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1.
Artigo em Inglês | MEDLINE | ID: mdl-34525887

RESUMO

OBJECTIVE: The goal is to perform a comparative analysis of multiple sclerosis patients' access to medicines in Bulgaria and Greece. MATERIALS AND METHODS: A comparative analysis of pharmaceutical legislation of Bulgaria and Greece focusing on medicines for multiple sclerosis (MS) was performed. Patients' access to therapy is assessed through the guideline compliance index (GCI) and availability index. RESULTS: The procedures for marketing authorization, pricing and reimbursement, and inclusion of medicines in the positive drug list (PDL) are identical in both European Union member states. Almost all MS medicines authorized for sale in the European Union are included in the Bulgarian and Greek PDL. In both PDLs are included medicines from different groups: immunostimulants, other immunostimulants, immunosuppressors, selective immunosuppressors, and other immunosuppressors. All medicines are fully paid by the health insurance funds in both countries. The average time for inclusion of medicines for MS in the PDL of Bulgaria after their marketing authorization is 3 years. The analysis of pharmacotherapeutic guidelines showed high GCI as it is higher for Bulgaria: 0.846 vs. 0.769 out of 1. CONCLUSION: The existing legislative measures at the national level of Bulgaria and Greece ensure adequate and timely access of patients with MS to treatment.

2.
BMJ Open ; 11(9): e049733, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34588251

RESUMO

OBJECTIVES: To compare costs associated with different models of outpatient parenteral antimicrobial therapy (OPAT) delivery with costs of inpatient (IP) care across key infection groups managed via OPAT in the UK. DESIGN: A cost-minimisation design was used due to evidence of similarities in patient and treatment outcomes between OPAT and IP care. A bottom-up approach was undertaken for the evaluation of OPAT associated costs. The British Society of Antimicrobial Chemotherapy National Outcomes Registry System was used to determine key infection diagnoses, mean duration of treatment and most frequent antibiotics used. SETTING: Several OPAT delivery settings were considered and compared with IP care. INTERVENTIONS: OPAT models considered were OP clinic model, nurse home visits, self (or carer)-administration by a bolus intravenous, self-administration by a commercially prefilled elastomeric device, continuous intravenous infusion of piperacillin with tazobactam or flucloxacillin with elastomeric device as OP once daily and, specifically for bone and joint and diabetic foot infections, complex outpatient oral antibiotic therapies. RESULTS: Base case and a range of scenario results showed all evaluated OPAT service delivery models to be less costly than IP stay of equivalent duration. The extent of savings varied by OPAT healthcare delivery models. Estimated OPAT costs as a proportion of IP costs were estimated at 0.23-0.53 (skin and soft-tissue infections), 0.34-0.46 (complex urinary tract infections), 0.23-0.51 (orthopaedic infections), 0.24-0.42 (diabetic foot infections) 0.40-0.56 (exacerbations of bronchiectasis) and 0.25-0.42 (intra-abdominal infections). Partial or full complex oral antibiotic therapies in orthopaedic or diabetic foot infections costs were estimated to be 0.13-0.26 of IP costs. Main OPAT costs were associated with staff time and antimicrobial medications. CONCLUSIONS: OPAT is a cost-effective use of National Health Service resources for the treatment of a range of infections in the UK in patients who can be safely managed in a non-IP setting.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34553334

