Association Between Segmental Noninvasive Myocardial Work and Microvascular Perfusion in ST-Segment Elevation Myocardial Infarction: Implications for Left Ventricular Functional Recovery and Clinical Outcomes.

BACKGROUND: Predicting left ventricular recovery (LVR) after acute ST-segment elevation myocardial infarction (STEMI) is of prognostic importance. This study aims to explore the prognostic implications of segmental noninvasive myocardial work (MW) and microvascular perfusion (MVP) after STEMI. METHODS: In this retrospective study, 112 patients with STEMI who underwent primary percutaneous coronary intervention and transthoracic echocardiography after percutaneous coronary intervention were enrolled. Microvascular perfusion was analyzed by myocardial contrast echocardiography, and segmental MW was analyzed by noninvasive pressure-strain loops. A total of 671 segments with abnormal function at baseline were analyzed. The degrees of MVP were observed following intermittent high-mechanical index impulses: replenishment within 4 seconds (normal MVP), replenishment >4 seconds and within 10 seconds (delayed MVP), and persistent defect (microvascular obstruction). The correlation between MW and MVP was analyzed. The correlation of the MW and MVP with LVR (normalization of wall thickening, >25%) was assessed. The prognostic value of segmental MW and MVP for cardiac events (cardiac death, admission for congestive heart failure, or recurrent myocardial infarction) was evaluated. RESULTS: Normal MVP was seen in 70 segments, delayed MVP in 236, and microvascular obstruction in 365. The segmental MW indices were independently correlated with MVP; 244 (36.4%) segments had segmental LVR at 3-month follow-up. Segmental MW efficiency and MVP were independently associated with segmental LVR (P < .05). The χ2 of combination of segmental MW efficiency and MVP was higher than either index alone for identifying segmental LVR (P < .001). At a median follow-up of 42.0 months, cardiac events occurred in 13 patients; all regional MW parameters, high sensitivity troponin I, regional longitudinal strain, and so on were associated with cardiac events. CONCLUSIONS: Segmental MW indices are associated with MVP within the infarct zone following reperfused STEMI. Both are independently associated with segmental LVR, and regional MW is associated with cardiac events, providing prognostic value in STEMI patients.

Evaluation of left atrial function and mechanical dispersion in breast cancer patients after chemotherapy.

BACKGROUND: Left atrial (LA) function and mechanical dispersion changes in breast cancer patients treated with chemotherapy remain unclear. HYPOTHESIS: LA function and LA mechanical dispersion in breast cancer patients would be impaired after chemotherapy. METHODS: This single-center retrospective study included 91 consecutive breast cancer patients treated with chemotherapy and 30 controls. Patients were examined by echocardiography three times at intervals. Conventional parameters, left ventricular strain, LA strain, and LA mechanical dispersion were evaluated and compared. RESULTS: LA strain during reservoir phase (LASr), conduit phase (LAScd), and contraction phase (LASct) all decreased markedly after chemotherapy and were lower than those of the controls (all p < .01). The standard deviation of time to peak positive strain during LA reservoir phase corrected by R-R interval (LA SD-TPSr) was significantly increased after chemotherapy and was higher than that of the controls (p < .001). The change of LA function was expressed as Δ. Multivariate linear regression analyses showed that LAVIp (0.399, 95% confidence interval [CI]: 0.610, 1.756, p = .000) was independently associated with ΔLASr, LAPEF (-0.325, 95% CI: -45.123, -10.676, p = .002) and age (0.227, 95% CI: 0.021, 0.350, p = .027) were independently associated with ΔLAScd, and LAVImax (0.341, 95% CI: 0.192, 0.723, p = .001) was independently associated with ΔLASct. LAVImax (0.505, 95% CI: 0.000, 0.001, p = .039) and mitral E (-0.256, 95% CI: 0.000, 0.000, p = .024）were independently associated with ΔLA SD-TPSr. CONCLUSIONS: Mechanical function of LA declined after chemotherapy in breast cancer patients. With the decrease of LA mechanical function, LA mechanical dispersion assessed by two-dimensional speckle-tracking echocardiography increased significantly, and its clinical value needs to be further studied.

Expanding the Deceased Donor Pool in Manitoba Using Hepatitis C-Viremic Donors: Program Report.

