RESUMO
Human genetic studies identified a strong association between loss of function mutations in RBFOX2 and hypoplastic left heart syndrome (HLHS). There are currently no Rbfox2 mouse models that recapitulate HLHS. Therefore, it is still unknown how RBFOX2 as an RNA binding protein contributes to heart development. To address this, we conditionally deleted Rbfox2 in embryonic mouse hearts and found profound defects in cardiac chamber and yolk sac vasculature formation. Importantly, our Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. To determine the molecular drivers of these cardiac defects, we performed RNA-sequencing in Rbfox2 mutant hearts and identified dysregulated alternative splicing (AS) networks that affect cell adhesion to extracellular matrix (ECM) mediated by Rho GTPases. We identified two Rho GTPase cycling genes as targets of RBFOX2. Modulating AS of these two genes using antisense oligos led to cell cycle and cell-ECM adhesion defects. Consistently, Rbfox2 mutant hearts displayed cell cycle defects and inability to undergo endocardial-mesenchymal transition, processes dependent on cell-ECM adhesion and that are seen in HLHS. Overall, our work not only revealed that loss of Rbfox2 leads to heart development defects resembling HLHS, but also identified RBFOX2-regulated AS networks that influence cell-ECM communication vital for heart development.
Assuntos
Processamento Alternativo , Coração/embriologia , Fatores de Processamento de RNA/metabolismo , Animais , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Knockout , Organogênese , RNA/metabolismo , Fatores de Processamento de RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: Sexual minority men (SMM; gay, bisexual, and other men who have sex with men) report higher rates of substance use compared to other populations. Social connectedness is a critical component for promoting and maintaining recovery from substance use disorders. However, the degree of social connectedness among SMM who report substance use is largely unknown. OBJECTIVES: We examined substance use, social connectedness (past 30-d participation in formal recovery support, past 30-d interaction with supportive family/friends, relationship satisfaction, and types of support) and mental health among SMM at the time of their enrollment in a behavioral substance use program from September 2019 to October 2021. RESULTS: Of the107 SMM, 80% of the sample reported past 30-d illicit substance use, with methamphetamine representing the most commonly reported drug used (53%). Participants used a variety of social connections for support, including self-help groups (44% voluntary; 5% religious-affiliated; 20% other) and family/friends (81%). Importantly, 15% reported they had no one to turn to when having trouble and 36% were either dissatisfied or very dissatisfied with their relationships. Participants who endorsed significant depressive (58%) and anxiety (70%) symptoms were more likely to endorse relationship dissatisfaction than participants who did not endorse symptoms (p < 0.01). CONCLUSIONS: One-third of SMM enrolled in a substance use recovery program expressed relationship dissatisfaction, particularly those struggling with depression or anxiety. Future research and programming should examine ways of leveraging existing social connectedness or forging new social supports to enhance mental health and substance use recovery for SMM using substances.
Assuntos
Minorias Sexuais e de Gênero , Transtornos Relacionados ao Uso de Substâncias , Masculino , Humanos , Saúde Mental , Homossexualidade Masculina , Comportamento SexualRESUMO
HIV pre-exposure prophylaxis (PrEP) use is limited among male sex workers, who are at exceptionally high-risk for HIV infection. We developed a theory-informed, two-pronged intervention ("PrEPare-for-Work") to optimize PrEP initiation and adherence among male sex workers, which was preliminarily evaluated in a two-stage pilot randomized controlled trial of 110 male sex workers in the US Northeast. Individuals randomized to the Stage 1 PrEPare-for-Work Case Management arm were three times as likely as those in the standard of care (SOC) arm to initiate PrEP (RR = 2.95, 95% CI = 1.57-5.57). Participants who initiated PrEP and were randomized to the Stage 2 PrEPare-for-Work Adherence Counseling arm had higher rates of prevention-effective adherence (measured via tenofovir in hair) compared to those in the SOC arm (RR = 1.7, 95% CI 0.64-4.77; 55.6% vs. 28.6%, respectively); though not statistically significant. Given the need and the promise of this pilot RCT, further efficacy testing is warranted and should be prioritized.
