Oxidative stress and food as medicine.

There has been a sea of change in our understanding of the contribution of food to both our well-being and disease states. When one addresses "food as medicine," the concept of oxidative stress needs to be included. This review interconnects the basic science findings of oxidative stress and redox balance with the medicinal use of food, emphasizing optimization of the redox balance. To better illustrate the impacts of oxidative stress, the concept of the "triple oxidant sink" is introduced as a theoretical gauge of redox balance. Utilizing the concept, the true importance of dietary and lifestyle factors can be emphasized, including the limitations of supplements or a handful of "superfoods," if the remainder of the factors are pro-oxidant. The effects of a whole plant food diet compared with those of dietary supplements, processed foods, animal based nutrients, or additional lifestyle factors can be visually demonstrated with this concept. This paper provides an overview of the process, acknowledging that food is not the only mechanism for balancing the redox status, but one that can be strategically used to dramatically improve the oxidative state, and thus should be used as medicine.

Administrative Analysis of the Home-Based Older Persons Upstreaming Prevention Physical Therapy Program: A Pilot Observational Study.

Introduction Traditionally, physical therapist (PT) services do not commence until an injury, fall, or health issue has already occurred although there is increasing evidence that preventative programs administered by PTs may decrease the fall risk among elderly individuals. The purpose of this study was to examine billing, reimbursement, and administrative outcomes of the previously established and investigated prevention-based screening and intervention HOP-UP-PT (Home-based Older Persons Upstreaming Prevention-Physical Therapy) program delivered by a physical therapist in the home of older adults after being referred by a community partner. A randomized controlled trial of the HOP-UP-PT program demonstrated an 8-fold reduction in falls for participants at moderate and high fall risk compared to those who did not participate in the program. Methods A prospective observational study was performed to examine administrative and payment outcomes of HOP-UP-PT participation. Participants were referred into the HOP-UP-PT program via a local community center. Physician authorization for physical therapy participation was obtained for each participant as required for payment under United States' Center for Medicare and Medicaid Services (CMS) guidelines. The HOP-UP-PT program is preventative physical therapy delivered in the person's home with five in person visits (approximately one per month) followed by a monthly telehealth visit and a final in-person visit. Interventions included a balance program, home safety recommendations, health coaching, and addressing individual risks of falling or becoming homebound. A retrospective analysis was performed on the administrative and insurance payment data from this study which was then analyzed descriptively. Results Six participants with four different insurances completed the 7-month program (mean age=77 years) in 2021. The physical therapy visits were submitted to the participants' Medicare Part B plan. One participant's physical therapy visits were not submitted for payment as the health system did not have an active agreement with that health insurer. Due to the unclear status of telehealth visits in 2021, these services were not submitted to the insurance company for payment. All other PT visits were paid by the insurance companies. The mean amount paid for the initial evaluation code was $102.83 and the mean payment for the ~15 minute treatment codes was $25.90 per unit. Initial pilot data demonstrated a potential for a 4.2% positive operating margin when considering salary costs and travel. The mean delay from the initial referral into the HOP-UP-PT program until the physician provided written authorization for physical therapy was 69.7 days. Conclusion This study demonstrated initial evidence that payment for prevention-focused outpatient physical therapist services delivered in the home was feasible, however delays and costs in procuring physician authorization was a substantial barrier to prevention-focused physical therapy. A 4.2% operating margin demonstrated that, when efficiently operated, similar programs are likely to be viable. Furthermore, if telehealth services would have been paid, the operating margin was estimated to increase to 32%. Physical therapists are highly qualified to deliver efficient, effective preventative services which has the potential to reduce falls and institutionalization and subsequent healthcare cost savings.

Commercial infant products influence body position and muscle use.

