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Importance: Approximately 40% of patients with heart failure (HF) who are eligible for cardiac resynchronization therapy (CRT) either fail to respond or are untreatable due to anatomical constraints. Objective: To assess the safety and efficacy of a novel, leadless, left ventricular (LV) endocardial pacing system for patients at high risk for a CRT upgrade or whose coronary sinus (CS) lead placement/pacing with a conventional CRT system failed. Design, Setting, and Participants: The SOLVE-CRT study was a prospective multicenter trial, enrolling January 2018 through September 2022, with follow-up in March 2023. Data were analyzed from DATE MONTH, YEAR, through DATE MONTH, YEAR. The trial combined data from an initial randomized, double-blind study (n = 108) and a subsequent single-arm part (n = 75). It took place at 36 centers across Australia, Europe, and the US. Participants were nonresponders, previously untreatable (PU), or high-risk upgrades (HRU). All participants contributed to the safety analysis. The primary efficacy analysis (n = 100) included 75 PU-HRU patients from the single-arm part and 25 PU-HRU patients from the randomized treatment arm. Interventions: Patients were implanted with the WiSE CRT System (EBR Systems) consisting of a leadless LV endocardial pacing electrode stimulated with ultrasound energy delivered by a subcutaneously implanted transmitter and battery. Main Outcomes and Measures: The primary safety end point was freedom from type I complications. The primary efficacy end point was a reduction in mean LV end systolic volume (LVESV). Results: The study included 183 participants; mean age was 68.1 (SD, 10.3) years and 141 were male (77%). The trial was terminated at an interim analysis for meeting prespecified stopping criteria. In the safety population, patients were either New York Heart Association Class II (34.6%) or III (65.4%). The primary efficacy end point was met with a 16.4% (95% CI, -21.0% to -11.7%) reduction in mean LVESV (P = .003). The primary safety end point was met with an 80.9% rate of freedom from type I complications (P < .001), which included 12 study device system events (6.6%), 5 vascular events (2.7%), 3 strokes (1.6%), and 7 cardiac perforations which mostly occurred early in the study (3.8%). Conclusions and Relevance: The SOLVE-CRT study has demonstrated that leadless LV endocardial pacing with the WiSE CRT system is associated with a reduction in LVESV in patients with HF. This novel system may represent an alternative to conventional CRT implants in some HF patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT0292203.
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BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.
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Exercício Físico , Síndrome do QT Longo , Humanos , Síndrome do QT Longo/terapia , Síndrome do QT Longo/congênito , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/mortalidade , Feminino , Masculino , Adolescente , Criança , Estudos Prospectivos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/epidemiologia , Fatores de RiscoRESUMO
CONTEXT: A rare, large single centre study covering all long-term health outcomes of paediatric allogeneic HSCT survivors, to provide comprehensive local data, and identify gaps and future directions for improved care. OBJECTIVE: To document endocrine sequelae and other late effects of all HSCT recipients. DESIGN: Retrospective review. SETTING: Royal Children's Hospital Melbourne. PATIENTS: 384 children and adolescents received HSCT. 228 formed the study cohort; 212 were alive at commencement of data accrual. INTERVENTION: None. MAIN OUTCOME MEASURES: Incidence of endocrinopathies; fertility, growth, bone and metabolic status; subsequent malignant neoplasms (SMNs). RESULTS: Gonadotoxicity was more common in females (p<0.001). Total body irradiation (TBI) conditioning was more toxic than chemotherapy alone. All females receiving TBI or higher cyclophosphamide equivalent doses (CED) developed premature ovarian insufficiency (POI) . In males, impaired spermatogenesis +/- testicular endocrine dysfunction was associated with increasing testicular radiation exposure. Preservation of gonadal function was associated with younger age at HSCT. Of sexually active females, 22% reported spontaneous pregnancies. Short stature was common, with growth hormone axis disruption in 30% of these. Of patients exposed to thyroid radiation 51% developed nodules, 30% malignant. Metabolic disturbances included hypertension, dyslipidemias, with both excess and underweight reported. Fragility fractures occurred in 6%; avascular necrosis in 6%. 13% developed SMNs, risk continuing to rise throughout follow-up. CONCLUSIONS: We confirm gonadal dysfunction, multiple endocrine and metabolic abnormalities, thyroid cancer and SMNs, as common sequelae of HSCT, and identify gaps in management - particularly the need for informed fertility counselling and pretreatment fertility preservation, evaluation and management of bone health, and underline need for early lifestyle modification, long-term surveillance, and prospective planned studies aimed at reducing complication risk.