RESUMO

BACKGROUND: Efficiency and transparency of pricing and reimbursement (P&R) rules and procedures as well as their implementation in South-eastern Europe (SEE) lag substantially behind Western European practice. Nevertheless, P&R systems in SEE are rarely critically assessed, warranting a detailed and wider-encompassing exploration. OBJECTIVE: Our study provides a comparative assessment of P&R processes for patent-protected medicines in ten SEE countries-EU member states: Croatia, Slovenia, Hungary, Romania and Bulgaria; and non-EU countries: Albania, Montenegro, Serbia, North Maceodina, Bosnia and Herzegovina. P&R systems are compared and evaluated through a research framework that focuses on: (1) public financing of patent-protected medicines, (2) definition of benefit packages, (3) requirements for the submission of reimbursement dossiers, (4) assessment and appraisal processes, (5) reimbursement decision making, (6) processes that occur post reimbursement, and (7) pricing. The study aims to contribute to the discussion on improving the efficiency and quality of P&R of patent-protected medicines in the region. METHODS: We conducted a non-systematic literature review of published literature, as well as policy briefs and reports on healthcare systems in the SEE region along with legal documents framing the P&R procedures in local languages. The information gathered from these various sources was then discussed and clarified through structured telephone interviews with relevant national experts from each SEE country, mainly current and former senior officials and/or executives of the funding and assessment/ appraisal bodies (total of 20 interviews conducted in late 2019). RESULTS: Capacity building through sharing knowledge and information on successful reforms across borders is an opportunity for SEE countries to further develop their P&R policies and increase (equitable) access to patent-protected medicines (especially expensive medicines), increasing affordability and containing costs. Simple yet robust and systematic decision-making frameworks that rely on international health technology assessment (HTA) procedures and are based on the pursuit of transparency seem to be the most cost-effective approach to strengthening P&R systems in SEE. CONCLUSIONS: Further reforms aiming to develop transparent and robust national decision-making frameworks (including oversight) and build institutional HTA-related and decision-making capacity are awaited in most of SEE countries, especially the non-EU members. In non-EU SEE countries, these efforts could increase access to patent-protected medicines, which is-at the moment-very limited. The EU-member SEE countries operate more developed P&R systems but could further benefit from developing their procedures, oversight and value-for-money assessment toolbox and capacity, hence further improving the transparency and efficiency of procedures that regulate access to patent-protected medicines.

4.
Nucleic Acids Res ; 49(15): 8900-8922, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34370034

RESUMO

In eukaryotes, the major nuclear export pathway for mature mRNAs uses the dimeric receptor TAP/p15, which is recruited to mRNAs via the multisubunit TREX complex, comprising the THO core and different export adaptors. Viruses that replicate in the nucleus adopt different strategies to hijack cellular export factors and achieve cytoplasmic translation of their mRNAs. No export receptors are known in plants, but Arabidopsis TREX resembles the mammalian complex, with a conserved hexameric THO core associated with ALY and UIEF proteins, as well as UAP56 and MOS11. The latter protein is an orthologue of mammalian CIP29. The nuclear export mechanism for viral mRNAs has not been described in plants. To understand this process, we investigated the export of mRNAs of the pararetrovirus CaMV in Arabidopsis and demonstrated that it is inhibited in plants deficient in ALY, MOS11 and/or TEX1. Deficiency for these factors renders plants partially resistant to CaMV infection. Two CaMV proteins, the coat protein P4 and reverse transcriptase P5, are important for nuclear export. P4 and P5 interact and co-localise in the nucleus with the cellular export factor MOS11. The highly structured 5' leader region of 35S RNAs was identified as an export enhancing element that interacts with ALY1, ALY3 and MOS11 in vitro.


Assuntos
Regiões 5' não Traduzidas , Proteínas de Arabidopsis/metabolismo , Núcleo Celular/virologia , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Proteínas Virais/metabolismo , Transporte Ativo do Núcleo Celular , Arabidopsis/virologia , Proteínas de Arabidopsis/fisiologia , Proteínas do Capsídeo/metabolismo , Caulimovirus/genética , Caulimovirus/metabolismo , Núcleo Celular/metabolismo , Doenças das Plantas/virologia , RNA Viral/química , DNA Polimerase Dirigida por RNA/metabolismo
5.
Br J Ophthalmol ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34340976

