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In India, ST-elevation myocardial infarction (STEMI) is the predominant form of acute coronary syndrome. It is estimated to affect approximately 30 million people in India. The mainstay treatment approach for STEMI management is primary percutaneous coronary intervention (PCI) within 90 min after the first medical contact. However, due to existent clinical and practical barriers in performing timely PCI, optimal treatment is not offered on a timely basis. The challenges or barriers to timely PCI can be overcome by a pharmaco-invasive approach, in which thrombolysis is performed as soon as the patient is diagnosed with STEMI and transferred for PCI. Pharmaco-invasive approach is effective in shortening time to reperfusion therapy by allowing prompt initiation of thrombolysis followed by PCI as soon as possible. An experts' panel discussion was conducted involving 47 cardiologists all over India to review evidence-based concept of pharmaco-invasive treatment approach and to gain their expert opinion on emergency management of STEMI patients in the Indian setting. The experts highlighted that thrombolysis is the most implemented reperfusion strategy in India, especially when primary PCI is not available for STEMI patients. According to them, pharmaco-invasive approach would be appropriate to gain time to treatment in the event of expected treatment delays. Among thrombolytic agents, the experts recommended using third-generation thrombolytic agents because of their faster patency, more effectiveness, and ease of administration. They also emphasized on various clinical factors and practical considerations to be assessed before employing thrombolytic agents. In their opinion, bolus thrombolytic agents such as tenecteplase and reteplase offer effective, safer, easier, and faster administration for varied clinical profiles in all practical ways. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (MTB) causes TB disease and millions of deaths are reported every year. Drug resistance TB and its complex treatment is a big problem worldwide. The present study aimed to design new and safer antitubercular compounds to tackle this serious threat. The unique drug target is the MtrAB Two-component regulatory system (2CRS) of mycobacteria. MtrAB system consists of MtrB sensor kinase (SK) and MtrA response regulator (RR). This system is essential in MTB and is involved in mycobacteria's proliferation. This important physiological process is operated by the phosphorylation of MtrB and then to MtrA. The phosphorylation mechanism triggers modulation in the expression of MtrA targets genes and helps perform appropriate function. This phenomenon depends on the active and inactive confirmation of MtrA, which involves a ligand (Metal ion complex e.g. Mg2+). In this study, anti-cancerous compounds were selected for the inhibition of MtrA. However, molecular docking exhibited binding affinity ranging from -10.8 to -4.7 kcal/mol, targeting the binding pocket of the selected Tuberculosis-MtrA protein (PDB ID: 5L8X). This energy difference between the native ligand and docked compounds showed that the six molecules: (Risperidone, 2-(benzofuran-2-yl)-6,7-dimethyl-4H-chromen-4-one, (2E)-1-(4-hydroxyphenyl)-3-(quinolin-4-yl)prop-2-en-1-one, Estradiol Cypionate, (2Z)-6-hydroxy-2-(3,4,5-trimethoxybenzylidene)-1-benzofuran-3(2H)-one, (2E)-3-(2,3-dihydro-1,4 -benzodioxin-6-yl)-1-(3-hydroxyphenyl)prop-2-en-1-one) mentioned are more potent than the native ligand. These six molecules were first time reported as the inhibitor for MtrA of MtrAB Two-component regulatory system and can be utelize for further study. [ABSTRACT FROM AUTHOR]

A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol suppresses inwardly rectifying K+ (Kir2) channels that are responsible for maintaining membrane potential in a variety of cell types. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C terminus of the cytosolic domain of the channel, the CD loop. Within this loop, the L2221 mutation in Kir2.1 abrogates the sensitivity of the channel to cholesterol whereas a reverse mutation in the corresponding position in Kir2.3, 1214L has the opposite effect, increasing cholesterol sensitivity. Furthermore, the 12221 mutation has a dominant negative effect on cholesterol sensitivity of Kir2.1 WT. Mutations of 2 additional residues in the CD loop in Kir2.1, N216D and K219Q, partially affect the sensitivity of the channel to cholesterol. Yet, whereas these mutations have been shown to affect activation of the channel by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [Pl(4,5)P2], other mutations outside the CD loop that have been previously shown to affect activation of the channel by Pl(4,5)P2 had no effect on cholesterol sensitivity. Mutations of the lipid-facing residues of the outer transmembrane helix also had no effect. These findings provide insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol, and introduce the critical role of the cytosolic domain in cholesterol dependent channel regulation. [ABSTRACT FROM AUTHOR]

Cites that the death of animals infected with anthrax is due to anthrax lethal toxin. Production of anthrax lethal toxin by the bacterium bacillus anthracis; Inactivation of the members of the mitogen-activated protein kinase kinase; Performance of deletion mutant analysis.

B Learning Objectives: b The preferred area for extracorporeal membrane oxygenation (ECMO) cannulation is in the operating room in a controlled setting with experienced staff. B Conclusions: b A structured process for pre-cannulation preparedness maximizes efficiency in team readiness for a bedside ECMO cannulation. [Extracted from the article]

OBJECTIVES This study aimed to determine the oxygenator impact on alterations of remdesivir (RDV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i oxygenator. METHODS One-quarter--inch and a 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A 1-time dose of RDV was administered into the circuits and serial preoxygenator and postoxygenator concentrations were obtained at 0 to 5 minutes, and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-hour time points. The RDV was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. RESULTS For the 1/4-inch circuits with an oxygenator, there was a 35% to 60% RDV loss during the study period. For the 1/4-inch circuits without an oxygenator, there was a 5% to 20% RDV loss during the study period. For the 3/8-inch circuit with and without an oxygenator, there was a 60% to 70% RDV loss during the study period. CONCLUSIONS There was RDV loss within the circuit during the study period and the RDV loss was more pronounced with the larger 3/8-inch circuit when compared with the 1/4-inch circuit. The impact of the oxygenator on RDV loss appears to be variable and possibly dependent on the size of the circuit and oxygenator. These preliminary data suggest RDV dosing may need to be adjusted for concern of drug loss via the ECMO circuit. Additional single- and multiple-dose studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

