Examining health-related quality of life in pediatric cancer patients with febrile neutropenia: Factors predicting poor recovery in children and their parents.

BACKGROUND: The impact febrile neutropenia (FN) has on the health-related quality of life (HRQoL) of children with cancer and their families is poorly understood. We sought to characterize the course of child and parent HRQoL during and following FN episodes. METHOD: Data on HRQoL were collected in the multisite Australian Predicting Infectious ComplicatioNs in Children with Cancer (PICNICC) study. Participants were enrolled between November 2016 to January 2018. The Child Health Utility (CHU9D) was used to assess HRQoL in children (N = 167 FN events) and the Assessment of Quality of Life (AQoL-8D) was used to assess HRQoL parents (N = 218 FN events) at three time points: 0-3 days, 7-days and 30-days following the onset of FN. Group-based trajectory modeling (GBTM) was used to characterize the course of HRQoL. FINDINGS: For children, three distinct groups were identified: persistently low HRQoL over the 30-day course of follow-up (chronic: N = 78/167; 47%), increasing HRQoL after the onset of FN to 30 days follow-up (recovering: N = 36/167; 22%), and persistently high HRQoL at all three timepoints (resilient: N = 53/167; 32%). Applying these definitions, parents were classified into two distinct groups: chronic (N = 107/218, 49%) and resilient (N = 111/218, 51%). The child being male, having solid cancer, the presence of financial stress, and relationship difficulties between the parent and child were significant predictors of chronic group membership for both parents and children. Children classified as high-risk FN were significantly more likely to belong to the recovery group. Being female, having blood cancers and the absence of financial or relationship difficulties were predictive of both parents and children being in the resilient group. INTERPRETATION: Approximately half the children and parents had chronically low HRQoL scores, which did not improve following resolution of the FN episode. The child's sex, cancer type, and presence of financial and relationship stress were predictive of chronic group membership for both parents and children. These families may benefit from increased financial and psychosocial support during anti-cancer treatment. FUNDING: National Health and Medical Research Council Grant (APP1104527).

Epitope-targeting platform for broadly protective influenza vaccines.

Seasonal influenza vaccines are often ineffective because they elicit strain-specific antibody responses to mutation-prone sites on the hemagglutinin (HA) head. Vaccines that provide long-lasting immunity to conserved epitopes are needed. Recently, we reported a nanoparticle-based vaccine platform produced by solid-phase peptide synthesis (SPPS) for targeting linear and helical protein-based epitopes. Here, we illustrate its potential for building broadly protective influenza vaccines. Targeting known epitopes in the HA stem, neuraminidase (NA) active site, and M2 ectodomain (M2e) conferred 50-75% survival against 5LD50 influenza B and H1N1 challenge; combining stem and M2e antigens increased survival to 90%. Additionally, protein sequence and structural information were employed in tandem to identify alternative epitopes that stimulate greater protection; we report three novel HA and NA sites that are highly conserved in type B viruses. One new target in the HA stem stimulated 100% survival, highlighting the value of this simple epitope discovery strategy. A candidate influenza B vaccine targeting two adjacent HA stem sites led to >104-fold reduction in pulmonary viral load. These studies describe a compelling platform for building vaccines that target conserved influenza epitopes.

Epitope targeting with self-assembled peptide vaccines.

Nanoparticle-based delivery systems are being used to simplify and accelerate new vaccine development. Previously, we described the solid-phase synthesis of a 61-amino acid conjugate vaccine carrier comprising a α-helical domain followed by two universal T cell epitopes. Circular dichroism, analytical centrifugation, and dynamic light scattering indicate that this carrier forms coiled-coil nanoparticles. Here we expand the potential of this carrier by appending B cell epitopes to its amino acid sequence, thereby eliminating the need for traditional conjugation reactions. Peptides containing Tau or amyloid-ß epitopes at either terminus assemble into ~20 nm particles and induce antibody responses in outbred mice. Vaccine function was verified in three experiments. The first targeted gonadotropin-releasing hormone, a 10-amino acid neuropeptide that regulates sexual development. Induction of peak antibody titers in male mice stimulated a dramatic loss in fertility and marked testis degeneration. The second experiment generated antibodies to an epitope on the murine IgE heavy chain analogous to human IgE sequence recognized by omalizumab, the first monoclonal antibody approved for the treatment of allergic asthma. Like omalizumab, the anti-IgE antibodies in immunized mice reduced the concentrations of circulating free IgE and prevented IgE-induced anaphylaxis. Finally, a peptide containing the highly conserved Helix A epitope within the influenza hemagglutinin stem domain induced antibodies that successfully protected mice against a lethal H1N1 challenge. These results establish the utility of a new vaccine platform for eliciting prophylactic and therapeutic antibodies to linear and helical B cell epitopes.