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Imaging techniques permit the study of the molecular interactions that underlie health and disease. Each imaging technique collects unique chemical information about the cellular environment. Multimodal imaging, using a single probe that can be detected by multiple imaging modalities, can maximise the information extracted from a single cellular sample by combining the results of different imaging techniques. Of particular interest in biological imaging is the combination of the specificity and sensitivity of optical fluorescence microscopy (OFM) with the quantitative and element-specific nature of X-ray fluorescence microscopy (XFM). Together, these techniques give a greater understanding of how native elements or therapeutics affect the cellular environment. This review focuses on recent studies where both techniques were used in conjunction to study cellular systems, demonstrating the breadth of biological models to which this combination of techniques can be applied and the potential for these techniques to unlock untapped knowledge of disease states.
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Microscopia , Imagem Óptica , Raios XRESUMO
AIMS: RECOVER AF evaluated the performance of whole-chamber non-contact charge-density mapping to guide the ablation of non-pulmonary vein (PV) targets in persistent atrial fibrillation (AF) patients following either a first or second failed procedure. METHODS AND RESULTS: RECOVER AF was a prospective, non-randomized trial that enrolled patients scheduled for a first or second ablation retreatment for recurrent AF. The PVs were assessed and re-isolated if necessary. The AF maps were used to guide the ablation of non-PV targets through elimination of pathologic conduction patterns (PCPs). Primary endpoint was freedom from AF on or off antiarrhythmic drugs (AADs) at 12 months. Patients undergoing retreatment with the AcQMap System (n = 103) were 76% AF-free at 12 months [67% after single procedure (SP)] on or off AADs (80% free from AF on AADs). Patients who had only received a pulmonary vein isolation (PVI) prior to study treatment of non-PV targets with the AcQMap System were 91% AF-free at 12 months (83% SP). No major adverse events were reported. CONCLUSION: Non-contact mapping can be used to target and guide the ablation of PCPs beyond the PVs in persistent AF patients returning for a first or second retreatment with 76% freedom from AF at 12 months. The AF freedom was particularly high, 91% (43/47), for patients enrolled having only a prior de novo PVI, and freedom from all atrial arrhythmias for this cohort was 74% (35/47). These early results are encouraging and suggest that guiding individualized targeted ablation of PCPs may therefore be advantageous to target at the earliest opportunity in patients with persistent AF.
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Fibrilação Atrial , Ablação por Cateter , Veias Pulmonares , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/cirurgia , Fibrilação Atrial/etiologia , Estudos Prospectivos , Veias Pulmonares/cirurgia , Retratamento , Antiarrítmicos , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Resultado do Tratamento , RecidivaRESUMO
Intravenous administration of the last-line polymyxins results in poor drug exposure in the lungs and potential nephrotoxicity; while inhalation therapy offers better pharmacokinetics/pharmacodynamics for pulmonary infections by delivering the antibiotic to the infection site directly. However, polymyxin inhalation therapy has not been optimized and adverse effects can occur. This study aimed to quantitatively determine the intracellular accumulation and distribution of polymyxins in single human alveolar epithelial A549 cells. Cells were treated with an iodine-labeled polymyxin probe FADDI-096 (5.0 and 10.0 µM) for 1, 4, and 24 h. Concentrations of FADDI-096 in single A549 cells were determined by synchrotron-based X-ray fluorescence microscopy. Concentration- and time-dependent accumulation of FADDI-096 within A549 cells was observed. The intracellular concentrations (mean ± SEM, n ≥ 189) of FADDI-096 were 1.58 ± 0.11, 2.25 ± 0.10, and 2.46 ± 0.07 mM following 1, 4 and 24 h of treatment at 10 µM, respectively. The corresponding intracellular concentrations following the treatment at 5 µM were 0.05 ± 0.01, 0.24 ± 0.04, and 0.25 ± 0.02 mM (n ≥ 189). FADDI-096 was mainly localized throughout the cytoplasm and nuclear region over 24 h. The intracellular zinc concentration increased in a concentration- and time-dependent manner. This is the first study to quantitatively map the accumulation of polymyxins in human alveolar epithelial cells and provides crucial insights for deciphering the mechanisms of their pulmonary toxicity. Importantly, our results may shed light on the optimization of inhaled polymyxins in patients and the development of new-generation safer polymyxins.
