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1.
Proc Natl Acad Sci U S A ; 120(4): e2200057120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36649432

RESUMO

Antibody delivery to the CNS remains a huge hurdle for the clinical application of antibodies targeting a CNS antigen. The blood-brain barrier and blood-CSF barrier restrict access of therapeutic antibodies to their CNS targets in a major way. The very high amounts of therapeutic antibodies that are administered systemically in recent clinical trials to reach CNS targets are barely viable cost-wise for broad, routine applications. Though global CNS delivery of antibodies can be achieved by intrathecal application, these procedures are invasive. A non-invasive method to bring antibodies into the CNS reliably and reproducibly remains an important unmet need in neurology. In the present study, we show that intranasal application of a mouse monoclonal antibody against the neurite growth-inhibiting and plasticity-restricting membrane protein Nogo-A leads to a rapid transfer of significant amounts of antibody to the brain and spinal cord in intact adult rats. Daily intranasal application for 2 wk of anti-Nogo-A antibody enhanced growth and compensatory sprouting of corticofugal projections and functional recovery in rats after large unilateral cortical strokes. These findings are a starting point for clinical translation for a less invasive route of application of therapeutic antibodies to CNS targets for many neurological indications.


Assuntos
Anticorpos Monoclonais , Proteínas da Mielina , Animais , Ratos , Encéfalo/metabolismo , Proteínas da Mielina/metabolismo , Proteínas Nogo , Medula Espinal/metabolismo , Anticorpos Monoclonais/administração & dosagem , Administração Intranasal
2.
Womens Health (Lond) ; 19: 17455057221147382, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36633116

RESUMO

BACKGROUND: The COVID-19 pandemic has impacted access to and use of maternal, newborn, and child health services. Due to lockdowns and travel restrictions implemented during the first wave of the pandemic, the provision of essential maternal health services such as family planning was critically affected. Unlike most healthcare, contraception-related services are impractical for virtual care provision as women need to attend the clinic in person. Therefore, most women across the world might have been left with an unmet need for contraception during the lockdown period. Interruptions in contraception services have led to an increased number of unintended pregnancies. With the emergence of several pocket studies, it is essential to pool the available evidence reporting the effects of COVID-19 on contraception to inform maternal health policy and practice. OBJECTIVE: The aims of this review are (1) to determine the effects of the COVID-19 pandemic on access to contraceptives among sexually active women and (2) to identify the magnitude of unintended pregnancy linked to interruptions of contraceptives due to the COVID-19 pandemic. METHODS: The protocol for this systematic review was registered in PROSPERO (CRD42021267077). Electronic databases such as MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, and Google Scholar will be searched for articles using appropriate key terms. The identified articles will be assessed against the eligibility criteria. Two reviewers (A.B. and T.B.) will independently screen titles and abstracts of all retrieved articles followed by a full-text review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. The quality of the papers will be assessed by using the Risk of Bias Assessment tool for Non-Randomized Studies. Quantitative findings will be pooled using a random-effects model meta-analysis, while qualitative findings will be presented using a narrative synthesis. ETHICS AND DISSEMINATION: Ethical approval is not required. The findings will be disseminated through conference presentations and peer-reviewed publications. DISCUSSION: This systematic review will present current data needed to design evidence-based programmes for improving access to contraception and preventing unintended pregnancy during the COVID-19 pandemic and future emergencies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021267077.


