Valuing quality of life for economic evaluations in cancer: navigating multiple methods.

INTRODUCTION: Utility values offer a quantitative means to evaluate the impact of novel cancer treatments on patients' quality of life (QoL). However, the multiple methods available for valuing QoL present challenges in selecting the most appropriate method across different contexts. AREAS COVERED: This review provides cancer clinicians and researchers with an overview of methods to value QoL for economic evaluations, including standalone and derived preference-based measures (PBMs) and direct preference elicitation methods. Recent developments are described, including the comparative performance of cancer-specific PBMs versus generic PBMs, measurement of outcomes beyond health-related QoL, and increased use of discrete choice experiments to elicit preferences. Recommendations and considerations are provided to guide the choice of method for cancer research. EXPERT OPINION: We foresee continued adoption of the QLU-C10D and FACT-8D in cancer clinical trials given the extensive use of the EORTC QLQ-C30 and FACT-G in cancer research. While these cancer-specific PBMs offer the convenience of eliciting utility values without needing a standalone PBM, researchers should consider potential limitations if they intend to substitute them for generic PBMs. As the field advances, there is a greater need for consensus on the approach to selection and integration of various methods in cancer clinical trials.

In vivo selection in non-human primates identifies AAV capsids for on-target CSF delivery to spinal cord.

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal (IT) delivery of AAV vectors into cerebral spinal fluid can avoid many issues, although distribution of the vector throughout the spinal cord is limited, and vector entry to the periphery sometimes initiates hepatotoxicity. Here we performed biopanning in non-human primates (NHPs) with an IT injected AAV9 peptide display library. We identified top candidates by sequencing inserts of AAV DNA isolated from whole tissue, nuclei, or nuclei from transgene-expressing cells. These barcoded candidates were pooled with AAV9 and compared for biodistribution and transgene expression in spinal cord and liver of IT injected NHPs. Most candidates displayed increased retention in spinal cord compared with AAV9. Greater spread from the lumbar to the thoracic and cervical regions was observed for several capsids. Furthermore, several capsids displayed decreased biodistribution to the liver compared with AAV9, providing a high on-target/low off-target biodistribution. Finally, we tested top candidates in human spinal cord organoids and found them to outperform AAV9 in efficiency of transgene expression in neurons and astrocytes. These capsids have potential to serve as leading-edge delivery vehicles for spinal cord-directed gene therapies.

What matters most to people with metastatic uveal melanoma? A qualitative study to inform future measurement of health-related quality of life.

Metastatic uveal melanoma (mUM) is a rare cancer with poor prognosis, but novel treatments are emerging. Currently, there are no mUM-specific health-related quality of life (HRQL) questionnaires available for clinical research. We aimed to explore how mUM and its treatment affect HRQL and assess the content validity of existing questionnaires. Participants were patients with mUM and healthcare professionals involved in their care. Qualitative data were collected using semi-structured interviews and focus groups. Data collection and analysis used an integrative approach involving inductive questions/coding to elicit new concepts and deductive questions/coding based on domains of existing HRQL questionnaires. Initial interviews/focus groups focussed on HRQL questionnaires designed for patients with uveal melanoma or liver metastases. As new concepts were elicited, domains and items from other questionnaires were subsequently added. Seventeen patients and 16 clinicians participated. HRQL concerns assessed by uveal melanoma-specific questionnaires were largely resolved by the time of metastasis. The Functional Assessment of Cancer Therapy - Immunotherapy Module (FACT-ICM) adequately captured most immunotherapy-related side effects during initial treatment cycles. However, most patients emphasised emotional impacts over physical ones, focussing on the existential threat posed by disease amidst uncertainty about treatment accessibility and effectiveness. Patients were also concerned with treatment burden, including time commitment, travel, need for hospitalisation, and expenses. The relative importance of HRQL issues varied over time and across treatment modalities, with no single questionnaire being sufficient. Pending further development and psychometric testing, clinical researchers may need to take a modular approach to measuring the HRQL impacts of mUM.

In vivo selection in non-human primates identifies superior AAV capsids for on-target CSF delivery to spinal cord.

