Unveiling the impact of interprofessional education on shaping students' interprofessional identity and collaboration perception: a mixed-method study.

BACKGROUND: Interprofessional education (IPE) has the potential to shape students' collaboration perception and interprofessional identity but remains understudied. This study aims to understand the effects of the IPE program as a contextual trigger to promote collaboration perception change and interprofessional identity formation among healthcare professional students. METHODS: Using concurrent triangulation mixed-methods, we examined the relationship between collaboration perception and interprofessional identity change among health profession students (N = 263), and explored their perspectives on how their IPE experiences influenced their perception and identity. Participants completed the Interdisciplinary Education Perception Scale and Extended Professional Identity Scale and responded to open-ended questions before and after the IPE intervention. Pearson's correlation, t-tests, regression (quantitative), and thematic analysis (qualitative) were conducted. RESULTS: Teams with initially lower collaboration perception (M = 3.59) and lower interprofessional identity (M = 3.59) showed a significant increase in collaboration perception (M = 3.76, t = 2.63; p = .02) and interprofessional identity (M = 3.97, t = 4.86; p < .001) after participating in IPE. The positive relationship between collaboration perception and interprofessional identity strengthened after participating in IPE, as evident from the correlation (Time 1: r = .69; p < .001; Time 2: r = .79; p < .001). Furthermore, collaboration perception in Time 1 significantly predicted the variance in interprofessional identity at Time 2 (ß = 0.347, p < .001). Qualitative findings indicated that 85.2% of students expressed that IPE played a role in promoting their interprofessional identity and collaboration attitudes. CONCLUSIONS: Incorporating the IPE program into the curriculum can effectively enhance students' collaboration perception and interprofessional identity, ultimately preparing them for collaborative practice in the healthcare system. By engaging students in interprofessional teamwork, communication, and joint decision-making processes, the IPE program provides a valuable context for students to develop a sense of belonging and commitment to interprofessional collaboration.

Towards a global partnership model in interprofessional education for cross-sector problem-solving.

OBJECTIVES: A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. METHODS: This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data. RESULTS: We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation. CONCLUSIONS: The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education.

Comprehensive Analysis of Photoreceptor Outer Segments: Flow Cytometry Characterization and Stress-Driven Impact on Retinal Pigment Epithelium Phagocytosis.

Phagocytosis is one of the key functions of retinal pigment epithelium (RPE) cells, which maintain photoreceptor health by removing photoreceptor outer segments (POSs) that are regularly shed. A deficiency in RPE function to phagocytose POSs may lead to vision loss in inherited retinal diseases and eventually to age-related macular degeneration (AMD) with geographic atrophy. Significant progress has been made in the field of cell replacement therapy for AMD using stem-cell-derived RPE. To test their function, RPE cells are incubated with purified bovine POSs for the demonstration of efficient binding, internalization, and digestion of POSs. Here, we present an image-based method to measure phagocytosis activity by using POSs labeled with a pH-sensitive fluorescent dye, which has low fluorescence at neutral pH outside of the cell and high fluorescence at low pH inside the phagosome. Further, we introduce a unique flow-cytometry-based method for the characterization of POSs by measuring specific markers for POSs such as rhodopsin and opsin. Using this method, we demonstrated a comparable quality of several bovine POS isolation batches and a reliable assessment of POS quality on RPE phagocytosis assay performance when subjected to different stress conditions. This work provides new tools to characterize POSs and insight into RPE phagocytosis assay development for the functional evaluation of RPE cells in the field of cell replacement therapy.

Warfarin-induced skin necrosis after the use of an anticoagulation reversal agent.

Anticoagulant-induced skin necrosis is a rare and potentially life-threatening complication of anticoagulant therapy. The majority of cases of anticoagulant-induced skin necrosis have been attributed to warfarin, known as warfarin-induced skin necrosis (WISN). The use of anticoagulation reversal agents such as Prothrombinex-VF in the development of WISN is not a commonly documented phenomenon. The authors present a case of WISN post-recommencement of warfarin and the use of Prothrombinex-VF.

Team cohesiveness and collective efficacy explain outcomes in interprofessional education.