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BACKGROUND: Patients with Crohn's disease (CD) have a high likelihood of being sarcopenic. Several studies have shown a positive correlation between sarcopenia measured as skeletal muscle index (SMI) and poor surgical outcomes in patients with CD. Our primary aim was to correlate SMI with the psoas muscle index (PMI), an easier measurement of sarcopenia. Secondary aim was to correlate SMI and PMI with clinical outcomes in a cohort of CD patients requiring surgery. METHODS: A retrospective cohort study of CD patients who underwent surgery at a public health service from January 2010 to December 2019. Using computed tomography and magnetic resonance enterography studies, skeletal muscle area was measured at the third lumbar vertebra level. SMI and PMI were calculated and correlated. Correlation between SMI and PMI with surgical outcomes was performed. RESULTS: Seventy-six patients were included. Median length of stay (LOS) was 6 days (IQR, 5 to 9). Eleven patients (14.5%) required ICU admission, nine patients (11.8%) required TPN and thirteen patients (17.1%) had complications. The prevalence of sarcopenia was 63.2% based on the SMI threshold of 52.4 and 38.5 cm2 /m2 for men and women, respectively. A positive correlation between SMI and PMI was found (r = 0.72, P < 0.0001). Sarcopenia status based on reported thresholds for SMI and for PMI showed no significant correlation with outcomes (LOS, ICU admission and complications). CONCLUSIONS: SMI and PMI show good correlation but there is insufficient evidence to suggest that sarcopenia status using either measurement has a significant impact on predicting clinical outcomes.
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Doença de Crohn , Sarcopenia , Masculino , Humanos , Feminino , Sarcopenia/complicações , Sarcopenia/diagnóstico por imagem , Sarcopenia/epidemiologia , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Doença de Crohn/patologia , Estudos Retrospectivos , Músculos Psoas/diagnóstico por imagem , Músculo Esquelético/patologia , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: Computed tomography (CT), computed tomography enterography (CTE) and magnetic resonance enterography (MRE) are commonly used pre-operatively in surgical planning in Crohn's Disease (CD). The findings on CT, CTE and MRE may not, however, correlate with operative findings. This study aims to establish the sensitivity of these imaging modalities and analyse radiologist inter-rater reliability by comparing imaging findings of strictures, fistulas and abscesses with intra-operative findings. METHODS: A retrospective review of CD patients who had either CT, CTE and/or MRE imaging and CD related surgical intervention at a public health service from 2010 to 2019 inclusive. The number and locations of strictures, fistulas and abscesses on pre-operative original radiology reports (OR) were recorded. Subsequently, all scans were re-read by two specialist abdominal radiologists and consensus recorded (SR). Lesions recorded from both OR and SR were compared to those found intra-operatively. RESULTS: Eighty-three patients were included. For strictures, sensitivity was 67%, 74% and 79% for OR and 88%, 71% and 87% for SR for CT, CTE and MRE respectively. The frequency of fistulas and abscesses were small hence a conclusion could not be drawn. The level of agreement between radiologists ranged from 44% to 82% for strictures and 64 to 100% for fistulas and abscesses across all three imaging modalities. CONCLUSIONS: CT and MRE have similarly high sensitivities for the identification of strictures pre-operatively when read by specialist radiologists. Inter-rater reliability calculations found similar agreement levels between specialist radiologists and between OR and SR for strictures, fistulas and abscesses across CT, CTE and MRE.