The musculoskeletal and motor development of infants is affected by their environment, which varies from being held, lying on a firm flat surface, to seated in various nursery products. Nursery products can alter the body position of infants, particularly the position of the head/neck and trunk, which may inhibit an infant's ability to breathe. With U.S. infants spending an increasing amount of time in seated products, the purpose of this study was to assess muscle activation and body position in four commercial infant products (carrier, bouncer, rocker, and swing) during supine and prone positioning, compared to a firm flat surface. Thirteen healthy infants (age: 4.2 ± 1.4 months; 7 M/6F) were enrolled in this IRB-approved in-vivo biomechanics study. Surface electromyography sensors recorded muscle activity of the erector spinae, cervical paraspinals, quadriceps, and abdominal muscles and retro-reflective markers tracked movements to determine head-neck, trunk, and torso-pelvis flexion/extension in the sagittal plane. While supine, infants exhibited increased head-neck and trunk flexion of up to 21° and 27° above the playmat, respectively, in all seated products. While prone, high abdominal muscle activation compared to the playmat indicates that infants will fatigue faster in seated products. Additionally, the lower muscle activation levels exhibited in younger infants (< 4 months) compared to older infants (≥ 4 months) indicates that younger infants rely on the product design to maintain body position. However, offering infants a variety of environments to move within is important to avoid motor delay, therefore future work should explore how long-term use may impact an infant's development.

Proximity to cancer rehabilitation and exercise oncology by geography, race, and socioeconomic status.

BACKGROUND: Cancer rehabilitation and exercise oncology (CR/EO) have documented benefits for people living with and beyond cancer. The authors examined proximity to CR/EO programs across the United States with respect to population density, race and ethnicity, socioeconomic status, and cancer incidence and mortality rates. METHODS: This cross-sectional study was conducted in 2022-2023. Online searches were initiated to identify CR/EO programs. Geocoding was used to obtain latitudinal and longitudinal geospatial coordinates. Demographic data were abstracted from the 2020 5-year American Community Survey. Cancer incidence and mortality data were obtained from the Centers for Disease Control and Prevention. US 2013 Rural-Urban Continuum Code (RUCC) classification was used to define counties as either urban (RUCC 1-3) or rural (RUCC 4-9). Multivariable logistic regression was used to evaluate the association between being far from a program and census-tract level factors. RESULTS: In total, 2133 CR/EO programs were identified nationwide. The distance from a program increased with decreasing population density: rural tracts were 17.68 ± 0.24 miles farther from a program compared with urban tracts (p < .001). Program proximity decreased as the neighborhood deprivation index increased (p < .001). Exercise oncology programs were less common than cancer rehabilitation programs in tracts with a larger proportion of minority residents (p < .001). CONCLUSIONS: Prior research has documented that underrepresented populations have worse cancer-related symptoms and higher cancer mortality. Herein, the authors document their findings that these same populations are less likely to have proximity to CR/EO programs, which are associated with improved cancer-related symptoms and cancer mortality outcomes. To realize the positive outcomes from CR/EO programming, efforts must focus on supporting expanded programming and sustainable payment for these services.

Molecular classification to refine surgical and radiotherapeutic decision-making in meningioma.

Treatment of the tumor and dural margin with surgery and sometimes radiation are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease; however, response to treatment remains heterogeneous. In this study, we used retrospective data on 2,824 meningiomas, including molecular data on 1,686 tumors and 100 prospective meningiomas, from the RTOG-0539 phase 2 trial to define molecular biomarkers of treatment response. Using propensity score matching, we found that gross tumor resection was associated with longer progression-free survival (PFS) across all molecular groups and longer overall survival in proliferative meningiomas. Dural margin treatment (Simpson grade 1/2) prolonged PFS compared to no treatment (Simpson grade 3). Molecular group classification predicted response to radiotherapy, including in the RTOG-0539 cohort. We subsequently developed a molecular model to predict response to radiotherapy that discriminates outcome better than standard-of-care classification. This study highlights the potential for molecular profiling to refine surgical and radiotherapy decision-making.

"The Psychiatric Domain of Post-Intensive Care Syndrome: A Review for the Intensivist".

