RESUMO
Wild waterfowl serve as a reservoir of some astroviruses. Fecal samples from wild waterfowl collected at Hong Kong's Marshes were tested using pan-astrovirus reverse transcription-PCR. Positive samples underwent subsequent host identification using DNA barcoding. Based on deduced partial sequences, noteworthy samples from three astrovirus groups (mammalian, avian and unclassified astroviruses) were further analyzed by next-generation sequencing. One sample of Avastrovirus 4 clade, MP22-196, had a nearly complete genome identified. The results of ORF2 phylogenetic analysis and genetic distance analysis indicate that Avastrovirus 4 is classified as a distinct subclade within Avastrovirus. MP22-196 has typical astrovirus genome characteristics. The unique characteristics and potential differences of this genome, compared to other avian astrovirus sequences, involve the identification of a modified sgRNA sequence situated near the ORF2 start codon, which precedes the ORF1b stop codon. Additionally, the 3' UTR of MP22-196 is shorter than other avian astroviruses. This study expands our understanding of the Avastrovirus 4 clade.
Assuntos
Infecções por Astroviridae , Aves , Fezes , Variação Genética , Genoma Viral , Filogenia , Animais , Hong Kong , Aves/virologia , Fezes/virologia , Infecções por Astroviridae/veterinária , Infecções por Astroviridae/virologia , Animais Selvagens/virologia , Doenças das Aves/virologia , Sequenciamento de Nucleotídeos em Larga Escala , Avastrovirus/genética , Avastrovirus/classificação , Avastrovirus/isolamento & purificação , RNA Viral/genética , Fases de Leitura Aberta , Astroviridae/genética , Astroviridae/isolamento & purificação , Astroviridae/classificaçãoRESUMO
BACKGROUND: COVID-19 vaccines are authorized for use in children in the United States; real-world assessment of vaccine effectiveness in children is needed. This study's objective was to estimate the effectiveness of receiving a complete primary series of monovalent BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine in US children. METHODS: This cohort study identified children aged 5-17 years vaccinated with BNT162b2 matched with unvaccinated children. Participants and BNT162b2 vaccinations were identified in Optum and CVS Health insurance administrative claims databases linked with Immunization Information System (IIS) COVID-19 vaccination records from 16 US jurisdictions between December 11, 2020, and May 31, 2022 (end date varied by database and IIS). Vaccinated children were followed from their first BNT162b2 dose and matched to unvaccinated children on calendar date, US county of residence, and demographic and clinical factors. Censoring occurred if vaccinated children failed to receive a timely dose 2 or if unvaccinated children received any dose. Two COVID-19 outcome definitions were evaluated: COVID-19 diagnosis in any medical setting and COVID-19 diagnosis in hospitals/emergency departments (EDs). Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox proportional hazards models, and vaccine effectiveness (VE) was estimated as 1 minus HR. VE was estimated overall, within age subgroups, and within variant-specific eras. Sensitivity, negative control, and quantitative bias analyses evaluated various potential biases. RESULTS: There were 453,655 eligible vaccinated children one-to-one matched to unvaccinated comparators (mean age 12 years; 50% female). COVID-19 hospitalizations/ED visits were rare in children, regardless of vaccination status (Optum, 41.2 per 10,000 person-years; CVS Health, 44.1 per 10,000 person-years). Overall, vaccination was associated with reduced incidence of any medically diagnosed COVID-19 (meta-analyzed VE = 38% [95% CI, 36-40%]) and hospital/ED-diagnosed COVID-19 (meta-analyzed VE = 61% [95% CI, 56-65%]). VE estimates were lowest among children 5-11 years and during the Omicron-variant era. CONCLUSIONS: Receipt of a complete BNT162b2 vaccine primary series was associated with overall reduced medically diagnosed COVID-19 and hospital/ED-diagnosed COVID-19 in children; observed VE estimates differed by age group and variant era. REGISTRATION: The study protocol was publicly posted on the BEST Initiative website ( https://bestinitiative.org/wp-content/uploads/2022/03/C19-VX-Effectiveness-Protocol_2022_508.pdf ).