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Doença de Crohn , Abscesso , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/cirurgia , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/cirurgia , Humanos , Imageamento por Ressonância Magnética/métodos , Radiologistas , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
AIMS: Cardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades. METHOD AND RESULTS: Prospective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). CONCLUSION: Despite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.
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Terapia de Ressincronização Cardíaca , Seio Coronário , Insuficiência Cardíaca , Seio Coronário/diagnóstico por imagem , Endocárdio , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Humanos , Estudos Prospectivos , Resultado do TratamentoRESUMO
Biodiversity indicators are used to inform decisions and measure progress toward global targets, such as the United Nations Sustainable Development Goals. Indicators aggregate and simplify complex information, so underlying information influencing its reliability and interpretation (e.g., variability in data and uncertainty in indicator values) can be lost. Communicating uncertainty is necessary to ensure robust decisions and limit misinterpretations of trends, yet variability and uncertainty are rarely quantified in biodiversity indicators. We developed a guide to representing uncertainty and variability in biodiversity indicators. We considered the key purposes of biodiversity indicators and commonly used methods for representing uncertainty (standard error, bootstrap resampling, and jackknife resampling) and variability (quantiles, standard deviation, median absolute deviation, and mean absolute deviation) with intervals. Using 3 high-profile biodiversity indicators (Red List Index, Living Planet Index, and Ocean Health Index), we tested the use, suitability, and interpretation of each interval method based on the formulation and data types underpinning the indicators. The methods revealed vastly different information; indicator formula and data distribution affected the suitability of each interval method. Because the data underpinning each indicator were not normally distributed, methods relying on normality or symmetrical spread were unsuitable. Quantiles, bootstrapping, and jackknifing provided useful information about the underlying variability and uncertainty. We built a decision tree to inform selection of the appropriate interval method to represent uncertainty or variation in biodiversity indicators, depending on data type and objectives. Our guide supports transparent and effective communication of biodiversity indicator trends to facilitate accurate interpretation by decision makers.
Los indicadores de biodiversidad se usan para orientar las decisiones y medir el progreso hacia los objetivos globales, como los Objetivos de Desarrollo Sustentable de las Naciones Unidas. Los indicadores agregan y simplifican la información compleja, por lo que la información subyacente que influye sobre su confiabilidad e interpretación (p. ej.: variabilidad en los datos e incertidumbre en los valores indicadores) puede perderse. Es necesario comunicar la incertidumbre para asegurar decisiones sólidas y limitar las malas interpretaciones de las tendencias. Aun así, rara vez se cuantifican la variabilidad y la incertidumbre en los indicadores de biodiversidad. Desarrollamos una guía para representar la incertidumbre y la variabilidad en los indicadores de biodiversidad. Consideramos los propósitos importantes de los indicadores de biodiversidad y los métodos comúnmente usados para representar la incertidumbre (error estándar, remuestreo bootstrap, remuestreo jackknife) y la variabilidad (quantiles, desviación estándar, desviación mediana absoluta, desviación media absoluta) con intervalos. Usamos tres indicadores de biodiversidad de alto perfil (Red List Index, Living Planet Index, Ocean Health Index) para analizar el uso, idoneidad e interpretación de cada método de intervalo con base en la formulación y los tipos de datos fundamentales para los indicadores. Los métodos revelaron información ampliamente diferente; la fórmula del indicador y la distribución de los datos afectaron la idoneidad de cada método de intervalo. Ya que los datos fundamentales para cada indicador no tuvieron una distribución normal, los métodos que dependen de la normalidad o el esparcimiento simétrico no fueron idóneos. Los quantiles, el bootstrap y el jackknife proporcionaron información útil sobre la variabilidad y la incertidumbre subyacentes. Construimos un árbol de decisiones para guiar la selección del método de intervalo apropiado para representar la incertidumbre o la variación en los indicadores de biodiversidad, dependiendo del tipo de datos y de los objetivos. Nuestra guía respalda la comunicación efectiva y transparente de las tendencias en los indicadores de biodiversidad para facilitarle al órgano decisorio la interpretación acertada de estas tendencias.