BACKGROUND: Team cohesiveness and collective efficacy have been construed as important characteristics of a high-functioning team. However, the psychological mechanism through which they promote positive outcomes remains unknown. Understanding this psychological process is important to teachers and programme implementers to yield actionable interventions that can be used to craft effective practices for optimizing team outcomes. This is especially true in interprofessional education (IPE) in medical education, where a team-based approach to patient management is promoted. Drawing from the social-cognitive theory, we examined a hypothesized model where team cohesiveness predicts collaboration outcomes (teamwork satisfaction, overall satisfaction with the team experience, and IPE goal attainment) via collective efficacy. METHODS: We used data from Chinese medicine, medicine, nursing, and social work students in Hong Kong (n = 285) who were enrolled in IPE. They were invited to respond to scales in two time points. We performed mediation analysis using structural equations modelling to test the indirect effect model: team cohesiveness → collective efficacy → outcomes. RESULTS: Results of structural equation modelling revealed that collective efficacy fully mediated the relationships between team cohesiveness and all three team outcomes, providing support for the hypothesised model [RMSEA = 0.08, NFI = 0.90, CFI = 0.93, IFI = 0.93, TLI = 0.93]. Team cohesiveness predicted the achievement of collaboration outcomes via collective efficacy. CONCLUSION: The findings demonstrated the important roles of team cohesiveness and collective efficacy in promoting successful team collaboration. Team cohesiveness predicted collective efficacy, and collective efficacy, in turn, predicted collaboration outcomes. This study contributed to theorising the pathways towards successful team collaboration outcomes.

Factors influencing primary care provider referral for bariatric surgery: Systematic review.

OBJECTIVE: To identify barriers to and facilitators of primary care provider (PCP) referral for bariatric surgery in patients with obesity. DATA SOURCES: MEDLINE, EMBASE, and PsycINFO databases were searched and reference lists of included articles were screened to identify additional relevant articles. Two reviewers independently reviewed citations and full-text articles, and appraised the quality of the included articles using the Critical Appraisal Skills Programme Tool Qualitative Checklist and the Appraisal Tool for Cross-Sectional Studies. They extracted data on the study characteristics and the barriers to and facilitators of PCP referral for bariatric surgery. Appraisal discrepancies were resolved through consensus among authors. STUDY SELECTION: Overall, 882 citations were identified and 18 articles were then selected for this review. SYNTHESIS: Barriers included fear of surgery complications and side effects, cost, lack of availability, perception that surgery is a quick fix or a last resort, and prior negative experiences. Facilitators included direct requests from patients, patient motivation, previously failed weight-loss interventions, and obesity-related comorbidities. Those PCPs who were knowledgeable about the risks and benefits of bariatric surgery were more likely to refer their patients. CONCLUSION: Education and continuing professional development programs regarding bariatric surgery are needed to improve PCP knowledge and capacity to manage patients with obesity. Also, educating the general public on obesity, weight management, and available treatment options can empower patients and families to manage their weight and pursue evidence-informed treatments.

Survey of perceptions and educational needs of primary care providers regarding management of patients with class II and III obesity in Ontario, Canada.

BACKGROUND: Primary care providers (PCPs) are typically the primary contact for patients with obesity seeking medical and surgical weight loss interventions; however, previous studies suggest that fewer than 7% of eligible adult patients are referred to publically funded medical and surgical weight loss interventions (MSWLI). METHODS: We performed an anonymous survey study between October 2017 and June 2018 to explore the knowledge, experiences, perceptions, and educational needs of PCPs in Southeastern Ontario in managing patients with class II and III obesity. RESULTS: Surveys were distributed to 591 PCPs (n = 538 family physicians; n = 53 nurse practitioners) identified as practicing in the Southeastern Ontario and 92 (15.6%) participated. PCPs serving a rural population estimated that 14.2 ± 10.9% of patients would qualify for MSWLI compared to 9.9 ± 8.5% of patients of PCPs serving an urban population (p = .049). Overall, 57.5% of respondents did not feel competent prescribing MSWLI to patients with class II/III obesity, while 69.8% stated they had 'good' knowledge of the referral criteria for MSWLI. 22.2% of respondents were hesitant to refer patients for bariatric surgery (BS) due to concerns about postoperative surgical complications and risks associated with surgery. Only 25% of respondents were comfortable providing long-term follow up after BS, and only 39.1% had participated in continuing education on management of patients with class II/III obesity in the past 5 years. CONCLUSION: The majority of PCPs believe there is a need for additional education about MSWLI for patients with class II/III obesity. Future studies are needed to develop and compare the effectiveness of additional education and professional development around risks of contemporary BS, indications to consider referral for MSWLI, management and long-term follow-up of patients after BS.

Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events.

BACKGROUND: The treatment response to new immunotherapy in advanced melanoma patients remains varied between individuals. Immune-related cutaneous side effects might have prognostic value. OBJECTIVE: To determine whether development of ≥1 of the 3 immune-mediated cutaneous events (eczema, lichenoid reaction, or vitiligo-like depigmentation) is associated with improved progression-free survival. METHODS: A cohort study of adults with stage IIIC-IV melanoma treated with pembrolizumab or nivolumab during May 1, 2012-February 1, 2018, at Westmead Hospital, Sydney, Australia. Treatment response was based on iRECIST version 1.1. RESULTS: In total, 82 patients of an average age of 59.9 years were included. Median follow-up was 40.7 months; 33 patients had ≥1 target skin reaction. Skin reactions developed in one-third of individuals by 6 months. At any given time, the instantaneous risk of disease progression and death was lower for individuals who had ≥1 cutaneous adverse event (CAE) develop. Compared with individuals with no CAE, the hazard ratio for disease progression and death for individuals who had ≥1 CAE develop was 0.46 (95% confidence interval 0.23-0.91; P = .025) by the time-dependent Cox proportional hazards model. LIMITATIONS: Single-center study. CONCLUSION: This study demonstrates an association between the development of ≥1 of 3 CAEs and improved progression-free survival in this cohort of patients.

One-Year Outcomes in Caregivers of Critically Ill Patients.

BACKGROUND: Few resources are available to support caregivers of patients who have survived critical illness; consequently, the caregivers' own health may suffer. We studied caregiver and patient characteristics to determine which characteristics were associated with caregivers' health outcomes during the first year after patient discharge from an intensive care unit (ICU). METHODS: We prospectively enrolled 280 caregivers of patients who had received 7 or more days of mechanical ventilation in an ICU. Using hospital data and self-administered questionnaires, we collected information on caregiver and patient characteristics, including caregiver depressive symptoms, psychological well-being, health-related quality of life, sense of control over life, and effect of providing care on other activities. Assessments occurred 7 days and 3, 6, and 12 months after ICU discharge. RESULTS: The caregivers' mean age was 53 years, 70% were women, and 61% were caring for a spouse. A large percentage of caregivers (67% initially and 43% at 1 year) reported high levels of depressive symptoms. Depressive symptoms decreased at least partially with time in 84% of the caregivers but did not in 16%. Variables that were significantly associated with worse mental health outcomes in caregivers were younger age, greater effect of patient care on other activities, less social support, less sense of control over life, and less personal growth. No patient variables were consistently associated with caregiver outcomes over time. CONCLUSIONS: In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).

An Evaluation of Optimal PEGylation Strategies for Maximizing the Lymphatic Exposure and Antiviral Activity of Interferon after Subcutaneous Administration.

Interferon α2 is an antiviral/antiproliferative protein that is currently used to treat hepatitis C infections and several forms of cancer. Two PEGylated variants of interferon α2 (containing 12 and 40 kDa PEGs) are currently marketed and display longer plasma circulation times than that of unmodified interferon. With increasing realization that the lymphatic system plays an important role in the extrahepatic replication of the hepatitis C virus and in the metastatic dissemination of cancers, this study sought to evaluate PEGylation strategies to optimally enhance the antiviral activity and plasma and lymphatic exposure of interferon after subcutaneous administration in rats. The results showed that conjugation with a linear 20 kDa PEG provided the most ideal balance between activity and plasma and lymph exposure. A linear 5 kDa PEG variant also exhibited excellent plasma and lymph exposure to interferon activity when compared to those of unmodified interferon and the clinically available linear 12 kDa PEGylated construct.

The RECOVER Program: Disability Risk Groups and 1-Year Outcome after 7 or More Days of Mechanical Ventilation.