RESUMEN: El uso de la profilaxis prexposición (PrEP) para prevenir la adquisición del VIH es limitado entre trabajadores sexuales masculinos, que están en muy alto riesgo de contraerlo. Desarrollamos una intervención de dos partes basada en la teoría para optimizar el inicio y la observancia del tratamiento de la PrEP entre trabajadores sexuales masculinos, que se evaluó preliminarmente en un ensayo piloto controlado y aleatorizado (ECA) de dos fases de 110 trabajadores sexuales masculinos en el noreste de Estados Unidos. Las personas aleatorizadas al grupo de intervención (la primera fase de nuestro programa "PrEPare for Work" la atención individualizada) eran tres veces más probable que las aleatorizadas al grupo control (la norma de atención) a iniciar la PrEP (RR = 2.95, 95% IC = 1.575.57). Los participantes que iniciaron la PrEP y se aleatorizaron al grupo de intervención (la segunda fase de "PrEPare for Work" la terapia para aumentar la adherencia al tratamiento) tenían tasas más altas de adherencia al tratamiento (medido por tenofovir en el cabello) que los aleatorizados al grupo control (RR = 1.7, 95% IC 0.644.77; 55.6% vs. 28.6%, respectivamente); aunque la diferencia no fue estadísticamente significativa. En vista de la necesidad y el potencial de este ECA piloto, más pruebas de eficacia son necesarias y deben ser priorizadas.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profissionais do Sexo , Masculino , Humanos , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Projetos Piloto , Tenofovir/uso terapêuticoRESUMO
COVID-19 has disproportionately affected vulnerable populations across the U.S. Street-based sex workers are one vulnerable population whose health and impact of COVID-19 have been understudied to date. The goal of this study was to evaluate findings from a community needs assessment with street-based sex workers on impact of COVID-19 on health behaviors and social circumstances. A brief survey was developed at a community-based harm reduction and recovery services organization. Surveys were administered by peer specialists to street-based sex workers during street outreach in April and May 2020. A total of 46 surveys were analyzed. Many individuals reported continuing to do sex work and use substances during the COVID pandemic. Slightly more than a quarter of individuals (n = 13; 28.3%) indicated using personal protective equipment while doing sex work and described challenges to using precautions when working with clients. Individuals had used marijuana (n = 32, 71.1%), cocaine (n = 17, 39.5%), prescription stimulants (n = 9, 21.4%), methamphetamines (n = 5, 11.9%), prescription opioids (n = 12, 27.3%), street opioids (n = 12, 27.3%), sedatives (n = 11, 25.0%), hallucinogens (n = 3, 6.8%), inhalants (n = 3, 7.0%), or some other substance (n = 4, 8.7%) in the past 30 days. About half (48.8%) reported that COVID-19 had a major impact on their lives. This study is among the first to characterize the impact of COVID-19 on street-based sex workers. From a public health standpoint, this group also represents a high-priority population given their vulnerability and close contact with others, which increases the potential for community spread.
Assuntos
COVID-19/epidemiologia , Infecções por HIV/epidemiologia , Profissionais do Sexo/estatística & dados numéricos , Populações Vulneráveis , Adolescente , Adulto , Feminino , Identidade de Gênero , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Sindemia , Adulto JovemRESUMO
BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients' long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality. (Funded by Cardiorentis; TRUE-AHF ClinicalTrials.gov number, NCT01661634 .).
Assuntos
Fator Natriurético Atrial/uso terapêutico , Doenças Cardiovasculares/mortalidade , Diuréticos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator Natriurético Atrial/efeitos adversos , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/efeitos adversos , Método Duplo-Cego , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Hipotensão/induzido quimicamente , Infusões Intravenosas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/uso terapêutico , Troponina T/sangueRESUMO
High-throughput transcriptomics and proteomics approaches have recently identified a large number of germ cell-specific genes with many that remain to be studied through functional genetics approaches. Serine proteases (PRSS) constitute nearly one-third of all proteases, and, in our bioinformatics screens, we identified many that are testis specific. In this study, we chose to focus on Prss44, Prss46, and Prss54, which we confirmed as testis specific in mouse and human. Based on the analysis of developmental expression in the mouse, expression of all four genes is restricted to the late stage of spermatogenesis concomitant with a potential functional role in spermiogenesis, spermiation, or sperm function. To best understand the male reproductive requirement and functional roles of these serine proteases, each gene was individually ablated by CRISPR/Cas9-mediated ES cell or zygote approach. Homozygous deletion mutants for each gene were obtained and analyzed for phenotypic changes. Analyses of testis weights, testis and epididymis histology, sperm morphology, and fertility revealed no significant differences in Prss44, Prss46, and Prss54 knockout mice in comparison to controls. Our results thereby demonstrate that these genes are not required for normal fertility in mice, although do not preclude the possibility that these genes may function in a redundant manner. Elucidating the individual functional requirement or lack thereof of these novel genes is necessary to build a better understanding of the factors underlying spermatogenesis and sperm maturation, which has implications in understanding the etiology of male infertility and the development of male contraceptives.