RESUMO

BACKGROUND/AIMS: To evaluate the cost-effectiveness of non-invasive monitoring tests to detect the onset of neovascular age-related macular degeneration (nAMD) in the unaffected second eye of patients receiving treatment for unilateral nAMD in a UK National Health Service (NHS) hospital outpatient setting. METHODS: A patient-level state transition model was constructed to simulate the onset, detection, and treatment of nAMD in the second eye. Five index tests were compared: self-reported change in visual function, Amsler test, clinic measured change in visual acuity from baseline, fundus assessment by clinical examination or colour photography, and spectral domain optical coherence tomography (SD-OCT). Diagnosis of nAMD was confirmed by fundus fluorescein angiography (FFA) before prompt initiation of antivascular endothelial growth factor treatment. Quality-adjusted life-years (QALYs) and costs of health and social care were modelled over a 25-year time horizon. RESULTS: SD-OCT generated more QALYs (SD-OCT, 5.830; fundus assessment, 5.787; Amsler grid, 5.736, patient's subjective assessment, 5.630; and visual acuity, 5.600) and lower health and social care costs (SD-OCT, £19 406; fundus assessment, £19 649; Amsler grid, £19 751; patient's subjective assessment, £20 198 and visual acuity, £20 444) per patient compared with other individual monitoring tests. Probabilistic sensitivity analysis indicated a high probability (97%-99%) of SD-OCT being the preferred test across a range of cost-effectiveness thresholds (£13 000-£30 000) applied in the UK NHS. CONCLUSIONS: Early treatment of the second eye following FFA confirmation of SD-OCT positive findings is expected to maintain better visual acuity and health-related quality of life and may reduce costs of health and social care over the lifetime of patients.

6.
J Phys Chem A ; 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34161099

RESUMO

The pseudo-π model yields current densities and induced magnetic fields that mimic the π-component, allowing investigations of large molecular structures, whether they are planar or not, at a low computational cost but with high accuracy. Herein the π-contribution to the magnetically induced current densities and induced magnetic fields of large planar molecules and nonplanar molecules (such as [10]cyclophenacene and chiral toroidal nanotubes C2016 and C2196) were computed using the pseudo-π model with the gauge-including magnetically induced currents method. Additionally, we provide a way to determine the π-component of the ring-current strengths, which can be used for assessing the aromatic character of large carbon molecules.

8.
Front Endocrinol (Lausanne) ; 12: 636959, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796074

RESUMO

Introduction: Diabetes monitoring systems (DMS) are a possible approach for regular control of glucose levels in patients with Type 1 or 2 diabetes in order to improve therapeutic outcomes or to identify and modify inappropriate patient behaviors in a timely manner. Despite the significant number of studies observing the DMS, no collective evidence is available about the effect of all devices. Goal: To review and consolidate evidences from multiple systematic reviews on the diabetes monitoring systems and the outcomes achieved. Materials and methods: Internet-based search in PubMed, EMBASE, and Cochrane was performed to identify all studies relevant to the research question. The data regarding type of intervention, type of diabetes mellitus, type of study, change in clinical parameter(s), or another relevant outcome were extracted and summarized. Results: Thirty-three out of 1,495 initially identified studies, involving more than 44,100 patients with Type 1, Type 2, or gestational diabetes for real-time or retrospective Continuous Glucose Monitoring (CGMS), Sensor Augmented Pump Therapy (SAPT), Self-monitoring Blood Glucose (SMBG), Continuous subcutaneous insulin infusion (CSII), Flash Glucose Monitoring (FGM), Closed-loop systems and telemonitoring, were included. Most of the studies observed small nominal effectiveness of DMS. In total 11 systematic reviews and 15 meta-analyses, with most focusing on patients with Type 1 diabetes (10 and 6, respectively), reported a reduction in glycated hemoglobin (HbA1c) levels from 0.17 to 0.70% after use of DMS. Conclusion: Current systematic review of already published systematic reviews and meta-analyses suggests that no statistically significant difference exists between the values of HbA1c as a result of application of any type of DMS. The changes in HbA1c values, number and frequency of hypoglycemic episodes, and time in glucose range are the most valuable for assessing the appropriateness and effectiveness of DMS. Future more comprehensive studies assessing the effectiveness, cost-effectiveness, and comparative effectiveness of DMS are needed to stratify them for the most suitable diabetes patients' subgroups.