Assuntos
Vacina BNT162 , COVID-19 , Eficácia de Vacinas , Humanos , Vacina BNT162/administração & dosagem , Criança , Pré-Escolar , Estados Unidos/epidemiologia , Feminino , Masculino , COVID-19/prevenção & controle , COVID-19/epidemiologia , Adolescente , Eficácia de Vacinas/estatística & dados numéricos , Estudos de Coortes , Vacinas contra COVID-19/administração & dosagem , SARS-CoV-2 , Vacinação/estatística & dados numéricosRESUMO
Importance: Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed. Objective: To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% concentration for delaying the onset of myopia. Design, Setting, and Participants: This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022. Interventions: Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years. Main Outcomes and Measures: The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at least -0.50 D in either eye) and the percentage of participants with fast myopic shift (spherical equivalent myopic shift of at least 1.00 D). Results: Of the 474 randomized patients (mean age, 6.8 years; 50% female), 353 (74.5%) completed the trial. The 2-year cumulative incidence of myopia in the 0.05% atropine, 0.01% atropine, and placebo groups were 28.4% (33/116), 45.9% (56/122), and 53.0% (61/115), respectively, and the percentages of participants with fast myopic shift at 2 years were 25.0%, 45.1%, and 53.9%. Compared with the placebo group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 24.6% [95% CI, 12.0%-36.4%]) and percentage of patients with fast myopic shift (difference, 28.9% [95% CI, 16.5%-40.5%]). Compared with the 0.01% atropine group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 17.5% [95% CI, 5.2%-29.2%]) and percentage of patients with fast myopic shift (difference, 20.1% [95% CI, 8.0%-31.6%]). The 0.01% atropine and placebo groups were not significantly different in 2-year cumulative myopia incidence or percentage of patients with fast myopic shift. Photophobia was the most common adverse event and was reported by 12.9% of participants in the 0.05% atropine group, 18.9% in the 0.01% atropine group, and 12.2% in the placebo group in the second year. Conclusions and Relevance: Among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years. There was no significant difference between 0.01% atropine and placebo. Further research is needed to replicate the findings, to understand whether this represents a delay or prevention of myopia, and to assess longer-term safety. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-15006883.
Assuntos
Atropina , Miopia , Criança , Feminino , Humanos , Masculino , Atropina/administração & dosagem , Atropina/efeitos adversos , Atropina/uso terapêutico , Progressão da Doença , Incidência , Midriáticos/efeitos adversos , Miopia/diagnóstico , Miopia/prevenção & controle , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/efeitos adversos , Soluções Oftálmicas/uso terapêutico , Refração Ocular , Idade de Início , Método Duplo-Cego , Pré-EscolarRESUMO
OBJECTIVES: Ventricular assist devices (VADs) are increasingly used in pediatric heart failure as bridges to heart transplantation, although 25% will die with VADs. Family experiences in this population are not well-described. The objective is to understand bereaved families' perspectives on VAD and end-of-life decision-making. DESIGN: Semistructured interviews with bereaved caregivers of pediatric VAD patients. SETTING: Tertiary children's hospital. PATIENTS: Families of six pediatric VAD patients who died from 2014 to 2020. INTERVENTIONS: Not available. MEASUREMENTS AND MAIN RESULTS: Applying a grounded theory framework, interviews were coded by two independent readers using qualitative software. Themes were discussed in iterative multidisciplinary meetings. Participants were interviewed at a median 2.4 years after their child died. Three major themes emerged: 1) "lack of regret" for VAD implantation despite the outcome; 2) "caregiver-child accord" (via patient's verbal assent or physical cues) at implantation and end-of-life was important in family decision-making; and 3) development of a "local surrogate family" (medical team and peer families) provided powerful support. CONCLUSIONS: Bereaved families' perspectives provide insight into quality decision-making for major interventions and end-of-life care in pediatric patients with chronic illness who face decisions regarding technology dependence.
