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1.
Braz. j. biol ; 83: e246389, 2023. graf
Artigo em Inglês | LILACS-Express | MEDLINE, LILACSEXPRESS | ID: biblio-1285638

RESUMO

Abstract Poultry industry is expanding rapidly and producing million tons of feather waste annually. Massive production of keratinaceous byproducts in the form of industrial wastes throughout the world necessitates its justified utilization. Chemical treatment of keratin waste is proclaimed as an eco-destructive approach by various researchers since it generates secondary pollutants. Keratinase released by a variety of microbes (bacteria and fungi) can be used for the effective treatment of keratin waste. Microbial degradation of keratin waste is an emerging and eco-friendly approach and offers dual benefits, i.e., treatment of recalcitrant pollutant (keratin) and procurement of a commercially important enzyme (keratinase). This study involves the isolation, characterization, and potential utility of fungal species for the degradation of chicken-feather waste through submerged and solid-state fermentation. The isolated fungus was identified and characterized as Aspergillus (A.) flavus. In a trial of 30 days, it was appeared that 74 and 8% feather weight was reduced through sub-merged and solid-state fermentation, respectively by A. flavus. The pH of the growth media in submerged fermentation was changed from 4.8 to 8.35. The exploited application of keratinolytic microbes is, therefore, recommended for the treatment of keratinaceous wastes to achieve dual benefits of remediation.


Resumo A indústria avícola está se expandindo rapidamente e produzindo milhões de toneladas de resíduos de penas anualmente. A produção massiva de subprodutos queratinosos na forma de resíduos agrícolas e industriais em todo o mundo exige sua utilização justificada. O tratamento químico de resíduos de queratina é proclamado como uma abordagem ecodestrutiva por vários pesquisadores, uma vez que gera poluentes secundários. A queratinase liberada por uma variedade de micróbios (bactérias e fungos) pode ser usada para o tratamento eficaz de resíduos de queratina. A degradação microbiana de resíduos de queratina é uma abordagem emergente e ecológica e oferece benefícios duplos, ou seja, tratamento de poluente recalcitrante (queratina) e obtenção de uma enzima comercialmente importante (queratinase). Este estudo envolve o isolamento, caracterização e utilidade potencial de espécies de fungos para a degradação de resíduos de penas de frango por meio da fermentação submersa e em estado sólido. O fungo isolado foi identificado e caracterizado como Aspergillus (A.) flavus. Em um ensaio de 30 dias, constatou-se que 74% e 8% do peso das penas foram reduzidos por A. flavus, respectivamente, por meio da fermentação submersa e em estado sólido. O pH do meio de crescimento em fermentação submersa foi alterado de 4,8 para 8,35. A aplicação explorada de micróbios queratinolíticos é, portanto, recomendada para o tratamento de resíduos ceratinosos para obter benefícios duplos de remediação.

3.
Math Biosci Eng ; 18(5): 5321-5346, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34517490

RESUMO

Glaucoma is a chronic ocular degenerative disease that can cause blindness if left untreated in its early stages. Deep Convolutional Neural Networks (Deep CNNs) and its variants have provided superior performance in glaucoma classification, segmentation, and detection. In this paper, we propose a two-staged glaucoma classification scheme based on Deep CNN architectures. In stage one, four different ImageNet pre-trained Deep CNN architectures, i.e., AlexNet, InceptionV3, InceptionResNetV2, and NasNet-Large are used and it is observed that NasNet-Large architecture provides superior performance in terms of sensitivity (99.1%), specificity (99.4%), accuracy (99.3%), and area under the receiver operating characteristic curve (97.8%) metrics. A detailed performance comparison is also presented among these on public datasets, i.e., ACRIMA, ORIGA-Light, and RIM-ONE as well as locally available datasets, i.e., AFIO, and HMC. In the second stage, we propose an ensemble classifier with two novel ensembling techniques, i.e., accuracy based weighted voting, and accuracy/score based weighted averaging to further improve the glaucoma classification results. It is shown that ensemble with accuracy/score based scheme improves the accuracy (99.5%) for diverse databases. As an outcome of this study, it is presented that the NasNet-Large architecture is a feasible option in terms of its performance as a single classifier while ensemble classifier further improves the generalized performance for automatic glaucoma classification.