Post-intensive care syndrome (PICS) is a clinical syndrome characterized by new or worsening changes in mental health, cognition, or physical function that persist following critical illness. The psychiatric domain of PICS encompasses new or worsened psychiatric burdens following critical illness, including post-traumatic stress disorder (PTSD), depression, and anxiety. Many of the established predisposing and precipitating factors for the psychiatric domain of PICS are commonly found in the setting of critical illness, including mechanical ventilation (MV), exposure to sedating medications, and physical restraint. Importantly, previous psychiatric history is a strong risk factor for the development of the psychiatric domain of PICS and should be considered when screening patients to diagnose psychiatric impairment and interventions. Delirium has been associated with psychiatric symptoms following ICU admission, therefore prevention warrants careful consideration. Dexmedetomidine has been shown to have the lowest risk for development of delirium when compared to other sedatives and has been the only sedative studied in relation to the psychiatric domain of PICS. Nocturnal dexmedetomidine and intensive care unit (ICU) diaries have been associated with decreased psychiatric burden after ICU discharge. Studies evaluating the impact of other intra-ICU practices on the development of the psychiatric domain of PICS, including the ABCDEF bundle, depth of sedation, and daily spontaneous awakening trials, have been limited and inconclusive. The psychiatric domain of PICS is difficult to treat and may be less responsive to multidisciplinary post-discharge programs and targeted interventions than the cognitive and physical domains of PICS. Given the high morbidity associated with the psychiatric domain of PICS, intensivists should familiarize themselves with the risk factors and intra-ICU interventions that can mitigate this important and under-recognized condition.

Bdelloid rotifers deploy horizontally acquired biosynthetic genes against a fungal pathogen.

Coevolutionary antagonism generates relentless selection that can favour genetic exchange, including transfer of antibiotic synthesis and resistance genes among bacteria, and sexual recombination of disease resistance alleles in eukaryotes. We report an unusual link between biological conflict and DNA transfer in bdelloid rotifers, microscopic animals whose genomes show elevated levels of horizontal gene transfer from non-metazoan taxa. When rotifers were challenged with a fungal pathogen, horizontally acquired genes were over twice as likely to be upregulated as other genes - a stronger enrichment than observed for abiotic stressors. Among hundreds of upregulated genes, the most markedly overrepresented were clusters resembling bacterial polyketide and nonribosomal peptide synthetases that produce antibiotics. Upregulation of these clusters in a pathogen-resistant rotifer species was nearly ten times stronger than in a susceptible species. By acquiring, domesticating, and expressing non-metazoan biosynthetic pathways, bdelloids may have evolved to resist natural enemies using antimicrobial mechanisms absent from other animals.

Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

Metatranscriptomic Analysis Reveals Synergistic Activities of Comammox and Anammox Bacteria in Full-Scale Attached Growth Nitrogen Removal System.

Leveraging comammox Nitrospira and anammox bacteria for shortcut nitrogen removal can drastically lower the carbon footprint of wastewater treatment facilities by decreasing aeration energy, carbon, alkalinity, and tank volume requirements while also potentially reducing nitrous oxide emissions. However, their co-occurrence as dominant nitrifying bacteria is rarely reported in full-scale wastewater treatment. As a result, there is a poor understanding of how operational parameters, in particular, dissolved oxygen, impact their activity and synergistic behavior. Here, we report the impact of dissolved oxygen concentration (DO = 2, 4, 6 mg/L) on the microbial community's transcriptomic expression in a full-scale integrated fixed film activated sludge (IFAS) municipal wastewater treatment facility where nitrogen removal is predominantly performed by comammox Nitrospira and anammox bacterial populations. 16S rRNA transcript compositions revealed anammox bacteria and Nitrospira were significantly more active in IFAS biofilms compared to suspended sludge biomass. In IFAS biofilms, anammox bacteria significantly increased hzo expression at lower dissolved oxygen concentrations and this increase was highly correlated with the amoA expression levels of comammox bacteria. Interestingly, the genes involved in nitrite oxidation by comammox bacteria were significantly more upregulated, relative to the genes involved in ammonia oxidation with decreasing dissolved oxygen concentrations. Ultimately, our findings suggest that comammox Nitrospira supplies anammox bacteria with nitrite via ammonia oxidation and that this synergistic behavior is dependent on dissolved oxygen concentrations.

Outcomes of Home Emergency Physical Readiness Education for Older Adults.