Assuntos
Insuficiência Cardíaca , Coração Auxiliar , Assistência Terminal , Criança , Humanos , Cuidadores , Insuficiência Cardíaca/cirurgia , MorteRESUMO
The contributory roles of vitamin D in ocular and visual health have long been discussed, with numerous studies pointing to the adverse effects of vitamin D deficiency. In this paper, we provide a systematic review of recent findings on the association between vitamin D and different ocular diseases, including myopia, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), dry eye syndrome (DES), thyroid eye disease (TED), uveitis, retinoblastoma (RB), cataract, and others, from epidemiological, clinical and basic studies, and briefly discuss vitamin D metabolism in the eye. We searched two research databases for articles examining the association between vitamin D deficiency and different ocular diseases. One hundred and sixty-two studies were found. There is evidence on the association between vitamin D and myopia, AMD, DR, and DES. Overall, 17 out of 27 studies reported an association between vitamin D and AMD, while 48 out of 54 studies reported that vitamin D was associated with DR, and 25 out of 27 studies reported an association between vitamin D and DES. However, the available evidence for the association with other ocular diseases, such as glaucoma, TED, and RB, remains limited.
Assuntos
Retinopatia Diabética , Glaucoma , Degeneração Macular , Miopia , Deficiência de Vitamina D , Retinopatia Diabética/complicações , Olho , Glaucoma/complicações , Glaucoma/etiologia , Humanos , Degeneração Macular/complicações , Degeneração Macular/etiologia , Vitamina D , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , VitaminasRESUMO
BACKGROUND: Human spillovers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to dogs and the emergence of a highly contagious avian-origin H3N2 canine influenza virus have raised concerns on the role of dogs in the spread of SARS-CoV-2 and their susceptibility to existing human and avian influenza viruses, which might result in further reassortment. METHODS: We systematically studied the replication kinetics of SARS-CoV-2, SARS-CoV, influenza A viruses of H1, H3, H5, H7, and H9 subtypes, and influenza B viruses of Yamagata-like and Victoria-like lineages in ex vivo canine nasal cavity, soft palate, trachea, and lung tissue explant cultures and examined ACE2 and sialic acid (SA) receptor distribution in these tissues. RESULTS: There was limited productive replication of SARS-CoV-2 in canine nasal cavity and SARS-CoV in canine nasal cavity, soft palate, and lung, with unexpectedly high ACE2 levels in canine nasal cavity and soft palate. Canine tissues were susceptible to a wide range of human and avian influenza viruses, which matched with the abundance of both human and avian SA receptors. CONCLUSIONS: Existence of suitable receptors and tropism for the same tissue foster virus adaptation and reassortment. Continuous surveillance in dog populations should be conducted given the many chances for spillover during outbreaks.
