Etiologies and Impact of Exclusion Rates for Transcatheter Mitral and Tricuspid Valve Structural Heart Clinical Trials at a High-Volume Quaternary Care Hospital.

There are various devices under clinical investigation for transcatheter mitral valve intervention and transcatheter tricuspid valve intervention (TTVI); however, the exclusion rates remain high. We aimed to investigate the exclusion rates for transcatheter mitral valve repair (TMVr), transcatheter mitral valve replacement (TMVR), transcatheter tricuspid valve repair (TTVr), and transcatheter tricuspid valve replacement (TTVR). There were 129 patients who were referred to St. Francis Hospital & Heart Center valve clinic and completed screening between January 2021 and July 2022. The causes for exclusion were classified into 4 categories: patient withdrawal, anatomic unsuitability, clinical criteria, and medical futility. In 129 patients, the exclusion rates for TMVr, TMVR, TTVr, and TTVR were 81%, 85%, 91%, and 87%, respectively. Patient withdrawal and medical futility were leading etiologies for exclusion, followed by anatomic unsuitability. TMVr had the highest rate of patient withdrawal (64%) and the lowest anatomic unsuitability (5%) because of short posterior leaflet length. Replacement interventions have a higher anatomic unsuitability (33%) than repair interventions (17%) (p = 0.04). Most exclusions of anatomic unsuitability were because of mitral stenosis or small annulus size for TMVR and large annulus size for TTVR. A total of 50% of exclusions from TTVr were because of the presence of pacemaker/defibrillator leads. In patients excluded from their respective trials, patients being referred for TMVr had the highest recurrent hospitalization and repair group had a higher mortality (p <0.01 and p = 0.01, respectively). In conclusion, the exclusion rates for transcatheter mitral valve intervention and TTVI trials remain high because of various reasons, limiting patient enrollment and treatment. This supports the need for further device improvement or exploring alternative means of therapy.

Pseudomonas aeruginosa ventricular assist device infections: findings from ineffective phage therapies in five cases.

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration.

Adequacy of thyroid hormone replacement for people with hypothyroidism in real-world settings: A systematic review and meta-analysis of observational studies.

OBJECTIVE: Thyroid hormone under-replacement and over-replacement are associated with adverse health outcomes. This systematic review aimed to evaluate the extent of thyroid hormone replacement adequacy for patients with known hypothyroidism in real-word settings, excluding those receiving thyroid hormone suppressive therapy as thyroid cancer treatment. DESIGN: Four electronic databases (Embase [Ovid], Medline [Ovid], PubMed and SCOPUS) were searched for published and unpublished observational studies until 12 December 2022. The results of the studies were meta-analysed to calculate pooled prevalence estimates for thyroid hormone supplementation adequacy, over-replacement and under-replacement. Quality assessment of studies was performed using the Joanna-Briggs appraisal tool for prevalence studies. RESULTS: Seven studies with a total of 4230 patients were eligible for quantitative synthesis. The pooled prevalence estimates of adequate thyroid replacement, over-replacement and under-replacement were 0.55 (95% confidence interval [CI]: 0.49-0.60, p = .001), 0.20 (95% CI: 0.14-0.27, p = .001) and 0.24 (95% CI: 0.13-0.36, p = .001), respectively. Four studies subclassified hypothyroidism and hyperthyroidism into overt and subclinical. The pooled prevalence of overt and subclinical hyperthyroidism was 0.04 (95% CI: 0.00-0.11, p = .01) and 0.17 (95% CI: 0.09-0.27 p = .001), respectively. For overt and subclinical hypothyroidism, the pooled prevalence was 0.02 (95% CI: 0.01-0.03, p = .001) and 0.20 (95% CI: 0.12-0.29, p = .001), respectively. CONCLUSIONS: On average, approximately half of patients with hypothyroidism are only treated to target euthyroidism. In real-world practice, a significant number of patients are over-treated or under-treated, leading to adverse healthcare outcomes. It is imperative that more effective thyroid monitoring strategies be implemented, with an emphasis on primary care thyroid function monitoring, to minimise inappropriate thyroid replacement treatments and optimise healthcare outcomes at a population level.