Assuntos
Fertilidade/fisiologia , Infertilidade Masculina/metabolismo , Serina Endopeptidases/metabolismo , Espermatogênese/genética , Espermatozoides/metabolismo , Testículo/metabolismo , Animais , Forma Celular/fisiologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão/fisiologia , Serina Endopeptidases/genética , Espermatozoides/citologiaRESUMO
BACKGROUND: Central sleep apnoea is a serious breathing disorder associated with poor outcomes. The remedé system (Respicardia Inc, Minnetonka, MN, USA) is an implantable device which transvenously stimulates a nerve causing diaphragmatic contraction similar to normal breathing. We evaluated the safety and effectiveness of unilateral neurostimulation in patients with central sleep apnoea. METHODS: We recruited patients from 31 hospital-based centres in Germany, Poland, and the USA in this prospective, multicentre, randomised trial. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an apnoea-hypopnoea index (AHI) of at least 20 events per h, tested by a polysomnography, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness endpoint in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50% or greater AHI reduction from baseline to 6 months, measured by a full-night polysomnography assessed by masked investigators in a core laboratory. The primary safety endpoint of 12-month freedom from serious adverse events related to the procedure, system, or therapy was evaluated in all patients. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov (NCT01816776). FINDINGS: Between April 17, 2013, and May 28, 2015, we randomly assigned 151 eligible patients to the treatment (n=73) or control (n=78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51%] of 68) had an AHI reduction from baseline of 50% or greater at 6 months than had those in the control group (eight [11%] of 73; difference between groups 41%, 95% CI 25-54, p<0·0001). 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomisation period when neurostimulation was delivered to only the treatment group and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. 27 (37%) of 73 patients in the treatment group reported non-serious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients, but was unresolved in one (1%) patient. INTERPRETATION: Transvenous neurostimulation significantly reduced the severity of central sleep apnoea, including improvements in sleep metrics, and was well tolerated. The clinically meaningful effects of the therapy are supported by the concordant improvements in oxygenation and quality of life, making transvenous neurostimulation a promising therapeutic approach for central sleep apnoea. FUNDING: Respicardia Inc.
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Neuroestimuladores Implantáveis , Apneia do Sono Tipo Central/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Polissonografia , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
AIMS: Atrial tachyarrhythmias (ATs) detected by implanted devices are often atrial fibrillation or flutter (AF) associated with stroke. We hypothesized that introduction and termination of anticoagulation based upon AT monitoring would reduce both stroke and bleeding. METHODS AND RESULTS: We randomized 2718 patients with dual-chamber and biventricular defibrillators to start and stop anticoagulation based on remote rhythm monitoring vs. usual office-based follow-up with anticoagulation determined by standard clinical criteria. The primary analysis compared the composite endpoint of stroke, systemic embolism, and major bleeding with the two strategies. The trial was stopped after 2 years median follow-up based on futility of finding a difference in primary endpoints between groups. A total of 945 patients (34.8%) developed AT, 264 meeting study anticoagulation criteria. Adjudicated atrial electrograms confirmed AF in 91%; median time to initiate anticoagulation was 3 vs. 54 days in the intervention and control groups, respectively (P < 0.001). Primary events (2.4 vs. 2.3 per 100 patient-years) did not differ between groups (HR 1.06; 95% CI 0.75-1.51; P = 0.732). Major bleeding occurred at 1.6 vs. 1.2 per 100 patient-years (HR 1.39; 95% CI 0.89-2.17; P = 0.145). In patients with AT, thromboembolism rates were 1.0 vs. 1.6 per 100 patient-years (relative risk -35.3%; 95% CI -70.8 to 35.3%; P = 0.251). Although AT burden was associated with thromboembolism, there was no temporal relationship between AT and stroke. CONCLUSION: In patients with implanted defibrillators, the strategy of early initiation and interruption of anticoagulation based on remotely detected AT did not prevent thromboembolism and bleeding. CLINICAL TRIAL REGISTRATION: IMPACT ClinicalTrials.gov identifier: NCT00559988 ( http://clinicaltrials.gov/ct2/show/NCT00559988?term=NCT00559988&rank=1 ).
