Understanding the In Vitro-In Vivo Nexus: Advanced correlation models predict clinical performance of liposomal doxorubicin.

In the century of precision medicine and predictive modeling, addressing quality-related issues in the medical supply chain is critical, with 62 % of the disruptions being attributable to quality challenges. This study centers on the development and safety of liposomal doxorubicin, where animal studies alone often do not adequately explain the complex interplay between critical quality attributes and in vivo performances. Anchored in our aim to elucidate this in vitro-in vivo nexus, we compared TLD-1, a novel liposomal doxorubicin delivery system, against the established formulations Doxil® and Lipodox®. Robust in vitro-in vivo correlations (IVIVCs) with excellent coefficients of determination (R2 > 0.98) were obtained in the presence of serum under dynamic high-shear conditions. They provided the foundation for an advanced characterization and benchmarking strategy. Despite the smaller vesicle size and reduced core crystallinity of TLD-1, its release behavior closely resembled that of Doxil®. Nevertheless, subtle differences between the dosage forms observed in the in vitro setting were reflected in the bioavailabilities observed in vivo. Data from a Phase-I clinical trial facilitated the development of patient-specific IVIVCs using the physiologically-based nanocarrier biopharmaceutics model, enabling a more accurate estimation of doxorubicin exposure. This advancement could impact clinical practice by allowing for more precise dose estimation and aiding in the assessment of the interchangeability of generic liposomal doxorubicin.

Translation and validation of Cerebral Palsy Quality of Life Questionnaire-Teen in Hong Kong Chinese population [CP QoL-Teen (HK)].

Cerebral palsy (CP) is an early onset, non-progressive, neuromotor disorder. Adolescence is the transition from childhood to adulthood when changes in physical and emotional aspects and self-perception occur further imposing an impact to quality of life (QoL) in individuals with CP. Cerebral Palsy Quality of Life (CP QoL) Teen is a questionnaire examining different domains of QoL for adolescents with CP. This study is aimed at translating and validating self-report and proxy-report CP QoL-Teen (HK). Prior approval of translation has been obtained. Forward and backward translations were performed following standardized translation procedures. Participants and their caregivers were asked to complete self-report and proxy-report CP QoL-Teen (HK), and Child Health Questionnaire (CHQ). Internal consistency and test-retest reliability were assessed by Cronbach's alpha and intraclass correlation coefficient (ICC), respectively. Concurrent validity was evaluated by Spearman's rank correlation between subscales of CP QoL-Teen (HK) and CHQ as well as expanded and revised version of Gross Motor Function Classification System (GMFCS-E&R). Ninety-six participants completed the study. Of these, twenty participants completed CP QoL-Teen (HK) twice. Cronbach's α of CP QoL-Teen (HK) ranged from 0.84 to 0.95 suggesting excellent internal consistency. Moderate to excellent test-retest reliability were demonstrated in all subscales of CP QoL-Teen (HK) (self-report: ICC = 0.46-0.8; proxy-report: ICC = 0.40-0.72, p < 0.05). Weak to moderate association between subscales of CP QoL-Teen (HK) and CHQ (self-report: rs = 0.24-0.61; proxy-report: rs = - 0.41-0.60) was reported. CONCLUSION: This study showed that CP QoL-Teen (HK) has good psychometric properties. It is a valid and reliable tool to assess quality of life of adolescents with CP. WHAT IS KNOWN: • Cerebral Palsy Quality of life-Teen (CP QoL-Teen) is a validated tool with strong psychometric properties and clinical utility in gauging the QoL in adolescents with CP during their transition from childhood to adulthood when changes in physical and emotional aspects and self-perception occur. Yet, a locally validated tool is lacking in measuring the QoL for adolescents with CP in Hong Kong. WHAT IS NEW: • The Chinese translated version CP QoL-Teen (HK) is a valid and reliable tool to assess quality of life of adolescents with CP tailoring to the local cultural and social background with good psychometric properties being demonstrated.

Assessing Lung Parenchymal Enhancement on Dual-Energy CT Pulmonary Angiograms: Potential utility of dual-energy technique as an angiographic and parenchymal 'one-stop shop' in the initial workup of patients with pulmonary symptoms.