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Biodiversidade , Conservação dos Recursos Naturais , Reprodutibilidade dos Testes , Incerteza , Nações UnidasRESUMO
All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termed ferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime in Caenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evident when ferroptosis is inhibited, consistent with this cell death process acting at specific life phases to induce organismal frailty, rather than contributing to a constant aging rate. Because excess age-related iron elevation in somatic tissue, particularly in brain, is thought to contribute to degenerative disease, post-developmental interventions to limit ferroptosis may promote healthy aging.
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Envelhecimento/metabolismo , Caenorhabditis elegans/metabolismo , Ferroptose/fisiologia , Fragilidade/fisiopatologia , Glutationa/metabolismo , Ferro/metabolismo , AnimaisRESUMO
BACKGROUND: Endocardial pacing may be beneficial in patients who fail to improve following conventional epicardial cardiac resynchronization therapy (CRT). The potential to pace anywhere inside the left ventricle thus avoiding myocardial scar and targeting the latest activating segments may be particularly important. The WiSE-CRT system (EBR systems, Sunnyvale, CA) reliably produces wireless, endocardial left ventricular (LV) pacing. The purpose of this analysis was to determine whether this system improved symptoms or led to LV remodeling in patients who were nonresponders to conventional CRT. METHOD: An international, multicenter registry of patients who were nonresponders to conventional CRT and underwent implantation with the WiSE-CRT system was collected. RESULTS: Twenty-two patients were included; 20 patients underwent successful implantation with confirmation of endocardial biventricular pacing and in 2 patients, there was a failure of electrode capture. Eighteen patients proceeded to 6-month follow-up; endocardial pacing resulted in a significant reduction in QRS duration compared with intrinsic QRS duration (26.6 ± 24.4 ms; P = .002) and improvement in left ventricular ejection fraction (LVEF) (4.7 ± 7.9%; P = .021). The mean reduction in left ventricular end-diastolic volume was 8.3 ± 42.3 cm3 (P = .458) and left ventricular end-systolic volume (LVESV) was 13.1 ± 44.3 cm3 (P = .271), which were statistically nonsignificant. Overall, 55.6% of patients had improvement in their clinical composite score and 66.7% had a reduction in LVESV ≥15% and/or absolute improvement in LVEF ≥5%. CONCLUSION: Nonresponders to conventional CRT have few remaining treatment options. We have shown in this high-risk patient group that the WiSE-CRT system results in improvement in their clinical composite scores and leads to LV remodeling.