Flow Dynamics in Children With Bicuspid Aortic Valve: A Blood Speckle Tracking Study.

OBJECTIVE: Bicuspid aortic valve (BAV) is associated with progressive aortic dilation. Although the etiology is complex, altered flow dynamics is thought to play an important role. Blood speckle tracking (BST) allows for visualization and quantification of complex flow, which could be useful in identifying patients at risk of root dilation and could aid in surgical planning. The aims of this study were to assess and quantify flow in the aortic root and left ventricle using BST in children with bicuspid aortic valves. METHODS AND RESULTS: A total of 38 children <10 y of age were included (24 controls, 14 with BAV). Flow dynamics were examined using BST in the aortic root and left ventricle. Children with BAV had altered systolic flow patterns in the aortic root and higher aortic root average vorticity (25.9 [23.4-29.2] Hz vs. 17.8 [9.0-26.2] Hz, p < 0.05), vector complexity (0.17 [0.14-0.31] vs. 0.05 [0.02-0.13], p < 0.01) and rate of energy loss (7.9 [4.9-12.1] mW/m vs. 2.7 [1.2-7.4] mW/m, p = 0.01). Left ventricular average diastolic vorticity (20.9 ± 5.8 Hz vs. 11.4 ± 5.2 Hz, p < 0.01), kinetic energy (0.11 ± 0.05 J/m vs. 0.04 ± 0.02 J/m, p < 0.01), vector complexity (0.38 ± 0.1 vs. 0.23 ± 0.1, p < 0.01) and rate of energy loss (11.1 ± 4.8 mW/m vs. 2.7 ± 1.9 mW/m, p < 0.01) were higher in children with BAV. CONCLUSION: Children with BAV exhibit altered flow dynamics in the aortic root and left ventricle in the absence of significant aortic root dilation. This may represent a substrate and potential predictor for future dilation and diastolic dysfunction.

Local arterial stiffness measured by ultrafast ultrasound imaging in childhood cancer survivors treated with anthracyclines.

Background: There is conflicting literature regarding the long-term effect of anthracycline treatment on arterial stiffness. This study assessed local arterial stiffness using ultrafast ultrasound imaging (UUI) in anthracycline treated childhood cancer survivors, at rest and during exercise. Methods: 20 childhood cancer survivors (mean age 21.02 ± 9.45 years) treated with anthracyclines (mean cumulative dose 200.7 ± 126.80 mg/m2) and 21 healthy controls (mean age 26.00 ± 8.91 years) were included. Participants completed a demographic survey, fasting bloodwork for cardiovascular biomarkers, and performed a submaximal exercise test on a semi-supine bicycle. Pulse wave velocity (PWV) was measured in the left common carotid artery by direct pulse wave imaging using UUI at rest and submaximal exercise. Both PWV at the systolic foot (PWV-SF) and dicrotic notch (PWV-DN) were measured. Central (carotid-femoral) PWV was obtained by applanation tonometry. Carotid measurements were taken by conventional ultrasound. Measures were compared using two-tailed Students t-test or Chi-squared test, as appropriate. Results: There was no statistically significant difference (p > 0.05) between childhood cancer survivors and healthy controls in demographic parameters (age, sex, weight, height, BMI), blood biomarkers (total cholesterol, triglycerides, LDL-c, HDL-c, hs-CRP, fasting glucose, insulin, Hb A1c), cardiovascular parameters (intima media thickness, systolic and diastolic blood pressure, heart rate, carotid diameters, distensibility) or PWV measured by UUI at rest or at exercise. There was also no difference in the cardiovascular adaptation between rest and exercise in the two groups (p > 0.05). Multivariate analysis revealed age (p = 0.024) and LDL-c (p = 0.019) to be significant correlates of PWV-SF in childhood cancer survivors, in line with previously published data. Conclusion: We did not identify a significant impact of anthracycline treatment in young survivors of childhood cancer on local arterial stiffness in the left common carotid artery as measured by UUI.

Attendance Improves Student Electrocardiography Interpretation Skills Using the Flipped Classroom Format.