Assuntos
Glaucoma , Redes Neurais de Computação , Bases de Dados Factuais , Humanos , Fotografação , Curva ROC
4.
J Anim Breed Genet ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559415

RESUMO

Vietnamese smallholder dairy cows (VDC) are the result of crossbreeding between different zebu (ZEB) and taurine dairy breeds through many undefined generations. Thus, the predominant breed composition of VDC is currently unknown. This study aimed to evaluate the level of genetic diversity and breed composition of VDC. The SNP data of 344 animals from 32 farms located across four dairy regions of Vietnam were collected and merged with genomic reference data, which included three ZEB breeds: Red Sindhi, Sahiwal and Brahman, three taurine breeds: Holstein (HOL), Jersey (JER) and Brown Swiss (BSW), and a composite breed: Chinese Yellow cattle. Diversity and admixture analyses were applied to the merged data set. The VDC were not excessively inbred, as indicated by very low inbreeding coefficients (Wright's FIS ranged from -0.017 to 0.003). The genetic fractions in the test herds suggested that the VDC are primarily composed of HOL (85.0%); however, JER (6.0%), BSW 5.3%) and ZEB (4.5%) had also contributed. Furthermore, major genotype groupings in the test herds were pure HOL (48%), B3:15/16HOL_1/16ZEB (22%) and B2:7/8HOL_1/8ZEB (12%). The genetic makeup of the VDC is mainly components of various dairy breeds but also has a small percentage of ZEB; thus, the VDC could be a good genetic base for selecting high milk-producing cows with some degree of adaptation to tropical conditions.

5.
Curr Med Res Opin ; 37(11): 1933-1944, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34384311

RESUMO

OBJECTIVE: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes. METHODS: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM). RESULTS: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively). CONCLUSIONS: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Anticorpos Monoclonais Humanizados , Azetidinas , Compostos de Benzil , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Estudos de Viabilidade , Cloridrato de Fingolimode , Humanos , Imunossupressores , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pontuação de Propensão
6.
Braz J Biol ; 83: e246389, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34320050

RESUMO

Poultry industry is expanding rapidly and producing million tons of feather waste annually. Massive production of keratinaceous byproducts in the form of industrial wastes throughout the world necessitates its justified utilization. Chemical treatment of keratin waste is proclaimed as an eco-destructive approach by various researchers since it generates secondary pollutants. Keratinase released by a variety of microbes (bacteria and fungi) can be used for the effective treatment of keratin waste. Microbial degradation of keratin waste is an emerging and eco-friendly approach and offers dual benefits, i.e., treatment of recalcitrant pollutant (keratin) and procurement of a commercially important enzyme (keratinase). This study involves the isolation, characterization, and potential utility of fungal species for the degradation of chicken-feather waste through submerged and solid-state fermentation. The isolated fungus was identified and characterized as Aspergillus (A.) flavus. In a trial of 30 days, it was appeared that 74 and 8% feather weight was reduced through sub-merged and solid-state fermentation, respectively by A. flavus. The pH of the growth media in submerged fermentation was changed from 4.8 to 8.35. The exploited application of keratinolytic microbes is, therefore, recommended for the treatment of keratinaceous wastes to achieve dual benefits of remediation.


Assuntos
Galinhas , Plumas , Animais , Fermentação , Fungos , Resíduos Industriais , Queratinas/metabolismo
7.
Curr Med Res Opin ; 37(10): 1779-1788, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34256668

RESUMO

OBJECTIVE: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the approved idecabtagene vicleucel (ide-cel) dose range of 300-460 × 106 CAR-positive T-cells for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed) using matching-adjusted indirect treatment comparisons (MAICs). METHODS: MAICs were performed with individual patient data for cilta-cel (CARTITUDE-1; NCT03548207) and published summary-level data for ide-cel (KarMMa; NCT03361748). Treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa were included in the analyses. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was estimated for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RESULTS: Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.49 [95% CI: 2.47, 12.21; p < .0001]; RR: 2.21), DoR (hazard ratio [HR]: 0.50 [95% CI: 0.29, 0.87; p = .0137]), and PFS (HR: 0.37 [95% CI: 0.22, 0.62; p = .0002]) when compared with ide-cel. For OS, the results were in favor of cilta-cel and clinically meaningful but with a CI overlapping one (HR: 0.55 [95% CI: 0.29, 1.05; p = .0702]). CONCLUSIONS: These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes, highlighting its therapeutic potential in patients with triple-class exposed RRMM.