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/terapia , Dispositivos de Terapia de Ressincronização Cardíaca , Desfibriladores Implantáveis , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial/métodos , Método Simples-Cego , Acidente Vascular Cerebral/prevenção & controle , Telemedicina/métodos , Tromboembolia/prevenção & controle , Resultado do Tratamento , Tecnologia sem FioRESUMO
Access to biomedical HIV prevention technologies such as pre-exposure prophylaxis (PrEP) requires individuals to disclose risk behavior to clinicians, but experiences of discrimination and medical mistrust may limit disclosure among male sex workers and other MSM. We explored experiences of perceived discrimination, medical mistrust, and behavior disclosure among male sex workers compared to other men who have sex with men (MSM). We conducted 56 interviews with MSM and compared findings about medical mistrust, discrimination, and disclosure for 31 men who engaged in sex work vs. 25 men who did not. MSM who engaged in sex work reported more medical mistrust and healthcare discrimination due to issues beyond MSM behavior/identity (e.g., homelessness, substance use, poverty). MSM who did not report sex work described disclosing sex with men to clinicians more often. Both subgroups reported low PrEP awareness, but willingness to disclose behavior to obtain PrEP. Medical mistrust and perceived discrimination create barriers for sexual behavior disclosure to clinicians, potentially impeding access to PrEP and other forms of biomedical HIV prevention. These barriers may be higher among male sex workers compared to other MSM, given overlapping stigmas including sex work, substance use, homelessness, and poverty. An intersectionality framework for understanding multiple stigmas can help to identify how these dynamics may limit access to biomedical HIV prevention among male sex workers, as well as suggesting strategies for addressing stigmas to improve the delivery of PrEP and other HIV prevention approaches in this population.
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Infecções por HIV/prevenção & controle , Homofobia/psicologia , Homossexualidade Masculina/psicologia , Relações Médico-Paciente , Autorrevelação , Profissionais do Sexo/psicologia , Confiança/psicologia , Sexo sem Proteção/psicologia , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/psicologia , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Profilaxia Pré-Exposição , Pesquisa Qualitativa , Adulto JovemRESUMO
OBJECTIVE: Evaluate the performance of glycated albumin (GA) monitoring by comparing it to other measures of glycemic control during intensification of antidiabetic therapy. METHODS: This 12-week, prospective, multicenter study compared the diagnostic clinical performance of GA to glycated hemoglobin A1C (A1C), fructosamine corrected for albumin (FRA), fasting plasma glucose (FPG), and mean blood glucose (MBG) estimated from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in 30 patients with suboptimally controlled type 1 or 2 diabetes. RESULTS: Mean A1C decreased from 9.5% to 8.1%. Mean SMBG correlated closely with CGM (Pearson r = 0.783 for daily estimates and r = 0.746 for weekly estimates, P<.0001). Both GA and FRA levels significantly correlated with changes from baseline in A1C and mean weekly SMBG (P<.001). The lowest observed median GA occurred at 4 weeks, followed by a small increase and then a slight reduction, mirroring changes in overall mean SMBG values. The median A1C fell throughout the treatment period, failing to reflect short-term changes in SMBG. A ≥1% reduction in GA at 4 weeks was significantly associated with a ≥0.5% change in A1C at 12 weeks (odds ratio [OR] = 19.0, 95% confidence interval [CI]: 1.4, 944, P = .018). CONCLUSION: In patients receiving glucose-lowering therapy, changes in GA at 4 weeks were concordant with changes in A1C at 12 weeks, and both GA and FRA more accurately reflected short-term blood glucose fluctuations than A1C.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Hemoglobinas Glicadas/metabolismo , Albumina Sérica/metabolismo , Adulto , Idoso , Glicemia/efeitos dos fármacos , Automonitorização da Glicemia/instrumentação , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Frutosamina/sangue , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/efeitos dos fármacos , Produtos Finais de Glicação Avançada , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Albumina Sérica/análise , Albumina Sérica/efeitos dos fármacos , Fatores de Tempo , Albumina Sérica GlicadaRESUMO
We examined data derived from a needs assessment of the personal and social characteristics and HIV risk behavior of street-based male sex workers, in Providence, Rhode Island, who engage in transactional sexual intercourse with other men. Substance use, injected drugs, needle sharing, and psychosocial distress were highly prevalent among the sample. History of physical, sexual, and emotional abuse was associated with increased risk of condomless anal sexual intercourse with paying male clients.