Emergency preparedness initiatives are a Medicare condition of participation in home healthcare, yet limited evidence on the impact of associated programming is available. The purpose of this exploratory pilot study was to examine the outcomes of an individualized emergency preparedness educational program provided by a physical therapist (PT) in the homes of older adults. The investigators recruited older adults (n = 30) using convenience sampling. An emergency preparedness education module was developed. Demographics, functional and environmental outcome measures, a pre- and post-education confidence survey, and learning outcomes were ascertained and analyzed. Participants reported being female (n = 23), 70 to 79 years (n = 15), and 19 individuals reported 35 different lifetime emergency events. Hearing and vision impairments, inability to change a battery or navigate stairs, and environmental deficits including clutter and poor lighting were identified. Closing bedroom doors at nighttime, functioning carbon monoxide and smoke detectors, creating an evacuation plan, and assembling first aid kits were learning outcomes. Trends toward increased confidence were identified, with statistically significant improvements in the ability to respond to a fire (P = .01), a heat wave (P = .03), and to crawl on hands and knees (P = .05) identified. This study provides emerging evidence that PTs have a role in improving an older adult's confidence to prepare for and respond to an emergency event.

Identification of core competencies for exercise oncology professionals: A Delphi study of United States and Australian participants.

INTRODUCTION: Integration of exercise into standard oncology care requires a highly skilled workforce of exercise professionals; however, competency requirements have not kept pace with advancements in the field. Therefore, the aim of this study was to obtain consensus on core competencies required for an exercise professional to be qualified to work with adults undergoing active cancer treatment. MATERIALS AND METHODS: A three-round modified electronic Delphi process was used. In Round 1, an international group of 64 exercise oncology stakeholders (i.e., exercise oncology professionals (n = 29), clinical referrers (n = 21), and people with lived experience (n = 14)) responded to open-ended prompts eliciting perspectives regarding competencies needed for an exercise oncology professional to work with adults receiving active cancer treatment. Subsequently, only exercise oncology professionals participated, ranking the importance of competencies. In Round 2, professionals received summary feedback, ranked new competencies generated from open-ended responses, and reranked competencies not reaching consensus. In the final round, professionals finalized consensus ranking and rated frequency and mastery level for each. RESULTS: Consensus was reached on 103 core competencies required for exercise professionals to be qualified to deliver care to adults undergoing active cancer treatment. The core competencies represent 10 content areas and reflect the needs of clinical referrers and people with lived experience of receiving cancer treatment. CONCLUSIONS: The core competencies identified reflect significant advancements in the field of exercise oncology. Results will underpin the development of education, certification, and employment requirements for exercise oncology professionals, providing a critical step toward achieving routine integration of exercise into standard oncology care.

COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator.

Silent hypoxemia, or "happy hypoxia," is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation ( SaO 2 < 80%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model of the respiratory neural network (Diekman et al. in J Neurophysiol 118(4):2194-2215, 2017) can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or the nucleus tractus solitarii are responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection.

Characteristics of healthcare personnel with SARS-CoV-2 infection: 10 emerging infections program sites in the United States, April 2020-December 2021.

BACKGROUND: Understanding characteristics of healthcare personnel (HCP) with SARS-CoV-2 infection supports the development and prioritization of interventions to protect this important workforce. We report detailed characteristics of HCP who tested positive for SARS-CoV-2 from April 20, 2020 through December 31, 2021. METHODS: CDC collaborated with Emerging Infections Program sites in 10 states to interview HCP with SARS-CoV-2 infection (case-HCP) about their demographics, underlying medical conditions, healthcare roles, exposures, personal protective equipment (PPE) use, and COVID-19 vaccination status. We grouped case-HCP by healthcare role. To describe residential social vulnerability, we merged geocoded HCP residential addresses with CDC/ATSDR Social Vulnerability Index (SVI) values at the census tract level. We defined highest and lowest SVI quartiles as high and low social vulnerability, respectively. RESULTS: Our analysis included 7,531 case-HCP. Most case-HCP with roles as certified nursing assistant (CNA) (444, 61.3%), medical assistant (252, 65.3%), or home healthcare worker (HHW) (225, 59.5%) reported their race and ethnicity as either non-Hispanic Black or Hispanic. More than one third of HHWs (166, 45.2%), CNAs (283, 41.7%), and medical assistants (138, 37.9%) reported a residential address in the high social vulnerability category. The proportion of case-HCP who reported using recommended PPE at all times when caring for patients with COVID-19 was lowest among HHWs compared with other roles. CONCLUSIONS: To mitigate SARS-CoV-2 infection risk in healthcare settings, infection prevention, and control interventions should be specific to HCP roles and educational backgrounds. Additional interventions are needed to address high social vulnerability among HHWs, CNAs, and medical assistants.