OBJECTIVES To describe the pharmacokinetics of levofloxacin in an obese adolescent patient in the pediatric intensive care unit. METHODS A single-patient medical record review was conducted. RESULTS A 168-kg, 15-year-old female with past medical history of Prader-Willi syndrome and asthma initially presented with respiratory distress secondary to asthma exacerbation. She failed non-invasive ventilation and was subsequently intubated for respiratory failure and progressed to high-frequency oscillatory ventilation. On hospital day 1 (HD 1) an infectious workup was begun because of a fever, worsening clinical status, and initiation of vasopressors and an empiric antimicrobial regimen of cefepime and clindamycin. The urine culture subsequently grew Escherichia coli and the respiratory culture grew Pseudomonas aeruginosa. She continued to be febrile, which was thought to be due to an intra-abdominal abscess. On HD 14, the antimicrobial regimen was changed to levofloxacin because of continued fevers and no significant clinical improvement. Levofloxacin was initiated at 1000 mg IV every 24 hours. Levofloxacin serum levels were obtained at 0.5, 3.5, and 11.5 hours after infusion, which were 8.61, 5.76, and 2.7 mg/L, respectively. These concentrations translated into a peak level of 8.79 mg/L, a half-life of 6.4 hours, and an AUC of 80 mg·hr/L, which are discordant from the expected peak of 16 mg/L, a half-life of 8 hours, and an AUC of 120 mg·hr/L. Based on these values, the levofloxacin regimen was adjusted to 1000 mg IV every 12 hours, and repeat levels 0.5, 3.5, and 11.5 hours after infusion were 9.91, 6.56, and 3.27 mg/L, respectively, corresponding to a peak of 10.5 mg/L, a half-life of 5.18 hours, and an AUC of 200 mg·hr/L. After the adjustment in levofloxacin regimen, she became afebrile, WBC resolution and improvement in her overall clinical status, and she received a total duration for levofloxacin of 21 days. CONCLUSION A levofloxacin regimen of 1000 mg IV every 12 hours was successful in providing for an appropriate AUC exposure and was associated with a successful clinical outcome in this morbidly obese adolescent. ABBREVIATIONS AUC, area under the concentration-time curve; CL, clearance; Cmax, maximum concentrations; Ct, concentration at specified time; ke, elimination rate constant; HD, hospital day; MIC, minimum inhibitory concentration; PICU, pediatric intensive care unit; t1/2, half-life; Vd, volume of distribution; WBC, white blood cell. [ABSTRACT FROM AUTHOR]

OBJECTIVE Our primary objective was to determine the utility of procalcitonin (PCT) in detection of bacterial coinfection in children < 5 years admitted to the pediatric intensive care unit with viral lower respiratory tract infection (LRTI). METHODS Electronic medical record review of children < 5 years admitted to the pediatric intensive care unit with a viral LRTI who also had at least 1 PCT concentration measurement. RESULTS Seventy-five patients were admitted to the intensive care unit and met the inclusion criteria for this investigation. The PCT threshold concentrations of 0.9, 1, 1.4, and 2 ng/mL were found to be statistically significant in determining the presence of a bacterial coinfection. The PCT concentration with the most utility was 1.4 ng/mL with sensitivity, specificity, positive and negative predictive values of 46%, 83%, 68%, and 76%, respectively. For patients with serial PCTs, the second PCT correctly influenced treatment decisions for 11 of 25 patients (44%). CONCLUSIONS A PCT value of 1.4 ng/mL determined the presence of a bacterial coinfection primarily owing to the high specificity and negative predictive value. Our data add evidence to the relatively high negative predictive value of PCT concentrations in identifying patients with bacterial coinfection, specifically in the case of viral LRTI. In addition, our preliminary data indicate serial PCT measurements may help further influence correct treatment decisions. Prospective, controlled studies are warranted to validate an appropriate PCT threshold concentration to help in identifying bacterial coinfection as well as to further explore the role of serial PCT values in determining the absence or presence of a bacterial coinfection. [ABSTRACT FROM AUTHOR]

Background: The objective was to determine the alterations of daptomycin (DAP) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extracorporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: Quarter-inch and 3/8-inch, simulated, closed-loop, ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. A one-time dose of DAP was administered into the circuit and serial pre- and post-oxygenator concentrations were obtained at 0-5 minutes and 1, 2, 3, 4, 5, 6 and 24-hour time points. DAP was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For both the 1/4-inch and 3/8-inch circuits, there was no significant DAP loss at 24 hours. Additionally, the reference DAP concentrations remained relatively constant during the entire 24-hour study period. Conclusion: This ex-vivo investigation demonstrated no significant DAP loss within an ECMO circuit with both sizes of the Quadrox-i oxygenator at 24 hours. Therapeutic concentrations of DAP in the setting of ECMO may be anticipated with current recommended doses, depending on the amount of extracorporeal volume needed for circuit maintenance in comparison to the patient’s apparent volume of distribution. Additional studies with a larger sample size are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Purpose: The Mental Health Act in Scotland is under review. Previous iterations increased patients' rights but the maximum time for short-term detentions remains unchanged, despite evolving psychiatric treatment models. We explored length, mode of ending and factors of influence on the application of short-term detention certificates (STDCs), which can last up to 28 days, across Scotland between 2006 and 2018. Methods: Data on age, gender, ethnicity, date of commencement and ending of the STDC and detention site from all 42,493 STDCs issued to 30,464 patients over 12 years were extracted from the national repository for detentions under the Mental Health (Care and Treatment) (Scotland) Act 2003 and analysed using mixed models. Results: One in five STDCs lapsed on day 28. Two in five were revoked and the remainder extended to a treatment order. STDCs that were not extended averaged 19 days, and revoked STDCs 14 days. The probability of a detention lapsing varied across hospitals and increased with patient age. The odds of a detention lapsing on day 28 were 62% lower and revoked detentions 10% shorter in 2018 relative to 2006. The odds of a detention extending decreased significantly from 2012 to 2018. Extended STDCs were associated with increased patient age, male gender, and ethnicity other than White Scottish. There was little initiation of or active revocation of STDCs on weekend days. Conclusion: The length of STDCs reduced over time, fewer detentions lapsed, and weekday patterning was evident in each year. These data can inform legislative and service reviews. [ABSTRACT FROM AUTHOR]

Objective: There is increasing data in pediatrics demonstrating procalcitonin (PCT) is more sensitive and specific than other biomarkers in the setting of bacterial infections. However, the use of PCT in neonatal and pediatric extracorporeal membrane oxygenation (ECMO) is not well described. Therefore, the purpose of this study was to describe the clinical utility of PCT in determining the absence or presence of bacterial infections in neonatal and pediatric patients on ECMO. Methods: This was a retrospective electronic medical record (EMR) review of data between January 1, 2010 to June 30, 2016 at a single, free-standing, children's hospital. All patients on ECMO with ≥1 PCT level obtained while receiving ECMO support were eligible for inclusion. The EMR was searched for chest radiographs (CXR) and bacterial culture results (urine, blood, cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL) and respiratory cultures). All bacterial and viral cultures obtained within 5 days of PCT levels being obtained were analyzed. PCT levels of 0.5, 0.9, 1.0, 1.4 and 2.0 were used as the initial cut-off values for the analysis. The sensitivity, specificity, positive predictive value (PPV), negative predictive values (NPV) and likelihood ratios were calculated for each of the PCT levels. Results: Twenty-seven patients met the inclusion criteria and contributed 193 PCT values for the analysis. The median age was 8 months (range 0 days to 18 years). Linear regression analysis demonstrated that a PCT cut-off of 0.5, 0.9 and 1.4 predicted the presence of a bacterial infection. The PCT value with the most utility was 0.5, with a sensitivity of 92%, a specificity of 43%, a positive predictive value of 60% and a negative predictive value (NPV) of 86%. Conclusion: This is the largest data set evaluating PCT in neonatal and pediatric patients on ECMO. A PCT value of 0.5 ng/mL had the most utility for determining the absence or presence of a bacterial infection in the setting of ECMO with a high sensitivity and NPV. [ABSTRACT FROM AUTHOR]