Optimization of a multivalent peptide vaccine for nicotine addiction.

We have been optimizing the design of a conjugate vaccine for nicotine addiction that employs a peptide-based hapten carrier. This peptide, which is produced by solid-phase protein synthesis, contains B cell and T cell epitope domains and eliminates the non-relevant, but highly immunogenic sequences in microbial carriers. In this report, the amino acid sequences in the T cell domain were optimized for improved vaccine activity and multivalent formulations containing structurally distinct haptens were tested for the induction of additive antibody responses. Trivalent vaccines produced antibody concentrations in mice that were 100 times greater than the amount of nicotine measured in smokers, and significantly reduced acute nicotine toxicity in rats. Two additional features were explored that distinguish the peptide from traditional recombinant carriers. The first is the minimal induction of an anti-carrier response, which can suppress nicotine vaccine activity. The second employs solid-phase synthesis to manufacture haptenated peptide. This approach obviates conventional conjugation chemistries and streamlines production of a more potent vaccine antigen.

Practice Guidelines for Hypertension.

Hypertension is very prevalent in South Dakota affecting approximately one-third of the adult population. Management and treatment of the disease has recently been the subject of considerable debate centered on what should be the blood pressure goal depending on the patient's age and co-morbid conditions. Recently, a randomized trial of intensive versus standard blood pressure control indicated that a systolic blood pressure of less than 120 mmHg in patients at high risk for cardiovascular events but without diabetes, resulted in significantly lower rates of non-fatal major cardiovascular events and death from any cause. Several studies have also looked at goals for hypertensive patients with diabetes. This article will review some of these recent studies and controversies associated with them. Medication and non-medication recommendations for control of blood pressure will also be discussed.

Construction of an enantiopure bivalent nicotine vaccine using synthetic peptides.

Clinical outcomes of anti-nicotine vaccines may be improved through enhancements in serum antibody affinity and concentration. Two strategies were explored to improve vaccine efficacy in outbred mice: the use of enantiopure haptens and formulation of a bivalent vaccine. Vaccines incorporating natural (-) nicotine haptens improved relative antibody affinities >10-fold over (+) haptens, stimulated a two-fold boost in nicotine serum binding capacity, and following injection with 3 cigarette equivalents of nicotine, prevented a larger proportion of nicotine (>85%) from reaching the brain. The activity of a bivalent vaccine containing (-) 3'AmNic and (-) 1'SNic haptens was then compared to dose-matched monovalent groups. It was confirmed that antisera generated by these structurally distinct haptens have minimal cross-reactivity and stimulate different B cell populations. Equivalent antibody affinities were detected between the three groups, but the bivalent group showed two-fold higher titers and an additive increase in nicotine serum binding capacity as compared to the monovalent groups. Mice immunized with the bivalent formulation also performed better in a nicotine challenge experiment, and prevented >85% of a nicotine dose equivalent to 12 cigarettes from reaching the brain. Overall, enantiopure conjugate vaccines appear to improve serum antibody affinity, while multivalent formulations increase total antibody concentration. These findings may help improve the performance of future clinical candidate vaccines.

Flexible and twistable non-volatile memory cell array with all-organic one diode-one resistor architecture.

Flexible organic memory devices are one of the integral components for future flexible organic electronics. However, high-density all-organic memory cell arrays on malleable substrates without cross-talk have not been demonstrated because of difficulties in their fabrication and relatively poor performances to date. Here we demonstrate the first flexible all-organic 64-bit memory cell array possessing one diode-one resistor architectures. Our all-organic one diode-one resistor cell exhibits excellent rewritable switching characteristics, even during and after harsh physical stresses. The write-read-erase-read output sequence of the cells perfectly correspond to the external pulse signal regardless of substrate deformation. The one diode-one resistor cell array is clearly addressed at the specified cells and encoded letters based on the standard ASCII character code. Our study on integrated organic memory cell arrays suggests that the all-organic one diode-one resistor cell architecture is suitable for high-density flexible organic memory applications in the future.