Assuntos
COVID-19 , Anticoncepção , Anticoncepcionais , Acesso aos Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Gravidez não Planejada , Feminino , Humanos , Gravidez , Controle de Doenças Transmissíveis/métodos , Anticoncepcionais/administração & dosagem , Metanálise como Assunto , Pandemias , Literatura de Revisão como Assunto , Revisões Sistemáticas como Assunto , Quarentena
3.
Medicine (Baltimore) ; 102(4): e32783, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705381

RESUMO

To explore factors related to local injection of Lauromacrogol combined with curettage in the treatment of cesarean scar pregnancy. A total of 24 successful and 8 unsuccessful cases were included. The age, gravidity, parity, times of cesarean section, interval from the last cesarean section, preoperative human chorionic gonadotropin (HCG), HCG on the first day after operation, decreasing rate of HCG on the first day after operation, average diameter of gestational sac, and preoperative vaginal bleeding days were analyzed. There were no significant differences of age, gravidity, parity, previous cesarean section times between groups. The differences of preoperative HCG, HCG on the first day after operation, the decreasing rate of HCG, gestational sac diameter, preoperative vaginal bleeding days were statistically significant between groups. The interval from the last cesarean section and the decreasing rate of HCG were protective factors, while the mean diameter of gestational sac and period of vaginal bleeding before operation were risk factors for the success of the treatment. The mean diameter of gestational sac owned the best predictive value.


Assuntos
Cesárea , Cicatriz , Curetagem , Polidocanol , Gravidez Ectópica , Soluções Esclerosantes , Feminino , Humanos , Gravidez , Cesárea/efeitos adversos , Gonadotropina Coriônica , Cicatriz/tratamento farmacológico , Cicatriz/etiologia , Cicatriz/cirurgia , Paridade , Polidocanol/administração & dosagem , Polidocanol/uso terapêutico , Gravidez Ectópica/tratamento farmacológico , Gravidez Ectópica/etiologia , Gravidez Ectópica/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Hemorragia Uterina/etiologia , Soluções Esclerosantes/administração & dosagem , Soluções Esclerosantes/uso terapêutico , Injeções Intralesionais
5.
In Vivo ; 37(1): 286-293, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593062

RESUMO

BACKGROUND/AIM: Vitamin D3 (VD3) affects the regulation of the immune system, including the differentiation and function of regulatory T-cells (Tregs). Tregs play an important role in maintaining immune homeostasis in patients with colorectal cancer (CRC). The effects of VD3 on Treg-associated immune function were investigated in Thai patients in the early stages of CRC. MATERIALS AND METHODS: Twenty-eight patients were randomized to one of two groups: Untreated or treatment with VD3 for 3 months. Whole blood samples were collected at baseline, and at 1 and 3 months. Peripheral blood mononuclear cells were isolated and the populations of forkhead box P3-positive Treg cells was analyzed by flow cytometry. The levels of Treg-associated cytokines, interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-ß1), were measured by enzyme-linked immunosorbent assays. RESULTS: Serum VD3 levels of the VD3-treated group were significantly increased at 1 (p=0.017) and 3 months (p<0.001) compared to the untreated control group. The mean percentage of Tregs was maintained between 1 and 3 months in the VD3-treated group. At 3 months, the untreated group had significantly lower Treg levels than the VD3-treated group (p=0.043). Serum IL-10 levels of the VD3-treated group were statistically increased at 1 month compared to the control group (p=0.032). No significant difference in serum TGF-ß1 levels was observed between the two groups. However, the TGF-ß1 level in the VD3-treated group at 1 month was lower than that of the control. CONCLUSION: Our findings suggest that VD3 supplementation can maintain immune responses in the early stages of CRC, helping to control Treg function. Therefore, VD3 should be supplemented to maintain immune homeostasis, especially in patients with vitamin D deficiency.


Assuntos
Colecalciferol , Neoplasias Colorretais , Linfócitos T Reguladores , Humanos , Colecalciferol/administração & dosagem , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/cirurgia , Suplementos Nutricionais , Homeostase , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologia
9.
Nihon Yakurigaku Zasshi ; 158(1): 89-100, 2023.
Artigo em Japonês | MEDLINE | ID: mdl-36596498