Assuntos
COVID-19/virologia , Vírus da Influenza A/fisiologia , Pulmão/virologia , Cavidade Nasal/virologia , SARS-CoV-2/fisiologia , Traqueia/virologia , Tropismo Viral/fisiologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , Cães , Humanos , Influenza Humana/metabolismo , Influenza Humana/virologia , Pulmão/metabolismo , Cavidade Nasal/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Traqueia/metabolismoRESUMO
The numerous global outbreaks and continuous reassortments of highly pathogenic avian influenza (HPAI) A(H5N6/H5N8) clade 2.3.4.4 viruses in birds pose a major risk to the public health. We investigated the tropism and innate host responses of 5 recent HPAI A(H5N6/H5N8) avian isolates of clades 2.3.4.4b, e, and h in human airway organoids and primary human alveolar epithelial cells. The HPAI A(H5N6/H5N8) avian isolates replicated productively but with lower competence than the influenza A(H1N1)pdm09, HPAI A(H5N1), and HPAI A(H5N6) isolates from humans in both or either models. They showed differential cellular tropism in human airway organoids; some infected all 4 major epithelial cell types: ciliated cells, club cells, goblet cells, and basal cells. Our results suggest zoonotic potential but low transmissibility of the HPAI A(H5N6/H5N8) avian isolates among humans. These viruses induced low levels of proinflammatory cytokines/chemokines, which are unlikely to contribute to the pathogenesis of severe disease.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A Subtipo H5N8 , Influenza Aviária , Influenza Humana , Animais , Aves , Humanos , Virus da Influenza A Subtipo H5N1/genética , Influenza Aviária/epidemiologia , Medição de RiscoRESUMO
Huanglongbing (HLB) is the most devastating citrus disease in the world. Almost all commercial citrus varieties are susceptible to the causal bacterium, Candidatus Liberibacter asiaticus (CLas), which is transmitted by the Asian citrus psyllid (ACP). Currently, there are no effective management strategies to control HLB. HLB-tolerant traits have been reported in some citrus relatives and citrus hybrids, which offer a direct pathway for discovering natural defence regulators to combat HLB. Through comparative analysis of small RNA profiles and target gene expression between an HLB-tolerant citrus hybrid (Poncirus trifoliata × Citrus reticulata) and a susceptible citrus variety, we identified a panel of candidate defence regulators for HLB-tolerance. These regulators display similar expression patterns in another HLB-tolerant citrus relative, with a distinct genetic and geographic background, the Sydney hybrid (Microcitrus virgata). Because the functional validation of candidate regulators in tree crops is always challenging, we developed a novel rapid functional screening method, using a C. Liberibacter solanacearum (CLso)/potato psyllid/Nicotiana benthamiana interaction system to mimic the natural transmission and infection circuit of the HLB complex. When combined with efficient virus-induced gene silencing in N. benthamiana, this innovative and cost-effective screening method allows for rapid identification and functional characterization of regulators involved in plant immune responses against HLB, such as the positive regulator BRCA1-Associated Protein, and the negative regulator Vascular Associated Death Protein.
Assuntos
Citrus , Hemípteros , Poncirus , Rhizobiaceae , Animais , Citrus/genética , Doenças das PlantasRESUMO
PURPOSE: Strategies to identify and validate acute myocardial infarction (AMI) and stroke in primary-care electronic records may impact effect measures, but to an unknown extent. Additionally, the validity of cardiovascular risk factors that could act as confounders in studies on those endpoints has not been thoroughly assessed in the United Kingdom Clinical Practice Research Datalink's (CPRD's) GOLD database. We explored the validity of algorithms to identify cardiovascular outcomes and risk factors and evaluated different outcome-identification strategies using these algorithms for estimation of adjusted incidence rate ratios (IRRs). METHODS: First, we identified AMI, stroke, smoking, obesity, and menopausal status in a cohort treated for overactive bladder by applying computerized algorithms to primary care medical records (2004-2012). We validated these cardiovascular outcomes and risk factors with physician questionnaires (gold standard for this analysis). Second, we estimated IRRs for AMI and stroke using algorithm-identified and questionnaire-confirmed cases, comparing these with IRRs from cases identified through linkage with hospitalization/mortality data (best estimate). RESULTS: For AMI, the algorithm's positive predictive value (PPV) was >90%. Initial algorithms for stroke performed less well because of inclusion of codes for prevalent stroke; algorithm refinement increased PPV to 80% but decreased sensitivity by 20%. Algorithms for smoking and obesity were considered valid. IRRs based on questionnaire-confirmed cases only were closer to IRRs estimated from hospitalization/mortality data than IRRs from algorithm-identified cases. CONCLUSIONS: AMI, stroke, smoking, obesity, and postmenopausal status can be accurately identified in CPRD. Physician questionnaire-validated AMI and stroke cases yield IRRs closest to the best estimate.