The implementation of classroom capture and casting technologies has changed how content can be accessed. Students can access live, streaming, and/or recorded formats of material. Broadening this accessibility has, in turn, introduced flexibility for both the learner and the instructor. This flexibility has impacted the necessity of attendance to access classroom-delivered content. There are many reports that investigate the changing attendance climate as well as the potential impact of attendance on student outcomes. Here we investigated the impact of attending classroom activities on student performance with two common content delivery methods in an undergraduate, pre-clinical cardiology course. Electrocardiography (ECG) interpretation was taught using a flipped classroom format which allowed for the practice of interpretive skills with faculty guidance. Other components of the course related to the diagnosis, treatment, and management of cardiovascular disease were delivered using a lecture-based format. The results demonstrate that attendees outperform their classmates in the ability to interpret ECGs and related content. However, the attending student does not appear to have a performance advantage when content is delivered by lecture. The results provide evidence for students to prioritize their time when making decisions about attendance, based on teaching modality, when given a choice. Further, the information can guide curricular change and help colleges and programs identify curricular activities that have a clear attendance benefit for students. Supplementary Information: The online version contains supplementary material available at 10.1007/s40670-022-01689-5.

Multicentric validation of a prognostic tool for predicting brain death following out-of-hospital cardiac arrest in children.

AIM: Out-of-hospital cardiac arrest (OHCA) in pediatric patients is associated with high rates of mortality and neurologic injury, with no definitive evidence-based method to predict outcomes available. A prognostic scoring tool for adults, The Brain Death After Cardiac Arrest (BDCA) score, was recently developed and validated. We aimed to validate this score in pediatric patients. METHODS: Retrospective cohort study of pediatric patients admitted to 5 PICUs after OHCA between 2011 and 2021. We extracted BDCA score elements for those who survived at least 24 hours but died as a result of their OHCA. We assessed score discrimination for the definitive outcome of brain death. Subgroup analysis was performed for infants < 12mo versus children ≥ 12mo, those who likely had brain death but had withdrawal of life sustaining therapy (WLST) prior to declaration, and by etiology and duration of arrest. RESULTS: 389 subjects were identified across 5 institutions, with 282 meeting inclusion criteria. 169 (59.9%) were formally declared brain dead; 58 (20.6%) had findings consistent with brain death but had withdrawal of life sustaining therapies prior to completion of formal declaration. Area under the receiver operating characteristic curve for the age ≥ 12mo cohort was 0.82 [95% CI 0.75, 0.90], which mirrored the adult subject AUCs of 0.82 [0.77, 0.86] and 0.81 [0.76, 0.86] in the development and validation cohorts. Scores demonstrated worse discrimination in the infant cohort (AUC = 0.61). CONCLUSIONS: The BDCA score shows promise in children ≥ 12mo following OHCA and may be considered in conjunction with existing multimodal prognostication approaches.

Assessment of Early Diastolic Intraventricular Pressure Difference in Children by Blood Speckle-Tracking Echocardiography.

BACKGROUND: The lack of reliable echocardiographic techniques to assess diastolic function in children is a major clinical limitation. Our aim was to develop and validate the intraventricular pressure difference (IVPD) calculation using blood speckle-tracking (BST) and investigate the method's potential role in the assessment of diastolic function in children. METHODS: Blood speckle-tracking allows two-dimensional angle-independent blood flow velocity estimation. Blood speckle-tracking images of left ventricular (LV) inflow from the apical 4-chamber view in 138 controls, 10 patients with dilated cardiomyopathies (DCMs), and 21 patients with hypertrophic cardiomyopathies (HCMs) <18 years of age were analyzed to study LV IVPD during early diastole. Reproducibility of the IVPD analysis was assessed, IVPD estimates from BST and color M mode were compared, and the validity of the BST-based IVPD calculations was tested in a computer flow model. RESULTS: Mean IVPD was significantly higher in controls (-2.28 ± 0.62 mm Hg) compared with in DCM (-1.21 ± 0.39 mm Hg, P < .001) and HCM (-1.57 ± 0.47 mm Hg, P < .001) patients. Feasibility was 88.3% in controls, 80% in DCM patients, and 90.4% in HCM patients. The peak relative negative pressure occurred earlier at the apex than at the base and preceded the peak E-wave LV filling velocity, indicating that it represents diastolic suction. Intraclass correlation coefficients for intra- and interobserver variability were 0.908 and 0.702, respectively. There was a nonsignificant mean difference of 0.15 mm Hg between IVPD from BST and color M mode. Estimation from two-dimensional velocities revealed a difference in peak IVPD of 0.12 mm Hg (6.6%) when simulated in a three-dimensional fluid mechanics model. CONCLUSIONS: Intraventricular pressure difference calculation from BST is highly feasible and provides information on diastolic suction and early filling in children with heart disease. Intraventricular pressure difference was significantly reduced in children with DCM and HCM compared with controls, indicating reduced early diastolic suction in these patient groups.