Systemic administration of adeno-associated virus (AAV) vectors for spinal cord gene therapy has challenges including toxicity at high doses and pre-existing immunity that reduces efficacy. Intrathecal delivery of AAV vectors into the cerebral spinal fluid (CSF) can avoid many of the issues of systemic delivery, although achieving broad distribution of the vector and transgene expression throughout the spinal cord is challenging and vector entry to the periphery occurs, sometimes initiating hepatotoxicity. Here we performed two rounds of in vivo biopanning in non-human primates (NHPs) with an AAV9 peptide display library injected intrathecally and performed insert sequencing on DNA isolated from either whole tissue (conventional selection), isolated nuclei, or nuclei from transgene-expressing cells. A subsequent barcoded pool of candidates and AAV9 was compared at the DNA (biodistribution) and RNA (expression) level in spinal cord and liver of intrathecally injected NHPs. Most of the candidates displayed enhanced biodistribution compared to AAV9 at all levels of spinal cord ranging from 2 to 265-fold. Nuclear isolation or expression-based selection yielded 4 of 7 candidate capsids with enhanced transgene expression in spinal cord (up to 2.4-fold), while no capsid obtained by conventional selection achieved that level. Furthermore, several capsids displayed lower biodistribution to the liver of up to 1,250-fold, compared to AAV9, providing a remarkable on target/off target biodistribution ratio. These capsids may have potential for gene therapy programs directed at the spinal cord and the selection method described here should be useful in clinically relevant large animal models.

Effects of Moderate- to High-Impact Exercise Training on Bone Structure Across the Lifespan: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Moderate- to high-impact exercise improves bone mineral density (BMD) across the lifespan, but its effects on bone structure, which predicts fracture independent of areal BMD, are unclear. This systematic review and meta-analysis investigated effects of impact exercise on volumetric BMD (vBMD) and bone structure. Four databases (PubMed, Embase, SPORTDiscus, Web of Science) were searched up to March 2022 for randomized controlled trials (RCTs) investigating the effects of impact exercise, with ground reaction forces equal to or greater than running, compared with sham or habitual activity, on bone vBMD and structure. Bone variables were measured by quantitative computed tomography or magnetic resonance imaging at the tibia, radius, lumbar spine, and femur. Percentage changes in bone variables were compared among groups using mean differences (MD) and 95% confidence intervals (CI) calculated via random effects meta-analyses. Subgroup analyses were performed in children/adolescents (<18 years), adults (18-50 years), postmenopausal women, and older men. Twenty-eight RCTs (n = 2985) were included. Across all studies, impact exercise improved trabecular vBMD at the distal tibia (MD = 0.54% [95% CI 0.17, 0.90%]), total vBMD at the proximal femur (3.11% [1.07, 5.14%]), and cortical thickness at the mid/proximal radius (1.78% [0.21, 3.36%]). There was no effect on vBMD and bone structure at the distal radius, femoral shaft, or lumbar spine across all studies or in any subgroup. In adults, impact exercise decreased mid/proximal tibia cortical vBMD (-0.20% [-0.24, -0.15%]). In postmenopausal women, impact exercise improved distal tibia trabecular vBMD (0.79% [0.32, 1.25%]). There was no effect on bone parameters in children/adolescents in overall analyses, and there were insufficient studies in older men to perform meta-analyses. Impact exercise may have beneficial effects on bone structure and vBMD at various skeletal sites, but additional high-quality RCTs in different age and sex subgroups are needed to identify optimal exercise protocols for improving bone health across the lifespan. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature.

Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs). We performed two rounds of in vivo selection with an AAV capsid scaffold displaying a heptamer peptide library to isolate capsids that traffic to the brain after intravenous delivery. One identified capsid, termed AAV-PR, demonstrated high transduction of the brain vasculature, in contrast to the parental capsid, AAV9, which transduces mainly neurons and astrocytes. Further analysis using tissue clearing, volumetric rendering, and colocalization revealed that AAV-PR enabled high transduction of cerebral pericytes located on small-caliber vessels and SMCs in the larger arterioles and penetrating pial arteries. Analysis of tissues in the periphery indicated that AAV-PR also transduced SMCs in large vessels associated with the systemic vasculature. AAV-PR was also able to transduce primary human brain pericytes with higher efficiency than AAV9. Compared with previously published AAV capsids tropisms, AAV-PR represents the first capsid to allow for effective transduction of brain pericytes and SMCs and offers the possibility of genetically modulating these cell types in the context of neurodegeneration and other neurological diseases.