OBJECTIVE: The aim of this study was to assess the enhancement of lung parenchyma on dual-energy (DE) computed tomogram (CT) by comparing attenuation between routine post-contrast and dual-energy generated virtual unenhanced (VU) images. METHODS: Patients presenting to the Emergency Department who subsequently underwent DE-CT pulmonary angiogram from the 1st to the 30th of November were enrolled. The DE data set obtained was used to generate VU images. Attenuation in Hounsfield units (HU) was measured at two sites for each patient and compared between VU and routine post-contrast (PC) reconstructions. Statistical analysis was performed using paired-samples t-test. RESULTS: There is a statistical difference between lung parenchymal attenuation value between the CV and PC images, denser in the PC dataset and also towards the bases, with a mean HU of -841 and -817 (difference of 24) respectively. CONCLUSIONS: This study confirms increased lung parenchymal density when comparing PC and VU reconstructions. Based on results, the paper recommends utilising dual-energy capabilities for VU reconstructions in CTPAs to optimise assessment of lung parenchyma.

Development of Gross Motor Evaluation for Children Aged 18 to 42 Months.

PURPOSE: To test the reliability and validity of the gross motor items making up a new instrument, Hong Kong Comprehensive Assessment Scales for Toddlers (HKCAS-T) for quantifying gross motor development among children aged 18 to 42 months. METHODS: The 37 items were administered to 330 children, including 258 typically developing children and 72 children with gross motor delay. RESULTS: Rasch analyzes indicated that the fit statistics of the 37 items were within the acceptable range. The assessment was found able to differentiate between typically developing children and those with gross motor delay and among children of different ages. The raw score reliability (KR-20) was 0.94. CONCLUSION: The new instrument is a promising alternative for assessing young children's gross motor development.

Reminiscing to teach others and prepare for death is associated with meaning in life through generative behavior in elderlies from four cultures.

Objectives: Reminiscence is considered an important aspect of successful ageing. Prominent reminiscence functions in old age are to pass on important experiences (Teach/Inform) and to prepare for death (Death Preparation). These reminiscence functions were hypothesized to be associated with generative behavior which in turn was hypothesized to be associated with meaning in life. Thus, we tested an indirect effect of reminiscence functions on meaning in life mediated by generative behavior.Method: Elderly participants provided information on reminiscence functions, generative behavior, and meaning in life. Participants were recruited in Cameroon, China (Hong Kong), the Czech Republic, and Germany, to test the generalizability of findings.Results: The assumed indirect effect was identified: Reminiscence functions were associated with meaning in life via generative behavior. This pattern was found for all cultural samples.Conclusion: Albeit results have to be interpreted with caution as they are based on cross-sectional data, findings suggest that these reminiscence functions motivate generative behavior and thus indirectly affect meaning in life in elderlies from all four cultural contexts. In future studies, this effect needs to be replicated with a broader age range and a more fine-grained measure of generative behavior to account for potential differences in culturally appropriate generative outlets.

Efficacy and safety of 20% albumin fluid loading in healthy subjects: a comparison of four resuscitation fluids.

Recently, buffered salt solutions and 20% albumin (small volume resuscitation) have been advocated as an alternative fluid for intravenous resuscitation. The relative comparative efficacy and potential adverse effects of these solutions have not been evaluated. In a randomized, double blind, cross-over study of six healthy male subjects we compared the pulmonary and hemodynamic effects of intravenous administration of 30 ml/kg of 0.9% saline, Hartmann's solution and 4% albumin, and 6 ml/kg of 20% albumin (albumin dose equivalent). Lung tests (spirometry, ultrasound, impulse oscillometry, diffusion capacity, and plethysmography), two- to three-dimensional Doppler echocardiography, carotid applanation tonometry, blood gases, serum/urine markers of endothelial, and kidney injury were measured before and after each fluid bolus. Data were analyzed with repeated measures ANOVA with effect of fluid type examined as an interaction. Crystalloids caused lung edema [increase in ultrasound B line (P = 0.006) and airway resistance (P = 0.009)], but evidence of lung injury [increased angiopoietin-2 (P = 0.019)] and glycocalyx injury [increased syndecan (P = 0.026)] was only observed with 0.9% saline. The colloids caused greater left atrial stretch, decrease in lung volumes, and increase in diffusion capacity than the crystalloids, but without pulmonary edema. Stroke work increased proportionally to increase in preload with all four fluids (R2 = 0.71). There was a greater increase in cardiac output and stroke volume after colloid administration, associated with a reduction in afterload. Hartmann's solution did not significantly alter ventricular performance. Markers of kidney injury were not affected by any of the fluids administrated. Bolus administration of 20% albumin is both effective and safe in healthy subjects. NEW & NOTEWORTHY Bolus administration of 20% albumin is both effective and safe in healthy subjects when compared with other commonly available crystalloids and colloidal solution.