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Estimulação Cardíaca Artificial/métodos , Terapia de Ressincronização Cardíaca/efeitos adversos , Endocárdio/fisiopatologia , Marca-Passo Artificial , Idoso , Feminino , Humanos , Masculino , Desenho de Prótese , Sistema de Registros , Falha de Tratamento , Remodelação VentricularRESUMO
BACKGROUND: Biventricular endocardial pacing (BiV ENDO) is a therapy for heart failure patients who cannot receive transvenous epicardial cardiac resynchronization therapy (CRT) or have not responded adequately to CRT. BiV ENDO CRT can be delivered by a new wireless LV ENDO pacing system (WiSE-CRT system; EBR Systems, Sunnyvale, CA), without the requirement for lifelong anticoagulation. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of the WiSE-CRT system during real-world clinical use in an international registry. METHODS: Data were prospectively collected from 14 centers implanting the WiSE-CRT system as part of the WiCS-LV Post Market Surveillance Registry. (ClinicalTrials.gov Identifier: NCT02610673). RESULTS: Ninety patients from 14 European centers underwent implantation with the WiSE-CRT system. Patients were predominantly male, age 68.2 ± 10.5 years, left ventricular ejection fraction 30.6% ± 8.9%, mean QRS duration 180.7 ± 27.0 ms, and 40% with ischemic etiology. Successful implantation and delivery of BiV ENDO pacing was achieved in 94.4% of patients. Acute (<24 hours), 1- to 30-day, and 1- to 6-month complications rates were 4.4%, 18.8%, and 6.7%, respectively. Five deaths (5.6%) occurred within 6 months (3 procedure related). Seventy percent of patients had improvement in heart failure symptoms. CONCLUSION: BiV ENDO pacing with the WiSE-CRT system seems to be technically feasible, with a high success rate. Three procedural deaths occurred during the study. Procedural complications mandate adequate operator training and implantation at centers with immediately available cardiothoracic and vascular surgical support.
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Dispositivos de Terapia de Ressincronização Cardíaca , Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/terapia , Ventrículos do Coração/fisiopatologia , Sistema de Registros , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Idoso , Endocárdio , Desenho de Equipamento , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Resultado do TratamentoRESUMO
INTRODUCTION: Limited evidence is available concerning experience with use of zoledronic acid (ZA) and treatment for conditions other than primary bone fragility. MATERIALS AND METHODS: A retrospective review of all Royal Children Hospital patients who had been administered at least 1 dose of intravenous ZA from 2002 to 2015 was undertaken. RESULTS: The audit included 309 children with 228 being treated for bone fragility conditions. Of the 228, 68 had height-adjusted lumbar spine bone mineral density Z-scores available over up to a 5-year period, and median increases were +2.0 SD (median absolute deviation = 0.9) (N = 36, p value for median increase of at least 0.5 in Z-score <0.001), for patients with osteogenesis imperfecta or other primary bone fragility disorders, +1.0 SD (0.9) (N = 14, p = 0.029), for immobility conditions, +0.5 SD (0.7) (N = 10, p = 0.399), and for glucocorticoid-induced secondary osteoporosis, +0.7 SD (0.6) (N = 8, p = 0.015). 81/309 children were treated for bone abnormality indications (e.g., avascular necrosis [AVN], fibrous dysplasia, and bone cysts). Of 39 with AVN, outcome data were available for 33, with joint integrity maintained for 24/33 from 6 to 24 months after last ZA, subjective reports (22/28) of reduced pain. Reduction in bone lesion size was seen in 2/4 patients with bone cysts within 12 months of ZA commencement. DISCUSSION/CONCLUSION: This is the largest cohort of reported outcomes of ZA use in a paediatric population. Results demonstrate a good efficacy profile and associated improved bone density for osteoporotic conditions and stabilization of non-traumatic AVN with a low rate of joint collapse.
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Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas/tratamento farmacológico , Ácido Zoledrônico/uso terapêutico , Adolescente , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Ácido Zoledrônico/farmacologiaRESUMO
Background: Neuroinflammation and biometal dyshomeostasis are key pathological features of several neurodegenerative diseases, including Alzheimer's disease (AD). Inflammation and biometals are linked at the molecular level through regulation of metal buffering proteins such as the metallothioneins. Even though the molecular connections between metals and inflammation have been demonstrated, little information exists on the effect of copper modulation on brain inflammation. Methods: We demonstrate the immunomodulatory potential of the copper bis(thiosemicarbazone) complex CuII(atsm) in an neuroinflammatory model in vivo and describe its anti-inflammatory effects on microglia and astrocytes in vitro. Results: By using a sophisticated in vivo magnetic resonance imaging (MRI) approach, we report the efficacy of CuII(atsm) in reducing acute cerebrovascular inflammation caused by peripheral administration of bacterial lipopolysaccharide (LPS). CuII(atsm) also induced anti-inflammatory outcomes in primary microglia [significant reductions in nitric oxide (NO), monocyte chemoattractant protein 1 (MCP-1), and tumor necrosis factor (TNF)] and astrocytes [significantly reduced NO, MCP-1, and interleukin 6 (IL-6)] in vitro. These anti-inflammatory actions were associated with increased cellular copper levels and increased the neuroprotective protein metallothionein-1 (MT1) in microglia and astrocytes. Conclusion: The beneficial effects of CuII(atsm) on the neuroimmune system suggest copper complexes are potential therapeutics for the treatment of neuroinflammatory conditions.