Associations of body mass index, body fat percentage and sarcopenia components with bone health estimated by second-generation high-resolution peripheral quantitative computed tomography in older adults with obesity.

PURPOSE: To investigate associations between body mass index (BMI), body fat percentage, and components of sarcopenia (muscle mass and muscle strength/power), with bone microarchitecture measured by high-resolution peripheral computed tomography (HR-pQCT) in older adults with obesity. METHODS: Seventy-four adults aged ≥ 55 years with body fat percentage ≥ 30 % (men) or ≥40 % (women) were included. Fat mass, lean mass and total hip, femoral neck, and lumbar spine areal bone mineral density (aBMD) were measured by dual-energy X-ray absorptiometry. Appendicular lean mass (ALM) was calculated as the sum of lean mass in the upper- and lower-limbs. BMI was calculated and participants completed physical function assessments including stair climb power test. Distal tibial bone microarchitecture was assessed using HR-pQCT. Linear regression (ß-coefficients and 95 % confidence intervals) analyses were performed with adjustment for confounders including age, sex, smoking status, vitamin D and self-reported moderate to vigorous physical activity. RESULTS: BMI and ALM/height2 were both positively associated with total hip, femoral neck and lumbar spine aBMD and trabecular bone volume fraction after adjusting for confounders (all p < 0.05). Body fat percentage was not associated with aBMD or any trabecular bone parameters but was negatively associated with cortical area (p < 0.05). Stair climb power (indicating better performance) was positively associated with cortical area and negatively associated with bone failure load (both p < 0.05). CONCLUSION: Higher BMI, ALM/height2 and muscle power were associated with more favourable bone microarchitecture, but higher body fat percentage was negatively associated with cortical bone area. These findings suggest that high BMI may be protective for fractures and that this might be attributable to higher muscle mass and/or forces, while higher relative body fat is not associated with better bone health in older adults with obesity.

Reduced Peak Bone Mass in Young Adults With Low Motor Competence.

Although suboptimal bone health has been reported in children and adolescents with low motor competence (LMC), it is not known whether such deficits are present at the time of peak bone mass. We examined the impact of LMC on bone mineral density (BMD) in 1043 participants (484 females) from the Raine Cohort Study. Participants had motor competence assessed using the McCarron Assessment of Neuromuscular Development at 10, 14, and 17 years, and a whole-body dual-energy X-ray absorptiometry (DXA) scan at 20 years. Bone loading from physical activity was estimated from the International Physical Activity Questionnaire at the age of 17 years. The association between LMC and BMD was determined using general linear models that controlled for sex, age, body mass index, vitamin D status, and prior bone loading. Results indicated LMC status (present in 29.6% males and 21.9% females) was associated with a 1.8% to 2.6% decrease in BMD at all load-bearing bone sites. Assessment by sex showed that the association was mainly in males. Osteogenic potential of physical activity was associated with increased BMD dependent on sex and LMC status, with males with LMC showing a reduced effect from increasing bone loading. As such, although engagement in osteogenic physical activity is associated with BMD, other factors involved in physical activity, eg, diversity, movement quality, may also contribute to BMD differences based upon LMC status. The finding of lower peak bone mass for individuals with LMC may reflect a higher risk of osteoporosis, especially for males; however, further research is required. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Physical activity estimated by osteogenic potential and energy expenditure has differing associations with bone mass in young adults: the raine study.