Convection in a volatile nitrogen-ice-rich layer drives Pluto's geological vigour.

The vast, deep, volatile-ice-filled basin informally named Sputnik Planum is central to Pluto's vigorous geological activity. Composed of molecular nitrogen, methane, and carbon monoxide ices, but dominated by nitrogen ice, this layer is organized into cells or polygons, typically about 10 to 40 kilometres across, that resemble the surface manifestation of solid-state convection. Here we report, on the basis of available rheological measurements, that solid layers of nitrogen ice with a thickness in excess of about one kilometre should undergo convection for estimated present-day heat-flow conditions on Pluto. More importantly, we show numerically that convective overturn in a several-kilometre-thick layer of solid nitrogen can explain the great lateral width of the cells. The temperature dependence of nitrogen-ice viscosity implies that the ice layer convects in the so-called sluggish lid regime, a unique convective mode not previously definitively observed in the Solar System. Average surface horizontal velocities of a few centimetres a year imply surface transport or renewal times of about 500,000 years, well under the ten-million-year upper-limit crater retention age for Sputnik Planum. Similar convective surface renewal may also occur on other dwarf planets in the Kuiper belt, which may help to explain the high albedos shown by some of these bodies.

Generativity does not necessarily satisfy all your needs: Associations among cultural demand for generativity, generative concern, generative action, and need satisfaction in the elderly in four cultures.

The present study examines the association between various facets of generativity, that is, cultural demand for generativity, generative concern, and generative action, with the satisfaction of the needs for relatedness, competence, and autonomy in samples of elderly from Cameroon, China (Hong Kong), the Czech Republic, and Germany. Participants provided information on self-transcendence values (internalized cultural demand), generative concern and action, and need satisfaction. Results suggest, first, that internalized cultural demand affects generative action indirectly through generative concern, second, that generative concern has a positive direct effect on need satisfaction, but that, third, there is also an indirect effect of generative concern on need satisfaction through generative action, which, fourth, is positive for the needs for relatedness and competence but negative for the need for autonomy. These findings were culture-invariant in our study, suggesting generalizability to other cultures. They are discussed with respect to the role of values in generativity and a possible trade-off of generative action for the satisfaction of needs at least in the elderly.

Pharmacokinetic drug-drug interaction assessment of peptibody trebananib in combination with chemotherapies.

PURPOSE: To provide the first evaluation of pharmacokinetic (PK) drug-drug interactions (DDIs) between trebananib and chemotherapies across tumor types. METHODS: PK data of trebananib and chemotherapies (paclitaxel, carboplatin, pegylated liposomal doxorubicin, topotecan, capecitabine, lapatinib, 5-FU, irinotecan, or docetaxel) were collected from trials of ovarian cancer, metastatic breast cancer, colorectal carcinoma, and mixed solid tumor. A dedicated PK DDI study of trebananib and paclitaxel in patients with mixed solid tumors was also conducted. The geometric least squares mean (GLSM) ratios and corresponding 90 % confidence intervals (CI) of C max and AUC were estimated for DDI evaluations. RESULTS: In the PK DDI study of trebananib and paclitaxel, the GLSM ratio (90 % CI) was 1.17 (1.10-1.25) for paclitaxel AUC and 1.30 (1.15-1.48) for paclitaxel C max. The GLSM ratio (90 % CI) for the effect of paclitaxel on trebananib PK was 0.92 (0.87-0.97) for trebananib AUC and 0.98 (0.92-1.05) for trebananib C max. In the remaining studies, the GLSM ratios (90 % CI) of C max and AUC generally ranged from 0.8 to 1.25 or exhibited less than twofold PK variabilities across chemotherapeutic agents. No dose-dependent DDIs were evident. CONCLUSIONS: No PK DDI was deemed clinically meaningful between trebananib and the tested chemotherapeutic agents to warrant dose adjustments.