PURPOSE OF PROGRAM: The ongoing shortage of organs for transplant combined with Manitoba having the highest prevalence of end-stage renal disease (ESRD) in Canada has resulted in long wait times on the deceased donor waitlist. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes the use of prophylactic pan-genotypic direct-acting anti-viral agents (DAA) for transplanting hepatitis C (HCV)-viremic kidneys (HCV antibody positive/nucleic acid [nucleic acid amplification testing, NAT] positive) to HCV-naïve recipients as routine standard of care. We will evaluate the provincial implementation of this protocol as a prospective observational cohort study. SOURCES OF INFORMATION: Scoping literature review and key stakeholder engagement with interdisciplinary health care providers and health system leaders/decision markers. METHODS: Patients will be screened pre-transplant for eligibility and undergo a multilevel education and consent process to participate in this expanded donor program. Incident adult HCV-naïve recipients of an HCV-viremic kidney transplant will be treated prophylactically with glecaprevir-pibrentasvir with the first dose administered on call to the operation. Glecaprevir-pibrentasvir will be used for 8 weeks with viral monitoring and hepatology follow-up. Primary outcomes are sustained virologic response (SVR) at 12 weeks and the tolerability of DAA therapy. Secondary outcomes within the first year post-transplant are patient and graft survival, graft function, biopsy-proven rejection, HCV transmission to recipient (HCV NAT positive), and HCV nonstructural protein 5A (NS5A) resistance. Safety outcomes within the first year post-transplant include fibrosing cholestatic hepatitis, acute liver failure, primary and secondary DAA treatment failure, HCV transmission to a recipient's partner, elevated liver enzymes ≥2-fold, abnormal international normalized ratio (INR), angioedema, anaphylaxis, cirrhosis, and hepatocellular carcinoma. KEY FINDINGS: This program successfully advocated for and obtained hospital formulary, provincial Exceptional Drug Status (EDS), and Non-Insured Health Benefits (NIHB) to provide prophylactic DAA therapy for this indication, and this information may be useful to other provincial transplant organizations seeking to establish an HCV-viremic kidney transplant program with prophylactic DAA drug coverage. LIMITATIONS: (1) Patient engagement was not undertaken during the program design phase, but patient-reported experience measures will be obtained for continuous quality improvement. (2) Only standard criteria donors (optimal kidney donor profile index [KDPI] ≤60) will be used. If this approach is safe and feasible, then higher KDPI donors may be included. IMPLICATIONS: The goal of this quality improvement project is to improve access to kidney transplantation for Manitobans. This program will provide prophylactic DAA therapy for HCV-viremic kidney transplant to HCV-naïve recipients as routine standard of care outside a clinical trial protocol. We anticipate this program will be a safe and effective way to expand kidney transplantation from a previously unutilized donor pool.

OBJECTIF DU PROGRAMME: La pénurie actuelle d'organes à transplanter, combinée au fait que le Manitoba est la province qui présente la plus forte prévalence d'insuffisance rénale terminale au Canada, entraîne de longs délais sur la liste d'attente d'un organe provenant d'un donneur décédé. Le programme de transplantation rénale pour les adultes du Manitoba (Transplant Manitoba Adult Kidney Program) a mis en place des initiatives d'amélioration continue de la qualité afin d'élargir le bassin de donneurs décédés. Ce protocole clinique de transplantation décrit l'emploi, comme traitement habituel, d'agents antiviraux directs (AAD) pan-génotypiques prophylactiques pour la transplantation de reins provenant de donneurs infectés par le virus de l'hépatite C (VHC) (individus positifs pour les anticorps VHC et acides nucléiques [NAT]) à des receveurs naïfs pour VHC. La mise en œuvre provinciale de ce protocole sera évaluée en tant qu'étude de cohorte prospective et observationnelle. SOURCES: Examen de la documentation et évaluation de l'engagement des principaux intervenants avec les fournisseurs de soins de santé interdisciplinaires et les dirigeants/décideurs du système de santé. MÉTHODOLOGIE: L'admissibilité au programme sera évaluée avant la greffe. Pour participer à ce programme élargi de donneurs, les patients devront se soumettre à un processus d'information et de consentement à plusieurs niveaux. Les adultes incidents naïfs pour VHC devant recevoir un rein virémique-VHC seront traités de façon prophylactique par glécaprévir+pibrentasvir; la première dose administrée au moment de l'appel pour l'opération. Le traitement par glécaprévir+pibrentasvir sera administré pendant 8 semaines avec surveillance virale et suivi hépatologique. Les principaux résultats évalués seront une réponse virologique prolongée (RVP) à 12 semaines et la tolérance au traitement par AAD. Les résultats secondaires mesurés dans la première année suivant la greffe seront la survie du patient et du greffon; la fonction du greffon; le rejet avéré par biopsie; la transmission du VHC au receveur (positif pour VHC et NAT) et la résistance aux protéines non structurelles 5A (NS5A) du VHC. Les résultats relatifs à l'innocuité dans la première année suivant la greffe comprennent la cholestase hépatique fibrosante; l'insuffisance hépatique aiguë; l'échec primaire et secondaire du traitement par AAD; la transmission du VHC au partenaire d'un receveur; une élévation supérieure à 2 fois du taux d'enzymes hépatiques; un INR anormal; un angio-œdème; l'anaphylaxie; une cirrhose ou un carcinome hépatocellulaire. PRINCIPAUX RÉSULTATS: Le programme a recommandé et obtenu l'inscription du traitement prophylactique par AAD sur la liste de médicaments des hôpitaux pour cette indication, en plus du statut de médicament d'exception provincial et de son ajout au Programme des services de santé non assurés (SSNA). Ces renseignements pourraient être utiles à d'autres organismes provinciaux de transplantation qui cherchent à mettre en œuvre un programme de transplantation rénale virémique-VHC avec un traitement prophylactique par AAD. LIMITES: (1) La participation des patients n'a pas été entreprise pendant la phase de conception du programme, mais des mesures de l'expérience des patients seront obtenues pour l'amélioration continue de la qualité. (2) Seuls les donneurs satisfaisant aux critères standards (Kidney Donor Profile Index [KDPI] ≤ 60) seront inclus. Si cette approche est sécuritaire et faisable, des donneurs de KDPI plus élevés pourront être inclus. CONCLUSION: L'objectif de ce projet d'amélioration de la qualité est d'améliorer l'accès aux transplantations rénales pour les Manitobains. Ce programme offrira un traitement prophylactique aux AAD pour les greffes de reins virémiques-VHC à des receveurs naïfs pour VHC comme traitement de référence habituel en dehors d'un protocole d'essai clinique. Nous pensons que ce programme sera un moyen sûr et efficace d'étendre la transplantation rénale à partir d'un bassin de donneurs auparavant non utilisés.