9.
J Phys Chem A ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605721

RESUMO

We develop a methodology for calculating, analyzing, and visualizing nuclear magnetic shielding densities which are calculated from the current density via the Biot-Savart relation. Atomic contributions to nuclear magnetic shielding constants can be estimated within our framework with a Becke partitioning scheme. The new features have been implemented in the GIMIC program and are applied in this work to the study of the 1H and 13C nuclear magnetic shieldings in benzene (C6H6) and cyclobutadiene (C4H4). The new methodology allows a visual inspection of the spatial origins of the positive (shielding) and negative (deshielding) contributions to the nuclear magnetic shielding constant of a single nucleus, something which has not been hitherto easily accomplished. Analysis of the shielding densities shows that diatropic and paratropic current-density fluxes yield both shielding and deshielding contributions, as the shielding or deshielding is determined by the direction of the current-density flux with respect to the studied nucleus instead of the tropicity. Becke partitioning of the magnetic shieldings shows that the magnetic shielding contributions mainly originate from the studied atom and its nearest neighbors, confirming the localized character of nuclear magnetic shieldings.

10.
J Chem Theory Comput ; 17(3): 1457-1468, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33599491

RESUMO

We have assessed the accuracy of the magnetic properties of a set of 51 density functional approximations, including both recently published and already established functionals. The accuracy assessment considers a series of 27 small molecules and is based on comparing the predicted magnetizabilities to literature reference values calculated using coupled-cluster theory with full singles and doubles and perturbative triples [CCSD(T)] employing large basis sets. The most accurate magnetizabilities, defined as the smallest mean absolute error, are obtained with the BHandHLYP functional. Three of the six studied Berkeley functionals and the three range-separated Florida functionals also yield accurate magnetizabilities. Also, some older functionals like CAM-B3LYP, KT1, BHLYP (BHandH), B3LYP, and PBE0 perform rather well. In contrast, unsatisfactory performance is generally obtained with Minnesota functionals, which are therefore not recommended for calculations of magnetically induced current density susceptibilities and related magnetic properties such as magnetizabilities and nuclear magnetic shieldings. We also demonstrate that magnetizabilities can be calculated by numerical integration of magnetizability density; we have implemented this approach as a new feature in the gauge-including magnetically induced current (GIMIC) method. Magnetizabilities can be calculated from magnetically induced current density susceptibilities within this approach even when analytical approaches for magnetizabilities as the second derivative of the energy have not been implemented. The magnetizability density can also be visualized, providing additional information that is not otherwise easily accessible on the spatial origin of magnetizabilities.