We aimed to critically evaluate the effectiveness of a designated ECMO team in our ECMO selection process and patient outcomes in the first 3 years of our low-volume pediatric ECMO program. We conducted a retrospective chart review of patients who received an ECMO consultation between the start of our program in March 2015 and May 2018. We gathered clinical and demographic information on patients who did and did not receive ECMO, and described our selection process. We reflected on the processes used to initiate our program and our outcomes in the first 3 years. Sixty-nine patients received consultations, and of those, 50 patients were potential candidates. 19 (38%) of the candidates were ultimately placed on ECMO. There were statistically significant differences in oxygen saturation, paO2, oxygenation index, A-aDO2, lactate, and pH between the patients who went on ECMO and who did not. We improved our outcomes from 0% survival to discharge in 2015, to 60% in 2018, with an average of 63% survival to discharge over the first 3 years of our program. In a low-volume pediatric ECMO center, having a designated team to assist in the patient selection process and management can help provide safe and efficient care to these patients, and improve patient outcomes. Having a strict management protocol and simulation sessions involving all members of the medical team yields comfort for the providers and optimal care for patients. This study describes our novel structure, processes, and outcomes, which we hope will be helpful to others seeking to develop a new pediatric ECMO program. [ABSTRACT FROM AUTHOR]

Although pediatric brain death guidelines stipulate when ancillary testing should be used during brain death determination, little is known about the way these recommendations are implemented in clinical practice. We conducted a survey of pediatric intensivists and neurologists in the United States on the use of ancillary testing. Although most respondents noted they only performed an ancillary test if the clinical examination and apnea test could not be completed, 20% of 195 respondents performed an ancillary test for other reasons, including (1) to convince a family that objected to the brain death determination that a patient is truly dead (n = 21), (2) personal preference (n = 14), and (3) institutional requirement (n = 5). Our findings suggest that pediatricians use ancillary tests for a variety of reasons during brain death determination. Medical societies and governmental regulatory bodies must reinforce the need for homogeneity in practice. [ABSTRACT FROM AUTHOR]

Objectives: We sought to 1) evaluate how pediatricians approach situations in which families request continuation of organ support after declaration of death by neurologic criteria and 2) explore potential interventions to make these situations less challenging.Design: A survey on management and personal experience with death by neurologic criteria was distributed electronically to pediatric intensivists and neurologists. We compared responses from individuals who practice in states with accommodation exceptions (accommodation states where religious or moral beliefs must be taken into consideration when declaring death: California, Illinois, New Jersey, New York) to those from non-accommodation states.Setting: United States.Subjects: The survey was opened by 254 recipients, with 186 meeting inclusion criteria and providing data about the region in which they practice; of these, 26% were from accommodation states.Interventions: None.Measurements and Main Results: More than half of physicians (61% from both accommodation states and non-accommodation states) reported they cared for a pediatric patient whose family requested continuation of organ support after declaration of death by neurologic criteria (outside of organ donation; range, 1-17 times). Over half of physicians (53%) reported they would not feel comfortable handling a situation in which a pediatric patient's family requested care be continued after declaration of death by neurologic criteria. Nearly every physician (98%) endorsed that something needs to be done to make situations involving families who object to discontinuation of organ support after declaration of death by neurologic criteria easier to handle. Respondents felt that public education, physician education, and uniform state laws about these situations are warranted.Conclusions: It is relatively common for pediatricians who care for critically ill patients to encounter families who object to discontinuation of organ support after death by neurologic criteria. Management of these situations is challenging, and guidance for medical professionals and the public is needed. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to determine the oxygenator impact on alterations of peramivir (PRV) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra-corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of PRV was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5-min and 1-, 2-, 3-, 4-, 5-, 6-, 8-, 12-, and 24-h time points. PRV was also maintained in a glass vial, and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. Results: For the 1/4-in. circuit with an oxygenator, there was < 15% PRV loss, and for the 1/4-in. circuit without an oxygenator, there was < 3% PRV loss during the study period. For the 3/8-in. circuits with an oxygenator, there was < 15% PRV loss, and for the 3/8-in. circuits without an oxygenator, there was < 3% PRV loss during the study period. Conclusion: There was no significant PRV loss over the 24-h study period in either the 1/4-in. or 3/8-in circuit, regardless of the presence of the oxygenator. The concentrations obtained pre- and post-oxygenator appeared to approximate each other, suggesting there may be no drug loss via the oxygenator. This preliminary data suggests PRV dosing may not need to be adjusted for concern of drug loss via the oxygenator. Additional single and multiple dose studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

The Mental Capacity Act 2005 provides a variety of legal mechanisms for people to plan for periods of incapacity for decisions relating to personal care, medical treatment, and financial matters. Little research has however been done to determine the degree to which these are actually implemented, and the approach to such advance planning by service users and professionals. This paper looks at the use of advance planning by people with bipolar disorder, using qualitative and quantitative surveys both of people with bipolar disorder and psychiatrists. The study finds that the mechanisms are under-used in this group, despite official policy in support of them, largely because of a lack of knowledge about them among service users, and there is considerable confusion among service users and professionals alike as to how the mechanisms operate. Recording is at best inconsistent, raising questions as to whether the mechanisms will be followed. [ABSTRACT FROM PUBLISHER]

Background: User involvement and recovery are now widely used terms within the mental health policy, research and practice discourse. However, there is a question mark about the impact these ideas have in everyday practice. Of interest is the degree of involvement in key transitions of care. In particular, admission to and discharge from acute inpatient mental health wards. Objective: To explore the nature of service user involvement in the admission and discharge process into and out of acute inpatient mental health care. Design: A qualitative study using focus groups. Setting and Participants: One acute, inpatient mental health ward was the focus of the study. Seven uniprofessional focus group interviews were conducted with ward staff, community staff and service users (total number of participants = 52). Conventional, thematic qualitative techniques were used to analyse the data. Results: The data analysed and presented in this article relate to the loss of the service user voice at the key transition points into and out of acute inpatient care. Due to the lack of resources (inpatient beds and community care follow‐up), the role service users could play was diminished. In their narratives, clinical staff associated the person with the process and used language which dehumanized the individual. Conclusion: Service users experience numerous care transitions into and out of hospital. As there is the potential for these encounters to have a lasting negative effect, the importance of ensuring service users have a voice in what is happening to them is crucial. [ABSTRACT FROM AUTHOR]

Purpose. The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported. Methods. Chlorothiazide and furo-semide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectros-copy (LC-MS/MS) system with an elec-trospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC-MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection. Results. LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours. Conclusion. Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light. [ABSTRACT FROM AUTHOR]