Assuntos
Infarto do Miocárdio , Bases de Dados Factuais , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Valor Preditivo dos Testes , Fatores de Risco , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: Combined cardiothoracic surgery and liver transplantation (cCSLT) recently increasingly has been used. Despite that, liver transplant immediately after cardiothoracic surgery has not been well-characterized. The authors aimed to compare perioperative management and postoperative outcomes between patients undergoing cCSLT and isolated liver transplantation (iLT). DESIGN: A retrospective study. SETTING: University tertiary medical center. PARTICIPANTS: Twenty-five cCSLT patients and 1091 iLT patients at a single institution from 2010 to 2017. INTERVENTIONS: Twenty-five cCSLT patients were compared with 100 randomly selected and 100 propensity-matched iLT patients. MEASUREMENTS AND MAIN RESULTS: All cCSLT patients underwent comprehensive preoperative evaluation by a multidisciplinary team. Of 25 cardiothoracic surgeries, heart transplant (nâ¯=â¯9) was most common, followed by coronary artery bypass grafting (nâ¯=â¯5) and lung transplant (nâ¯=â¯3). Intraoperative management of cCSLT was provided by 2 separate teams, one for cardiothoracic surgery and one for liver transplantation. Patients undergoing cCSLT often required cardiopulmonary bypass, an intra-aortic balloon pump, extracorporeal membrane oxygenation, or cardiac pharmacologic therapies and, additionally, needed more interventions including antifibrinolytic administration, venovenous bypass, massive blood transfusion, and platelet transfusions compared with iLT patients. Ninety-day survival rates were similar in the cCSLT (100%) and iLT groups (random iLT 87% and matched iLT 93%, log-rank test pâ¯=â¯0.089). CONCLUSIONS: Despite having end-stage liver disease and advanced cardiothoracic disorders and experiencing a complex intraoperative course, cCSLT patients had comparable 90-day survival to iLT patients. Comprehensive planning before transplant, optimal patient/donor selection, the multiple-team model, and meticulous intraoperative management are critical to the success of cCSLT.
Assuntos
Transplante de Coração , Transplante de Fígado , Ponte Cardiopulmonar , Ponte de Artéria Coronária , Humanos , Complicações Pós-Operatórias , Estudos Retrospectivos , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: The present review aims to address the feasibility of opioid free anesthesia (OFA). The use of opioids to provide adequate perioperative pain management has been a central practice of anesthesia, and only recently has been challenged. Understanding the goals and challenges of OFA is essential as the approach to intraoperative analgesia and postsurgical management of pain has shifted in response to the opioid epidemic in the United States. RECENT FINDINGS: OFA is an opioid sparing technique, which focuses on multimodal or balanced analgesia, relying on nonopioid adjuncts and regional anesthesia. Enhanced recovery after surgery protocols, often under the auspices of a perioperative pain service, can help guide and promote opioid reduced and OFA, without negatively impacting perioperative pain management or recovery. SUMMARY: The feasibility of OFA is evident. However, there are limitations of this approach that warrant discussion including the potential for adverse drug interactions with multimodal analgesics, the need for providers trained in regional anesthesia, and the management of pain expectations. Additionally, minimizing opioid use perioperatively also requires a change in current prescribing practices. Monitors that can reliably quantify nociception would be helpful in the titration of these analgesics and enable anesthesiologists to achieve the goal in providing personalized perioperative medicine.