11.
Health Technol Assess ; 24(70): 1-144, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33289476

RESUMO

BACKGROUND: Urinary incontinence affects one in three women worldwide. Pelvic floor muscle training is an effective treatment. Electromyography biofeedback (providing visual or auditory feedback of internal muscle movement) is an adjunct that may improve outcomes. OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of biofeedback-mediated intensive pelvic floor muscle training (biofeedback pelvic floor muscle training) compared with basic pelvic floor muscle training for treating female stress urinary incontinence or mixed urinary incontinence. DESIGN: A multicentre, parallel-group randomised controlled trial of the clinical effectiveness and cost-effectiveness of biofeedback pelvic floor muscle training compared with basic pelvic floor muscle training, with a mixed-methods process evaluation and a longitudinal qualitative case study. Group allocation was by web-based application, with minimisation by urinary incontinence type, centre, age and baseline urinary incontinence severity. Participants, therapy providers and researchers were not blinded to group allocation. Six-month pelvic floor muscle assessments were conducted by a blinded assessor. SETTING: This trial was set in UK community and outpatient care settings. PARTICIPANTS: Women aged ≥ 18 years, with new stress urinary incontinence or mixed urinary incontinence. The following women were excluded: those with urgency urinary incontinence alone, those who had received formal instruction in pelvic floor muscle training in the previous year, those unable to contract their pelvic floor muscles, those pregnant or < 6 months postnatal, those with prolapse greater than stage II, those currently having treatment for pelvic cancer, those with cognitive impairment affecting capacity to give informed consent, those with neurological disease, those with a known nickel allergy or sensitivity and those currently participating in other research relating to their urinary incontinence. INTERVENTIONS: Both groups were offered six appointments over 16 weeks to receive biofeedback pelvic floor muscle training or basic pelvic floor muscle training. Home biofeedback units were provided to the biofeedback pelvic floor muscle training group. Behaviour change techniques were built in to both interventions. MAIN OUTCOME MEASURES: The primary outcome was urinary incontinence severity at 24 months (measured using the International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score, range 0-21, with a higher score indicating greater severity). The secondary outcomes were urinary incontinence cure/improvement, other urinary and pelvic floor symptoms, urinary incontinence-specific quality of life, self-efficacy for pelvic floor muscle training, global impression of improvement in urinary incontinence, adherence to the exercise, uptake of other urinary incontinence treatment and pelvic floor muscle function. The primary health economic outcome was incremental cost per quality-adjusted-life-year gained at 24 months. RESULTS: A total of 300 participants were randomised per group. The primary analysis included 225 and 235 participants (biofeedback and basic pelvic floor muscle training, respectively). The mean 24-month International Consultation on Incontinence Questionnaire Urinary Incontinence Short Form score was 8.2 (standard deviation 5.1) for biofeedback pelvic floor muscle training and 8.5 (standard deviation 4.9) for basic pelvic floor muscle training (adjusted mean difference -0.09, 95% confidence interval -0.92 to 0.75; p = 0.84). A total of 48 participants had a non-serious adverse event (34 in the biofeedback pelvic floor muscle training group and 14 in the basic pelvic floor muscle training group), of whom 23 (21 in the biofeedback pelvic floor muscle training group and 2 in the basic pelvic floor muscle training group) had an event related/possibly related to the interventions. In addition, there were eight serious adverse events (six in the biofeedback pelvic floor muscle training group and two in the basic pelvic floor muscle training group), all unrelated to the interventions. At 24 months, biofeedback pelvic floor muscle training was not significantly more expensive than basic pelvic floor muscle training, but neither was it associated with significantly more quality-adjusted life-years. The probability that biofeedback pelvic floor muscle training would be cost-effective was 48% at a £20,000 willingness to pay for a quality-adjusted life-year threshold. The process evaluation confirmed that the biofeedback pelvic floor muscle training group received an intensified intervention and both groups received basic pelvic floor muscle training core components. Women were positive about both interventions, adherence to both interventions was similar and both interventions were facilitated by desire to improve their urinary incontinence and hindered by lack of time. LIMITATIONS: Women unable to contract their muscles were excluded, as biofeedback is recommended for these women. CONCLUSIONS: There was no evidence of a difference between biofeedback pelvic floor muscle training and basic pelvic floor muscle training. FUTURE WORK: Research should investigate other ways to intensify pelvic floor muscle training to improve continence outcomes. TRIAL REGISTRATION: Current Controlled Trial ISRCTN57746448. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 70. See the NIHR Journals Library website for further project information.

12.
Folia Med (Plovdiv) ; 62(3): 539-545, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33009754

RESUMO

INTRODUCTION: Cognitive problems in patients with obstructive sleep apnea have been suspected since the 1980s. Several studies have investigated different cognitive domains. A similar widespread survey has not been done in the Bulgarian population. AIM: This study aimed to evaluate global cognitive functioning and memory function in patients with obstructive sleep apnea and to examine the potential influence of comorbidities on cognitive functions. MATERIALS AND METHODS: The study examined the neurocognitive profile of 103 consecutive patients newly diagnosed with OSA and 31 healthy controls. A list of inclusion and exclusion criteria was developed. Sleep breathing was examined in both groups. The other methods were: a medical history of patients, clinical examination, neuropsychological assessment, statistical analysis. RESULTS: The study found that the global cognitive functioning of patients with OSA and the memory function was impaired. Short-term memory has been found affected predominantly. Only obesity was distinguished as a major factor relevant to the severity of cognitive changes in the study group. A statistically significant difference between the groups with and without obesity was found for the applied memory tests, except for the delayed recall and word recognition. The duration of exposure to hypoxia and sleep fragmentation is important for the severity of cognitive deficits. The results confirmed this theory showing that this factor is among the major severity factors. CONCLUSION: The study found that the global cognitive functioning of patients with OSA, as well as memory function, were impaired. The role of comorbidities is complex and far from clear.