Introduction: To determine the oxygenator impact on alterations of meropenem (MEM)/vaborbactam (VBR) in a contemporary neonatal/pediatric (1/4-inch) and adolescent/adult (3/8-inch) extra corporeal membrane oxygenation (ECMO) circuit including the Quadrox-i® oxygenator. Methods: 1/4-inch and 3/8-inch, simulated closed-loop ECMO circuits were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. Additionally, 1/4-inch and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of MEM/VBR was administered into the circuits and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, 8, 12, and 24-hour time points. MEM/VBR was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation. Results: For the 1/4-inch circuit, there was an approximate mean 55% MEM loss with the oxygenator in series and a mean 33%–40% MEM loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean 70% MEM loss with the oxygenator in series and a mean 30%–38% MEM loss without an oxygenator in series at 24 hours. For both the 1/4-inch circuit and 3/8-inch circuits with and without an oxygenator, there was <10% VBR loss for the duration of the experiment. Conclusions: This ex-vivo investigation demonstrated substantial MEM loss within an ECMO circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant VBR loss. Further evaluations with multiple dose in-vitro and in-vivo investigations are needed before specific MEM/VBR dosing recommendations can be made for clinical application with ECMO. [ABSTRACT FROM AUTHOR]

Morriss R, Yang M, Chopra A, Bentall R, Paykel E, Scott J. Differential effects of depression and mania symptoms on social adjustment: prospective study in bipolar disorder. Bipolar Disord 2013: 15: 80-91. © 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd. Objectives: Previous studies of social adjustment in bipolar disorder have been cross-sectional and small in sample size, have examined a limited number of roles, or were not controlled for baseline mood and other clinical, social, or treatment confounders. We aimed to prospectively explore the strength and stability of correlations between depression and mania-type symptoms and impairment in a broad range of social adjustment roles and domains. Methods: Multilevel modeling analysis of correlation coefficients between depression and mania-type symptoms with roles and domains of the modified social adjustment scale (overall, work, social/leisure, extended family, marital, parental social adjustment roles, performance, interpersonal behavior, friction, dependency, overactivity domains) was used. Interview assessments were made at eight-week intervals beginning at eight weeks and continuing through 72 weeks after baseline in 253 patients in a multicenter randomized controlled trial. Results: After controlling for baseline mood episodes, and other clinical, social, and treatment variables, depression symptoms showed strong and stable correlations over time with performance, overall social adjustment, and the work role; and a moderate but stable relationship with interpersonal behavior. The relationships of depression symptoms with the other roles were weak, non-significant, or not stable. For mania-type symptoms, only the correlation with interpersonal friction was moderately strong and reasonably stable over time. Mood episodes, substance use disorder, and borderline/antisocial personality disorder increased role impairment, while employment and marriage mildly decreased it. Conclusions: Depression and mania-type symptoms have specific effects on social adjustment in bipolar I disorder. Depression symptoms are correlated strongly with performance and moderately with interpersonal behavior, while mania-type symptoms are correlated moderately with interpersonal friction. [ABSTRACT FROM AUTHOR]

Anthrax lethal toxin (LeTx) is a virulence factor of Bacilillus anthracis that is a bivalent toxin, containing lethal factor (LF) and protective Ag proteins, which causes cytotoxicity and altered macrophage function. LeTx exposure results in early K+ efflux from macrophages associated with caspase-1 activation and increased IL-1β release. The mechanism of this toxin-induced K+ efflux is unknown. The goals of the current study were to determine whether LeTx-induced K+ efflux from macrophages is mediated by toxin effects on specific K+ channels and whether altered K+-channel activity is involved in LeTx-induced IL-1β release. Exposure of macrophages to LeTx induced a significant increase in the activities of two types of K+ channels that have been identified in mouse macrophages: Ba2+-sensitive inwardly rectifying K+ (Kir) channels and 4-aminopyridine-sensitive outwardly rectifying voltage-gated K+ (Kv) channels. LeTx enhancement of both Kir and Kv required the proteolytic activity of LF, because exposure of macrophages to a mutant LF-protein (LFE687C) combined with protective Ag protein had no effect on the currents. Furthermore, blocking Kir and Kv channels significantly decreased LeTx-induced release of IL-1β. In addition, retroviral transduction of macrophages with wild-type Kir enhanced LeTx-induced release of IL-1β, whereas transduction of dominant-negative Kir blocked LeTx-induced release of IL-1β. Activation of caspase-1 was not required for LeTx-induced activation of either of the K+ channels. These data indicate that a major mechanism through which LeTx stimulates macrophages to release IL-1β involves an LF-protease effect that enhances Kir and Kv channel function during toxin stimulation. [ABSTRACT FROM AUTHOR]

(J Card Surg 2010;25:672-674) [ABSTRACT FROM AUTHOR]

Introduction: To determine the oxygenator impact on alterations of voriconazole in a contemporary neonatal/pediatric (1/4 inch) and adolescent/adult (3/8 inch) extracorporeal membrane oxygenation circuit including the Quadrox-i® oxygenator. Methods: Simulated closed-loop extracorporeal membrane oxygenation circuits (1/4 and 3/8 inch) were prepared with a Quadrox-i pediatric and Quadrox-i adult oxygenator and blood primed. In addition, 1/4- and 3/8-inch circuits were also prepared without an oxygenator in series. A one-time dose of voriconazole was administered into the circuits, and serial pre- and post-oxygenator concentrations were obtained at 5 minutes, 1, 2, 3, 4, 5, 6, and 24 hour time points. Voriconazole was also maintained in a glass vial and samples were taken from the vial at the same time periods for control purposes to assess for spontaneous drug degradation Results: For the 1/4-inch circuit, there was an approximate mean of 64-67% voriconazole loss with the oxygenator in series and mean of 15-20% voriconazole loss without an oxygenator in series at 24 hours. For the 3/8-inch circuit, there was an approximate mean of 44-51% voriconazole loss with the oxygenator in series and a mean of 8-12% voriconazole loss without an oxygenator in series at 24 hours. The reference voriconazole concentrations remained relatively constant during the entire study period demonstrating that the drug loss in each size of the extracorporeal membrane oxygenation circuit with or without an oxygenator was not a result of spontaneous drug degradation. Conclusion: This ex vivo investigation demonstrated substantial voriconazole loss within an extracorporeal membrane oxygenation circuit with an oxygenator in series with both sizes of the Quadrox-i oxygenator at 24 hours and no significant voriconazole loss in the absence of an oxygenator. Further evaluations with multiple dose in vitro and in vivo investigations are needed before specific voriconazole dosing recommendations can be made for clinical application with extracorporeal membrane oxygenation. [ABSTRACT FROM AUTHOR]