Lifelong, universal Pneumocystis jirovecii pneumonia prophylaxis: Patient uptake and adherence after kidney transplant.

INTRODUCTION: Pneumocystis jirovecii pneumonia (PJP) is a significant cause of morbidity and mortality in transplant patients yet little is known about their adherence to prophylaxis. The goal of this study was to evaluate patient uptake and long-term adherence after implementing universal, lifelong PJP prophylaxis. MATERIALS AND METHODS: This retrospective cohort study evaluated an adult kidney transplant program 18-months after initiating trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg thrice-weekly following a cluster of PJP cases. The protocol incorporated multi-modal patient education and drug tolerability strategies to improve adherence, including a modified re-challenge strategy for TMP-SMX intolerance. Adherence was independently confirmed by the transplant pharmacist and nurse for each patient, with an a priori target ≥ 75% population on prophylaxis. RESULTS: Initial uptake was high with 237/250 (94.8%) patients starting prophylaxis. Long-term maintenance was high with 192/237 (81.0%) patients remaining on prophylaxis at 18-months. Of the remaining 45 patients who initiated prophylaxis, 36/237 (15.2%) were non-adherent and 9/237 (3.8%) discontinued prophylaxis by 18-months. Reasons for non-adherence included gastrointestinal upset, fear of drug reactions and cost; but the majority of reasons were not delineated by the patients (31/36, 86.1%). There was a statistically significant increase in serum creatinine 3.3 µmol/L (0.3-6.3 µmol/L 95% CI) and potassium 0.08 mmol/L (0.03-0.15 mmol/L 95% CI) in those prescribed TMP-SMX with only 3/237 (1.3%) patients discontinuing TMP-SMX for an increase in creatinine. CONCLUSION: High rates of patient uptake (94.8%) and long-term adherence (81.0%) were observed after implementing universal lifelong PJP prophylaxis. This may be due in part to the in-depth patient education and drug tolerability strategies employed.

Three putative DNA replication/repair elements encoding genes confer self-resistance to distamycin in Streptomyces netropsis.

Distamycin (DST) is a well-characterized DNA minor groove binder with antivirus activity and antitumor potency. Two separate gene clusters (a 28-kb cluster and a 7-kb cluster) have recently been identified to coordinately encode the biosynthetic machinery of DST in Streptomyces netropsis. Here we report a gene cassette, which is linked to the aforementioned smaller dst gene cluster and plays an important role in the self-resistance to DST in S. netropsis. This cassette consists of three uncharacterized genes that might be implicated in DNA replication/repair. Knockout of the cassette led to the decrease in the production of DST, while heterologous expression of part of the cassette in S. lividans made it become resistant to both DST and mitomycin C, another DNA-binding agent. More interestingly, homologs of these three genes were found in genomes of other actinomyces that produce DNA-binding antibiotics, suggesting that a novel common mechanism in addition to pumping may enable these strains to resist the cytotoxic metabolites they produced.