RESUMO

Andexanet alfa is a modified recombinant human factor Xa (FXa) that was designed to serve as a binding target for FXa inhibitors as decoy protein. It sequesters FXa inhibitors from binding to endogenous FXa, thereby reversing anticoagulant effect of FXa inhibitors. Andexanet alfa has been approved in March 2022 in Japan for patients with life-threatening or uncontrolled bleeding while on treatment with a FXa inhibitor, apixaban, rivaroxaban, or edoxaban tosilate hydrate. It is administered via two dosing regimens, based on the type of FXa inhibitor, dose, and time since the last dose. In nonclinical studies, andexanet alfa significantly inhibited bleeding induced by FXa inhibitors in animal bleeding models. In the development for Japanese patients, the following two clinical studies have been conducted to confirm the efficacy and safety. First, safety and the reversal effect of andexanet alfa on the FXa inhibitor-mediated anticoagulant activity in healthy adults were confirmed in the overseas phase 2 study including Japanese subjects. Next, the reversal effect of andexanet alfa on the anticoagulation activity and the hemostasis were demonstrated in patients with acute major bleeding while on FXa inhibitor treatment in the global phase 3b/4 study (ANNEXA-4 study). The subgroup analysis of Japanese population showed that the efficacy and safety results were consistent with those of overall population. Andexanet alfa is the first approved reversal agent for FXa inhibitors in Japan and is expected to contribute to the improvement of prognosis in patients with fatal and/or uncontrolled bleeding by timely reversing anticoagulant effect of FXa inhibitors.


Assuntos
Inibidores do Fator Xa , Fator Xa , Hemorragia , Proteínas Recombinantes , Adulto , Animais , Humanos , Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Injeções Intravenosas , Proteínas Recombinantes/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Fase IV como Assunto
10.
Trials ; 24(1): 2, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36597163

RESUMO

BACKGROUND: Oral chloral hydrate is widely used in pediatric sedation. Intranasal dexmedetomidine has been increasingly used for pediatric sedation; however, its improvement is warranted. The combination of dexmedetomidine with ketamine can improve onset and hemodynamic stability while maintaining sedative efficacy. This study aims to determine the efficacy and safety of intranasal combination of dexmedetomidine and ketamine compared to oral chloral hydrate. METHODS: This is a prospective, parallel-arm, single-blinded, two-center, superiority randomized controlled trial with 1:1 allocation, designed to compare the effects of intranasal combination of dexmedetomidine and ketamine with those of oral chloral hydrate. We shall enroll 136 patients aged < 7 years old in this study. Prior to the procedure, we shall randomize each patient into the control group (oral chloral hydrate 50 mg/kg) or study group (intranasal dexmedetomidine 2 µg/kg and ketamine 3 mg/kg). The primary outcome will be the rate of achieving an adequate sedation level (6-point Pediatric Sedation State Scale 1, 2, or 3) within 15 min. In addition, we shall measure the sedation time, sedation failure rate, completion of procedure, adverse events, patient acceptance, and physician satisfaction. DISCUSSION: This study will provide evidence of the efficacy and safety of the intranasal combination of dexmedetomidine and ketamine in comparison with oral chloral hydrate. TRIAL REGISTRATION: ClinicalTrials.gov , NCT04820205. Registered on 19th March 2021.


Assuntos
Dexmedetomidina , Ketamina , Criança , Humanos , Administração Intranasal , Administração Oral , Hidrato de Cloral/administração & dosagem , Dexmedetomidina/administração & dosagem , Hipnóticos e Sedativos/administração & dosagem , Ketamina/administração & dosagem , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Combinação de Medicamentos
13.
Cochrane Database Syst Rev ; 1: CD004917, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645238