13.
Folia Med (Plovdiv) ; 62(3): 431-437, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33009758

RESUMO

The immunology of stroke can be approached in several ways. By viewing stroke from an immunological standpoint, we are trying to achieve new insights in its pathogenesis and reach new therapeutic options. To review and summarize the findings from publications on immunology of stroke. Infections are a well-known risk factor for stroke. This is due to activated immune cells interacting with throm-bocytes and releasing coagulation factors, which affect the formation of the thrombus. Aseptic inflammation in the ischemic lesion leads to cellular invasion of the area and triggers a pro-inflammatory response, which has an impact on further destruction of ischemic brain tissue. Another aspect of stroke is systemic immune suppression, which is a predisposing factor towards a systemic bacterial infection. Infection itself is also an independent risk factor for negative clinical outcomes and increased mortality. The immunological approach to the topic of ischemic stroke holds significant value for future research.

14.
BMJ ; 371: m3719, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33055247

RESUMO

OBJECTIVE: To assess the effectiveness of pelvic floor muscle training (PFMT) plus electromyographic biofeedback or PFMT alone for stress or mixed urinary incontinence in women. DESIGN: Parallel group randomised controlled trial. SETTING: 23 community and secondary care centres providing continence care in Scotland and England. PARTICIPANTS: 600 women aged 18 and older, newly presenting with stress or mixed urinary incontinence between February 2014 and July 2016: 300 were randomised to PFMT plus electromyographic biofeedback and 300 to PFMT alone. INTERVENTIONS: Participants in both groups were offered six appointments with a continence therapist over 16 weeks. Participants in the biofeedback PFMT group received supervised PFMT and a home PFMT programme, incorporating electromyographic biofeedback during clinic appointments and at home. The PFMT group received supervised PFMT and a home PFMT programme. PFMT programmes were progressed over the appointments. MAIN OUTCOME MEASURES: The primary outcome was self-reported severity of urinary incontinence (International Consultation on Incontinence Questionnaire-urinary incontinence short form (ICIQ-UI SF), range 0 to 21, higher scores indicating greater severity) at 24 months. Secondary outcomes were cure or improvement, other pelvic floor symptoms, condition specific quality of life, women's perception of improvement, pelvic floor muscle function, uptake of other urinary incontinence treatment, PFMT self-efficacy, adherence, intervention costs, and quality adjusted life years. RESULTS: Mean ICIQ-UI SF scores at 24 months were 8.2 (SD 5.1, n=225) in the biofeedback PFMT group and 8.5 (SD 4.9, n=235) in the PFMT group (mean difference -0.09, 95% confidence interval -0.92 to 0.75, P=0.84). Biofeedback PFMT had similar costs (mean difference £121 ($154; €133), -£409 to £651, P=0.64) and quality adjusted life years (-0.04, -0.12 to 0.04, P=0.28) to PFMT. 48 participants reported an adverse event: for 23 this was related or possibly related to the interventions. CONCLUSIONS: At 24 months no evidence was found of any important difference in severity of urinary incontinence between PFMT plus electromyographic biofeedback and PFMT alone groups. Routine use of electromyographic biofeedback with PFMT should not be recommended. Other ways of maximising the effects of PFMT should be investigated. TRIAL REGISTRATION: ISRCTN57756448.


Assuntos
Eletromiografia/métodos , Terapia por Exercício/métodos , Neurorretroalimentação/métodos , Incontinência Urinária/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Diafragma da Pelve/fisiopatologia , Qualidade de Vida , Resultado do Tratamento , Incontinência Urinária/fisiopatologia
15.
Viruses ; 12(9)2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32932882

