxidizing bacteria (NOB). With influent nitrogen of about 200 mg/L and operating conditions of high dissolved oxygen, long sludge retention time, and moderate temperature, a lab-scale acidic bioreactor with FNA up to 2 mg of HNO2-N/L successfully established stable nitrite accumulation in the effluent for 200 days, with an average ratio [NO2-/(NO2- + NO3-)] exceeding 95%. A 16S rRNA amplicon sequencing analysis showed that Nitrosospira was the dominant AOB in the biomass of the bioreactor, while Nitrosomonas and Nitrospira, two typical nitrifying genera in neutral wastewater treatment, both disappeared after the startup of partial nitritation. Kinetic characterization revealed that Nitrosospira had a substrate affinity of 11.4-16.5 mg of total ammonia (NH4+ + NH3)/L. It also revealed that less than 3.5 mg of HNO2-N/L FNA did not inhibit AOB activity significantly. Acidic operation is economically attractive because it can be achieved via acidophilic ammonia oxidation without adding chemical acid. However, hazardous gas, nitric oxide (NO), should be removed from gas produced by acidic nitrifying bioreactors.

12.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(12): 1198-1202, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31874659

RESUMO

OBJECTIVE: To study the value of serum gamma-glutamyl transpeptidase (GGT) combined with direct bilirubin (DB) in the diagnosis of biliary atresia. METHODS: A total of 667 infants with cholestasis who were hospitalized and treated from July 2010 to December 2018 were enrolled as subjects. According to the results of intraoperative cholangiography and follow-up, they were divided into biliary atresia group with 234 infants and cholestasis group with 433 infants. The two groups were compared in terms of age of onset, sex, and serum levels of total bilirubin (TB), DB, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA), and GGT. A receiver operating characteristic (ROC) curve analysis was performed for indices with statistical significance, and the area under the ROC curve (AUC) and the optimal cut-off value for diagnosis were calculated. RESULTS: The biliary atresia group had a significantly younger age of onset than the cholestasis group (P<0.001). There were no significant differences in sex, ALT, and AST between the two groups (P>0.05), while the biliary atresia group had significantly higher serum levels of TB, DB, TBA, and GGT than the cholestasis group (P<0.05). GGT combined with DB had the highest AUC of 0.892 (95% confidence interval: 0.868-0.916) in the diagnosis of biliary atresia. At the optimal cut-off values of 324.0 U/L for GGT and 115.1 µmmol/L for DB, GGT combined with DB had a sensitivity of 79.8% and a specificity of 83.2% in the diagnosis of biliary atresia. CONCLUSIONS: GGT combined with DB has high sensitivity and specificity in the diagnosis of biliary atresia and can be used as an effective indicator for diagnosis of biliary atresia in infants.


Assuntos
Atresia Biliar , gama-Glutamiltransferase/sangue , Alanina Transaminase , Aspartato Aminotransferases , Atresia Biliar/diagnóstico , Bilirrubina , Humanos , Lactente
13.
Huan Jing Ke Xue ; 40(11): 5015-5023, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854569

RESUMO

To obtain the content level and treatment efficiency of typical antibiotics in wastewater treatment in large-scale dairy farms in Tianjin, the SPE-UPLC-MS/MS (ultra-high performance liquid chromatography tandem triple quadruple mass spectrometry combined with solid-phase extraction for pretreatment) technology was utilized to investigate and monitor seven typical antibiotics in wastewater from 12 large-scale dairy farms in Tianjin. Antibiotic residues were detected in 12 large-scale dairy farms before and after wastewater treatment. In the wastewater before treatment, the detection rates of tilmicosin (TIL), oxytetracycline hydrochloride (OTC), sparfloxacin (SPA), sulfathiazloe (STZ), ofloxacin (OFL), and sarafloxacin hydrochloride (SAR) were all 100%, whereas the detection rate of sulfadiazine (SDZ) was 83.33%. Among them, TIL and OTC were the main antibiotic components in untreated wastewater, the concentrations were 25.21 µg·L-1 and 9.87 µg·L-1, respectively. The detection rates of SDZ and OFL in the treated wastewater dropped to 25.00% and 41.66%, respectively. The main components were TIL and OTC and the concentrations were 11.30 µg·L-1 and 3.71 µg·L-1, respectively. There were significant decreases in the concentrations. The treatment effect on antibiotics from different farms ranged from 24.95% to 81.05%. The comprehensive treatment effect of the anaerobic-anoxic-oxic (AAO) treatment process was better than that of the anoxic-oxic (AO) treatment process. OFL, SAR, and OTC were the main high-risk pollutants in treated wastewater. Each large-scale dairy farm contained one or more antibiotic with RQs>1, and their emissions pose an ecological risk to the environment.


Assuntos
Antibacterianos , Indústria de Laticínios , Águas Residuárias , Poluentes Químicos da Água , Cromatografia Líquida , Fazendas , Medição de Risco , Espectrometria de Massas em Tandem
14.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614589

RESUMO

MADS-box genes play a pivotal role in various processes, including floral and seed development, controlling flowering time, regulation of fruits ripening, and respond to abiotic and biotic stressors in planta. Tobacco (Nicotiana tabacum) has been widely used as a model plant for analyzing the gene function, however, there has been less information on the regulation of flowering, and the associated genes. In the present study, a total of 168 NtMADS-box genes were identified from tobacco, and their phylogenetic relationship, chromosome locations, and gene structures were further analyzed. NtMADS-box genes can be clustered into four sub-families of Mα, Mγ, MIKC*, and MIKCC. A total of 111 NtMADS-box genes were distributed on 20 chromosomes, and 57 NtMADS-box genes were located on the unanchored scaffolds due to the complex and incomplete assembly of the tobacco genome. Expression profiles of NtMADS-box genes by microarray from 23 different tissues indicated that members in different NtMADS-box gene subfamilies might play specific roles in the growth and flower development, and the transcript levels of 24 NtMADS-box genes were confirmed by quantitative real-time PCR. Importantly, overexpressed NtSOC1/NtMADS133 could promote early flowering and dwarfism in transgenic tobacco plants. Therefore, our findings provide insights on the characterization of NtMADS-box genes to further study their functions in plant development.


