Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.

BACKGROUND: The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. METHODS: We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. RESULTS: There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. CONCLUSIONS: Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).

Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time.

BACKGROUND: Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus-only ECV). For large ECV, the bolus-only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis. PURPOSE: To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis. STUDY TYPE: Bolus-only and infusion ECV were prospectively measured. POPULATION: In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial. FIELD STRENGTH: Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany. ASSESSMENT: Bolus-only and infusion ECV were measured in all subjects using shortened modified Look-Locker inversion recovery (ShMOLLI) T1 mapping sequence. STATISTICAL TESTS: Pearson correlation coefficient (r); Bland-Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation. RESULTS: The difference between the bolus-only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were ±0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy. DATA CONCLUSION: In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1677-1684.

Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab.

OBJECTIVE: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma. METHODS: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated. RESULTS: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 - 16.85) and 99 mg (95% CI: 47 - 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 - 102%). The safety profile of mepolizumab was favorable. CONCLUSIONS: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship.

Inpatient falls in freestanding children's hospitals.

Patient falls are considered a significant safety risk, but little evidence regarding the significance of falls in children is available. A multisite, observational study of fall events occurring in pediatric inpatients (younger than 18 years of age) from Child Health Corporation of America member hospitals was conducted to determine the prevalence and significance of falls. Fall prevalence was 0.84 per 1,000 patient days with 48% classified as preventable. Injuries occurred in 32%, but only two falls resulted in an increased length of stay; none resulted in permanent disability or death. Only 47% of the children who fell were identified to be at risk for fall. Alert mechanisms were used in 60% and preventive measures in 23%. These findings suggest that while inpatient pediatric fall rates are lower than those of adults, greater diligence in identification and risk reduction may further reduce the prevalence of falls and the proportion of fall-related injuries.

How differing shift lengths relate to quality outcomes in pediatrics.

OBJECTIVE: The aims of this study were to describe the shift lengths of pediatric nurses and to measure the association of shift length with nurse job outcomes, nurse-reported patient outcomes, and nurse-assessed safety and quality of care in hospitals. BACKGROUND: Long work hours have been linked with poor patient outcomes in adult patient populations, but little is known about the relationship in pediatric settings. METHODS: A secondary analysis of cross-sectional nurse survey data was conducted. Our analysis focused on 3710 registered nurses who worked in 342 acute care hospitals that treated children. RESULTS: Most pediatric nurses worked 12-hour shifts, especially in intensive care settings. Nurses who worked extended shifts of more than 13 hours reported worse job outcomes and lower quality and safety for patients compared with nurses who worked 8-hour shifts. CONCLUSIONS: Allocating resources to nursing to improve working hours may be a productive strategy for administrators to improve the health and well-being of pediatric patients and nurses.

New knowledge, innovations, and improvement in a Magnet® Children's Hospital Cardiac Center.

Bedside nurses involved in research and evidence-based practice (EBP) have the ability to change policies, patient care, and outcomes. This article describes the journey of a research committee using the Magnet® component of new knowledge, innovation, and improvements. Using several tools, the unit-based committee developed skills in meeting management, nursing research methods, and EBP. Focusing to improve family and nurse communication about the plan of care, the committee recommended changes in the existing Plan of Care tool, including family input and recommendations for families to view and add to the sheet and participate in daily rounds, which was not the standard practice. Since this intervention was implemented, patient satisfaction has increased, as well as nurse engagement and intent to stay. This project exemplifies how nurse-driven innovations and family partnership led to new knowledge, innovations in learning about research, applying it to practice, and improving practice.

A descriptive study of complications of gastrostomy tubes in children.

OBJECTIVES: The purpose of this study was to determine the number and types of complications experienced by children with gastrostomy tubes. METHODS: This is a prospective study of children with gastrostomy tube complications. Enrollment occurred on the first 24 months of the study. Data were collected for 4 years, beginning at the enrollment of the first participant. Demographic data and information on infections, granulation tissue formation, and major complications were recorded. RESULTS: Infections occurred in 37% of patients, with most experiencing a single infection that occurred within the first 15 days after tube placement. Granulation tissue developed in 68% of patients, with 17% experiencing recurrent granulation tissue despite treatment. There was no difference in infection rates or granulation tissue formation between subgroups based on gender, ethnicity, or parents' education level. Major complications occurred in 4% of the patients. CONCLUSION: Complications of infection and granulation tissue occur frequently and likely are a cause of stress and increased burden of care for these children and families. Improved strategies for care are needed.

Reintegrating Veterans with Polytrauma into the Community and Workplace.