RESUMO

BACKGROUND: Infantile esotropia (IE) is the inward deviation of the eye. Various aspects of the clinical management of IE are unclear; mainly, the most effective type of intervention and the age at intervention. OBJECTIVES: To examine the effectiveness and optimal timing of surgical and non-surgical treatment options for IE to improve ocular alignment and achieve or allow the development of binocular single vision. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, one other database, and three trials registers (November 2021). We did not use any date or language restrictions in the electronic searches for trials.  SELECTION CRITERIA: We included randomized trials and quasi-randomized trials comparing any surgical or non-surgical intervention for IE. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and graded the certainty of the body of evidence for six outcomes using the GRADE classification. MAIN RESULTS: We included two studies with 234 children with IE. The first study enrolled 110 children (mean age 26.9 ± 14.5 months) with an onset of esotropia before six months of age, and large-angle IE defined as esotropia of ≥ 40 prism diopters. It was conducted between 2015 and 2018 in a tertiary care hospital in South Africa. It compared a maximum of three botulinum toxin injections with surgical intervention of bimedial rectus muscle recession, and children were followed for six months. There were limitations in study design and implementation; the risk of bias was high, or we had some concerns for most domains.  Surgery may increase the incidence of treatment success, defined as orthophoria or residual esotropia of ≤ 10 prism diopters, compared with botulinum toxin injections, but the evidence was very uncertain (risk ratio (RR) of treatment success 1.88, 95% confidence interval (CI) 1.27 to 2.77; 1 study, 101 participants; very low-certainty evidence). The results should be read with caution because 23 children with > 60 prism diopters at baseline in the surgery arm also received botulinum toxin at the time of surgery to augment the recessions. There was no evidence of an important difference between surgery and botulinum toxin injections for over-correction (> 10 prism diopters) of deviation (RR 0.29, 95% CI 0.06 to 1.37; 1 study, 101 participants; very low-certainty evidence), or additional interventions required (RR 0.66, 95% CI 0.36 to 1.19; 1 study, 101 participants; very low-certainty evidence). No major complications of surgery were observed in the surgery arm, while children experienced various complications in the botulinum toxin arm, including partial transient ptosis in 9 (16.7%) children, transient vertical deviation in 3 (5.6%) children, and consecutive exotropia in 13 (24.1%) children. No other outcome data for our prespecified outcomes were reported.  The second study enrolled 124 children with onset of esotropia before one year of age in 12 university hospitals in Germany and the Netherlands. It compared bilateral recession with unilateral recession surgeries, and followed children for three months postoperatively. Very low-certainty evidence suggested that there was no evidence of an important difference between bilateral and unilateral surgeries in the presence of binocular vision (numbers with event unclear, P = 0.35), and over-correction (RR of having exotropia 1.09, 95% CI 0.45 to 2.63; 1 study, 118 participants). Dissociated vertical deviation, latent nystagmus, or both were observed in 8% to 21% of participants. AUTHORS' CONCLUSIONS: Medial rectus recessions may increase the incidence of treatment success compared with botulinum toxin injections alone, but the evidence was very uncertain. No evidence of important difference was found between bilateral surgery and unilateral surgery.  Due to insufficient evidence, it was not possible to resolve the controversies regarding type of surgery, non-surgical intervention, or age of intervention in this review. There is clearly a need to conduct good quality trials in these areas to improve the evidence base for the management of IE.


Assuntos
Toxinas Botulínicas , Esotropia , Pré-Escolar , Humanos , Lactente , Toxinas Botulínicas/administração & dosagem , Toxinas Botulínicas/uso terapêutico , Esotropia/cirurgia , Esotropia/tratamento farmacológico , Exotropia/etiologia , Estrabismo/etiologia , Resultado do Tratamento , Procedimentos Cirúrgicos Oftalmológicos/efeitos adversos , Procedimentos Cirúrgicos Oftalmológicos/métodos
14.
Cochrane Database Syst Rev ; 1: CD015016, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645224