Assuntos
Perfilação da Expressão Gênica/métodos , Proteínas de Domínio MADS/genética , Análise de Sequência de DNA/métodos , Tabaco/crescimento & desenvolvimento , Mapeamento Cromossômico , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Regulação da Expressão Gênica de Plantas , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Filogenia , Proteínas de Plantas/genética , Tabaco/genética
15.
J Vet Res ; 63(3): 447-455, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31572827

RESUMO

Introduction: The miniature pig possesses unmatched advantages as an animal model because of its high homology with humans. Our experiment aimed to build a chronic renal failure (CRF) model in pigs via laparoscopy. Material and Methods: Laparoscopic surgery was performed twice to build a CRF model. The first surgery was a left partial nephrectomy and the second was a right radical nephrectomy. Pigs were grouped by the total renal tissue to be resected: ⅔, ¾ or ⅚. Physiological parameters (rectal temperature and heart rate), haematological parameters (WBC and RBC) and renal function (serum creatinine - CR and blood urea nitrogen - BUN) were measured preoperatively and every week postoperatively. Results: After renal resection the pigs manifested chronic renal failure. Heart rate and body temperature declined to varying degrees over 12 postoperative weeks. No significant difference was observed between the different groups. The result of renal function tests found that postoperative serum CR and BUN in all groups were continuously elevated, and the level of serum CR at two weeks post procedure differed very significantly from its preoperative value (P < 0.05). BUN was significantly elevated at one week (P < 0.05). The renal function decreased significantly faster in the ⅚ group than in the other two groups. The trend of renal function change was similar among groups, but progress was slower in the ⅔ and ¾ groups. Conclusion: ⅚ kidney resection was the optimal miniature pig model of CRF.

17.
JAMA ; 322(5): 422-429, 2019 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-31386135

RESUMO

Importance: Although independent charity patient assistance programs improve patient access to costly prescription drugs, recent federal investigations have raised questions about their potential to increase pharmaceutical spending and to violate the federal Anti-Kickback Statute. Little is known about the design of the programs, patient eligibility, or drug coverage. Objective: To examine the eligibility criteria of the independent charity patient assistance programs and the drugs covered by them. Design, Setting, and Participants: Descriptive cross-sectional study of the 6 largest independent charities offering patient assistance programs for patients including, but not limited to, Medicare beneficiaries in 2018. These charities offered 274 different disease-specific patient assistance programs. Drugs were identified for subgroup analysis that had any use reported on the Medicare Part D spending dashboard and any off-patent brand-name drugs that incurred more than $10 000 in Medicare spending per beneficiary in 2016. Exposures: Support by independent charity patient assistance programs. Main Outcomes and Measures: The primary outcomes were the characteristics of patient assistance programs, including assistance type, insurance coverage (vs uninsured), and income eligibility. The secondary outcomes were the cost of the drugs covered by the patient assistance programs and the coverage of expensive off-patent brand-name drugs vs substitutable generic drugs. Results: Among the 6 independent charity foundations included in the analysis, their total revenue in 2017 ranged from $24 million to $532 million, and expenditures on patient assistance programs ranged from $24 million to $353 million, representing on average, 86% of their revenue. Of the 274 patient assistance programs offered by these organizations, 168 (61%) provided only co-payment assistance, and the most common therapeutic area covered was cancer or cancer treatment-related symptoms (113 patient assistance programs; 41%). A total of 267 programs (97%) required insurance coverage as an eligibility criterion (ie, excluded uninsured patients). The most common income eligibility limit was 500% of the federal poverty level. The median annual cost of the drugs per beneficiary covered by the programs was $1157 (interquartile range, $247-$5609) compared with $367 (interquartile range, $100-$1500) for the noncovered drugs. Off-patent brand-name drugs (cost: >$10 000) were covered by a mean of 3.1 (SD, 2.0) patient assistance programs, whereas their generic equivalents were covered by a mean of 1.2 (SD, 1.0) patient assistance programs. Conclusions and Relevance: In 2018, among 274 patient assistance programs operated by the 6 independent charity foundations, the majority did not provide coverage for uninsured patients. Medications that were covered by the patient assistance programs were generally more expensive than those that were not covered.


Assuntos
Instituições de Caridade/economia , Definição da Elegibilidade , Renda , Pessoas sem Cobertura de Seguro de Saúde , Medicamentos sob Prescrição/economia , Instituições de Caridade/legislação & jurisprudência , Estudos Transversais , Custos de Medicamentos , Indústria Farmacêutica/economia , Gastos em Saúde , Humanos , Cobertura do Seguro , Assistência Médica/economia , Medicare Part D , Estados Unidos
18.
Clin Genet ; 96(5): 439-448, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31372974

RESUMO

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation-dependent probe amplification (MLPA) testing in all patients and next-generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.

20.
Health Aff (Millwood) ; 38(7): 1195-1200, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31260345

RESUMO

Charges for air ambulance services were 4.1-9.5 times higher than what Medicare paid for the same services in 2016. The median charge ratios (the charge divided by the Medicare rate) for the services increased by 46-61 percent in 2012-16. Air ambulance charges varied substantially across the US, and some of the largest providers had among the highest charges.

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