Assuntos
Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Profissionais do Sexo , Adulto , Humanos , Masculino , Avaliação das Necessidades , Rhode Island , Sexo sem Proteção/estatística & dados numéricosRESUMO
AIMS: Interatrial shunts are under evaluation as a treatment for heart failure (HF); however, their in vivo flow performance has not been quantitatively studied. We aimed to investigate the fluid dynamics properties of the 0.51 cm orifice diameter Ventura shunt and assess its lumen integrity with serial transesophageal echocardiography (TEE). METHODS AND RESULTS: Computational fluid dynamics (CFD) and bench flow tests were used to establish the flow-pressure relationship of the shunt. Open-label patients from the RELIEVE-HF trial underwent TEE at shunt implant and at 6 and 12 month follow-up. Shunt effective diameter (Deff) was derived from the vena contracta, and flow was determined by the continuity equation. CFD and bench studies independently validated that the shunt's discharge coefficient was 0.88 to 0.89. The device was successfully implanted in all 97 enrolled patients; mean age was 70 ± 11 years, 97% were NYHA class III, and 51% had LVEF ≤40%. Patency was confirmed in all instances, except for one stenotic shunt at 6 months. Deff remained unchanged from baseline at 12 months (0.47 ± 0.01 cm, P = 0.376), as did the trans-shunt mean pressure gradient (5.1 ± 3.9 mmHg, P = 0.316) and flow (1137 ± 463 mL/min, P = 0.384). TEE measured flow versus pressure closely correlated (R2 ≥ 0.98) with a fluid dynamics model. At 12 months, the pulmonary/systemic flow Qp/Qs ratio was 1.22 ± 0.12. CONCLUSIONS: When implanted in patients with advanced HF, this small interatrial shunt demonstrated predictable and durable patency and performance.
RESUMO
AIMS: Heart failure (HF) outcomes remain poor despite optimal guideline-directed medical therapy (GDMT). We assessed safety, effectiveness, and transthoracic echocardiographic (TTE) outcomes during the 12 months after Ventura shunt implantation in the RELIEVE-HF open-label roll-in cohort. METHODS AND RESULTS: Eligibility required symptomatic HF despite optimal GDMT with ≥1 HF hospitalization in the prior year or elevated natriuretic peptides. The safety endpoint was device-related major adverse cardiovascular or neurological events at 30 days, compared to a prespecified performance goal. Effectiveness evaluations included the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 1, 3, 6, and 12 months and TTE at baseline and 12 months. Overall, 97 patients were enrolled and implanted at 64 sites. Average age was 70 ± 11 years, 97% were in New York Heart Association class III, and half had left ventricular ejection fraction (LVEF) ≤40%. The safety endpoint was achieved (event rate 0%, p < 0.001). KCCQ overall summary score was improved by 12-16 points at all follow-up timepoints (all p < 0.004), with similar outcomes in patients with reduced and preserved LVEF. At 12 months, left ventricular end-systolic and end-diastolic volumes were reduced (p = 0.020 and p = 0.038, respectively), LVEF improved (p = 0.009), right ventricular end-systolic and end-diastolic areas were reduced (p = 0.001 and p = 0.030, respectively), and right ventricular fractional area change (p < 0.001) and tricuspid annular plane systolic excursion (p < 0.001) improved. CONCLUSION: Interatrial shunting with the Ventura device was safe and resulted in favourable clinical effects in patients with HF, regardless of LVEF. Improvements of left and right ventricular structure and function were consistent with reverse myocardial remodelling. These results would support the potential of this shunt device as a treatment for HF.