Assuntos
Antineoplásicos , Imunoterapia Adotiva , Mieloma Múltiplo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Mieloma Múltiplo/tratamento farmacológico , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos
8.
Animals (Basel) ; 11(3)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803763

RESUMO

Breeding for polled animals is deemed the most practical solution to eradicate horns naturally and circumvent management costs and risks on health and welfare. However, there has been a historical reluctance by some farmers to select polled animals due to perceived lower productivity of their calves. This study has compared estimated breeding values (EBVs) between horned and polled animals (N = 2,466,785) for 12 production and carcass traits to assess historical (before 2000) and recent (2000-2018) genetic implications of poll breeding. Older generations of the polled animals in most breeds had significantly lower (Bonferroni-corrected p = 0.05) genetic merits for live (birth to maturity) and carcass weights, milk, meat quality, and fat content traits. Substantial gains of genetic potential were achieved during 2000 to 2018 in each breed, such that polled animals have significantly improved for the majority of traits studied. Generally, polled cohorts showed advantageous EBVs for live and carcass weights irrespective of the lower birth weights in some breeds. While Polled Brahman showed inferior production parameters, the poll genetics' effect size (d) and correlation (r) were very small on recent birth weight (d = -0.30, r = -0.08), 200 days (-0.19, -0.05), 400 days (-0.06, -0.02), 600 days (-0.05, -0.01), mature cow live weight (-0.08, -0.02), and carcass weight (-0.19, -0.05). In conclusion, although there is some evidence that historical selection for polled breeding animals may have reduced productivity, there is strong evidence that more recent selection for polled genotypes in the breeds studied has not resulted in any adverse effects on genetic merit.

9.
Cureus ; 13(3): e13709, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33833923

RESUMO

Purpose It is often difficult for the clinician to isolate the etiology of pain occurring either in the neck or shoulder because of the reason that neck pain can refer to the shoulder and vice versa. Concordance research has found that around one in 10 patients who were referred for cervical radiculopathy had comorbid shoulder pathology. The goal of this research is to analyze and correlate risk factors for persistent shoulder pain (non-dermatomal) following cervical spine surgery. Methods This was a single-center, retrospective study. The medical records of patients admitted for anterior cervical discectomy and fusion (ACDF) were reviewed from August 2018 to Feb 2021. Patients of both sexes and age more than 18 years who underwent ACDF (single/multiple levels) were included and the medical record was checked for whether they had persistent shoulder pain following ACDF. The proportion of patients undergoing shoulder surgery for associated rotator cuff tears and subacromial impingement were recorded. Results Seventy patients presenting with cervical prolapsed intervertebral disc (PID) were studied. A majority of our patients were females (n=48, 68.6%) and males (n=22, 31.4%) with an M:F ratio of 1:2 and the majority of patients were between the ages of 40 to 60 years (n=34, 48.6%). After surgical intervention (ACDF), 48 patients (68.6%) noted the cessation of shoulder symptoms (pain, weakness, and numbness) during their last visit. Rotator cuff tear (supraspinatus mainly) was the predominant finding in MRI in those who didn't improve after ACDF (n=18, 25.7%, p-value: 0.001). Twenty patients (28.6%) underwent acromioplasty and rotator cuff tendon repair and four patients responded well to subacromial injection. The C6-7 level was most commonly affected (n=48, 68.6%) followed by C5-6 level (n=19, 27.1%). No significant association was found between cervical levels with shoulder pathologies (p-0.171), though a significant association between a visual analog scale (VAS) score >7 after surgery with shoulder pathologies (p-0.001) was found. The C6-7 level was commonly affected in females (p=0.038) but no significant association between gender and shoulder pathologies was found (p=0.332). Conclusion Dual pathologies in patients with cervical PID are very common. It needs careful attention by doing thorough clinical examination and correlating patient symptoms with radiological investigations. A patient who presents with persistent shoulder pain after cervical spine surgery had a higher chance of having concurrent shoulder pathology, and they should be properly investigated and managed to alleviate the suffering of the patient.