RATIONALE: Disability risk groups and 1-year outcome after greater than or equal to 7 days of mechanical ventilation (MV) in medical/surgical intensive care unit (ICU) patients are unknown and may inform education, prognostication, rehabilitation, and study design. OBJECTIVES: To stratify patients for post-ICU disability and recovery to 1 year after critical illness. METHODS: We evaluated a multicenter cohort of 391 medical/surgical ICU patients who received greater than or equal to 1 week of MV at 7 days and 3, 6, and 12 months after ICU discharge. Disability risk groups were identified using recursive partitioning modeling. MEASUREMENTS AND MAIN RESULTS: The 7-day post-ICU Functional Independence Measure (FIM) determined the recovery trajectory to 1-year after ICU discharge and was an independent risk factor for 1-year mortality. The 7-day post-ICU FIM was predicted by age and ICU length of stay. By 2 weeks of MV, ICU patients could be stratified into four disability groups characterized by increasing risk for post ICU disability, ICU and post-ICU healthcare use, and disposition. Patients less than 42 years with ICU length of stay less than 2 weeks had the best function and fewest deaths at 1 year compared with patients greater than 66 years with ICU length of stay greater than 2 weeks who sustained the worst disability and 40% 1-year mortality. Depressive symptoms (17%) and post-traumatic stress disorder (18%) persisted at 1 year. CONCLUSIONS: ICU survivors of greater than or equal to 1 week of MV may be stratified into four disability groups based on age and ICU length of stay. These groups determine 1-year recovery and healthcare use and are independent of admitting diagnosis and illness severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00896220).

Determination of the True Inclination Angle of the Main Bronchi Relative to the Median Sagittal Plane for Placement of a Left-Sided Double-Lumen Tube.

OBJECTIVES: This study aimed to determine the true inclination angle of the main bronchi relative to the median sagittal plane, using CT imaging to help increase accuracy of double-lumen tube (DLT) placement. DESIGN: In this retrospective study, 2 investigators independently measured normal chest CT scans from 50 male and 50 female patients. To determine the true AP axis, a mid-sagittal plane reference line (MSPRL) was drawn, intersecting the midsternum and the vertebral spinous process at the level of mid-carina. Lines were drawn through the center of each main bronchus to determine the inclination angle with regard to the MSPRL. SETTING: Research was conducted at a single institution, the Los Angeles County and University of Southern California Medical Center. PARTICIPANTS: Normal chest CT images from 50 women and 50 men. MAIN RESULTS: The mean true inclination angle between the main bronchi and trachea in the mid-sagittal plane was 108.4° on the left compared with 96.2° on the right (p<0.0001). INTERVENTIONS: No specific interventions were done because this was a retrospective study and CT scan analysis. CONCLUSION: The data suggested that the trachea does not merely branch in the horizontal plane but branches posteriorly as well, with a true mean anatomic angle between the left main bronchus and trachea of 108.4°. This finding concurred with the authors' suggestion that the DLT be rotated to 110° counterclockwise instead of the routine practice of 90°. The authors suggest clinicians rotate the DLT an additional 20° counterclockwise and direct the top of the DLT to the 11 o'clock position.

How the "Understanding Research Evidence" Web-Based Video Series From the National Collaborating Centre for Methods and Tools Contributes to Public Health Capacity to Practice Evidence-Informed Decision Making: Mixed-Methods Evaluation.

BACKGROUND: The National Collaborating Centre for Methods and Tools (NCCMT) offers workshops and webinars to build public health capacity for evidence-informed decision-making. Despite positive feedback for NCCMT workshops and resources, NCCMT users found key terms used in research papers difficult to understand. The Understanding Research Evidence (URE) videos use plain language, cartoon visuals, and public health examples to explain complex research concepts. The videos are posted on the NCCMT website and YouTube channel. OBJECTIVE: The first four videos in the URE web-based video series, which explained odds ratios (ORs), confidence intervals (CIs), clinical significance, and forest plots, were evaluated. The evaluation examined how the videos affected public health professionals' practice. A mixed-methods approach was used to examine the delivery mode and the content of the videos. Specifically, the evaluation explored (1) whether the videos were effective at increasing knowledge on the four video topics, (2) whether public health professionals were satisfied with the videos, and (3) how public health professionals applied the knowledge gained from the videos in their work. METHODS: A three-part evaluation was conducted to determine the effectiveness of the first four URE videos. The evaluation included a Web-based survey, telephone interviews, and pretest and posttests, which evaluated public health professionals' experience with the videos and how the videos affected their public health work. Participants were invited to participate in this evaluation through various open access, public health email lists, through informational flyers and posters at the Canadian Public Health Association (CPHA) conference, and through targeted recruitment to NCCMT's network. RESULTS: In the Web-based surveys (n=46), participants achieved higher scores on the knowledge assessment questions from watching the OR (P=.04), CI (P=.04), and clinical significance (P=.05) videos but not the forest plot (P=.12) video, as compared with participants who had not watched the videos. The pretest and posttest (n=124) demonstrated that participants had a better understanding of forest plots (P<.001) and CIs (P<.001) after watching the videos. Due to small sample size numbers, there were insufficient pretest and posttest data to conduct meaningful analyses on the clinical significance and OR videos. Telephone interview participants (n=18) thought the videos' use of animation, narration, and plain language was appropriate for people with different levels of understanding and learning styles. Participants felt that by increasing their understanding of research evidence, they could develop better interventions and design evaluations to measure the impact of public health initiatives. CONCLUSIONS: Overall, the results of the evaluation showed that watching the videos resulted in an increase in knowledge, and participants had an overall positive experience with the URE videos. With increased competence in using the best available evidence, professionals are empowered to contribute to decisions that can improve health outcomes of communities.

Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab' Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity.

The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab' as a model. Specifically, the Fab' was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3-4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab' displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab'. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab's against lymph-resident diseases, while no significant benefit is achieved with very large PEGs.

A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep.

PURPOSE: Cancer metastasis to pulmonary lymph nodes dictates the need to deliver chemotherapeutic and diagnostic agents to the lung and associated lymph nodes. Drug conjugation to dendrimer-based delivery systems has the potential to reduce toxicity, enhance lung retention and promote lymphatic distribution in rats. The current study therefore evaluated the pharmacokinetics and lung lymphatic exposure of a PEGylated dendrimer following inhaled administration. METHODS: Plasma pharmacokinetics and disposition of a 22 kDa PEGylated dendrimer were compared after aerosol administration to rats and sheep. Lung-derived lymph could not be sampled in rats and so lymphatic transport of the dendrimer from the lung was assessed in sheep. RESULTS: Higher plasma concentrations were achieved when dendrimer was administered to the lungs of rats as a liquid instillation when compared to an aerosol. Plasma pharmacokinetics were similar between sheep and rats, although some differences in disposition patterns were evident. Unexpectedly, less than 0.5% of the aerosol dose was recovered in pulmonary lymph. CONCLUSIONS: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.

PEGylation does not significantly change the initial intravenous or subcutaneous pharmacokinetics or lymphatic exposure of trastuzumab in rats but increases plasma clearance after subcutaneous administration.

The lymphatic system plays a major role in the metastatic dissemination of cancer and has an integral role in immunity. PEGylation enhances drainage and lymphatic uptake following subcutaneous (sc) administration of proteins and protein-like polymers, but the impact of PEGylation of very large proteins (such as antibodies) on subcutaneous and lymphatic pharmacokinetics is unknown. This study therefore aimed to evaluate the impact of PEGylation on the sc absorption and lymphatic disposition of the anti-HER2 antibody trastuzumab in rats. PEG-trastuzumab was generated via the conjugation of a single 40 kDa PEG-NHS ester to trastuzumab. PEG-trastuzumab showed a 5-fold reduction in HER2 binding affinity, however the in vitro growth inhibitory effects were preserved as a result of changes in cellular trafficking when compared to native trastuzumab. The lymphatic pharmacokinetics of PEG-trastuzumab was evaluated in thoracic lymph duct cannulated rats after iv and sc administration and compared to the pharmacokinetics of native trastuzumab. The iv pharmacokinetics and lymphatic exposure of PEG-trastuzumab was similar when compared to trastuzumab. After sc administration, initial plasma pharmacokinetics and lymphatic exposure were also similar between PEG-trastuzumab and trastuzumab, but the absolute bioavailability of PEG-trastuzumab was 100% when compared to 86.1% bioavailability for trastuzumab. In contrast to trastuzumab, PEG-trastuzumab showed accelerated plasma clearance beginning approximately 7 days after sc, but not iv, administration, presumably as a result of the generation of anti-PEG IgM. This work suggests that PEGylation does not significantly alter the lymphatic disposition of very large proteins, and further suggests that it is unlikely to benefit therapy with monoclonal antibodies.

Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumor-burdened lymph nodes after intravenous and subcutaneous administration in rats.

The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.

Fat distribution in children and adolescents with myelomeningocele.