This article addresses employment as a critical part of community reintegration for polytrauma patients. Interdisciplinary polytrauma teams can work to effectively identify and eliminate known barriers to employment for veterans and offer continued support and guidance. This article discusses key themes pertinent to vocational reentry for service members/veterans, identifies evidenced-based employment models, highlights the essential role of everyday technology in meeting support needs, and describes 2 exemplar polytrauma models: the Louis Stokes Cleveland Veteran Affairs Medical Center in Cleveland, Ohio, and the Service member Transitional Advanced Rehabilitation (STAR) program at the Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, Virginia.

Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.

Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of 123I-labeled SAP or of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.

Missed Nursing Care in Pediatrics.

OBJECTIVES: A growing literature suggests that missed nursing care is common in hospitals and may contribute to poor patient outcomes. There has been scant empirical evidence in pediatric populations. Our objectives were to describe the frequency and patterns of missed nursing care in inpatient pediatric settings and to determine whether missed nursing care is associated with unfavorable work environments and high nurse workloads. METHODS: A cross-sectional study using registered nurse survey data from 2006 to 2008 was conducted. Data from 2187 NICU, PICU, and general pediatric nurses in 223 hospitals in 4 US states were analyzed. For 12 nursing activities, nurses reported about necessary activities that were not done on their last shift because of time constraints. Nurses reported their patient assignment and rated their work environment. RESULTS: More than half of pediatric nurses had missed care on their previous shift. On average, pediatric nurses missed 1.5 necessary care activities. Missed care was more common in poor versus better work environments (1.9 vs 1.2; P < .01). For 9 of 12 nursing activities, the prevalence of missed care was significantly higher in the poor environments (P < .05). In regression models that controlled for nurse, nursing unit, and hospital characteristics, the odds that a nurse missed care were 40% lower in better environments and increased by 70% for each additional patient. CONCLUSIONS: Nurses in inpatient pediatric care settings that care for fewer patients each and practice in a professionally supportive work environment miss care less often, increasing quality of patient care.

The voices of breastfeeding resource nurses.

OBJECTIVE: To describe and evaluate the Breastfeeding Resource Nurse (BRN) role and program at The Children's Hospital of Philadelphia (CHOP). DESIGN: The primary study was a multimethod study including a survey and key informant interviews to meet the study's objectives: to describe how the BRN implements his or her role at the unit level throughout the hospital, to describe the successes and challenges of the BRN role, to provide data on how BRNs may be better supported in their roles, and provide data for the translation of the BRN program to other institutions. We present the qualitative descriptive component from the primary study. SETTING: The Children's Hospital of Philadelphia enterprise. PARTICIPANTS: Eighteen BRNs within the CHOP enterprise. METHODS: Semistructured interviews were conducted with the BRN participants. The data were analyzed with conventional content analysis. RESULTS: Four major themes emerged from the BRN interview data: Empowering through evidence, Advocacy, Going the extra mile, and Personal connections to breastfeeding. CONCLUSIONS: Compelling stories illustrated the role of the BRN as patient advocate and educator for staff and families. Knowing the evidence about lactation and breastfeeding empowered the BRN to be successful in his or her role. The BRNs derived great personal and professional satisfaction from their roles. The BRN program can be easily adapted to other pediatric care centers and will enable improved breastfeeding outcomes at the point of care.

Improving practice at the point of care through the optimization of the breastfeeding resource nurse model.

OBJECTIVE: To describe and understand the Breastfeeding Resource Nurse (BRN) role and program. DESIGN: The primary study was a multimethod prospective study in which quantitative surveys and qualitative interviews of nurses who received education through the BRN program were used. Results presented herein are from the quantitative arm of the primary study. SETTING: A large free-standing urban children's hospital with a birthing unit for specialized deliveries and a primary and specialty care network. PARTICIPANTS: A total of 425 of 600 nurses who took the BRN course responded to the survey. These nurses worked in all settings throughout the enterprise. METHODS: The research team created a Survey Monkey interview that was e-mailed to all current nurses with valid hospital e-mail addresses who had taken the BRN course. Monthly e-mail reminders were sent and nurse managers were asked to encourage their staff to fill out the survey. RESULTS: Nurses who received specialized education through BRN course integrated the provision of evidence-based breastfeeding support and care into their daily routines. Furthermore, nurses became breastfeeding advocates and supported family, friends, and members of their communities in their breastfeeding experiences. CONCLUSIONS: The type of education needed for nurses who work at children's hospitals and in neonatal intensive care units is different than traditional breastfeeding education for birth hospitals. Implementation of the BRN course resulted in positive outcomes for staff; the course is transferrable to other facilities worldwide.