Can we really diagnose diabetes during pregnancy?

OBJECTIVE: To identify the accuracy of diagnosing postpartum diabetes and glucose intolerance using antepartum glycosylated hemoglobin (HbA1c) and fasting glucose values. STUDY DESIGN: A retrospective Hawaiian cohort of women with gestational diabetes during 2004-2011 were evaluated. Antepartum HbA1c and postpartum 75-g glucose tolerance tests were obtained. RESULTS: An antepartum HbA1c value of ≥6.5% had a 45.7% sensitivity, a 96% specificity and a 40% positive predictive value (PPV) for predicting postpartum diabetes. An antepartum HbA1c value of ≥6.5% had a 6.6% sensitivity, a 94.2% specificity and a 27% PPV for predicting postpartum impaired glucose tolerance. An antepartum HbA1c value of ≥6.5% had a 10.3% sensitivity, a 95.7% specificity and a 33.3% PPV for predicting postpartum impaired fasting glucoses. CONCLUSION: We could not demonstrate a clinically useful PPV for diagnosing postpartum diabetes or glucose intolerance using an antepartum elevated HbA1c value of ≥6.5% or a fasting glucose level of ≥90 mg/dL.

Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs.

The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development.

For the benefit of others: generativity and meaning in life in the elderly in four cultures.

Generativity has been argued to be an important indicator of successful aging. Indeed, generative concern has been found to be associated with meaning in life. In the present study, this relationship is argued to be partly explained through generative goals. Moreover, the path between generative goals and meaning in life is hypothesized to be conditional on belief in the species (assessed through Machiavellianism as a proxy variable). This moderated mediation model is tested with data from 4 cultural samples: 856 Cameroonian, Czech, German, and Hong Kong Chinese participants aged at least 60 years provided information on their generative concern, generative goals, meaning in life, and Machiavellianism. Controlling for effects of relationship, level of education, everyday competence, and cognitive functioning on meaning in life, analyses confirmed the moderated mediation model in all cultural samples. That is, generative concern is partly associated with meaning in life because it leads to generative goals. In turn, these provide individuals with meaning in life. This association, however, depends on belief in the species in that meaning in life does not increase when Machiavellian attitudes compete with generative goals.

Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates.

Antibody drug conjugates (ADCs) are a therapeutic class offering promise for cancer therapy. The attachment of cytotoxic drugs to antibodies can result in an effective therapy with better safety potential than nontargeted cytotoxics. To understand the role of conjugation site, we developed an enzymatic method for site-specific antibody drug conjugation using microbial transglutaminase. This allowed us to attach diverse compounds at multiple positions and investigate how the site influences stability, toxicity, and efficacy. We show that the conjugation site has significant impact on ADC stability and pharmacokinetics in a species-dependent manner. These differences can be directly attributed to the position of the linkage rather than the chemical instability, as was observed with a maleimide linkage. With this method, it is possible to produce homogeneous ADCs and tune their properties to maximize the therapeutic window.

Impact of consultant operative supervision and surgical mortality in Australia.

BACKGROUND: In this study, the Australian and New Zealand Audit of Surgical Mortality evaluated the effect of operative supervision on certain post-operative outcomes in the surgical death subset. METHODS: This retrospective cohort study was based upon mortality data collected in 2009 which included 1673 patients who died and had surgery within 30 days of death or during the last admission. Cases were divided into three groups: consultant not supervising (group NS), consultant supervising (group S) and consultant performing the operation (group C). A comparison was done nationally and between participating states in Australia. Certain post-operative outcomes were compared between the three groups as well as between elective and emergency operations. RESULTS: There were significant variations in the levels of operative supervision among states in Australia. Group NS (n = 468) generally had more favourable post-operative outcomes than group S (n = 147) and group C (n = 1058), with post-operative complication rates of 24.8%, 37.4% and 40.9% for groups NS, S and C, respectively. The level of operative supervision in emergency operations was half that of elective operations. Nevertheless, the post-operative complications rate was significantly lower in emergency operations (30.6%) compared with elective operations (64.4%). The same trend was seen with clinical management deficiencies and unplanned return to theatre. CONCLUSION: Operative supervision in emergency setting within Australian hospitals appears to be potentially inadequate. However, the available data suggest that unsupervised surgery did not result in worse post-operative outcomes. In appropriately selected cases, the data support surgical registrars performing surgery without consultant supervision.