Assuntos
Analgesia/métodos , Analgésicos não Narcóticos/uso terapêutico , Analgésicos Opioides/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Analgésicos não Narcóticos/administração & dosagem , Humanos , Manejo da Dor/tendências , Estados UnidosRESUMO
BACKGROUND: Highly pathogenic avian influenza (HPAI)-H7N9 virus arising from low pathogenic avian influenza (LPAI)-H7N9 virus with polybasic amino acid substitutions in the hemagglutinin was detected in 2017. METHODS: We compared the tropism, replication competence, and cytokine induction of HPAI-H7N9, LPAI-H7N9, and HPAI-H5N1 in ex vivo human respiratory tract explants, in vitro culture of human alveolar epithelial cells (AECs) and pulmonary microvascular endothelial cells (HMVEC-L). RESULTS: Replication competence of HPAI- and LPAI-H7N9 were comparable in ex vivo cultures of bronchus and lung. HPAI-H7N9 predominantly infected AECs, whereas limited infection was observed in bronchus. The reduced tropism of HPAI-H7N9 in bronchial epithelium may explain the lack of human-to-human transmission despite a number of mammalian adaptation markers. Apical and basolateral release of virus was observed only in HPAI-H7N9- and H5N1-infected AECs regardless of infection route. HPAI-H7N9, but not LPAI-H7N9 efficiently replicated in HMVEC-L. CONCLUSIONS: Our findings demonstrate that a HPAI-H7N9 virus efficiently replicating in ex vivo cultures of human bronchus and lung. The HPAI-H7N9 was more efficient at replicating in human AECs and HMVEC-L than LPAI-H7N9 implying that endothelial tropism may involve in pathogenesis of HPAI-H7N9 disease.
Assuntos
Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Humana/virologia , Sistema Respiratório/virologia , Tropismo Viral , Replicação Viral , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/virologia , Brônquios/imunologia , Brônquios/virologia , Células Cultivadas , Citocinas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/virologia , Humanos , Subtipo H7N9 do Vírus da Influenza A/imunologia , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Humana/imunologia , Pulmão/imunologia , Pulmão/virologia , Sistema Respiratório/imunologia , Medição de RiscoRESUMO
Despite causing regular seasonal epidemics with substantial morbidity, mortality and socioeconomic burden, there is still a lack of research into influenza B viruses (IBVs). In this study, we provide for the first time a systematic investigation on the tropism, replication kinetics and pathogenesis of IBVs in the human respiratory tract.Physiologically relevant ex vivo explant cultures of human bronchus and lung, human airway organoids, and in vitro cultures of differentiated primary human bronchial epithelial cells and type-I-like alveolar epithelial cells were used to study the cellular and tissue tropism, replication competence and induced innate immune response of 16 IBV strains isolated from 1940 to 2012 in comparison with human seasonal influenza A viruses (IAVs), H1N1 and H3N2. IBVs from the diverged Yamagata- and Victoria-like lineages and the earlier undiverged period were included.The majority of IBVs replicated productively in human bronchus and lung with similar competence to seasonal IAVs. IBVs infected a variety of cell types, including ciliated cells, club cells, goblet cells and basal cells, in human airway organoids. Like seasonal IAVs, IBVs are low inducers of pro-inflammatory cytokines and chemokines. Most results suggested a higher preference for the conducting airway than the lower lung and strain-specific rather than lineage-specific pathogenicity of IBVs.Our results highlighted the non-negligible virulence of IBVs which require more attention and further investigation to alleviate the disease burden, especially when treatment options are limited.
Assuntos
Vírus da Influenza B/fisiologia , Organoides/patologia , Organoides/virologia , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Tropismo Viral , Animais , Brônquios/patologia , Diferenciação Celular , Cães , Células Epiteliais/virologia , Eritrócitos/citologia , Humanos , Imunidade Inata , Imuno-Histoquímica , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Concentração Inibidora 50 , Pulmão/patologia , Células Madin Darby de Rim Canino , Técnicas de Cultura de Órgãos , PerusRESUMO
PURPOSE: The purpose of the study is to evaluate the effectiveness of risk minimization measures-labeling changes and communication to health care professionals-recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. METHODS: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002-2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high-dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. RESULTS: We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high-dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). CONCLUSIONS: This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.