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OBJECTIVES: This study hypothesized that guided implants, in which the optimal left ventricular endocardial (LVENDO) pacing location was identified and targeted, would improve acute markers of contractility and chronic markers of cardiac resynchronization (CRT) response. BACKGROUND: Biventricular endocardial (BiVENDO) pacing may offer a potential benefit over standard CRT; however, the optimal LVENDO pacing site is highly variable. Indiscriminately delivered BiVENDO pacing is associated with a reverse remodeling response rate of between 40% and 60%. METHODS: Registry of centers implanting a wireless, LVENDO pacing system (WiSE-CRT System, EBR Systems, Sunnyvale, California); John Radcliffe Hospital (Oxford, United Kingdom), Guy's and St. Thomas' Hospital (London, United Kingdom), and The James Cook University Hospital (Middlesbrough, United Kingdom). Centers used a combination of preprocedural imaging and electroanatomical mapping the identify the optimal LVENDO site. RESULTS: A total of 26 patients across the 3 centers underwent a guided implant. Patients were predominantly male with a mean age of 68.8 ± 8.4 years, the mean LV ejection fraction was 34.2 ± 7.8%. The mean QRS duration was 163.8 ± 26.7 ms, and 30.8% of patients had an ischemic etiology. It proved technically feasible to selectively target and deploy the pacing electrode in a chosen endocardial segment in almost all cases, with a similar complication rate to that observed during indiscriminate BiVENDO. Ninety percent of patients met the definition of echocardiographic responder. Reverse remodeling was observed in 71%. CONCLUSIONS: Guided endocardial implants were associated with a higher degree of chronic LV remodeling compared with historical nonguided approaches.
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Dispositivos de Terapia de Ressincronização Cardíaca , Ventrículos do Coração , Hemodinâmica/fisiologia , Cirurgia Assistida por Computador/métodos , Idoso , Terapia de Ressincronização Cardíaca , Eletrocardiografia , Eletrodos Implantados , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Tecnologia sem FioRESUMO
INTRODUCTION: Improvements in the medical management of cystic fibrosis (CF) in recent years have resulted in increased prevalence of long-term sequelae of the condition, such as low bone mineral density (BMD) and hence an increased risk of fractures in later life. Aim To explore the interaction between BMD and lung function, nutrition, and genotype. METHODS: This study was a retrospective audit of 202 children with CF from August 2000 to January 2016 to investigate associations between BMD Z-scores with clinical status, nutrition, and genetics using dual-energy absorptiometry X-ray data from the Royal Children's Hospital Melbourne, Australia. RESULTS: Severity of both lung disease (P < 0.0001) and nutritional status (P < 0.05) was found to be strongly associated with BMD Z-scores. CONCLUSIONS: This is the biggest study to date to provide further evidence that the severity of pulmonary disease is related to BMD in CF patients and therefore screening guidelines for bone health in children with CF should target individuals with the poorest clinical status.
Assuntos
Densidade Óssea , Fibrose Cística/fisiopatologia , Absorciometria de Fóton , Adolescente , Austrália , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Estado Nutricional , Prevalência , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
In this issue of Cell Chemical Biology, Telling et al. (2017) apply advanced X-ray microscopy techniques to reveal magnetite iron species in plaques from a mouse model of Alzheimer's disease. The characterization of abnormal iron chemistry in the disease model highlights the potential for iron to combine with the ß-amyloid peptide and accelerate the disease process.