10.
Afr J Emerg Med ; 11(1): 118-122, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33680732

RESUMO

Introduction: Organophosphate poisoning (OPP) is a major health-care burden in South Africa. Recently, we have observed that patients admitted to our Intensive Care Unit (ICU) with OPP have followed a more complicated course in comparison to previous years. Objectives: To describe the differences in the clinical course and costs of patients with OPP between two time periods, namely 2012 and 2017. Methods: Retrospective comparison of patients admitted to the Intensive Care Unit (ICU) of Chris Hani Baragwanath Academic Hospital between January 2012 to December 2012 and January 2017 to December 2017. Results: Forty-one patients were found in the database. Patients from our 2017 cohort showed a significantly longer total median (IQR) length of stay 8 (4-17) days vs. 2 (2-3) days, p = 0.000, duration of antidote therapy 5 (3-10) days vs. 2 (2-3) days, p = 0.004 and duration of ventilation 4 (2-11) days vs 1 (1-2) day, p = 0.003. Patients presenting in 2017 were more likely to be admitted to ICU, odds ratio 5.6 (CI 1.2-26). There was a 31- fold increase in ICU costs between 2012 and 2017. Conclusion: Based on our experience, the clinical course of OPP requiring ICU admission has evolved into a condition with a longer length of stay, duration of antidote therapy, ventilatory support, increased risk of complications and additional costs.

11.
Front Genet ; 12: 593154, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643378

RESUMO

Dehorning is the process of physically removing horns to protect animals and humans from injury, but the process is costly, unpleasant, and faces increasing public scrutiny. Genetic selection for polled (hornless), which is genetically dominant to horned, is a long-term solution to eliminate the need for dehorning. However, due to the limited number of polled Australian Brahman bulls, the northern Australian beef cattle population remains predominantly horned. The potential to use gene editing to produce high-genetic-merit polled cattle was recently demonstrated. To further explore the concept, this study simulated introgression of the POLLED allele into a tropically adapted Australian beef cattle population via conventional breeding or gene editing (top 1% or 10% of seedstock bulls/year) for 3 polled mating schemes and compared results to baseline selection on genetic merit (Japan Ox selection index, $JapOx) alone, over the course of 20 years. The baseline scenario did not significantly decrease the 20-year HORNED allele frequency (80%), but resulted in one of the fastest rates of genetic gain ($8.00/year). Compared to the baseline, the conventional breeding scenarios where polled bulls were preferentially used for breeding, regardless of their genetic merit, significantly decreased the 20-year HORNED allele frequency (30%), but resulted in a significantly slower rate of genetic gain ($6.70/year, P ≤ 0.05). The mating scheme that required the exclusive use of homozygous polled bulls, resulted in the lowest 20-year HORNED allele frequency (8%), but this conventional breeding scenario resulted in the slowest rate of genetic gain ($5.50/year). The addition of gene editing the top 1% or 10% of seedstock bull calves/year to each conventional breeding scenario resulted in significantly faster rates of genetic gain (up to $8.10/year, P ≤ 0.05). Overall, our study demonstrates that, due to the limited number of polled Australian Brahman bulls, strong selection pressure on polled will be necessary to meaningfully increase the number of polled animals in this population. Moreover, these scenarios illustrate how gene editing could be a tool for accelerating the development of high-genetic-merit homozygous polled sires to mitigate the current trade-off of slower genetic gain associated with decreasing HORNED allele frequency in the Australian Brahman population.

13.
Breast ; 57: 5-17, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33677313

RESUMO

BACKGROUND: A systematic review and meta-analysis was conducted to assess breast cancer (BC) outcomes among patients with early-stage hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) BC, receiving adjuvant endocrine therapy. METHODS: Randomized controlled trials (RCTs) and real-world evidence (RWE) studies were identified using Ovid MEDLINE®, Embase, and Evidence-Based Medicine Reviews. Clinical and methodological similarities including alignment of outcome definitions with standardized definitions for efficacy endpoints criteria were assessed to evaluate feasibility of conducting a meta-analysis. Where feasible, 5-year probabilities of BC recurrence or death were estimated using a Bayesian hierarchical arm-based model. RESULTS: Of 21 included studies, 8 RCTs and 4 RWE studies reported outcome data of interest. There was heterogeneity in outcome reporting, as well as variation in recurrence risk amongst studies with aligned reporting. Of the 12 studies, 10 were considered for inclusion in a meta-analysis of BC recurrence or death. Only a subgroup analysis of node-positive patients (3 studies; n = 7307) was deemed feasible. The 5-year probability of BC recurrence or death was 17.2% (95% credible interval: 14.6%-20.3%). CONCLUSION: Although studies reporting recurrence outcomes were limited, there remains a high risk of BC recurrence, especially among node-positive patients. Approximately 1 in 6 women with node-positive HR+/HER2- early-stage BC receiving endocrine therapy experience recurrence or death within 5-years of initiating treatment, suggesting a need for novel treatments for this population.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Recidiva Local de Neoplasia/epidemiologia , Receptor ErbB-2/genética , Resultado do Tratamento
14.
Cureus ; 13(1): e12870, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33633899