Reliability estimates: behavioural stations and questionnaires in medical school admissions.

CONTEXT: Assessment centres used in evaluating the non-cognitive attributes of medical school candidates must generate scores that reflect as accurate a measurement as possible of these attributes. Thus far, reliability coefficients for such centres have been based on limited samples and individual administrations, without reference to the error of variance that may result from retesting, or from the existence of multiple centres designed to measure the same attributes. METHODS: The National Institute for Testing and Evaluation in Israel has developed and administered two assessment centres: MOR is used by two medical schools and one dental school, and MIRKAM by another medical school. Each centre comprises eight or nine behavioural stations, a standardised biographical questionnaire, and a judgement and decision-making questionnaire. We calculated generalisability coefficients for each centre's eight or nine stations by year, composite reliability coefficients for the overall assessment centres, test-retest correlation coefficients for repeaters, and a correlation coefficient between the centres. RESULTS: Between 2006 and 2009, 2662 and 2023 examinees participated in MOR and MIRKAM, respectively; 1479 of these participated in both. The average generalisability coefficients for the stations were 0.69 for MOR and 0.67 for MIRKAM. The composite reliability coefficients for the full centres (behavioural stations plus questionnaires) were 0.79 and 0.76 for MOR and MIRKAM, respectively. The correlations for repeaters, corrected for restriction of range, were 0.59 and 0.43 for MOR and MIRKAM stations, respectively, and 0.72 and 0.65 for the full MOR and MIRKAM assessments, respectively. The correlation between scores on the MOR and MIRKAM stations was 0.56 (0.75 for the overall score). DISCUSSION: The minimal reliability desirable for high-stakes decision making (0.80) was obtained only for 14 or 15 stations with questionnaires. Nevertheless, the values obtained are considerably higher than reliability coefficients for single interviews. The questionnaires contribute significantly to the accuracy of the measurement. These reliability measures constitute an upper threshold for measures of validity.

Reliability and responsiveness of the lower extremity functional scale and the anterior knee pain scale in patients with anterior knee pain.

STUDY DESIGN: Prospective methodological study of repeated measures using a sample of consecutive patients. OBJECTIVE: To determine the test-retest reliability and responsiveness of the Anterior Knee Pain Scale (AKPS) and the Lower Extremity Functional Scale (LEFS) in patients with anterior knee pain. BACKGROUND: Anterior knee pain is one of the most common orthopedic complaints affecting the knee. Yet there is currently no self-report outcome measure that has well-established reliability and responsiveness, specifically for this population. As a result, clinicians and researchers may be making inappropriate conclusions regarding patient outcomes by using questionnaires that are misleading. METHODS AND MEASURES: This multisite study involved 30 patients from 4 outpatient physical therapy clinics in Dallas, TX (24 women, 6 men; age range, 16-50 years; mean+/-SD age, 35.2+/-9.1 years). Patients receiving physical therapy for a chief complaint of anterior knee pain completed the AKPS and LEFS at their initial appointment and again 2 to 3 days later. Upon completion of physical therapy, the patients completed the AKPS, LEFS, and a global rating of change form. The treating therapist also completed a global rating of change form at the patient's final visit. The mean of the patient's and therapist's global rating of change was used as the criterion measure of change. RESULTS: Test-retest reliability was high for both questionnaires (ICC2,1 = 0.95 for the AKPS and 0.98 for the LEFS). A significant correlation was found between the criterion measure of change and both questionnaires. Receiver-operating characteristic curve analysis revealed that both questionnaires were moderately responsive with the area under the curve slightly higher for the LEFS (0.77) than the AKPS (0.69). CONCLUSION: The LEFS and the AKPS both demonstrated high test-retest reliability and appear to be moderately responsive to clinical change in patients with anterior knee pain. Reliability and responsiveness were slightly higher in the LEFS than the AKPS. Further research is needed to determine if these measures could be modified, or new measures created, to produce an even more sensitive tool for this population.