Pharmacokinetic data regarding ceftaroline fosamil (CPT) penetration into cerebrospinal fluid (CSF) are limited to a rabbit model (15% inflamed) and adult case reports. We describe serum and CSF CPT concentrations in a 21-year-old, 34.8 kg female, medically complex patient presented with a 4-day history of fevers (Tmax 39.2°C), tachypnea, tachycardia, fatigue, and a 1-week history of pus and blood draining from the ventriculopleural (VPL) shunt. A head CT and an ultrasound of the neck revealed septated complex fluid collection surrounding the shunt. Therapy was initiated with vancomycin and ceftriaxone. Blood and CSF cultures from hospital day (HD) 1 were positive for methicillin-resistant Staphylococcus aureus with a CPT MIC of 0.5 mg/L and a vancomycin MIC range of 0.5 to 1 mg/L. On HD 3, CPT was added. On HD 7, simultaneous serum (69.4, 44, and 30.2 mg/L) and CSF (1.7, 2.3, and 2.3 mg/L) concentrations were obtained at 0.25, 1.5, and 4.75 hours from the end of an infusion. Based on these concentrations, CPT CSF penetration ratio ranged from 2.4% to 7.6%. After addition of CPT, the blood and CSF cultures remained negative on a regimen of vancomycin plus CPT. On HD 14, a new left-sided VPL shunt was placed. The patient continued on CPT for a period of 7 days after the new VPL shunt placement. This case demonstrated CPT CSF penetration in a range of 2.4% to 7.6%, approximately half of the rabbit model. This allowed for CSF concentrations at least 50% free time > 4 to 6× MIC of the dosing interval with a dosing regimen of 600 mg IV every 8 hours in a 34.8 kg chronic patient and resulted in a successful clinical outcome with no identified adverse outcomes. [ABSTRACT FROM AUTHOR]

Background: The Mental Capacity Act (2005) (MCA) provides a legal framework for advance planning for both health and welfare in England and Wales for people if they lose mental capacity, for example, through mania or severe depression. Aims: To determine the proportion of people with bipolar disorder (BD) who utilise advance planning, their experience of using it and barriers to its implementation. Methods: National survey of people with clinical diagnosis of BD of their knowledge, use and experience of the MCA. Thematically analysed qualitative interviews with maximum variance sample of people with BD. Results: A total of 544 respondents with BD participated in the survey; 18 in the qualitative study. 403 (74.1%) believed making plans about their personal welfare if they lost capacity to be very important. A total of 199 (36.6%) participants knew about the MCA. A total 54 (10%), 62 (11%) and 21 (4%) participants made advanced decisions to refuse treatment, advance statements and lasting power of attorney, respectively. Barriers included not understanding its different forms, unrealistic expectations and advance plans ignored by services. Conclusion: In BD, the demand for advance plans about welfare with loss of capacity was high, but utilisation of the MCA was low with barriers at service user, clinician and organisation levels. [ABSTRACT FROM AUTHOR]

OBJECTIVES Influenza is an environmental pathogen and infection presents as a range from asymptomatic to fulminant illness. Though treatment is supportive, antiviral agents have a role in the management of infection. Pediatric use of peramivir is largely based on reports and extrapolations of pharmacokinetic data. We seek to describe efficacy and safety of peramivir in critically ill pediatric patients. METHODS This is a retrospective, institutional review board--approved chart review of all patients under 21 years of age, admitted to the PICU, and treated with peramivir for influenza H1N1 infection between January 1, 2016, and March 31, 2016, at a single-center, 12-bed PICU. The primary outcome was time to sustained resolution of fever; secondary outcomes included dose, duration, and adverse effects of peramivir therapy. RESULTS Seven patients were included with median age of 3.7 years. Median time to sustained resolution of fever was 49.3 hours, median duration of mechanical ventilation was 14.2 days, median ICU LOS was 18.7 days, and hospital LOS was 24.7 days. No patients suffered mortality. Three patients experienced leukopenia, one of which experienced a concurrent neutropenia. Three patients experienced hyperglycemia, 2 experienced hypertension, 1 experienced increased aspartate aminotransferase and increased alanine aminotransferase, and 1 experienced diarrhea. All adverse events assessed were classified as possible using published adverse event causality assessments. CONCLUSIONS Peramivir has been shown to be an effective therapy for the treatment of influenza H1N1 in critically ill pediatric patients. In our experience with 7 pediatric patients, peramivir was well tolerated at typical durations of therapy; however, increased vigilance is warranted during prolonged courses or in patients with reasons for altered pharmacokinetics and pharmacodynamics. [ABSTRACT FROM AUTHOR]

Objective: To describe the peramivir (PRV) pharmacokinetics in critically ill children treated for influenza A or B viral infections. Design: Retrospective electronic medical record review of prospectively collected data from critically ill children receiving peramivir for influenza A or B viral infections in the pediatric intensive care unit (PICU). Setting: A 189‐bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. Patients: Critically ill children admitted to the PICU who were infected with influenza between January 1, 2016 and March 31, 2018. Interventions: None. Results: Eleven patients, two females (18%) and nine males (82%), accounted for 24 peramivir samples for therapeutic drug management. The median age was 5 years (interquartile range 1.5–6.5 yrs) with a median weight of 16.4 kg (interquartile range 14–24 kg). Ten (91%) patients demonstrated a larger volume of distribution, 11 (100%) patients demonstrated an increase in clearance, and 11 (100%) patients demonstrated a shorter half‐life estimate as compared with the package insert and previous pediatric trial data for peramivir. Eight (73%) patients tested positive for a strain of influenza A and 3 (27%) patients tested positive for influenza B; 4 of 11 (36%) patients tested positive for multiple viruses. All patients had adjustments made to their dosing interval to a more frequent interval. Ten (91%) patients were adjusted to an every‐12‐hour regimen and 1 (9%) patient was adjusted to an every‐8‐hour regimen. No adverse events were associated with peramivir treatment. Conclusion: The pharmacokinetics of PRV demonstrated in this PICU cohort differs in comparison to healthy pediatric and adult patients, and alterations to dosing regimens may be needed in PICU patients to achieve pharmacodynamic exposures. Additional investigations in the PICU population are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to describe the pharmacokinetics of cefazolin in paediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) who received cefazolin for peri-operative surgical prophylaxis in addition to having cefazolin added to the CPB circuit priming solution. Secondary aims were to determine the pharmacodynamic exposure associated with the addition of cefazolin to the CPB priming solution and to assess whether a target cefazolin concentration range for the CPB priming solution could be identified.Methods: A multicentre, prospective, open-label pharmacokinetic study was carried out in children from birth to 16 years of age undergoing cardiac surgery.Results: Forty-one patients met the inclusion criteria and accounted for 492 samples for analysis. Cefazolin concentrations were best described by a one-compartment model with weight as a covariate on the volume of distribution (Vd) with allometric scaling. The mean ± standard deviation (SD) total body CL for the birth-6 month cohort was 0.009 ± 0.006 mL/min/kg with a mean ± SD Vd of 0.59 ± 0.26 L/kg, the mean ± SD total body CL for the 7 month-3 year cohort was 0.01 ± 0.005 mL/min/kg with a mean ± SD Vd of 0.79 ± 0.15 L/kg, and the mean ± SD total body CL for the 4-16 year cohort was 0.007 ± 0.004 mL/min/kg with a mean ± SD Vd of 3.4 ± 0.94 L/kg. The median cefazolin loss in the CPB circuit ranged from 78% to 95% and the median patient cefazolin concentration after CPB circuit detachment ranged from 92 to 197 mg/L.Conclusions: These data demonstrate that mixing cefazolin in the CPB circuit priming solution was effective in maintaining cefazolin serum concentrations during surgery. If this practice is utilized, re-dosing of cefazolin during the CPB run and upon CPB circuit detachment is most probably not needed. Larger pharmacokinetic studies are warranted. [ABSTRACT FROM AUTHOR]