RESUMO

BACKGROUND: Postoperative pain clinical management in neonates has always been a challenging medical issue. Worldwide, several systemic opioid regimens are available for pediatricians, neonatologists, and general practitioners to control pain in neonates undergoing surgical procedures. However, the most effective and safe regimen is still unknown in the current body of literature. OBJECTIVES: To determine the effects of different regimens of systemic opioid analgesics in neonates submitted to surgery on all-cause mortality, pain, and significant neurodevelopmental disability. Potentially assessed regimens might include: different doses of the same opioid, different routes of administration of the same opioid, continuous infusion versus bolus administration, or 'as needed' administration versus 'as scheduled' administration. SEARCH METHODS: Searches were conducted in June 2022 using the following databases: Cochrane Central Register of Controlled Trials [CENTRAL], PubMed, and CINAHL. Trial registration records were identified via CENTRAL and an independent search of the ISRCTN registry. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, and cross-over controlled trials evaluating systemic opioid regimens' effects on postoperative pain in neonates (pre-term or full-term). We considered suitable for inclusion: I) studies evaluating different doses of the same opioid; 2) studies evaluating different routes of administration of the same opioid; 3) studies evaluating the effectiveness of continuous infusion versus bolus infusion; and 4) studies establishing an assessment of an 'as needed' administration versus 'as scheduled' administration. DATA COLLECTION AND ANALYSIS: According to Cochrane methods, two investigators independently screened retrieved records, extracted data, and appraised the risk of bias. We stratified meta-analysis by the type of intervention: studies evaluating the use of opioids for postoperative pain in neonates through continuous infusion versus bolus infusion and studies assessing the 'as needed' administration versus 'as scheduled' administration. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD), standardized mean difference (SMD), median, and interquartile range (IQR) for continuous data. Finally, we used the GRADEpro approach for primary outcomes to evaluate the quality of the evidence across included studies. MAIN RESULTS: In this review, we included seven randomized controlled clinical trials (504 infants) from 1996 to 2020. We identified no studies comparing different doses of the same opioid, or different routes. The administration of continuous opioid infusion versus bolus administration of opioids was evaluated in six studies, while one study compared 'as needed' versus 'as scheduled' administration of morphine given by parents or nurses. Overall, the effectiveness of continuous infusion of opioids over bolus infusion as measured by the visual analog scale (MD 0.00, 95% confidence interval (CI) -0.23 to 0.23; 133 participants, 2 studies; I² = 0); or using the COMFORT scale (MD -0.07, 95% CI -0.89 to 0.75; 133 participants, 2 studies; I² = 0), remains unclear due to study designs' limitations, such as the unclear risk of attrition, reporting bias, and imprecision among reported results (very low certainty of the evidence).  None of the included studies reported data on other clinically important outcomes such as all-cause mortality rate during hospitalization, major neurodevelopmental disability, the incidence of severe retinopathy of prematurity or intraventricular hemorrhage, and cognitive- and educational-related outcomes.  AUTHORS' CONCLUSIONS: Limited evidence is available on continuous infusion compared to intermittent boluses of systemic opioids. We are uncertain whether continuous opioid infusion reduces pain compared with intermittent opioid boluses; none of the studies reported the other primary outcomes of this review, i.e. all-cause mortality during initial hospitalization, significant neurodevelopmental disability, or cognitive and educational outcomes among children older than five years old. Only one small study reported on morphine infusion with parent- or nurse-controlled analgesia.


Assuntos
Analgésicos Opioides , Morfina , Dor Pós-Operatória , Humanos , Recém-Nascido , Analgesia/métodos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Protocolos Clínicos , Morfina/administração & dosagem , Morfina/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico
15.
N Engl J Med ; 388(3): 228-239, 2023 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-36652354

RESUMO

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma , Inibidores de Proteínas Quinases , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Idoso , Humanos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Qualidade de Vida , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Antineoplásicos/administração & dosagem
16.
BMC Cardiovasc Disord ; 23(1): 16, 2023 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635657