Ground impacts during physical activity may be important for peak bone mass. We found differences in how energy expenditure and impact scores estimated from a physical activity questionnaire related to bone health in young adults. Using both estimate types can improve our understanding of the skeletal benefits of physical activity. PURPOSE: It is unclear whether mechanical loading during physical activity, estimated from physical activity questionnaires which assess metabolic equivalents of task (METs), is associated with skeletal health. This longitudinal study investigated how physical activity loading scores, assessed at ages 17 and 20 years, (a) compares with physical activity measured in METs, and (b) is associated with bone mass at age 20 years. METHODS: A total of 826 participants from the Raine Study Gen2 were assessed for physical activity energy expenditure via the International Physical Activity Questionnaire (IPAQ) at age 17 and 20 years. Loading scores (the product of peak force and application rate) per week were subsequently estimated from the IPAQ. Whole-body and appendicular bone mineral density (BMD) at age 20 years were assessed by dual-energy X-ray absorptiometry. RESULTS: Bland-Altman minimal detectable difference for physical activity Z- scores at age 17 and 20 years were 1.59 standard deviations (SDs) and 1.33 SDs, respectively, greater than the a priori minimal clinically important change of 0.5 SDs. Loading score, but not IPAQ score, had significant positive associations with whole-body and leg BMD after adjustment for covariates (ß = 0.008 and 0.012 g/cm2, respectively, for age 17 and 20 years loading scores). IPAQ score at age 20 years, but not loading score, had a significant positive association with arm BMD (ß = 0.007 g/cm2). CONCLUSION: This study revealed disagreement in associations of self-reported METs and loading score estimates with bone health in young adults. Coupling traditional energy expenditure questionnaire outcomes with bone-loading estimates may improve understanding of the location-specific skeletal benefits of physical activity in young adults.

The AAV9 Variant Capsid AAV-F Mediates Widespread Transgene Expression in Nonhuman Primate Spinal Cord After Intrathecal Administration.

Intrathecal delivery of AAV9 into the subarachnoid space has been shown to transduce spinal cord and brain and be less affected by preexisting antibodies, which are lower in cerebral spinal fluid. Still, efficiency of transduction needs to be improved. Recently, we identified a new capsid from a library selection in mice, called AAV-F, that allowed robust transduction of the spinal cord gray matter after lumbar injection. In this study, we test transduction of spinal cord by AAV-F (n = 3) compared to AAV9 (n = 2), using a reporter gene, in cynomolgus monkeys after lumbar intrathecal injection. Using an automated image analysis (IA) approach to sensitively quantitate reporter gene expression in spinal cord, we found that AAV-F capsid mediated slightly higher transgene expression (both in percentages of cells and intensity of immunostaining) in motor neurons and interneurons, in the lumbar and thoracic regions, compared to AAV9. Interestingly, although AAV-F mediated higher transgene expression in spinal cord, the number of genomes in spinal cord and periphery were on average lower for AAV-F than AAV9, which suggest that lower numbers of genomes were able to mediate higher transgene expression in spinal cord with this capsid. In contrast, dorsal root ganglion transduction efficiency was lower for AAV-F compared to AAV9 on average. Interestingly, we also observed transduction of Schwann cells in sciatic nerve in two nonhuman primates injected with AAV-F, but none with AAV9. Overall, our data demonstrate the utility of automated IA for quantitation of AAV transduction in the spinal cord and the favorable on-target:off-target transduction profile suggests that the AAV-F capsid be considered for gene therapy applications focused on treating the spinal cord after intrathecal delivery.

Neutralizing Antibody Evasion and Transduction with Purified Extracellular Vesicle-Enveloped Adeno-Associated Virus Vectors.

Adeno-associated virus (AAV) is classified as a nonenveloped DNA virus. However, several years ago, we discovered that in media of packaging cells producing recombinant AAV vectors, AAV capsids can associate with the interior and surface of extracellular vesicles (EVs), sometimes referred to as exosomes. Since then, we and others have demonstrated that exosome-enveloped AAV, exo-AAV, can enhance transduction in vivo as well as evade neutralizing antibodies. While promising, these data were generated with differential centrifugation to pellet the exo-AAV. This method results in a heterogeneous mixture of exo-AAV, coprecipitating proteins, as well as free AAV capsids. To define the properties of exo-AAV more accurately, in this study, we used a density gradient method to purify exo-AAV. We next performed head-to-head comparisons of standard AAV1, differential centrifuged exo-AAV1, and gradient purified exo-AAV1 for antibody evasion and transgene expression in the murine brain. We found purified exo-AAV1 to be more resistant to neutralizing antibodies than the other AAV preparations. Direct intracranial injection of purified exo-AAV1 into mice resulted in robust transduction, which transduced a larger area of brain than standard AAV1. We also identified the recently described membrane-associated accessory protein by mass spectrometry of purified exo-AAV1 preparations. Finally, we used a scalable method, size-exclusion chromatography to isolate exo-AAV1, and demonstrated functional transduction in cultured cells and increased antibody resistance. Together, these data suggest that higher purity exo-AAV will have beneficial characteristics for gene delivery and also may lead to mechanistic insights into the incorporation of AAV into EVs.