Meropenem‐vaborbactam is a new β‐lactam/β‐lactamase inhibitor combination designed to target Klebsiella pneumoniae carbapenemase (KPC)‐producing Enterobacteriaceae. Meropenem‐vaborbactam was United States Food and Drug Administration–approved for complicated urinary tract infections in patients 18 years of age or older. An understanding of the pharmacokinetics of meropenem when given in combination with vaborbactam is important to understanding the dosing of meropenem‐vaborbactam. In addition, the safety and efficacy of meropenem‐vaborbactam in a pediatric patient have yet to be described in the literature. The authors conducted a retrospective single‐patient chart review for a 4‐year‐old male patient with short bowel syndrome, colostomy and gastrojejunal tube, bronchopulmonary dysplasia, and a central line for chronic total parenteral nutrition and hydration management, complicated with multiple central line–associated bloodstream infections (BSIs). The patient was brought to our medical center with fever concerning for a BSI. On day 2, the patient was started on meropenem‐vaborbactam at a dosage of 40 mg/kg every 6 hours infused over 3 hours for KPC‐producing K. pneumoniae BSI. Meropenem serum concentrations obtained on day 5 of meropenem‐vaborbactam therapy, immediately following the completion of the infusion and 1 hour after the infusion, were 51.3 and 13.6 μg/ml, respectively. Serum concentrations correlated to a volume of distribution of 0.59 L/kg and a clearance of 13.1 ml/min/kg. Repeat blood cultures remained negative, and meropenem‐vaborbactam was continued for a total of 14 days. A meropenem‐vaborbactam regimen of 40 mg/kg every 6 hours given over 3 hours was successful in providing a target attainment of 100% for meropenem serum concentrations above the minimum inhibitory concentration for at least 40% of the dosing interval and was associated with successful bacteremia clearance in a pediatric patient. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether contemporary β-lactam anti-infective dosing recommendations in critically ill children achieve concentrations associated with maximal anti-infective activity. The secondary objective was to describe the microbiological and clinical outcomes associated with β-lactam therapeutic drug management.Design: Electronic Medical Record Review.Setting: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA.Patients: Patients admitted to the PICU from September 1, 2014, to May 31, 2017, with sepsis and those receiving extracorporal therapy with either extracorporeal membrane oxygenation or continuous renal replacement therapy that had routine β-lactam therapeutic drug management.Interventions: None.Measurements and Main Results: Eighty-two patients were in the total cohort and 23 patients in the infected cohort accounting for 248 samples for therapeutic drug management analysis. The median age was 1 year (range, 4 d to 18 yr) with a mean weight of 19.7 ± 22.3 kg (range, 2.7-116 kg). Twenty-three patients (28%) had growth of an identified pathogen from a normally sterile site. Seventy-eight of 82 patients (95%) had subtherapeutic anti-infective concentrations and did not attain the primary pharmacodynamic endpoint. All patients in the infected cohort achieved a microbiological response, and 22 of 23 (95.7%) had a positive clinical response.Conclusions: Overall, 95% of patients had subtherapeutic anti-infective concentrations and did not achieve the requisite pharmacodynamic exposure with current pediatric dosing recommendations. All patients achieved a microbiological response, and 95.7% achieved clinical response with active β-lactam therapeutic drug management. These data suggest β-lactam therapeutic drug management is a potentially valuable intervention to optimize anti-infective pharmacokinetics and the pharmacodynamic exposure. Further, these data also suggest the need for additional research in specific pediatric populations and assessing clinical outcomes associated with β-lactam therapeutic drug management in a larger cohort of pediatric patients. [ABSTRACT FROM AUTHOR]

The PK changes can result from drug binding to the oxygenator, alterations in clearance, and drug adsorption or sequestration. B Introduction: b Extra-corporeal membrane oxygenation (ECMO) is a treatment modality known to alter drug pharmacokinetics (PK). Additionally, there is limited data regarding the impact of the oxygenator on drug changes in ECMO circuits in comparison to the other components of the ECMO circuit. [Extracted from the article]

The article presents a case study of a 30-year-old male patient with congestive heart failure. The patient had a medical history significant for aortic valve replacement (AVR), aortic regurgitation (AR) and endocarditis. An echocardiogram showed an aortic aneurysm and right ventricular dysfunction. Echocardiogram results are explained in detail.

A 2-year-old female child was brought to the emergency department after she was accidentally shot by her father, while cleaning his air rifle loaded with the pointed type 0.22 (5.5 mm) caliber pellet. The pellet hit the front of chest from a distance of about 10–15 m. On physical examination, it was found that there was entrance wound in right lower parasternal area but no exit wound. She was hemodynamically stable with normal auscultatory findings. Chest roentgenogram ( Fig. 1 ) demonstrated a bullet overlying cardiac silhouette with no other findings. Two-dimensional transthoracic echocardiography ( Figs, 2, 3 , and movie clip 1) showed an echogenic density in the interventricular septum just beneath the insertion of tricuspid and mitral leaflets. The atrioventricular valves appear normal with no regurgitation. The biventricular function also appeared normal with no regional wall motion abnormalities. There was no pericardial effusion present. The echogenicity is most likely the pellet that punctured the chest wall and continued inward to lodge in the interventricular septum. Computed tomographic scan of the chest showed an intracardiac foreign body without other abnormalities. Up to 11 months, repeated scans have shown no changes. She will continue to receive ongoing follow-up to assess for late complications (migration, erosion, conduction, disturbance, etc.) To the best of our knowledge, she may be the youngest living patient having cardiac trauma with clinically stable presentation and asymptomatic short-term follow-up. [ABSTRACT FROM AUTHOR]

The article presents the diagnosis of a 36 years old man with pulmonary tuberculosis and presented with various complaints of dyspnea, cough and weight loss. The patient was admitted to the hospital due to severe dyspnea, heart failure and profuse sweating and put on antitubercular therapy. Because he did not respond to the therapy, transthoracic echocardiography was performed to examine the cause of patient's heart failure.