RESUMO

The nuclear export of cellular mRNAs is a complex process that requires the orchestrated participation of many proteins that are recruited during the early steps of mRNA synthesis and processing. This strategy allows the cell to guarantee the conformity of the messengers accessing the cytoplasm and the translation machinery. Most transcripts are exported by the exportin dimer Nuclear RNA export factor 1 (NXF1)-NTF2-related export protein 1 (NXT1) and the transcription-export complex 1 (TREX1). Some mRNAs that do not possess all the common messenger characteristics use either variants of the NXF1-NXT1 pathway or CRM1, a different exportin. Viruses whose mRNAs are synthesized in the nucleus (retroviruses, the vast majority of DNA viruses, and influenza viruses) exploit both these cellular export pathways. Viral mRNAs hijack the cellular export machinery via complex secondary structures recognized by cellular export factors and/or viral adapter proteins. This way, the viral transcripts succeed in escaping the host surveillance system and are efficiently exported for translation, allowing the infectious cycle to proceed. This review gives an overview of the cellular mRNA nuclear export mechanisms and presents detailed insights into the most important strategies that viruses use to export the different forms of their RNAs from the nucleus to the cytoplasm.


Assuntos
Transporte Ativo do Núcleo Celular/fisiologia , Núcleo Celular/virologia , RNA Viral/fisiologia , Citoplasma/metabolismo , Vírus de DNA/fisiologia , Humanos , Carioferinas/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Transporte de RNA , RNA Mensageiro , RNA Viral/genética , Retroviridae/fisiologia , Proteínas Virais/metabolismo
16.
Virologie (Montrouge) ; 24(4): 246-273, 2020 Aug 01.
Artigo em Francês | MEDLINE | ID: mdl-32795981

RESUMO

The nuclear export of mRNAs is a complex process, involving the participaton of numerous proteins, the recruitement of which starts during the early steps of mRNAs biosynthesis and maturation. This strategy allows the cell to export only mature and non-defective transcripts to the cytoplasm where they are directed to the translational machinery. The vast majority of mRNAs is exported by the dimeric transport receptor TAP-p15, which is mainly recruited by the large multiprotein complex TREX-1. Other mRNAs that do not display all typical features of a mature transcript use variants of the TAP-p15 export pathway or recruit the alternative export receptor CRM1. Most DNA viruses, retroviruses, and influenza viruses, the mRNAs of which are synthesized in the nucleus, also use TAP-p15 and/or CRM1 to export their mRNAs. The highjacking of the cellular export machinery by viral mRNAs usually involves the presence of constitutive structural elements that directly load cellular export factors and/or viral adaptor proteins. Associated with the host export machinery, viral mRNAs escape host surveillance, are efficiently exported in the cytoplasm in order to be translated, and thus make possible the progress toward the later events of the virus life cycles.


Assuntos
Núcleo Celular , RNA Viral , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Citoplasma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo
18.
SAGE Open Med ; 8: 2050312120922029, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547747

RESUMO

Aim: The aim of this study is to compare the differences in breast cancer therapy, health-care service practices, and their availability in ten European countries-Albania, Bosnia and Herzegovina, Bulgaria, Kosovo, Montenegro, Republic of North Macedonia, Croatia, Romania, Slovenia, and Republic of Serbia. Methods: An inquire survey was conducted among oncologists in the participating countries. The questionnaire was of qualitative character and focused on several key areas as screening practices, diagnosing, treatment, and health-care procedures utilization. The results were processed through comparative and percentage analysis. Results: All of the observed countries have national registries for breast cancer, but only in five, a mechanism of controlled action of early detection is implemented. Ninety percent of the countries have implemented in the national guidelines the European Society of Medical Oncology recommendations, while National Comprehensive Cancer Network is considered in only 50%. In all countries, digital mammography is a universal diagnostic method. Pathohistological analysis, including HER2 receptor expression and determination of the level of progesterone and estrogen receptors, is routinely performed in all countries prior to therapy. Some differences are observed in terms of FISH/CISH methods, determination of Ki-67 volume, and prognostic molecular assays. Trastuzumab is used as neo-adjuvant therapy in HER2-positive disease in all countries, while in Bosnia and Herzegovina and Croatia, only pertuzumab is used. Psychological support is integrated into the professional guidelines for treatment and monitoring in Bosnia and Herzegovina, Bulgaria, and Serbia. Conclusions: The international guidelines should be followed strictly, and some improvements in the health policies should be made in order to decrease the differences and inequalities in the availability of the breast cancer (BC) health services in the Central and Eastern European countries.