Assuntos
Doenças Cardiovasculares/epidemiologia , Cilostazol/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Serviços Preventivos de Saúde/organização & administração , Fumar/epidemiologia , Idoso , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/prevenção & controle , Cilostazol/administração & dosagem , Bases de Dados Factuais/estatística & dados numéricos , Relação Dose-Resposta a Droga , Rotulagem de Medicamentos , Feminino , Alemanha/epidemiologia , Implementação de Plano de Saúde/estatística & dados numéricos , Humanos , Claudicação Intermitente/tratamento farmacológico , Claudicação Intermitente/etiologia , Claudicação Intermitente/prevenção & controle , Masculino , Inibidores da Agregação Plaquetária/administração & dosagem , Prevalência , Serviços Preventivos de Saúde/métodos , Avaliação de Programas e Projetos de Saúde/estatística & dados numéricos , Fumar/efeitos adversos , Prevenção do Hábito de Fumar/métodos , Prevenção do Hábito de Fumar/organização & administração , Espanha/epidemiologia , Suécia/epidemiologia , Reino Unido/epidemiologiaRESUMO
Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1ß, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.
Assuntos
Displasia Broncopulmonar/tratamento farmacológico , Inflamação/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Proteína C/administração & dosagem , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/efeitos adversos , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Inflamação/complicações , Inflamação/patologia , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Gravidez , Proteína C/efeitos adversos , Alvéolos Pulmonares/efeitos dos fármacos , Alvéolos Pulmonares/patologiaRESUMO
PURPOSE: To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. METHODS: New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. RESULTS: We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. CONCLUSIONS: In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.
Assuntos
Bases de Dados Factuais/tendências , Rotulagem de Medicamentos/tendências , Uso de Medicamentos/tendências , Uso Off-Label , Inibidores da Agregação Plaquetária/uso terapêutico , Tetrazóis/uso terapêutico , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Cilostazol , Bases de Dados Factuais/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Uso Off-Label/estatística & dados numéricos , Espanha/epidemiologia , Suécia/epidemiologia , Reino Unido/epidemiologiaRESUMO
Bronchopulmonary dysplasia (BPD) is a chronic disease of extreme prematurity that has serious long-term consequences including increased asthma risk. We earlier identified IL-1 receptor antagonist (IL-1Ra) as a potent inhibitor of murine BPD induced by combining perinatal inflammation (intraperitoneal LPS to pregnant dams) and exposure of pups to hyperoxia (fraction of inspired oxygen = 0.65). In this study, we determined whether airway remodeling and hyperresponsiveness similar to asthma are evident in this model, and whether IL-1Ra is protective. During 28-day exposure to air or hyperoxia, pups received vehicle or 10 mg/kg IL-1Ra by daily subcutaneous injection. Lungs were then prepared for histology and morphometry of alveoli and airways, or for real-time PCR, or inflated with agarose to prepare precision-cut lung slices to visualize ex vivo intrapulmonary airway contraction and relaxation by phase-contrast microscopy. In pups reared under normoxic conditions, IL-1Ra treatment did not affect alveolar or airway structure or airway responses. Pups reared in hyperoxia developed a severe BPD-like lung disease, with fewer, larger alveoli, increased subepithelial collagen, and increased expression of α-smooth muscle actin and cyclin D1. After hyperoxia, methacholine elicited contraction with similar potency but with an increased maximum reduction in lumen area (air, 44%; hyperoxia, 89%), whereas dilator responses to salbutamol were maintained. IL-1Ra treatment prevented hyperoxia-induced alveolar disruption and airway fibrosis but, surprisingly, not the increase in methacholine-induced airway contraction. The current study is the first to demonstrate ex vivo airway hyperreactivity caused by systemic maternal inflammation and postnatal hyperoxia, and it reveals further preclinical mechanistic insights into IL-1Ra as a treatment targeting key pathophysiological features of BPD.