Assuntos
Ecocardiografia , Insuficiência Cardíaca , Volume Sistólico , Humanos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Feminino , Masculino , Idoso , Volume Sistólico/fisiologia , Ecocardiografia/métodos , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia , Átrios do Coração/fisiopatologia , Átrios do Coração/diagnóstico por imagem , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (CPR) with decreased intrathoracic pressure in the decompression phase can lead to improved haemodynamics compared with standard CPR. We aimed to assess effectiveness and safety of this intervention on survival with favourable neurological function after out-of-hospital cardiac arrest. METHODS: In our randomised trial of 46 emergency medical service agencies (serving 2·3 million people) in urban, suburban, and rural areas of the USA, we assessed outcomes for patients with out-of-hospital cardiac arrest according to Utstein guidelines. We provisionally enrolled patients to receive standard CPR or active compression-decompression CPR with augmented negative intrathoracic pressure (via an impedance-threshold device) with a computer-generated block randomisation weekly schedule in a one-to-one ratio. Adults (presumed age or age ≥18 years) who had a non-traumatic arrest of presumed cardiac cause and met initial and final selection criteria received designated CPR and were included in the final analyses. The primary endpoint was survival to hospital discharge with favourable neurological function (modified Rankin scale score of ≤3). All investigators apart from initial rescuers were masked to treatment group assignment. This trial is registered with ClinicalTrials.gov, number NCT00189423. FINDINGS: 2470 provisionally enrolled patients were randomly allocated to treatment groups. 813 (68%) of 1201 patients assigned to the standard CPR group (controls) and 840 (66%) of 1269 assigned to intervention CPR received designated CPR and were included in the final analyses. 47 (6%) of 813 controls survived to hospital discharge with favourable neurological function compared with 75 (9%) of 840 patients in the intervention group (odds ratio 1·58, 95% CI 1·07-2·36; p=0·019]. 74 (9%) of 840 patients survived to 1 year in the intervention group compared with 48 (6%) of 813 controls (p=0·03), with equivalent cognitive skills, disability ratings, and emotional-psychological statuses in both groups. The overall major adverse event rate did not differ between groups, but more patients had pulmonary oedema in the intervention group (94 [11%] of 840) than did controls (62 [7%] of 813; p=0·015). INTERPRETATION: On the basis of our findings showing increased effectiveness and generalisability of the study intervention, active compression-decompression CPR with augmentation of negative intrathoracic pressure should be considered as an alternative to standard CPR to increase long-term survival after cardiac arrest. FUNDING: US National Institutes of Health grant R44-HL065851-03, Advanced Circulatory Systems.
Assuntos
Reanimação Cardiopulmonar/instrumentação , Reanimação Cardiopulmonar/métodos , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Circulação Cerebrovascular , Circulação Coronária , Serviços Médicos de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Estudos Prospectivos , Edema Pulmonar/epidemiologia , Taquicardia Ventricular/mortalidade , Taquicardia Ventricular/terapia , Estados Unidos/epidemiologia , Fibrilação Ventricular/mortalidade , Fibrilação Ventricular/terapiaRESUMO
BACKGROUND: Despite the current drug and device therapies, heart failure remains associated with high rates of disability, morbidity, and mortality. There is a need for newer therapies. One investigational approach is the use of ventricular support devices. These devices reduce ventricular wall stress leading to decreases in left ventricular (LV) volumes, dimensions, and mass. Ventricular support devices have been shown to reverse pathological ventricular remodeling, improve systolic function, and improve symptoms of heart failure. The Prospective Evaluation of Elastic Restraint to LESSen the effects of Heart Failure (PEERLESS-HF) trial was designed to further evaluate the safety and efficacy of one such device, the HeartNet (Paracor Medical, Sunnyvale, CA). METHODS: The HeartNet is an elastic ventricular restraint device formed from nitinol and covered in silicone, implanted using a minimally invasive approach. The aim of this randomized controlled trial is to compare optimal heart failure drug and device therapy plus the HeartNet (treatment group) to optimal drug and device therapy alone (control group) in patients with advanced systolic heart failure (LV ejection fraction ≤35% and LV end diastolic diameter <85 mm). Primary efficacy end points include the change in peak VO(2), quality of life score, and 6-minute hall walk distance from baseline to 6 months. The primary safety objective is to demonstrate noninferiority for all-cause mortality at 12 months. Planned enrollment is for 272 patients at approximately 35 centers in North America. CONCLUSIONS: The PEERLESS-HF trial will evaluate the safety and efficacy of ventricular elastic support in advanced systolic heart failure, advancing our knowledge of this investigational approach to heart failure therapy.