RESUMO

Purpose The purpose of this study is to compare the effect of pregabalin in reducing the neuropathic pain in postoperative patients who have undergone single-level microdiscectomy for prolapsed intervertebral lumbar disc. Methods A randomized control clinical trial was conducted from June 2018 to April 2020 in three campuses Dr. Ziauddin University Hospital, Karachi, by two spinal surgeons. This study included 84 patients who underwent either emergency or elective microdiscectomy surgery. The patients randomized into two equal groups of 42, (group-A: pregabalin) and (group-B: placebo). Both groups also received routine analgesia along with the pregabalin and placebo capsules. In the intervention group, pregabalin was administered preoperative and postoperative defined times. The pain scores were recorded by visual analog scale (VAS) and Roland-Morris score system on the preoperative day and compared to the scores on follow-up on postoperative day seven. Results The pain scores were significantly better in group-A compared to group-B with similar baseline variables. The mean VAS scores of pains in group-A on postoperative day seven on follow-up were compared to VAS pain scores in group-B showing better pain control. The Roland-Morris scores were also significantly better for group-A. Conclusions The use of pregabalin in addition to the routine analgesia has better control of postoperative neuropathic pain in patients with single-level microdiscectomy compared to the patients who are receiving only routine analgesia. Other factors like cost, dose, side effects, and frequency should also be considered.

15.
J Comp Eff Res ; 10(6): 495-507, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33620251

RESUMO

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Cladribina/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Metanálise em Rede , Recidiva
16.
J Comp Eff Res ; 9(18): 1255-1274, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33090003

RESUMO

Aim: To compare the efficacy of ofatumumab to other disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS). Materials & methods: A network meta-analysis was conducted to determine the relative effect of ofatumumab on annualized relapse rate and confirmed disability progression at 3 months and 6 months. Results: For each outcome, ofatumumab was as effective as other highly efficacious monoclonal antibody DMTs (i.e., alemtuzumab, natalizumab and ocrelizumab). Conclusion: Ofatumumab offers beneficial outcomes for RMS by reducing relapse and disability progression risk.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Pesquisa Comparativa da Efetividade , Humanos , Metanálise em Rede , Recidiva
17.
Cancers (Basel) ; 12(8)2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32748838

RESUMO

Prostate Cancer (PCa) is a leading cause of cancer-related morbidity and mortality in men. Therefore, novel mechanistically-driven approaches are needed for PCa management. Here, we determined the effects of grape antioxidants quercetin and/or resveratrol (60 and 600 mg/kg, respectively, in diet) against PCa in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP)-model in prevention and intervention settings. We found resveratrol alone and in combination significantly inhibited prostate tumorigenesis in prevention setting, while the same was seen only in combination after intervention. The observed effects were associated with marked inhibition in proliferation, oxidative stress, and tumor survival markers, and induced apoptosis markers. Utilizing PCa PCR array analysis with prevention tumor tissues, we identified that quercetin-resveratrol modulates genes involved in promoter methylation, cell cycle, apoptosis, fatty acid metabolism, transcription factors, androgen response, PI3K/AKT and PTEN signaling. Ingenuity Pathway Analysis (IPA) identified IGF1 and BCL2 as central players in two gene networks. Functional annotation predicted increased apoptosis and inhibited cell viability/proliferation, hyperplasia, vasculogenesis, and angiogenesis with dual treatment. Furthermore, IPA predicted upstream inhibition of major PCa signaling VEGF, Ca2+, PI3K, CSF2, PTH). Based on PCR array, we identified decreased levels of EGFR, EGR3, and IL6, and increased levels of IGFBP7 and NKX3.1, overall supporting anti-PCa effects of quercetin-resveratrol.