Diagnosing Acute Heart Failure in the Pediatric Emergency Department Using Point-of-Care Ultrasound.

BACKGROUND: Acute heart failure (AHF) in children is associated with significant disease burden with high rates of morbidity, mortality, and resource utilization. These children often present to the emergency department with clinical features that mimic common childhood illnesses. Cardiac point-of-care ultrasound (POCUS) can be an effective tool for rapidly identifying abnormal cardiac function. CASE REPORTS: This case series documents 10 children presenting with AHF between 2016 and 2019 and demonstrates how pediatric emergency physicians used cardiac POCUS to expedite their diagnosis, management, and disposition. All cardiac POCUS was performed before comprehensive echocardiograms were completed. One case is described in detail; the other cases are summarized in a Table. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Early recognition of AHF is critical to reduce pediatric morbidity and mortality. With proper training, cardiac POCUS can be an effective adjunct and should be considered for the early diagnosis and treatment of infants and children with AHF.

The effect of point-of-care ultrasound on length of stay in the emergency department in children with neck swelling.

BACKGROUND: Ultrasound is the imaging modality of choice in children presenting to the emergency department (ED) with soft tissue neck swelling. Point of care ultrasound (POCUS) has good accuracy when compared to comprehensive radiology department ultrasound (RADUS). POCUS could potentially improve ED length of stay (LOS) by improving efficiency. We aimed to evaluate the LOS of pediatric patients seen in ED with soft tissue neck swelling who received POCUS compared to RADUS. We determined unscheduled 30-day return visit rates in both groups as a balancing measure. METHODS: We performed a retrospective review of the electronic medical record for our cross-sectional study of discharged patients ≤21 years of age who had a neck ultrasound performed by a credentialed POCUS physician or by the radiology department between July 2014 and January 2020. We included patients who had both POCUS and RADUS in the POCUS group. We compared median ED LOS in both groups using the Mann Whitney U test and proportion of unscheduled return visits to the ED in both groups using odds ratio and 95% CI. RESULTS: There were 925 patients: 76 with only POCUS, 6 with POCUS and RADUS, and 843 with only RADUS performed. Median LOS in the POCUS group was 68.5 min (IQR 38.3120.3) versus 154.0 min (IQR 111.0, 211.0) in the RADUS group (p < 0.001). Return visit overall was 7.6%: 13.2% in the POCUS group versus 7.1% in the RADUS group (p = 0.07). CONCLUSION: Pediatric patients evaluated in the ED for soft tissue neck swelling had a shorter LOS with POCUS than with RADUS without a statistically significant increase in 30-day return visits. We suggest a "POCUS First" approach to the care of these patients.

Higher-Impact Physical Activity Is Associated With Maintenance of Bone Mineral Density But Not Reduced Incident Falls or Fractures in Older Men: The Concord Health and Aging in Men Project.

High-impact physical activities with bone strains of high magnitude and frequency may benefit bone health. This study aimed to investigate the longitudinal associations between changes in loading intensities and application rates, estimated from self-reported physical activity, with bone mineral density (BMD) changes over 5 years and also with incident falls over 2 years and long-term incident fractures in community-dwelling older men. A total of 1599 men (mean age 76.8 ± 5.4 years) from the Concord Health and Aging in Men Project (CHAMP) were assessed at baseline (2005-2007) and at 2- and 5-year follow-up. At each time point, hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry, and physical activity energy expenditure over the past week was self-reported via the Physical Activity Scale for the Elderly (PASE) questionnaire. Sum effective load ratings (ELRs) and peak force were estimated from the PASE questionnaire, reflecting the total and highest loading intensity and application rate of physical activities, respectively. Participants were contacted every 4 months over 2 years to self-report falls and over 6.0 ± 2.2 years for fractures. Hip fractures were ascertained by data linkage for 8.9 ± 3.6 years. Compared with sum ELR and PASE scores, peak force demonstrated the greatest standardized effect size for BMD maintenance at the spine (ß = 9.77 mg/cm2 ), total hip (ß = 14.14 mg/cm2 ), and femoral neck (ß = 13.72 mg/cm2 ) after adjustment for covariates, including PASE components (all p < .01). Only PASE scores were significantly associated with reduced falls risk (standardized incident rate ratio = 0.90, 95% confidence interval 0.81-1.00, p = .04). All physical activity measures were significantly associated with reduced incident fractures in univariate analyses, but none remained significant after multivariable adjustments. Older men who engaged in physical activity of high and rapid impact maintained higher BMD, while higher energy expenditure was associated with reduced falls risk. Coupling traditional physical activity data with bone loading estimates may improve understanding of the relationships between physical activity and bone health. © 2020 American Society for Bone and Mineral Research (ASBMR).