RNAi acts as a host immune response against non-self molecules, including viruses. Viruses evolved to neutralize this response by expressing suppressor proteins. In the present study, we investigated dengue virus non structural protein 3 (dvNS3), for its RNAi-suppressor activity in human cell lines. Dengue virus (DV) NS3 reverts the GFP expression in GFP-silenced cell lines. Pull-down assays of dvNS3 revealed that it interacts with the host factor human heat shock cognate 70 (hHSC70). Down-regulation of hHSC70 resulted in accumulation of dengue viral genomic RNA. Also, the interaction of dvNS3 with hHSC70 perturbs the formation of RISC (RNA-induced silencing complex)- loading complex (RLC), by displacing TRBP (TAR RNAbinding protein) and possibly impairing the downstream activity of miRNAs. Interestingly, some of these miRNAs have earlier been reported to be down-regulated upon DV infection in Huh7 cells. Further studies on the miRNA-mRNA relationship along with mRNA profiling of samples overexpressing dvNS3 revealed up-regulation of TAZ (tafazzin) and SYNGR1 (synaptogyrin 1), known dengue viral host factors (DVHFs). Importantly, overexpression of dvNS3 in human embryonic kidney (HEK) 293T cells resulted in modulation of both mature and precursor miRNAs in human cell lines. Subsequent analysis suggested that dvNS3 induced stage-specific down-regulation ofmiRNAs. Taken together, these results suggest that dvNS3 affects biogenesis and function of host miRNAs to regulate DVHFs for favouring DV replication. [ABSTRACT FROM AUTHOR]

Neither guidelines nor best practices for the treatment of external ventricular drain (EVD) and ventriculoperitoneal shunt infections exist. An antimicrobial regimen with a broad spectrum of activity and adequate cerebrospinal fluid ( CSF) penetration is vital in the management of both EVD and ventriculoperitoneal infections. In this case report, we describe the pharmacokinetics of continuous-infusion meropenem for a 2-year-old girl with Serratia marcescens ventriculitis. A right frontal EVD was placed for the management of a posterior fossa mass with hydrocephalus and intraventricular hemorrhage. On hospital day 6, CSF specimens were cultured, which identified a pan-sensitive Serratia marcescens with an initial cefotaxime minimum inhibitory concentration of 1 μg/ml or less. The patient was treated with cefotaxime monotherapy from hospital days 6 to 17, during which her CSF cultures and Gram's stain remained positive. On hospital day 26, Serratia marcescens was noted to be resistant to cefotaxime (minimum inhibitory concentration > 16 μg/ml), and the antimicrobial regimen was ultimately changed to meropenem and amikacin. Meropenem was dosed at 40 mg/kg/dose intravenously every 6 hours, infused over 30 minutes, during which, simultaneous serum and CSF meropenem levels were measured. Meropenem serum and CSF levels were measured at 2 and 4 hours from the end of the infusion with the intent to perform a pharmacokinetic/pharmacodynamic analysis. The resulting serum meropenem levels were 12 μg/ml at 2 hours and 'undetectable' at 4 hours, with CSF levels of 1 and 0.5 μg/ml at 2 and 4 hours, respectively. On hospital day 27, the meropenem regimen was changed to a continuous infusion of 200 mg/kg/day, with repeat serum and CSF meropenem levels measured on hospital day 33. The serum and CSF levels were noted to be 13 and 0.5 μg/ml, respectively. The serum level of 13 μg/ml corresponds to an estimated meropenem clearance from the serum of 10.2 ml/kg/minute. Repeat meropenem levels from the serum and CSF on hospital day 37 were 15 and 0.5 μg/ml, respectively. After instituting the continuous-infusion meropenem regimen, only three positive CSF Gram's stains were noted, with the CSF cultures remaining negative. The continuous-infusion dosing regimen allowed for 100% probability of target attainment in the serum and CSF and a successful clinical outcome. [ABSTRACT FROM AUTHOR]

Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life-threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14-day-old female with disseminated HSV-1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patient's dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 × 108 copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patient's acyclovir serum concentrations measured at 24 and 72 hours after starting continuous-infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn. This is the first report to describe the pharmacokinetics of continuous-infusion acyclovir in a neonate receiving ECLS with concurrent CRRT. These data suggest that adding acyclovir to the dialysate fluid during CRRT is effective in achieving therapeutic drug concentrations despite the complications of adding ECLS and CRRT circuits to a small patient. [ABSTRACT FROM AUTHOR]

Meropenem, a broad-spectrum carbapenem, is commonly used for empirical and definitive therapy in the pediatric intensive care unit ( ICU). Pharmacokinetic data to guide dosing in children, however, are limited to healthy volunteers or patients who are not in the ICU. Adult data demonstrate that pharmacokinetic parameters such as the volume of distribution and clearance can be significantly altered in individuals receiving extracorporeal membrane oxygenation ( ECMO). Alterations in the volume of distribution and clearance of antimicrobials in patients with sepsis and septic shock have also been documented, and these patients have demonstrated lower than expected antimicrobial serum concentrations based on standard dosing regimens. Therefore, an understanding of the pharmacokinetic changes in critically ill children receiving ECMO is crucial to determining the most appropriate dose and dosing interval selection for any antimicrobial therapy. In this case report, we describe the pharmacokinetics of a continuous infusion of meropenem in a pediatric cardiac ICU patient who was receiving concurrent extracorporeal life support. The patient was an 8-month-old male infant who underwent a Glenn procedure and pulmonary artery reconstruction. Postoperatively, he required ECMO with a total run of 21 days. On day 11 of ECMO, a bronchoalveolar lavage was performed, and blood cultures from days 11 and 12 of ECMO grew Pseudomonas aeruginosa, with a meropenem minimum inhibitory concentration ( MIC) of 0.5 μg/ml. On ECMO day 13, meropenem was initiated with a loading dose of 40 mg/kg and infused over 30 minutes, followed by a continuous infusion of 200 mg/kg/day. A meropenem serum concentration measured 8 hours after the start of the infusion was 46 μg/ml. Repeat levels were measured on days 3 and 9 of meropenem therapy and were 39 and 42 μg/ml, respectively. Repeat blood and respiratory cultures remained negative. This meropenem regimen (40-mg/kg bolus followed by a continuous infusion of 200 mg/kg/day) was successful in providing a target attainment of 100% for serum and lung concentrations above the MIC for at least 40% of the dosing interval and was associated with a successful clinical outcome. [ABSTRACT FROM AUTHOR]

Background: PERSEVERE is a risk model for estimating mortality probability in pediatric septic shock, using five biomarkers measured within 24 hours of clinical presentation. Objective: Here, we derive and test a temporal version of PERSEVERE (tPERSEVERE) that considers biomarker values at the first and third day following presentation to estimate the probability of a “complicated course”, defined as persistence of ≥2 organ failures at seven days after meeting criteria for septic shock, or death within 28 days. Methods: Biomarkers were measured in the derivation cohort (n = 225) using serum samples obtained during days 1 and 3 of septic shock. Classification and Regression Tree (CART) analysis was used to derive a model to estimate the risk of a complicated course. The derived model was validated in the test cohort (n = 74), and subsequently updated using the combined derivation and test cohorts. Results: A complicated course occurred in 23% of the derivation cohort subjects. The derived model had a sensitivity for a complicated course of 90% (95% CI 78–96), specificity was 70% (62–77), positive predictive value was 47% (37–58), and negative predictive value was 96% (91–99). The area under the receiver operating characteristic curve was 0.85 (0.79–0.90). Similar test characteristics were observed in the test cohort. The updated model had a sensitivity of 91% (81–96), a specificity of 70% (64–76), a positive predictive value of 47% (39–56), and a negative predictive value of 96% (92–99). Conclusions: tPERSEVERE reasonably estimates the probability of a complicated course in children with septic shock. tPERSEVERE could potentially serve as an adjunct to physiological assessments for monitoring how risk for poor outcomes changes during early interventions in pediatric septic shock. [ABSTRACT FROM AUTHOR]