AIM: To evaluate fat distribution in children and adolescents with myelomeningocele using dual-energy X-ray absorptiometry (DXA). METHOD: Cross-sectional DXA measurements of the percentage of fat in the trunk, arms, legs, and whole body were compared between 82 children with myelomeningocele (45 males, 37 females; mean age 9y 8mo, SD 2y 7mo; 22 sacral, 13 low lumbar, 47 mid lumbar and above) and 119 comparison children (65 males, 54 females; mean age 10y 4mo, SD 2y 4mo). Differences in fat distribution between groups were evaluated using univariate and multivariate analyses. RESULTS: Children with myelomeningocele had higher total body fat (34% vs 31%, p=0.02) and leg fat (42% vs 35%, p<0.001) than comparison children, but no differences in trunk or arm fat after adjustment for anthropometric measures. INTERPRETATION: Children with myelomeningocele have higher than normal total body and leg fat, but only children with higher level lesions have increased trunk fat, which may be caused by greater obesity in this group. Quantifying segmental fat distribution may aid in better assessment of excess weight and, potentially, the associated health risks.

Brain structural and microstructural alterations associated with cerebral palsy and motor impairments in adolescents born extremely preterm and/or extremely low birthweight.

AIM: To elucidate neurobiological changes underlying motor impairments in adolescents born extremely preterm (gestation <28wks) and/or with extremely low birthweight (ELBW, <1000g), our aims were the following: (1) to compare corticospinal tract (CST) microstructure and primary motor cortex (M1) volume, area, and thickness between extremely preterm/ELBW adolescents and a comparison group with normal birthweight (>2499g); (2) to compare CST microstructure and M1 volume, area, and thickness between extremely preterm/ELBW adolescents with cerebral palsy (CP), motor impairment without CP, and no motor impairment; and (3) to investigate associations between CST microstructure and M1 measures. METHOD: This study used diffusion and structural magnetic resonance imaging to examine the CST and M1 in a geographical cohort of 191 extremely preterm/ELBW adolescents (mean age 18y 2.4mo [SD 9.6mo]; 87 males, 104 females) and 141 adolescents in the comparison group (mean age 18y 1.2mo [SD 9.6mo]; 59 males, 82 females). RESULTS: Extremely preterm/ELBW adolescents had higher CST axial, radial, and mean diffusivities and lower M1 thickness than the comparison group. Extremely preterm/ELBW adolescents with CP had higher CST diffusivities than non-motor-impaired extremely preterm/ELBW adolescents. CST diffusivities correlated with M1 volume and area. INTERPRETATION: Extremely preterm/ELBW adolescents have altered CST microstructure, which is associated with CP. Furthermore, the results elucidate how CST and M1 alterations interrelate to potentially influence motor function in extremely preterm/ELBW adolescents.

Long-term treatment with tenofovir in Asian-American chronic hepatitis B patients is associated with abnormal renal phosphate handling.

BACKGROUND: Increased risk of defective urinary phosphate reabsorption and osteoporosis has been reported in HIV and chronic hepatitis B (CHB) patients treated with tenofovir disoproxil fumarate (TDF). AIMS: Goals of this study were to evaluate the prevalence of renal phosphate wasting and abnormal bone mineral density in CHB patients taking TDF compared to CHB patients treated with entecavir (ETV) and untreated CHB patients. METHODS: This is a cross-sectional study of 146 consecutive Asian-American CHB patients who were treatment naïve (n = 60) or treated with either TDF (n = 42) or ETV (n = 44). Proximal tubular handling of phosphate was assessed by the maximal rate of tubular reabsorption of phosphate (TmPO4) divided by glomerular filtration rate (GFR) (TmPO4/GFR). Bone mineral density (BMD) was measured using dual X-ray absorptiometry. RESULTS: TmPO4/GFR was similar among CHB patients treated with TDF compared to untreated patients and patients taking ETV. However, among patients treated with ≥18 months of TDF or ETV, prevalence of abnormal TmPO4/GFR was higher among patients treated with TDF compared to ETV (48.5 % (16/33) vs. 12.5 % (3/24), p = 0.005). Overall prevalence of osteoporosis in this cohort of CHB patients was 14 %, with no significant difference between the three groups. Renal phosphate handling did not correlate with osteoporosis. CONCLUSIONS: Chronic hepatitis B patients treated with ≥18 months of TDF experienced an increased risk of proximal tubular dysfunction. TDF did not increase the risk of osteoporosis. Longitudinal studies are needed to confirm these findings.