19.
Front Public Health ; 8: 147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411649

RESUMO

Background: Acromegaly and its comorbidities affect the patients' quality of life, each healthcare system and the society. This study aimed to evaluate clinical characteristics and treatment patterns and the economic burden of acromegaly. Materials and methods: All patients with acromegaly treated with expensive medicines and regularly followed up at the main expert clinical center for acromegaly in the country were included in this nationwide, retrospective, observational, population-based study. Patient characteristics, treatment patterns, healthcare resource use, and costs were assessed for 1-year period (01.01.2018-31.12.2018). Results were processed through statistical analysis using MedCalc software version 16.4.1. Results: A total of 191 acromegaly patients were observed. Approximately 67% were female, 45.5% were between 41 and 60 years and the mean age at diagnosis was 40.73 years. Surgical treatment was preferred as a first-line therapy among almost 89% of all diagnosed patients. The level of comorbidities was very high as more than 95% suffered from at least one concomitant disease. The most frequent comorbidities were other endocrine and metabolic diseases (96.7%), followed by cardiovascular diseases (70.7%). The most common first-line pharmacotherapy was long-acting somatostatin analogs (SSA) (38%) followed by dual combination SSA + pegvisomant (21%). The total economic burden of acromegaly was estimated to be 2,674,499.90 € in 2018 as the direct costs (medication costs, hospitalization costs covered by the patients and the National Health Insurance Fund) outnumbered indirect costs (loss of productivity due to hospitalization): 2,630,568.58 € vs. 43,931.32 €. The average annual per-patient direct and indirect costs were 14,002.62 €. Conclusions: The current study demonstrates a significant clinical and socio-economic burden of acromegaly in the country. Proper diagnosing and regular follow up of acromegaly patients in a specialized pituitary center ensure appropriate innovative pharmacotherapy with achievement of disease control.


Assuntos
Acromegalia , Acromegalia/tratamento farmacológico , Bulgária/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Qualidade de Vida , Estudos Retrospectivos
20.
PLoS One ; 15(5): e0232815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32392235

RESUMO

AIMS: To evaluate the expected life expectancy in patients with diabetes in Bulgaria and to compare it to the expected life expectancy of the non-diabetic population in the country. METHODS: It is a retrospective observational population study on individuals diagnosed with diabetes, compared to the non-diabetic population in Bulgaria for the period 2012-2015. Data from the national diabetes register and national statistical institute were used to construct life-tables with probability of survival with t-test and Chi Square test. Confounder analysis was done by age, sex, and type of diabetes. All-cause mortality and deaths in diabetic patients were analyzed. Kaplan-Meier survival curves were constructed for each age group and a log-rank analysis was conducted. RESULTS: Average life expectancy in the non-diabetic population, patients with Type 1 DM and with Type 2 DM is 74.8; 70.96 and 75.19 years, respectively. For 2012-2015 the mortality in the non-diabetic population remained constant and lower (average-1.48%) compared to type-1 DM (5.25%) and Type-2 (4.27%). Relative risk of death in diabetics was higher overall (12%), after the age of 70 before which the relative risk was higher for the non-diabetic population. This was observed as a trend in all analyzed years. CONCLUSION: Patients with type 2 DM have a longer life-expectancy than patients with type-1 DM and overall Diabetics life expectancy equals that of the non-diabetic population, which could suggest improved disease control and its associated complications in Bulgaria. Male diabetics show slightly longer life expectancy than their counterparts in the non-diabetic population, by a marginal gain of 0.6 years for the entire observed period. Life expectancy in diabetic women increased by 1.3 years, which was not observed in the non-diabetic population. Prevalence of diabetes was higher for women. Improved diabetes control may explain this gain in life; however other studies are needed to confirm this.


Assuntos
Causas de Morte , Diabetes Mellitus/mortalidade , Expectativa de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biometria , Bulgária/epidemiologia , Criança , Pré-Escolar , Diabetes Mellitus/fisiopatologia , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Tábuas de Vida , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
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