Safe Fall Recovery Education for Older Adults.

High fall rates among older adults in combination with prolonged time on the floor after a fall have created an urgent need to preventatively address fall recovery strategies. The purpose of this study is to describe the outcomes of a novel safe fall recovery (SFR) educational module provided by physical therapists to older adults in their homes. A pre- and post-test descriptive study used a convenience sample to recruit 30 adults (≥65 years). A baseline assessment and SFR in-home education were provided. Pre- and post-education measures included the Steps for Safe Fall Recovery (Steps for SFR) tool, the Activity Specific Balance Confidence (ABC) scale, and a fall confidence survey. The Wilcoxon matched-pairs signed-rank test determined significance (P < .05). Participants were age 77.2 (6.8) years and 20 females. Eight reported a fall during the prior year. Statistically significant improvements were identified in the Steps to SFR tool (P = .001), the ABC scale (P = .004), and the fall recovery confidence survey (P = .001). Integration of an SFR educational intervention delivered to an older adult population in their home demonstrated improved safety and confidence to recover from a fall.

Quantum simulation of the bosonic Kitaev chain.

Superconducting quantum circuits are a natural platform for quantum simulations of a wide variety of important lattice models describing topological phenomena, spanning condensed matter and high-energy physics. One such model is the bosonic analog of the well-known fermionic Kitaev chain, a 1D tight-binding model with both nearest-neighbor hopping and pairing terms. Despite being fully Hermitian, the bosonic Kitaev chain exhibits a number of striking features associated with non-Hermitian systems, including chiral transport and a dramatic sensitivity to boundary conditions known as the non-Hermitian skin effect. Here, using a multimode superconducting parametric cavity, we implement the bosonic Kitaev chain in synthetic dimensions. The lattice sites are mapped to frequency modes of the cavity, and the in situ tunable complex hopping and pairing terms are created by parametric pumping at the mode-difference and mode-sum frequencies, respectively. We experimentally demonstrate important precursors of nontrivial topology and the non-Hermitian skin effect in the bosonic Kitaev chain, including chiral transport, quadrature wavefunction localization, and sensitivity to boundary conditions. Our experiment is an important first step towards exploring genuine many-body non-Hermitian quantum dynamics.

Characteristics of Patients With Initial Clostridioides difficile Infection (CDI) That Are Associated With Increased Risk of Multiple CDI Recurrences.

Background: Because interventions are available to prevent further recurrence in patients with recurrent Clostridioides difficile infection (rCDI), we identified predictors of multiple rCDI (mrCDI) in adults at the time of presentation with initial CDI (iCDI). Methods: iCDI was defined as a positive C difficile test in any clinical setting during January 2018-August 2019 in a person aged ≥18 years with no known prior positive test. rCDI was defined as a positive test ≥14 days from the previous positive test within 180 days after iCDI; mrCDI was defined as ≥2 rCDI. We performed multivariable logistic regression analysis. Results: Of 18 829 patients with iCDI, 882 (4.7%) had mrCDI; 437 with mrCDI and 7484 without mrCDI had full chart reviews. A higher proportion of patients with mrCDI than without mrCDI were aged ≥65 years (57.2% vs 40.7%; P < .0001) and had healthcare (59.1% vs 46.9%; P < .0001) and antibiotic (77.3% vs 67.3%; P < .0001) exposures in the 12 weeks preceding iCDI. In multivariable analysis, age ≥65 years (adjusted odds ratio [aOR], 1.91; 95% confidence interval [CI], 1.55-2.35), chronic hemodialysis (aOR, 2.28; 95% CI, 1.48-3.51), hospitalization (aOR, 1.64; 95% CI, 1.33-2.01), and nitrofurantoin use (aOR, 1.95; 95% CI, 1.18-3.23) in the 12 weeks preceding iCDI were associated with mrCDI. Conclusions: Patients with iCDI who are older, on hemodialysis, or had recent hospitalization or nitrofurantoin use had increased risk of mrCDI and may benefit from early use of adjunctive therapy to prevent mrCDI. If confirmed, these findings could aid in clinical decision making and interventional study designs.