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Insuficiência Cardíaca Sistólica/terapia , Coração Auxiliar , Projetos de Pesquisa , Remodelação Ventricular , Adulto , Idoso , Fármacos Cardiovasculares/administração & dosagem , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Insuficiência Cardíaca Sistólica/etiologia , Insuficiência Cardíaca Sistólica/fisiopatologia , Insuficiência Cardíaca Sistólica/cirurgia , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Oxigênio/sangue , Seleção de Pacientes , Estudos Prospectivos , Qualidade de Vida , Segurança , Índice de Gravidade de Doença , Volume Sistólico , Toracotomia/métodos , Fatores de Tempo , Resultado do Tratamento , CaminhadaRESUMO
BACKGROUND: Left ventricular (LV) remodeling predicts poor outcomes in heart failure (HF) patients. The HeartNet(®) cardiac restraint device (Paracor Medical Inc., Sunnyvale, CA) may reduce LV remodeling and improve functional capacity, quality of life, and outcomes in HF patients. To evaluate the safety and efficacy of the HeartNet Ventricular Support System in HF patients receiving optimal medical therapy. METHODS AND RESULTS: Prospective, randomized, controlled, multicenter trial in patients with symptomatic HF and LV ejection fraction ≤35% on optimal medical and device therapy. The primary efficacy end points were changes in peak VO(2), 6-minute walk (6MW) distance, and Minnesota Living with Heart Failure (MLWHF) quality of life score at 6 months. The primary safety end point was all-cause mortality at 12 months. Because the planned adaptive interim analysis of the first 122 subjects with a completed 6-month follow-up indicated futility to reach the peak VO(2) end point, trial enrollment was suspended. Hence, the results on the 96 treatment and 114 control subjects are reported. Groups were similar at baseline. At 6 months, responder frequency for a prespecified improvement was similar between groups for peak VO(2) (P = .502) and MLWHF score (P = .184) but borderline higher for improvement in 6MW distance in the treatment compared with the control group (33 [38%] vs. 25 [25%]; P = .044). At 6 months, the treatment group had a significantly greater improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) (P < .001) and decrease in LV mass (P = .032), LV end-diastolic diameter (P = .015), LV end-systolic diameter (P = .032), and LV end-diastolic volume (P = .031) as compared with controls. At 12 months, all-cause mortality and responder rates were similar in the 2 groups. Success rate for the HeartNet implantation was 99%. CONCLUSION: Enrollment in the trial was stopped because an interim analysis showed futility of reaching the peak VO(2) end point. However, because of the device safety and favorable signals for LV remodeling and quality of life, further investigation of this device is warranted.
Assuntos
Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Próteses e Implantes , Implantação de Prótese , Remodelação Ventricular/fisiologia , Adulto , Idoso , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Estudos Prospectivos , Desenho de Prótese , Qualidade de Vida , Inquéritos e Questionários , Resultado do Tratamento , Caminhada/fisiologia , Adulto JovemRESUMO
BACKGROUND: Infection following cardiovascular implantable electronic device (CIED) replacement is a serious complication, and rates of infection have increased. Analysis of procedural and clinical data from device replacement procedures collected by the REPLACE Registry may provide insights into infection prevention strategies and outcomes. METHODS: We prospectively evaluated procedural complications in patients undergoing CIED replacement over 6 months from 72 U.S. sites. Major and minor infections were predefined and adjudicated by an independent blinded clinical events committee. Data regarding infection prevention strategies and infectious outcomes were analyzed for their potential relationships. RESULTS: A total of 1,744 patients were included in REPLACE. All patients received preoperative intravenous antibiotics and 68.7% received postoperative systemic antibiotic therapy. CIED infection developed in 22 patients (1.3%), of which 14 cases were major (0.8%, 95% confidence interval [CI] 0.4%-1.3%) and eight were minor (0.5%, 95% CI 0.2%-0.9%). Patients with infections were more likely to have had postoperative hematomas (five of 22 [22.7%] vs 17 of 1,722 [0.98%], P = 0.002). Participating sites experiencing infection rates >5% were more likely to use povidone-iodine for topical antisepsis, had lower implantation volume, and had patients with higher Charlson Comorbidity Index (2.79 vs 2.32, 95% CI for difference 0.08-0.86, P = 0.019). CONCLUSIONS: In this multicenter prospective study with 6 months of follow-up, infections associated with CIED replacements were surprisingly infrequent, possibly due to the use of preoperative antibiotics. Patients with infections were more likely to have had a postoperative hematoma, and sites with higher infection rates had sicker patients and lower overall procedural volume.