18.
Curr Med Res Opin ; 36(7): 1145-1156, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32216597

RESUMO

Background: Indirect treatment comparisons (ITCs) provide valuable evidence on comparative efficacy where head-to-head clinical trials do not exist; however, differences in patient populations may introduce bias. Therefore, it is essential to assess between-trial heterogeneity to determine the suitability of synthesizing ITC results. We provide an illustrative case study in multiple sclerosis (MS) where we assess the feasibility of conducting ITCs between siponimod and interferon beta-1b (IFN ß-1b) and between siponimod and ocrelizumab.Methods: We assessed the feasibility of conducting ITCs using standard unadjusted methods (e.g. Bucher or network meta-analysis [NMA]) as well as matching-adjusted indirect comparisons (MAICs) using individual patient data (IPD) from the siponimod (EXPAND) trial, based on guidance from NICE. Time to confirmed disability progression (CDP) at 3 or 6 months was assessed.Results: Bucher ITCs and NMAs, which rely on summary-level data, were not able to account for important cross-trial differences. Comparisons between siponimod and IFN ß-1b were feasible using MAIC; the HRs (95% CI) for CDP-6 and CDP-3 were 0.55 (0.33-0.91) and 0.82 (0.42-1.63), respectively. ITCs were not feasible between siponimod and ocrelizumab because study designs and patient populations were too dissimilar to conduct a reliable ITC.Conclusions: This study highlights the importance of conducting a detailed feasibility assessment before undertaking ITCs to illuminate when excessive between-trial heterogeneity would cause biased results. MAIC was performed for siponimod and IFN ß-1b in the absence of a head-to-head trial and was considered a more valid approach than a traditional ITC to examine comparative effectiveness.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Humanos , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metanálise em Rede
19.
Curr Med Res Opin ; 36(7): 1157-1166, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32220214

RESUMO

Background: Siponimod, interferon beta-1a (IFNß-1a), IFNß-1b and natalizumab have been evaluated as treatments for secondary progressive multiple sclerosis (SPMS) in separate randomized controlled trials (RCTs), but not head-to-head. These trials included heterogeneous patient populations, which limits the use of standard network meta-analysis (NMA) for indirect treatment comparison (ITC) of relative efficacy. Matching-adjusted indirect comparison (MAIC) aims to correct these cross-trial differences. We compared siponimod to other disease modifying treatments (DMTs) in SPMS using MAIC.Methods: Individual patient data (IPD) were available for siponimod (EXPAND), while only published summary data were available for IFNß-1a (Nordic Study, SPECTRIMS, IMPACT), IFNß-1b (North American Study, European Study) and natalizumab (ASCEND). MAICs were conducted between siponimod and the other DMTs by re-weighting patients in EXPAND based on logistic regression.Results: Siponimod was determined to be statistically significantly more effective for the outcome of time to 6 month confirmed disability progression (CDP) compared with 22 µg IFNß-1a and 250 µg IFNß-1b, and for the outcome of time to CDP-3 compared with 60 µg IFNß-1a. Siponimod was numerically but not statistically superior for CDP in all other comparisons. For annualized relapse rate (ARR), with the exception of natalizumab, siponimod was numerically but not statistically superior to all comparators.Conclusions: EXPAND provides evidence of the efficacy of siponimod compared with placebo, and these MAICs complement this by demonstrating improved efficacy of siponimod relative to DMTs. Siponimod offers a significant therapeutic advance that may slow disease progression compared to other DMTs in an EXPAND-like population with secondary progressive disease.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Adulto , Feminino , Humanos , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Natalizumab/uso terapêutico
20.
Curr Med Res Opin ; 36(5): 799-808, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32011182

RESUMO

Objective: The comparative safety and efficacy of tafamidis, patisiran and inotersen treatments for transthyretin amyloidosis with polyneuropathy (ATTR-PN) has not been evaluated in clinical trials. In the absence of head-to-head evidence, indirect treatment comparisons such as network meta-analyses (NMAs) can be performed to evaluate relative effects of treatments. This study aims to assess the feasibility of conducting an NMA of available therapies for ATTR-PN patients.Methods: Pivotal trials for three approved ATTR-PN treatments, tafamidis (Fx-005), patisiran (APOLLO) and inotersen (NEURO-TTR), were compared in terms of study design, baseline population characteristics, outcome definitions and baseline risk. These assessments of heterogeneity informed the decision to perform Bayesian NMAs.Results: Despite similar study designs, clear differences in eligibility criteria between trials were accompanied by imbalances in baseline population characteristics considered to be plausible effect modifiers, such as disease stage and previous treatment. Of the outcomes assessed, only quality of life and adverse events were similarly reported in all trials. Neuropathy outcomes were not evaluated consistently between trials.Conclusions: An NMA of ATTR-PN treatments was not feasible, given the observed cross-trial heterogeneity. This decision highlights the importance of careful consideration for clinical heterogeneity that may threaten the validity of indirect comparisons.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/uso terapêutico , Metanálise em Rede , Oligonucleotídeos/uso terapêutico , Polineuropatias/tratamento farmacológico , RNA Interferente Pequeno/uso terapêutico , Adulto , Teorema de Bayes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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