Carboxymethyl konjac glucomannan mechanically reinforcing gellan gum microspheres for uranium removal.

Biosorbents have been a promising adsorbent to remove uranium while their poor mechanical properties prevent them from being widely used in practice. In this study, carboxymethyl konjac glucomannan (CMKGM) was incorporated to gellan gum to form a double-network gel micro spheres (CMKGM/GG-Al) for uranium removal with its mechanical strength fairly being reinforced. The compressive strength of the CMKGM/GG-Al microspheres was about 6 times than that of GG-Ca microspheres we prepared before while the adsorption capacity still be at a better value with the fitting maximum adsorption capacity being of 97.94 mg/g. Its uranium adsorption properties were investigated by considering the influence of pH, the adsorbent dosage, temperature, initial uranium concentration, time and coexisting ions. The adsorption mechanism was also investigated according to the SEM, EDX, FT-IR and XPS data analysis. The isotherm equilibrium data which were best fitted with Langmuir model and the kinetics data which were best fitted with pseudo-second-order model. It was inferred that the adsorption process was mainly the ion-exchange and the coordination with hydroxyl groups on the adsorbent surface and the adsorption process was endothermic and spontaneous. The CMKGM/GG-Al microspheres prepared in this study would be more conducive to practical application for uranium removal.

Quantitative analysis of mitral valve morphology in atrial functional mitral regurgitation using real-time 3-dimensional echocardiography atrial functional mitral regurgitation.

BACKGROUND: Atrial fibrillation (AF) can result in atrial functional mitral regurgitation (MR), but the mechanism remains controversial. Few data about the relationship between the 3-dimensional morphology of the MV and the degree of MR in AF exist. METHODS: Real-time 3-dimensional transesophageal echocardiography (3D-TEE) of the MV was acquired in 168 patients with AF (57.7% persistent AF), including 25 (14.9%) patients with moderate to severe MR (the MR+ group) and 25 patients without AF as controls. The 3-dimensional geometry of the MV apparatus was acquired using dedicated quantification software. RESULTS: Compared with the group of patients with no or mild MR (the MR- group) and the controls, the MR+ group had a larger left atrium (LA), a more dilated mitral annulus (MA), a reduced annular height to commissural width ratio (AHCWR), indicating flattening of the annular saddle shape, and greater leaflet surfaces and tethering. MR severity was correlated with the MA area (r2 = 0.43, P < 0.01) and the annulus circumference (r2 = 0.38, P < 0.01). A logistic regression analysis indicated that the MA area (OR: 1.02, 95% CI: 1.01-1.03, P < 0.01), AHCWR (OR: 0.24, 95% CI: 0.14-0.35, P = 0.04) and MV tenting volume (OR: 3.24, 95% CI: 1.16-9.08, P = 0.03) were independent predictors of MR severity in AF patients. CONCLUSIONS: The mechanisms of "atrial functional MR" are complex and include dilation of the MA, flattening of the annular saddle shape and greater leaflet tethering.

Accuracy of cardiac CT in evaluating severity of left atrial appendage spontaneous echo contrast: comparison with transesophageal echocardiography.

To investigate the capacity of biphasic cardiac CT (CCT) for qualitative and quantitative evaluation of different grades of left atrial appendage spontaneous echo contrast (LAASEC). The study included 267 inpatients with confirmed atrial fibrillation who underwent both CCT and transesophageal echocardiography (TEE). CT numbers for LAA, ascending aorta (AA), and left atrium (LA) were identified, and ROC curves for LAA, LAA/AA, and LAA/LA were plotted. With TEE as the standard, the sensitivity, specificity, PPV, NPV, and accuracy of CCT for LAASEC grade ≥ 1 were 60.3, 92.9, 92.4, 64.8, and 75.7%; and for grade ≥ 2 were 100.0, 84.4, 71.4, 100.0, and 88.8% respectively. The values of LAA, LAA/AA, and LAA/LA were significantly larger in LAASEC grade 0 versus 1 and in grade 1 versus 2, but were similar in grades 2 and 3 or in grades 3 and 4. The values of LAA/AA were larger in grade 2 versus 4. When the cutoff value for LAA/AA = 0.897, sensitivity, specificity, PPV, NPV, and accuracy of CCT for LAASEC grade ≥ 1 was 89.6, 83.2, 87.9, 85.5, and 86.9% and with a cutoff for LAA/AA of 0.524, the sensitivity, specificity, PPV, NPV, and accuracy for LAASEC grade ≥ 2 was 98.7, 92.7, 84.1, 99.4, and 94.4%. Although CCT showed limited diagnostic accuracy for grade 1 LAASEC, grade ≥ 2 LAASEC could be excluded when there was no LAA filling defect on first-phase CCT, and TEE can be avoided. CCT has an excellent accuracy in diagnosing LAASEC, and quantitative analysis (in particular LAA/AA) is superior.