Detection of SARS-CoV-2 IgA and IgG in human milk and breastfeeding infant stool 6 months after maternal COVID-19 vaccination.

OBJECTIVE: Assess presence, durability, and neutralization capacity of SARS-CoV-2-specific antibodies in breastfeeding infants' stool, mother's plasma and milk following maternal vaccination. DESIGN: Thirty-seven mothers and 25 infants were enrolled between December 2020 and November 2021 for this prospective observational study. All mothers were vaccinated during lactation except three, which were vaccinated during pregnancy. Milk, maternal plasma, and infants' stool was collected pre-vaccination and at periods up to 6 months following COVID-19 vaccine series initiation/completion. SARS-CoV-2 antibody levels and their neutralization capacities were assessed. RESULTS: SARS-CoV-2-specific IgA and IgG levels were higher in infant stool post-maternal vaccination amongst milk-fed compared to controls. Maternal SARS-CoV-2-specific IgA and IgG concentrations decreased over 6 months post-vaccination but remained higher than pre-vaccination levels. We observed improved neutralization capacity in milk and plasma after COVID-19 vaccination. CONCLUSIONS: The presence of SARS-CoV-2-specific antibodies in infant stool following maternal vaccination offers further evidence of the lasting transfer of these antibodies through breastfeeding.

Governing taste: data, temporality and everyday kiwifruit dry matter performances.

Data is essential to governing those emerging matters of concern that confront the agrifood every day. But data is no neutral intermediary. It disrupts, exposes, and creates new social, economic, political, and environmental possibilities, whilst simultaneously hiding, excluding, and foreclosing others. Scholars have become attuned to both the constitutive role of data in creating everyday worlds, and the need to develop critical accounts of the materialities, spatialities and multiplicities of data relationships. Whereas this emerging work develops insight to the capacity for data topologies to reterritorialise the spatial performances of everyday life, it has largely reduced the associated temporal dimensions to matters of fact. The effect of these performances has been to naturalize the temporal quality of speed and elide the multiple temporalities required to enact contemporary data worlds. Applying the lenses of infrastructuring, performativity and ferality, this paper explores temporality and data in the everyday worlds produced through the New Zealand kiwifruit industry's focus on dry matter. The paper argues that temporalities are deeply embedded in the kiwifruit industry's data relations. We show that while temporal data relations are critical to the industry, we also highlight ways in which those relations introduce new, potentially destabilizing performances into kiwifruit relations.

Detection of SARS-CoV-2 IgA and IgG in human milk and breastfeeding infant stool 6 months after maternal COVID-19 vaccination.

Objective Assess the presence, durability, and neutralization capacity of SARS-CoV-2-specific antibodies in breastfeeding infants' stools, mother's plasma, and human milk following maternal vaccination. Design Thirty-seven mothers and 25 infants were enrolled between December 2020 and November 2021 for this prospective observational study. Human milk, maternal plasma, and infants' stools were collected pre-vaccination and at periods up to 6 months following COVID-19 vaccine series initiation/completion. SARS-CoV-2 antibody levels and their neutralization capacities were assessed in collected samples. Results SARS-CoV-2-specific IgA and IgG levels were higher in infant stool post-maternal vaccination amongst milk-fed compared to pre-COVID controls. Human milk and plasma SARS-CoV-2-specific IgA and IgG concentrations decreased over 6 months post-vaccination but remained higher than pre-vaccination levels. We observed improved neutralization capacity in milk antibodies over time. Conclusions The presence of neutralizing SARS-CoV-2-specific antibodies in infant stool following maternal vaccination offers further evidence of the lasting transfer of these antibodies through breastfeeding and their protective effect.