RESUMO

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery, and its occurrence is closely related to inflammation. This paper intends to apply meta-analysis to investigate the effect of glucocorticoids on POAF. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched using the internationally recognized systematic evaluation and retrieval strategy. Two review authors independently selected relevant studies and extracted data based on the Cochrane handbook for systematic reviews of interventions approach. Stata 17 was used for data analysis. In the subgroup analysis, we grouped the participant data according to differences in glucocorticoids dose and type of surgery. At the same time, we also conducted a meta-analysis on the possible infection and gastrointestinal injury caused by glucocorticoids use. RESULTS: 27 studies and 14,442 patients were finally included. Results from the random-effects model indicated that the incidence of POAF was lower in glucocorticoid group (RR 0.80, 95% CI 0.71-0.92, P = 0.001). According to the subgroup analysis result, low doses of glucocorticoids reduced the incidence of POAF (RR 0.81, 95% CI 0.71-0.92, P = 0.001). The effect of high doses glucocorticoids on the POAF was not statistically significant (RR 0.81, 95% CI 0.56-1.19, P = 0.286). In the coronary artery bypass grafting (CABG) subgroup, the glucocorticoids reduced the incidence of POAF (RR 0.71, 95% CI 0.58-0.87, P = 0.001). In the CABG OR Valvular Surgery group, the effect of glucocorticoids on POAF was not statistically significant (RR 0.88, 95% CI 0.75-1.03, P = 0.108). 15 studies documented postoperative complications of infection, two studies were excluded from the system because the end point event was 0, and meta-analysis showed no increased risk of infection from glucocorticoid use (RR 0.85, 95% CI 0.68-1.06, P = 0.158). Eight studies documented the effects of glucocorticoids on gastrointestinal diseases, and meta-analysis showed no differences between the two groups (RR 1.12, 95% CI 0.83-1.50, P = 0.450). CONCLUSION: The use of glucocorticoids can reduce the incidence of POAF. The subgroup analysis result showed that low-dose glucocorticoids were more effective than high-dose glucocorticoids in inhibiting POAF. The use of glucocorticoids in CABG alone can better inhibit the occurrence of POAF. The effects of glucocorticoids on infection and gastrointestinal injury were not statistically significant. REVIEW REGISTRATION: PROSPERO, CRD42022304521.


Assuntos
Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Glucocorticoides , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ponte de Artéria Coronária/efeitos adversos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Fatores de Risco
17.
Mol Cells ; 46(1): 41-47, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36697236

RESUMO

The rapid development of mRNA vaccines has contributed to the management of the current coronavirus disease 2019 (COVID-19) pandemic, suggesting that this technology may be used to manage future outbreaks of infectious diseases. Because the antigens targeted by mRNA vaccines can be easily altered by simply changing the sequence present in the coding region of mRNA structures, it is more appropriate to develop vaccines, especially during rapidly developing outbreaks of infectious diseases. In addition to allowing rapid development, mRNA vaccines have great potential in inducing successful antigen-specific immunity by expressing target antigens in cells and simultaneously triggering immune responses. Indeed, the two COVID-19 mRNA vaccines approved by the U.S. Food and Drug Administration have shown significant efficacy in preventing infections. The ability of mRNAs to produce target proteins that are defective in specific diseases has enabled the development of options to treat intractable diseases. Clinical applications of mRNA vaccines/therapeutics require strategies to safely deliver the RNA molecules into targeted cells. The present review summarizes current knowledge about mRNA vaccines/ therapeutics, their clinical applications, and their delivery strategies.


Assuntos
Vacinas contra COVID-19 , Vacinas de mRNA , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/genética , Vacinas de mRNA/administração & dosagem , Fases de Leitura Aberta , Pandemias , Estados Unidos
18.
BMC Cardiovasc Disord ; 23(1): 45, 2023 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-36698055