Treatment and outcome of Pseudomonas aeruginosa bacteraemia: an antibiotic pharmacodynamic analysis.

OBJECTIVES: To conduct a retrospective study of antibiotic pharmacodynamics in the treatment of Pseudomonas aeruginosa bacteraemia, and to identify pharmacodynamic indices associated with clinical cure. METHODS: Cases of P. aeruginosa bacteraemia were identified, and information related to patient demographics, clinical status, antibiotic treatment and clinical outcome were documented. Anti-pseudomonal therapy was assessed, and concentration versus time profiles were constructed using measured levels for aminoglycosides, or population pharmacokinetic models for other antibiotics. P. aeruginosa isolates from all patients were retrieved and MICs for the anti-pseudomonal agents used to treat the episode of bacteraemia were determined. Patient- and treatment-related factors were tested for associations with clinical outcome using univariate and multivariate analyses. RESULTS: Fifty cases of P. aeruginosa bacteraemia were identified and 38 cases were included in the pharmacodynamic analysis. Eighty-seven percent of patients received an aminoglycoside or ciprofloxacin and 79% received piperacillin or ceftazidime. A majority of patients, 71%, were administered a combination of antibiotics. Treatment outcomes were documented as persistent infection in 21%, death within 2-30 days in 21% and clinical cure in 58% of cases. Peak/MIC (P=0.001) and AUC24/MIC (P=0.002) for aminoglycosides and ciprofloxacin were significant factors in univariate tests. Only peak/MIC was associated independently with treatment outcome (P=0.017) in logistic regression analysis. The predicted probability of cure was > or =90% when peak/MIC was at least 8. CONCLUSION: Pharmacodynamic considerations including aggressive dosing with targeted peak/MICs for aminoglycosides and ciprofloxacin are strongly associated with clinical outcome and essential to the appropriate management of P. aeruginosa bacteraemia.

AUC(0-t)/MIC is a continuous index of fluoroquinolone exposure and predictive of antibacterial response for Streptococcus pneumoniae in an in vitro infection model.

OBJECTIVE: To conduct a comprehensive pharmacodynamic analysis of moxifloxacin and levofloxacin against Streptococcus pneumoniae in an in vitro infection model. METHODS: In dose escalation studies, single doses with peak concentrations equivalent to 1 x, 2 x, 4 x, 8 x, 16 x and 32 x MIC against two isolates of S. pneumoniae were studied over 24 h. Traditional pharmacodynamic indices, including peak concentration divided by MIC (peak/MIC), time of concentration above MIC (T > MIC) and AUC24/MIC, were estimated for all regimens. As a continuous index of fluoroquinolone exposure, AUC0-t/MIC was also calculated, as AUC from time 0 to 1, 2 and 6 h divided by MIC. Correlations between pharmacodynamic indices and antibacterial effects were examined using linear and non-linear methods. In validation experiments, the pharmacodynamic model was used to predict bacterial kill curves, produced by simulated clinical doses of moxifloxacin and levofloxacin against two other S. pneumoniae isolates. RESULTS: Peak/MIC was most predictive of early bacterial kill, whereas T > MIC was significantly associated with final bacterial counts at 24 h. Antibacterial effects were bacteriostatic when T > MIC was 48% and bactericidal when values exceeded 55%. AUC0-t/MIC was strongly associated with bacterial kill throughout the dosing interval. Bactericidal activity and bacterial eradication were associated with AUC0-t/MICs of 28 and 135, respectively. AUC0-t/MIC was also highly predictive of bacterial kill curves produced by simulated clinical doses of moxifloxacin and levofloxacin (precision 0.36 log10 cfu/mL, bias 0.02 log10 cfu/mL). CONCLUSION: This study demonstrated the novel application of AUC0-t/MIC as a continuous index of antibiotic activity, and provided extensive characterization of fluoroquinolone pharmacodynamics against S. pneumoniae.