Evaluation of site-specific methylation of the CMV promoter and its role in CHO cell productivity of a recombinant monoclonal antibody.

We previously demonstrated that increased monoclonal antibody productivity in dihydrofolate reductase (DHFR)-amplified CHO cells correlates with phosphorylated transcription factor-cytomegalovirus (CMV) promoter interactions. In this article, we extend the characterization to include CMV promoter methylation and its influence on NFκB and CREB1 transcription factor binding to the CMV promoter in two families of DHFR-amplified CHO cell lines. CMV promoter methylation was determined using bisulfite sequencing. To overcome Sanger-sequencing limitations due to high CG bias and multiple transgenes copies, pyrosequencing was used to determine the frequency of methylated cytosines in regions proximal to and containing the NFκB and CREB1 transcription-factor consensus binding sites. Chromatin immunoprecipitation was performed to interrogate transcription factor-DNA interactions. Antibodies to CREB1 and NFκB were used to immunoprecipitate formaldehyde-crosslinked protein-DNA fractions, followed by reverse transcription quantitative real-time polymerase chain reaction to quantitate the number of copies of CMV-promoter DNA bound to the various transcription factors. The relative unmethylated fraction at the CREB1 and NFκB consensus binding sites determined by pyrosequencing was correlated with transcription factor binding as determined by chromatin immunoprecipitation. Azacytidine treatment reduced methylation in all treated samples, though not at all methylation sites, while increasing transcription. Distinct promoter methylation patterns arise upon clonal selection in different families of cell lines. In both cell line families, increased methylation was observed upon amplification. In one family, the NFκB binding-site methylation was accompanied by increased CREB1 interaction with the promoter. In the other cell line family, lower methylation frequency at the NFκB consensus binding site was accompanied by more NFκB recruitment to the promoter region.

Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy.

In 2016, a 68-year-old patient with a disseminated multidrug-resistant Acinetobacter baumannii infection was successfully treated using lytic bacteriophages. Here we report the genomes of the nine phages used for treatment and three strains of A. baumannii isolated prior to and during treatment. The phages used in the initial treatment are related, T4-like myophages. Analysis of 19 A. baumannii isolates collected before and during phage treatment shows that resistance to the T4-like phages appeared two days following the start of treatment. We generate complete genomic sequences for three A. baumannii strains (TP1, TP2 and TP3) collected before and during treatment, supporting a clonal relationship. Furthermore, we use strain TP1 to select for increased resistance to five of the phages in vitro, and identify mutations that are also found in phage-insensitive isolates TP2 and TP3 (which evolved in vivo during phage treatment). These results support that in vitro investigations can produce results that are relevant to the in vivo environment.

Imaging features of renal malperfusion in aortic dissection.

OBJECTIVES: Malperfusion syndrome accompanying aortic dissection is an independent predictor of death with in-hospital mortality rates >60%. Asymmetrically decreased renal enhancement on computed tomography angiography is often considered evidence of renal malperfusion. We investigated the associations between renal enhancement, baseline laboratory values and the diagnosis of renal malperfusion, as defined by invasive manometry, among patients with aortic dissection. METHODS: In this retrospective cohort study, we included all patients who were referred to our institution with acute dissection and suspected visceral malperfusion between 2010 and 2020. We determined asymmetric renal enhancement by visual assessment and quantitative density measurements of the renal cortex. We collected invasive renal artery pressures during invasive angiography at the aortic root and in the renal arteries. Logistic regression was performed to evaluate independent predictors of renal malperfusion. RESULTS: Among the 161 patients analysed, the majority of patients were male (78%) and had type A dissection (52%). Invasive angiography confirmed suspected renal malperfusion in 83% of patients. Global asymmetric renal enhancement was seen in 42% of patients who did not have renal malperfusion during invasive angiography. Asymmetrically decreased renal enhancement was 65% sensitive and 58% specific for renal malperfusion. Both global [odds ratio (OR) 4.43; 1.20-16.41, P = 0.03] and focal (OR 11.23; 1.12-112.90, P = 0.04) enhancement defects were independent predictors for renal malperfusion. CONCLUSIONS: In patients with aortic dissection, we found that differential enhancement of the kidney as seen on the computed tomography angiography is predictive, but not prescriptive for renal malperfusion. While detection of renal malperfusion is aided by computed tomography angiography, its diagnosis requires close monitoring and often invasive assessment.