Improving Point-of-Care Ultrasound Documentation and Billing Accuracy in a Pediatric Emergency Department.

OBJECTIVE: The performance and interpretation of point-of-care ultrasound (POCUS) should be documented appropriately in the electronic medical record (EMR) with correct billing codes assigned. We aimed to improve complete POCUS documentation from 62% to 80% and improve correct POCUS billing codes to 95% or higher through the implementation of a quality improvement initiative. METHODS: We collected POCUS documentation and billing data from the EMR. Interventions included: (1) staff education and feedback, (2) standardization of documentation and billing, and (3) changes to the EMR to support standardization. We used P charts to analyze our outcome measures between January 2017 and June 2018. RESULTS: Six hundred medical records of billed POCUS examinations were included. Complete POCUS documentation rate rose from 62% to 91%, and correct CPT code selection for billing increased from 92% to 95% after our interventions. CONCLUSIONS: The creation of a standardized documentation template incorporated into the EMR improved complete documentation compliance.

Parotitis on Ultrasound: The Pomegranate Sign.

The differential diagnosis for facial swelling is broad and can be a diagnostic challenge in the pediatric emergency department. We describe the first pediatric case of acute parotitis with sialolithiasis where the diagnosis was facilitated by point-of-care ultrasound.

Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons.

Fragile X syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in the 5'-UTR of the Fragile X mental retardation gene FMR1, triggering epigenetic silencing and the subsequent absence of the protein, FMRP. Reactivation of FMR1 represents an attractive therapeutic strategy targeting the genetic root cause of FXS. However, largely missing in the FXS field is an understanding of how much FMR1 reactivation is required to rescue FMRP-dependent mutant phenotypes. Here, we utilize FXS patient-derived excitatory neurons to model FXS in vitro and confirm that the absence of FMRP leads to neuronal hyperactivity. We further determined the levels of FMRP and the percentage of FMRP-positive cells necessary to correct this phenotype utilizing a mixed and mosaic neuronal culture system and a combination of CRISPR, antisense and expression technologies to titrate FMRP in FXS and WT neurons. Our data demonstrate that restoration of greater than 5% of overall FMRP expression levels or greater than 20% FMRP-expressing neurons in a mosaic pattern is sufficient to normalize a FMRP-dependent, hyperactive phenotype in FXS iPSC-derived neurons.

Selection of an Efficient AAV Vector for Robust CNS Transgene Expression.

Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F.

Associations of Health-Related Quality of Life, Fear of Falling and Objective Measures of Physical Function with Bone Health in Postmenopausal Women with Low Bone Mass.

Health-related quality of life (HRQoL) and physical function deteriorate with age and may adversely impact bone health in older adults. We determined associations of objective measures of physical function and HRQoL with bone health in postmenopausal women with low areal bone mineral density (aBMD). Fifty postmenopausal women (64.4 7.7 years old, mean standard deviation) with low spine, hip or femoral neck aBMD (T- or Z-score < -1.0) on dual-energy X-ray absorptiometry (DXA) participated. Femoral surface BMD, trabecular, integral and cortical volumetric BMD (vBMD) measurements were obtained using 3D-SHAPER software on DXA. Distal tibial vBMD and microarchitecture were assessed using high-resolution peripheral quantitative computed tomography (HRpQCT). Participants completed self-administered EuroQol-5D (EQ-5D) and modified falls efficacy scale (MFES) questionnaires, and physical function assessments. Stair climb power was positively associated with bone parameters at the hip, femoral neck, and distal tibia (all p < 0.05) in multivariable linear regression. EQ-5D demonstrated no significant associations with bone parameters and MFES was positively associated only with distal tibial cortical vBMD and cortical von Mises stress (both p < 0.05). Objective measures of physical function, particularly muscle power, are more consistently associated with bone parameters compared with self-administered HRQoL questionnaires.