The effects of infant feeding decisions on infant growth.

ISSUES AND PURPOSE: To determine the effects of feeding decisions on infant growth in the first 6 months of life. DESIGN AND METHODS: Growth measurements were collected twice during the first 6 months of infancy as part of a larger investigation of infant feeding practices (N = 52). RESULTS: Infants who received solid foods before the age of 4 to 6 months weighed less than those who received solid foods after 4 to 6 months. There were no differences in growth measurements between formula-fed and breast-fed infants, although breast-fed infants weighed more at birth. PRACTICE IMPLICATIONS: Emphasize the importance of feeding breast milk (preferably) or formula only for the first 6 months. Advise parents to withhold fruit juices until the infant is at least 6 months old.

Nurse reports on resource adequacy in hospitals that care for acutely ill children.

Despite the estimated 1.8 million children admitted to hospitals annually, little is known about the quality of care and the adequacy of resources in hospitals that care for acutely ill infants and children. Using survey data from 3,819 pediatric nurses working in 498 hospitals, we found that nursing resources vary significantly across different types of hospitals that care for children. Nurses working in a children's hospital within a hospital, and on a pediatric unit in a general hospital were more likely than nurses in freestanding children's hospitals to report inadequate nursing resources. We also found that inadequate nursing resources were associated with surveillance left undone and missed changes in patients' condition. These findings have implications for the quality and safety of pediatric care.

Pediatric temperature measurement and child/parent/nurse preference using three temperature measurement instruments.

This study compared the tympanic thermometer with the electronic and chemical dot thermometers used at the axillary site and evaluated child, parent, and nurse preferences for method of temperature measurement. The child's (n = 146) temperature was measured using each of the three methods. Each child, parent, and nurse was asked to select a preference for device and site. Results were analyzed using the Bland-Altman method. Results showed that most of the paired readings fell within the Bland-Altman limits of agreement (LOA). When the chemical dot and tympanic temperature readings were compared with the electronic axillary reading, the tympanic thermometer was found to be in closer agreement. The chemical dot thermometer placed in the axilla consistently read higher than the electronic thermometer in the same site. Children, parents, and nurses preferred the tympanic thermometer.

Comparing two methods to obtain blood specimens from pediatric central venous catheters.

The purpose of this study was to test agreement in blood values obtained from a discard method and a push-pull method in samples from central venous catheters in pediatric patients. The discard method causes blood loss beyond what is necessary for blood testing and increases potential for infection each time the central venous catheter is entered. Twenty-eight children ranging in age from 6 months to 12 years were enrolled in the study. A research protocol was developed to pair the 2 methods of blood collection for each sample. The Bland-Altman method was used to test agreement on each blood value for each paired sample. Of the 438 pairs of measured blood values, 420 (95.9%) fell within the limits of agreement. Nurses reported no difficulty in using the push-pull technique to obtain any samples. The push-pull method of obtaining blood specimens from pediatric central venous catheters should be considered. It can eliminate blood loss through discard and can reduce infection because it reduces the number of times a catheter is entered.

Hepatitis C transmission and HIV post-exposure prophylaxis after needle- and syringe-sharing in Australian prisons.

OBJECTIVES: To determine whether infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) occurred after two potential episodes of exposure through needle- and syringe-sharing in Australian prisons, and to examine use of post-exposure prophylaxis (PEP) against HIV infection in the prison setting. DESIGN: Cohort study of potential contacts of two prisoners infected with HIV, HBV and HCV followed up for up to 14 months. SETTING: Two Australian prisons between November 2000 (time of exposure) and December 2001. PARTICIPANTS: Two index patients (both infected with HIV and HCV; one also infectious for HBV) from two different prisons, and 104 inmates who shared needles and syringes. MAIN OUTCOME MEASURES: Seroconversions to HIV, HBV and HCV related to the high-risk exposure and uptake and completion of HIV PEP determined from medical records of inmates. RESULTS: There were four seroconversions to HCV within 14 months of the potential exposure (14% of those susceptible in the cohort), but no recorded HIV or HBV seroconversions. Forty-six inmates (82% of those eligible) were offered PEP, and 34 of these (74%) elected to receive it. Only eight (24% of the 34) completed the full PEP course. CONCLUSIONS: HCV transmission in the prison setting is related to high-risk needle- and syringe-sharing. Administering HIV PEP in the prison setting is complicated by challenging risk assessment and follow-up.