[Factors influencing the quality of life of elderly living in a pre-fabricated housing complex in the Sichuan earthquake area].

BACKGROUND: The 2008 Sichuan Earthquake caused great damage to the environment and property. In the aftermath, many citizens were relocated to live in newly constructed prefabricated (prefab) communities. PURPOSE: This paper explored the current quality of life (QOL) of elderly residents living in prefabricated communities in areas damaged by the Sichuan earthquake and identified factors of influence on QOL values. The ultimate objective was to provide evidence-based guidance for heath improvement measures. METHODS: The authors used the short form WHOQOL-BREF to assess the quality of life of 191 elderly residents of prefabricated communities in the Sichuan Province 2008 earthquake zone. A Student's t-test, variance analysis, and stepwise multivariate regression methods were used to test the impact of various factors on QOL. RESULTS: Results indicate the self-assessed QOL of participants as good, although scores in the physical (average 56.2) and psychological (average 45.7) domains were significantly lower than the norm in China. Marital status, capital loss in the earthquake, number of children, level of perceived stress, income, interest, and family harmony each correlated with at least one of the short form WHOQOL-BREF domains in t-test and one-way analyses. After excluding for factor interaction effects using multivariate regression, we found interest, family harmony, monthly income and stress to be significant predictors of physical domain QOL, explaining 13.8% of total variance. Family harmony and interest explained 15.3% of total variance for psychological domain QOL; stress, marital status, family harmony, capital loss in the earthquake, number of children and interest explained 19.5% of total variance for social domain QOL; and stress, family harmony and interest explained 16.5% of total variance for environmental domain QOL. Family harmony and interest were significant factors across all domains, while others influenced a smaller proportion. CONCLUSIONS: Quality of life for elderly living in prefab communities should be improved. The authors hope study findings will increase awareness among healthcare providers regarding the quality of life of this vulnerable population. Study results suggest that key steps to promoting QOL in this population include improving family harmony, helping to cultivate well-rounded interests, alleviating economic stresses, providing necessary medical and psychological counseling services, and affording more social support.

Investigation of the pharmacokinetics of romiplostim in rodents with a focus on the clearance mechanism.

PURPOSE: Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG(1). We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism. METHODS: Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants. RESULTS: FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination. CONCLUSION: Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.

Development and pilot-testing of a Decision Aid for use among Chinese women facing breast cancer surgery.

BACKGROUND: Women choosing breast cancer surgery encounter treatment decision-making (TDM) difficulties, which can cause psychological distress. Decision Aids (DAs) may facilitate TDM, but there are no DAs designed for Chinese populations. We developed a DA for Chinese women newly diagnosed with breast cancer, for use during the initial surgical consultation. AIMS: Conduct a pilot study to assess the DA acceptability and utility among Chinese women diagnosed with breast cancer. METHODS: Women preferred the DA in booklet format. A booklet was developed and revised and evaluated in two consecutive pilot studies (P1 and P2). On concluding their initial diagnostic consultation, 95 and 38 Chinese women newly diagnosed with breast cancer received the draft and revised draft DA booklet, respectively. Four-day post-consultation, women had questionnaires read out to them and to which they responded assessing attitudes towards the DA and their understanding of treatment options. RESULTS: The original DA was read/partially read by 66/22% (n = 84) of women, whilst the revised version was read/partially read by 74/16% (n = 35), including subliterate women (χ(2) = 0.76, P = 0.679). Knowledge scores varied with the extent the booklet was read (P1: F = 12.68, d.f. 2, P < 0.001; P2: F = 3.744, d.f. 2, P = 0.034). The revised, shorter version was graphically rich and resulted in improved perceived utility, [except for the 'treatment options' (χ(2) = 5.50, P = 0.019) and 'TDM guidance' (χ(2) = 8.19, P = 0.004) sections] without increasing anxiety (F = 0.689, P = 0.408; F = 3.45, P = 0.073). CONCLUSION: The DA was perceived as acceptable and useful for most women. The DA effectiveness is currently being evaluated using a randomized controlled trial.