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Desfibriladores Implantáveis/estatística & dados numéricos , Miocardite/epidemiologia , Miocardite/prevenção & controle , Marca-Passo Artificial/estatística & dados numéricos , Infecções Relacionadas à Prótese/epidemiologia , Infecções Relacionadas à Prótese/prevenção & controle , Idoso , Feminino , Humanos , Masculino , Prevalência , Medição de Risco , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Prospective studies defining the risk associated with pacemaker or implantable cardioverter-defibrillator replacement surgeries do not exist. These procedures are generally considered low risk despite results from recent retrospective series reporting higher rates. METHODS AND RESULTS: We prospectively assessed predefined procedure-related complication rates associated with elective pacemaker or implantable cardioverter-defibrillator generator replacements over 6 months of follow-up. Two groups were studied: those without (cohort 1) and those with (cohort 2) a planned transvenous lead addition for replacement or upgrade to a device capable of additional therapies. Complications were adjudicated by an independent events committee. Seventy-two US academic and private practice centers participated. Major complications occurred in 4.0% (95% confidence interval, 2.9 to 5.4) of 1031 cohort 1 patients and 15.3% (95% confidence interval, 12.7 to 18.1) of 713 cohort 2 patients. In both cohorts, major complications were higher with implantable cardioverter-defibrillator compared with pacemaker generator replacements. Complications were highest in patients who had an upgrade to or a revised cardiac resynchronization therapy device (18.7%; 95% confidence interval, 15.1 to 22.6). No periprocedural deaths occurred in either cohort, although 8 later procedure-related deaths occurred in cohort 2. The 6-month infection rates were 1.4% (95% confidence interval, 0.7 to 2.3) and 1.1% (95% confidence interval, 0.5 to 2.2) for cohorts 1 and 2, respectively. CONCLUSIONS: Pacemaker and implantable cardioverter-defibrillator generator replacements are associated with a notable complication risk, particularly those with lead additions. These data support careful decision making before device replacement, when managing device advisories, and when considering upgrades to more complex systems.
Assuntos
Desfibriladores Implantáveis , Remoção de Dispositivo , Marca-Passo Artificial , Complicações Pós-Operatórias/epidemiologia , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos , Estudos de Coortes , Falha de Equipamento , Feminino , Seguimentos , Parada Cardíaca/epidemiologia , Hematoma/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Fatores de Risco , Trombose Venosa/epidemiologiaRESUMO
Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen in family Togaviridae, genus Alphavirus. Although CHIKV is well known for its ability to cause debilitating rheumatoid-like arthritis, it has been also been observed to cause cardiovascular symptoms such as arrhythmias. Here, using samples from a previous study, we sequenced RNA from serum, kidney, skeletal muscle, and cardiac muscle from CHIKV- and mock-infected IFN-αR-/- mice using two sequencing techniques to investigate heart-specific changes in virus mutational profiles and host gene expression. Mutation rates were similar across muscle tissues although heart tissue carried heart-specific CHIKV minority variants, one of which had a coding change in the nsP3 gene and another in the 3'UTR. Importantly, heart-specific transcriptional changes included differential expression of genes critical for ion transport and muscle contraction. These results demonstrate that CHIKV replicates in the hearts of immunodeficient mice and induce heart-specific mutations and host responses with implications for cardiac pathologies.
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Febre de Chikungunya/fisiopatologia , Vírus Chikungunya , Coração , Animais , Vírus Chikungunya/genética , Vírus Chikungunya/patogenicidade , Modelos Animais de Doenças , Coração/microbiologia , Coração/fisiopatologia , Camundongos , Camundongos Nus , Proteínas não Estruturais Virais/genética , Replicação ViralRESUMO
RBFOX2, which has a well-established role in alternative splicing, is linked to heart diseases. However, it is unclear whether RBFOX2 has other roles in RNA processing that can influence gene expression in muscle cells, contributing to heart disease. Here, we employ both 3'-end and nanopore cDNA sequencing to reveal a previously unrecognized role for RBFOX2 in maintaining alternative polyadenylation (APA) signatures in myoblasts. RBFOX2-mediated APA modulates mRNA levels and/or isoform expression of a collection of genes, including contractile and mitochondrial genes. Depletion of RBFOX2 adversely affects mitochondrial health in myoblasts, correlating with disrupted APA of mitochondrial gene Slc25a4. Mechanistically, RBFOX2 regulation of Slc25a4 APA is mediated through consensus RBFOX2 binding motifs near the distal polyadenylation site, enforcing the use of the proximal polyadenylation site. In sum, our results unveil a role for RBFOX2 in fine-tuning expression of mitochondrial and contractile genes via APA in myoblasts relevant to heart diseases.