Pulmonary Hypertension in Children is Associated With Abnormal Flow Patterns in the Main Pulmonary Artery as Demonstrated by Blood Speckle Tracking.

Background: Paediatric pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance resulting in increased pulmonary artery (PA) and right ventricular pressure (RV). This is associated with disturbed flow dynamics in the PA and RV that are not well characterized. We aimed to compare flow dynamics in children with PAH compared with healthy controls using blood speckle tracking echocardiography. Methods: Patients <10 years of age with PAH and healthy controls were included. We examined flow dynamics in the main PA (MPA) and right ventricle based on acquisition blood speckle tracking images obtained from the RV and PA. Qualitative and quantitative analyses were performed. Results: Eighteen subjects were included in each group. A diastolic vortex in the MPA was identified in 16 of the patients with PAH, but not in controls. Significantly higher MPA systolic (4.84 vs 2.42 mW/m; P = 0.01) and diastolic (0.69 vs 0.14 mW/m; P = 0.01) energy loss, as well as increased vector complexity (systole: 0.21 vs 0.04, P = 0.003; diastole: 0.13 vs 0.05, P = 0.04) and diastolic vorticity (15.2 vs 4.4 Hz; P = 0.001), were noted in PAH compared with controls. Conclusion: This study demonstrates the presence of abnormal flow patterns in the MPA with diastolic vortex formation in most patients with PAH. This diastolic vortex likely results from reflected waves from the distal pulmonary bed. Our data indicate that the diastolic vortex could potentially be used in the diagnosis of PAH. The clinical significance of the energy loss findings warrants further investigation in a larger cohort of patients with PAH.

Contexte: L'hypertension artérielle pulmonaire (HTAP) pédiatrique est caractérisée par une résistance vasculaire pulmonaire accrue qui donne lieu à une augmentation de la pression dans l'artère pulmonaire (AP) et dans le ventricule droit (VD). Ce phénomène s'accompagne de perturbations de la dynamique des débits dans l'AP et le VD, qui n'ont pas encore été bien caractérisées. Nous avons cherché à comparer la dynamique des débits chez des enfants atteints d'HTAP avec celle de témoins en bonne santé en utilisant l'échocardiographie de suivi des marqueurs acoustiques du sang. Méthodologie: Des patients de moins de 10 ans atteints d'HTAP et des témoins en bonne santé ont participé à l'étude. La dynamique des débits du tronc pulmonaire (TP) et du ventricule droit a été examinée à partir d'images de suivi des marqueurs acoustiques du sang de l'AP et du VD. Des analyses qualitatives et quantitatives ont aussi été réalisées. Résultats: Dix-huit sujets ont été inclus dans chacun des groupes. Un vortex diastolique du TP a été observé chez 16 des patients atteints d'HTAP, mais n'était présent chez aucun des témoins. Une perte d'énergie significativement plus élevée dans le TP a été notée pour la systole (4,84 vs 2,42 mW/m; P = 0,01) et la diastole (0,69 vs 0,14 mW/m; P = 0,01) des patients atteints d'HTAP; de plus, une complexité vectorielle accrue (systole : 0,21 vs 0,04, P = 0,003; diastole : 0,13 vs 0,05, P = 0,04) et une vorticité diastolique accrue (15,2 vs 4,4 Hz; P = 0,001) ont été notées chez les patients atteints d'HTAP comparativement aux témoins. Conclusion: Notre étude fait état d'un profil circulatoire anormal caractérisé par la formation d'un vortex diastolique dans le TP chez la plupart des patients atteints d'HTAP. Ce vortex découle probablement d'ondes réfléchies du lit pulmonaire distal. Les données que nous avons obtenues indiquent que le vortex diastolique pourrait possiblement être utilisé dans le diagnostic de l'HTAP. Par contre, la signification clinique des résultats concernant la perte d'énergie nécessite d'autres études auprès d'une cohorte plus importante de patients atteints d'HTAP.