Objective: Observed associations between fluid balance and septic shock outcomes are likely confounded by initial mortality risk. We conducted a risk-stratified analysis of the association between post-ICU admission fluid balance and pediatric septic shock outcomes. Design: Retrospective analysis of an ongoing multicenter pediatric septic shock clinical and biological database. Setting: Seventeen PICUs in the United States. Patients: Three hundred and seventeen children with septic shock. Interventions: None. Measurements and Main Results: We stratified subjects into three mortality risk categories (low, intermediate, and high) using a validated biomarker-based stratification tool. Within each category, we assessed three fluid balance variables: total fluid intake/kg/d during the first 24 hours, percent positive fluid balance during the first 24 hours, and cumulative percent positive fluid balance up to 7 days. We used logistic regression to estimate the effect of fluid balance on the odds of 28-day mortality, and on complicated course, which we defined as either death within 28 days or persistence of two or more organ failures at 7 days. There were 40 deaths, and 91 subjects had a complicated course. Increased cumulative percent positive fluid balance was associated with mortality in the low-risk cohort (n = 204; odds ratio, 1.035; 95% CI, 1.004-1.066) but not in the intermediate- and high-risk cohorts. No other associations with mortality were observed. Fluid intake, percent positive fluid balance in the first 24 hours, and cumulative percent positive fluid balance were all associated with increased odds of a complicated course in the low-risk cohort but not in the intermediate- and high-risk cohorts. Conclusions: When stratified for mortality risk, increased fluid intake and positive fluid balance after ICU admission are associated with worse outcomes in pediatric septic shock patients with a low initial mortality risk but not in patients at moderate or high mortality risk. [ABSTRACT FROM AUTHOR]

Background: We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort. Objective: To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort. Methods: Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system. Results: Mortality in the test cohort was 13.2%. Using a risk cut-off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62–95), specificity was 75% (68–82), positive predictive value was 34% (22–47), and negative predictive value was 97% (91–99). The area under the receiver operating characteristic curve was 0.81 (0.70–0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47–1.35; p<0.001). Conclusions: The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system. [ABSTRACT FROM AUTHOR]

Molecular docking, molecular mechanics, molecular dynamics and relaxation matrix simulation protocols have been extensively used to generate the structural details of ligand-receptor complexes in order to understand the binding interactions between the two entities. Experimental methods like NMR spectroscopy and X-ray crystallography are known to provide structural information about ligand-receptor complexes. In addition, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and molecular docking have also been utilized to decode the phenomenon of the ligand-DNA interactions, with good correlation between experimental and computational results. The DNA binding affinity was demonstrated by analysing fluorescence spectral data. Structural rigidity of DNA upon ligand binding was identified by CD spectroscopy. Docking is carried out using the DNA-Dock program which results in the binding affinity data along with structural information like interatomic distances and H-bonding, etc. The complete structural analyses of various drug-DNA complexes have afforded results that indicate a specific DNA binding pattern of these ligands. It also exhibited that certain structural features of ligands can make a ligand to be AT- or GC-specific. It was also demonstrated that changing specificity from AT base pairs to GC base pairs further improved the DNA topoisomerase inhibiting activity in certain ligands. Thus, a specific molecular recognition signature encrypted in the structure of ligand can be decoded and can be effectively employed in designing more potent antiviral and antitumour agents. [ABSTRACT FROM AUTHOR]

The concentrations obtained pre- and post-oxygenator appeared to approximate each other suggesting there may be no drug loss via the oxygenator. The purpose of this study was to determine the impact of the Quadrox-i pediatric and adult oxygenators on the PK of peramivir (PRV) in contemporary ECMO circuits. B Introductions: b ECMO is a treatment modality known to alter drug pharmacokinetics (PK). [Extracted from the article]

A panel of variants with alanine substitutions in the small loop of anthrax toxin protective antigen domain 4 was created to determine individual amino acid residues critical for interactions with the cellular receptor and with a neutralizing monoclonal antibody, 14B7. Substituted protective antigen proteins were analyzed by cellular cytotoxicity assays, and their interactions with antibody were measured by plasmon surface resonance and analytical ultracentrifugation. Residue Asp[sup 683] was the most critical for cell binding and toxicity, causing an ∼1000-fold reduction in toxicity, but was not a large factor for interactions with 14B7. Substitutions in residues Tyr[sup 681], Asn[sup 652], and Pro[sup 686] also reduced toxicity significantly, by 10-100-fold. Of these, only Asn[sup 682] and Pro[sup 686] were also critical for interactions with 14B7. However, residues Lys[sup 684], Leu[sup 685], Leu[sup 687], and Tyr[sup 688] were critical for 14B7 binding without greatly affecting toxicity. The K684A and L685A variants exhibited wild type levels of toxicity in cell culture assays; the L657A and Y688A variants were reduced only 1.5- and 5-fold, respectively. [ABSTRACT FROM AUTHOR]

Presents a study on mitral valve repair in patients with rheumatic heart disease. Advantages of mitral valve repair over mitral valve replacement; Patients and methods; Results and discussion.

Scottish mental health legislation includes a unique criterion for the use of compulsion in the delivery of mental health care and treatment. Under the Mental Health (Care and Treatment) (Scotland) Act, 2003, patients must exhibit 'significantly impaired decision-making ability' (SIDMA) in order to be eligible for psychiatric detention or involuntary psychiatric treatment outside the forensic context. The SIDMA requirement represents a distinctive strategy in ongoing international efforts to rethink the conditions under which psychiatric compulsion is permissible. We reconstruct the history of the Scottish SIDMA requirement, analyse its differences from so-called 'fusion law,' and then examine how the SIDMA standard actually functions in practice. We analyse 100 reports that accompany applications for Compulsory Treatment Orders (CTOs). Based on this analysis, we provide a profile of the patient population that is found to exhibit SIDMA, identify the grounds upon which SIDMA is attributed to individual patients, and offer an assessment of the quality of the documentation of SIDMA. We demonstrate that there are systemic areas of poor practice in the reporting of SIDMA, with only 12% of CTOs satisfying the minimum standard of formal completeness endorsed by the Mental Welfare Commission. We consider what lessons might be drawn both for the ongoing review of mental health legislation in Scotland, and for law reform initiatives in other jurisdictions. [ABSTRACT FROM AUTHOR]

Acute thrombosis involving the left atrium and a bioprosthetic valve during the early postoperative period is an extremely rare complication of heparin-induced thrombocytopenia syndrome (HITS). We present a patient with early bioprosthetic mitral valve stenosis complicated by HITS in a patient with severe mitral regurgitation, atrial fibrillation, and severe left ventricular dysfunction. (J Card Surg 2011;26:369-371) [ABSTRACT FROM AUTHOR]