Assuntos
Remodelação das Vias Aéreas , Hiper-Reatividade Brônquica/complicações , Hiper-Reatividade Brônquica/metabolismo , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Albuterol/farmacologia , Animais , Hiper-Reatividade Brônquica/patologia , Hiper-Reatividade Brônquica/fisiopatologia , Displasia Broncopulmonar/patologia , Displasia Broncopulmonar/fisiopatologia , Modelos Animais de Doenças , Feminino , Hiperóxia/complicações , Hiperóxia/metabolismo , Hiperóxia/patologia , Hiperóxia/fisiopatologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Camundongos Endogâmicos C57BL , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Gravidez , Alvéolos Pulmonares/patologiaRESUMO
BACKGROUND: Solid organ transplant recipients (SOTRs) are 100 times more likely to develop cutaneous squamous cell carcinoma (SCC) with greater metastatic propensity compared with the general population, likely due to chronic immunosuppression and adverse drug effects on keratinocytes. Tumor-associated macrophages (TAMs) play critical roles in malignancies, either aiding in eradication of malignant cells or promoting tumor growth. OBJECTIVE: The authors examined whether TAM density and polarization states differ between SOTRs and nontransplant individuals. MATERIALS AND METHODS: The authors obtained normal skin, SCC in situ (SCCis), and SCC from SOTRs and nontransplant patients (N = 45) and stained with macrophage marker CD68, M1 marker CD40, and M2 marker arginase-1. RESULTS: The authors report a significantly higher density of TAMs in both SCCis and SCC. The intratumoral macrophage infiltration in SCCis from SOTR was significantly decreased compared with nontransplant patients. Tumor-associated macrophages in SCCis and SCC displayed both M1 and M2 polarization, and M2 activation levels were significantly lower in SCC from SOTR. CONCLUSION: Tumor-associated macrophages are present in early carcinogenesis and may play a critical role in the transition from SCCis to SCC, before invasion of the basement membrane by tumor cells. The intratumoral macrophage density in early stages of tumor development is significantly affected in SOTR.
Assuntos
Carcinoma de Células Escamosas/imunologia , Hospedeiro Imunocomprometido , Macrófagos/imunologia , Transplante de Órgãos , Neoplasias Cutâneas/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Arginase/análise , Antígenos CD40/análise , Carcinoma in Situ/imunologia , Carcinoma in Situ/patologia , Contagem de Células , Polaridade Celular , Feminino , Humanos , Ativação de Macrófagos/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To investigate major gastroesophageal and hemorrhagic complications that may be related to intraoperative transesophageal echocardiography (TEE) in liver transplant (LT) patients with high model for end-stage liver disease (MELD) score 25 or higher. DESIGN: Retrospective. SETTING: Single institution university setting. PARTICIPANTS: Of 906 transplant recipients, 656 who had MELD score 25 or higher were included for analysis. INTERVENTIONS: Patient demographics, pre- and intraoperative characteristics, and major gastroesophageal and hemorrhagic complications were compared between patients with and without TEE. MEASUREMENTS AND MAIN RESULTS: Sixty-six percent (433 patients) had intraoperative TEE and 34% (223 patients) did not. One patient in the TEE group had a major gastroesophageal complication (Mallory-Weiss tear). Eleven patients required postoperative gastrointestinal consultation. These patients were distributed evenly between the TEE and non-TEE groups. Eighteen (2.8%) had major hemorrhagic complication (defined as bloody nasogastric output>500 mL in 24 hours postoperatively). Multivariate analysis showed alcoholic cirrhosis had 5.3 higher odds of post-transplant gastroesophageal hemorrhage compared with other indications for transplant (95% confidence interval 1.8-15.8, p<0.001). TEE was not associated with an increased likelihood of major hemorrhagic complication after LT. CONCLUSIONS: The authors demonstrated that the incidence of major gastroesophageal and hemorrhagic complications following intraoperative TEE in LT patients with MELD score 25 or higher was low.