Successful Intratracheal Treatment of Phage and Antibiotic Combination Therapy of a Multi-Drug Resistant Pseudomonas aeruginosa Murine Model.

BACKGROUND: Pseudomonas aeruginosa (PsA) is a common etiology of bacteria-mediated lower respiratory tract infections, including pneumonia, hospital acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). Given the paucity of novel antibiotics in our foreseeable pipeline, developing novel non-antibiotic antimicrobial therapies saliently targeting drug resistant PsA isolates remains a priority. Lytic bacteriophages (or phages) have come under scrutiny as a potential antimicrobial for refractory bacterial infections. We evaluated intratracheally and intraperitoneally (IP) administered phage therapy (with/without meropenem) in an acute immunocompromised mouse model of multi-drug resistant (MDR) PsA pulmonary infection. The MDR P. aeruginosa respiratory disease model used in these studies was developed to investigate novel therapies that might have efficacy as either monotherapies or as combination therapy with meropenem. METHODS: We utilized eight-week-old, 18 g BALB/cJ female mice and an MDR strain of PsA (UNC-D). Mice were immunosuppressed with cyclophosphamide. We employed a three-phage cocktail targeting PsA (PaAH2ΦP (103), PaBAP5Φ2 (130), and PaΦ (134)), confirmed to exhibit in vitro suppression of the infecting isolate out to 45 h. Suppression was confirmed with phages acting in isolation and in combination with meropenem. RESULTS: IP administration of phage did not protect mice from death. A one-time delivery of phage directly to the lungs via a single intubation-mediated, intratracheal (IMIT) instillation protected mice from lethal infection. Protection was observed despite delaying therapy out to 6 h. Finally, we observed that, by slowing the progression of infection by treatment with a sub-efficacious dose of meropenem, we could protect the mice from lethal infection via IP phage administration coupled to meropenem, observing partial additive effects of phage-antibiotic combination therapy. CONCLUSIONS: A personalized phage cocktail administered via IMIT exhibits high therapeutic efficacy, despite delayed treatment of 6 h in a lethal MDR PsA pneumonia model. IP phage alone did not forestall mortality, but exhibited efficacy when combined with meropenem and IMIT-administered phage. These additive effects of combined IP phage and meropenem confirm that phage may indeed reach the lung bed via the systemic circulation and protect mice if the infection is not too acute. Therefore, adjunctive phage therapy with concerted attention to identifying optimal phage targeting of the infecting isolate in vitro may exhibit transformative potential for combating the specter of MDR bacterial infections. Phage should serve as an integral component of a four-pronged approach coupled with antibiotics, source control, and immune optimization.

Successful Treatment of Staphylococcus aureus Prosthetic Joint Infection with Bacteriophage Therapy.

Successful joint replacement is a life-enhancing procedure with significant growth in the past decade. Prosthetic joint infection occurs rarely; it is a biofilm-based infection that is poorly responsive to antibiotic alone. Recent interest in bacteriophage therapy has made it possible to treat some biofilm-based infections, as well as those caused by multidrug-resistant pathogens, successfully when conventional antibiotic therapy has failed. Here, we describe the case of a 61-year-old woman who was successfully treated after a second cycle of bacteriophage therapy administered at the time of a two-stage exchange procedure for a persistent methicillin-sensitive Staphylococcus aureus (MSSA) prosthetic knee-joint infection. We highlight the safety and efficacy of both intravenous and intra-articular infusions of bacteriophage therapy, a successful outcome with a single lytic phage, and the development of serum neutralization with prolonged treatment.