Recombination in bdelloid rotifer genomes: asexuality, transfer and stress.

Bdelloid rotifers constitute a class of microscopic animals living in freshwater habitats worldwide. Several strange features of bdelloids have drawn attention: their ability to tolerate desiccation and other stresses, a lack of reported males across the clade despite centuries of study, and unusually high numbers of horizontally acquired, non-metazoan genes. Genome sequencing is transforming our understanding of their lifestyle and its consequences, while in turn providing wider insights about recombination and genome organisation in animals. Many questions remain, not least how to reconcile apparent genomic signatures of sex with the continued absence of reported males, why bdelloids have so many horizontally acquired genes, and how their remarkable ability to survive stress interacts with recombination and other genomic processes.

What is the Long-term Wear of a 5-Mrad Highly Crosslinked Polyethylene Liner? A 14-year RSA Study.

BACKGROUND: Lower doses of irradiation (≤ 5 Mrad) during the manufacture of highly crosslinked polyethylene acetabular liners may result in less crosslinking and an increased wear rate. Radiostereometric analysis (RSA) studies have found that wear of more highly irradiated highly crosslinked polyethylene liners (7 to 10 Mrad) decreases at longer-term follow-up compared with earlier reports of the same cohorts. Although wear of 5-Mrad irradiated liners appears to increase at midterm follow-up, it is unclear whether that remains true at longer follow-up. QUESTIONS/PURPOSES: We asked: (1) In patients who underwent THA with a 5-Mrad highly crosslinked polyethylene liner, what is the wear rate evaluated with RSA during the first 14 years? (2) Does the wear rate decrease after 6 years in situ? METHODS: This is a brief follow-up of prior RSA studies performed at 2 and 6 years. We prospectively reviewed the longer-term wear rate in 13 patients who underwent primary THAs with the same design of a 5-MRad irradiated crosslinked acetabular liner and a 28-mm cobalt-chromium articulation. Of the initial 30 patients who were enrolled, 13 (43%) were available at the 14-year timepoint; nine patients had died, 1 patient had withdrawn, 1 had an intraoperative fracture, 3 patients were too infirm to have radiographs, 2 had no baseline RSA radiographs, and 1 had poor-quality RSA images. Tantalum markers were inserted during surgery, and all patients had RSA radiographic examinations at 1 week, 6 months, and 1, 2, 6, and 14 years postoperatively. RESULTS: The mean ± standard deviation proximal, 2D, and 3D wear rates calculated between 1 year and 14 years were 0.019 ± 0.013 mm, 0.022 ± 0.015 mm, and 0.025 ± 0.019 mm per year, respectively. No patient had proximal 2D or 3D wear rates exceeding 0.06 mm per year. An increasing wear rate over time was measured for proximal and 2D wear rates between 6 and 14 years (0.024 and 0.030 mm per year) compared with that between 1 and 6 years (0.008 and 0.010 mm per year; p = 0.03). CONCLUSION: The proximal, 2D, and 3D wear of a highly crosslinked polyethylene liner produced using 5-Mrad radiation remains low in the longer-term. With the small numbers available in a long-term RSA study such as this, we confirmed that the wear rate did not decrease at longer-term follow-up, unlike previous RSA studies of more highly irradiated highly crosslinked polyethylene liners. Nevertheless, the wear rate remains very low and below the threshold typically associated with the development of osteolysis (0.1 mm/year of wear). This should provide assurance to orthopaedic surgeons monitoring patients with this 5-Mrad irradiated liner in situ, while providing useful information to manufacturers of future highly crosslinked polyethylene liners. LEVEL OF EVIDENCE: Level IV therapeutic study.

Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer.

ABSTRACT: Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous; and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e-4 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.