RESUMO

BACKGROUND: Insertable cardiac monitors (ICMs) are a clinically effective means of detecting atrial fibrillation (AF) in high-risk patients, and guiding the initiation of non-vitamin K oral anticoagulants (NOACs). Their cost-effectiveness from a US clinical payer perspective is not yet known. The objective of this study was to evaluate the cost-effectiveness of ICMs compared to standard of care (SoC) for detecting AF in patients at high risk of stroke (CHADS2 ≥ 2), in the US. METHODS: Using patient data from the REVEAL AF trial (n = 393, average CHADS2 score = 2.9), a Markov model estimated the lifetime costs and benefits of detecting AF with an ICM or with SoC (specifically intermittent use of electrocardiograms and 24-h Holter monitors). Ischemic and hemorrhagic strokes, intra- and extra-cranial hemorrhages, and minor bleeds were modelled. Diagnostic and device costs, costs of treating stroke and bleeding events and medical therapy-specifically costs of NOACs were included. Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3% per annum, in line with standard practice in the US setting. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken. RESULTS: Lifetime per-patient cost for ICM was $31,116 versus $25,330 for SoC. ICMs generated a total of 7.75 QALYs versus 7.59 for SoC, with 34 fewer strokes projected per 1000 patients. The model estimates a number needed to treat of 29 per stroke avoided. The incremental cost-effectiveness ratio was $35,528 per QALY gained. ICMs were cost-effective in 75% of PSA simulations, using a $50,000 per QALY threshold, and a 100% probability of being cost-effective at a WTP threshold of $150,000 per QALY. CONCLUSIONS: The use of ICMs to identify AF in a high-risk population is likely to be cost-effective in the US healthcare setting.


Assuntos
Fibrilação Atrial , Humanos , Administração Oral , Anticoagulantes/administração & dosagem , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Análise Custo-Benefício , Hemorragia , Anos de Vida Ajustados por Qualidade de Vida , Acidente Vascular Cerebral , Ensaios Clínicos como Assunto
19.
Clin J Am Soc Nephrol ; 18(1): 130-145, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36719162

RESUMO

Treatment of patients with diabetes and CKD includes optimizing glycemic control using lifestyle modifications and drugs that safely control glycemia and improve clinical kidney and cardiovascular disease outcomes. However, patients with advanced CKD, defined as eGFR <30 ml/min per 1.73 m2 or kidney disease treated with dialysis, have limitations to the use of some preferred glucose-lowering medications, are often treated with insulin, and experience high rates of severe hypoglycemia. Moreover, hemoglobin A1c accuracy decreases as GFR deteriorates. Hence, there is a need for better glycemic monitoring tools. Continuous glucose monitoring allows for 24-hour glycemic monitoring to understand patterns and the effects of lifestyle and medications. Real-time continuous glucose monitoring can be used to guide the administration of insulin and noninsulin therapies. Continuous glucose monitoring can overcome the limitations of self-monitored capillary glucose testing and hemoglobin A1c and has been shown to prevent hypoglycemic excursions in some populations. More data are needed to understand whether similar benefits can be obtained for patients with diabetes and advanced CKD. This review provides an updated approach to management of glycemia in advanced CKD, focusing on the role of continuous glucose monitoring in this high-risk population.


Assuntos
Automonitorização da Glicemia , Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Hipoglicemiantes , Insuficiência Renal Crônica , Humanos , Glicemia/análise , Automonitorização da Glicemia/métodos , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Insulina/uso terapêutico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/terapia
20.
N Engl J Med ; 388(4): 310-318, 2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36720133

RESUMO

BACKGROUND: Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS: We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS: In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS: In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).


Assuntos
Coagulantes , Fator VIII , Hemofilia A , Hemorragia , Humanos , Esquema de Medicação , Meia-Vida , Hemofilia A/complicações , Hemofilia A/tratamento farmacológico , Hemorragia/tratamento farmacológico , Hemorragia/etiologia , Hemorragia/prevenção & controle , Fator de von Willebrand/administração & dosagem , Fator de von Willebrand/uso terapêutico , Quimioprevenção , Fator VIII/administração & dosagem , Fator VIII/uso terapêutico , Coagulantes/administração & dosagem , Coagulantes/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico
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