Ultra culture-ultra reality: a content analysis of YouTube depictions of ultra endurance sport and comparisons to scientific literature.

Introduction: Interest in ultra endurance sport (UES) is increasing, with relevant events growing in popularity. However, these activities may encompass more complex characteristics and demands that do not correspond to scientifically validated correlations between physical activity and improved health. It is unknown whether high volume training for UES can have adverse implications, although certain sociocultural aspects of western society, such as an emphasis on autonomy and self-directed success, may encourage participation as a representation of personal achievement. As media depictions of UES can be highly influential, we aimed to explore prominent messages to better comprehend the values and aspirations of established and aspiring ultra endurance athletes (UEA). Methods: Using qualitative, conventional content analysis techniques, we evaluated n = 15 popular YouTube videos on various UES to synthesize the most common themes. A YouTube search was conducted, and videos were selected based on sport and relevance. Subsequently, videos were analyzed and coded to discern the most frequently repeated themes. Results: Five recurring themes were identified: discussion of the mental aspects of UES participation; the adoption of folk-tale storytelling; dietary habits of UEA; a focus on pain and suffering; the use of words associated with mental illness as a colloquial descriptor of UES/UEA. Discussion: YouTube depictions of UES participation appear to accentuate suffering and co-occurring phenomena as attractive qualities. These resonate with sociocultural ideologies in western contexts, which emphasize fitness and personal success, but appear inconsistent with evidence around potentially adverse health-related implications of UES. Conclusion: Discrepancies between popular portrayals of UES and scientific evidence suggest a need for greater community education and information sharing about sport-specific risk factors for physical and mental health conditions and appropriate training protocols. Further research is also required to better define the relationship between motivations for UES participation and overall health using interdisciplinary approaches.

Designing systems for the care we need: A transformation journey in Southwestern Ontario.

Primary care is considered the foundation of any health system. In Ontario, Canada Bills 41 and 74 introduced in 2016 and 2019, respectively, aimed to move towards a primary care-focused and sustainable integrated care approach designed around the needs of local populations. These bills collectively set the stage for integrated care and population health management in Ontario, with Ontario Health Teams (OHTs) introduced as a model of integrated care delivery systems. OHTs aim to streamline patient connectivity through the healthcare system and improve outcomes aligned with the Quadruple Aim. When Ontario released a call for health system partners to apply to become an OHT, providers, administrators, and patient/caregiver partners from the Middlesex-London area were quick to respond. We highlight the critical elements and journey of the Middlesex-London Ontario Health Team since its start.

High-efficacy therapies reduce clinical and radiological events more effectively than traditional treatments in neuromyelitis optica spectrum disorder.

BACKGROUND: People with neuromyelitis optica spectrum disorder (pwNMOSD) experience debilitating neurological attacks, resulting in permanent disability. OBJECTIVE: To evaluate if high-efficacy treatment was better than traditional agents at preventing disease advancement in pwNMOSD. METHODS: A retrospective study of pwNMOSD at one academic center was performed. Timelines were created for treatments subjects were exposed to along with clinical/radiological events related to disease worsening. High-efficacy treatments included eculizumab, inebilizumab, satralizumab, rituximab, ocrelizumab, tocilizumab, and sarilumab while therapies such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil were classified as traditional agents. Poisson regression and mixed effects logistics models were constructed, and a subject-specific random intercept was used for intrasubject correlation. RESULTS: Of 189 pwNMOSD identified, 161 were aquaporin-4 IgG positive (AQP4 +) with 92 (77 female; median disease duration (MDD) (range) of 6.6 years (y) (1.2-18.6)) exposed only to high-efficacy therapy, 33 (28 female; 10.4 y (0.8-32.7)) only to traditional therapy, and 64 (54 female; 10.8 y (0.7-20.2)) to both. High-efficacy treatments reduced the rate of MRI advancement by 62.4% (95% CrI = [- 86.9%, - 16.8%]), relapses by 99.8% (95% CrI = [- 99.9%, - 99.6%]), and hospitalizations by 99.3% (95% CrI = [- 99.6%, - 98.8%]) when compared to traditional treatments. For AQP4 + subjects, a 655.7-fold increase in the odds of new spinal cord lesion development (95% CrI = [+ 37.4-fold, + 3239.5-fold]) was observed with traditional agents (p < 0.0001). CONCLUSION: High-efficacy treatments maximize opportunity for preventing disease advancement in newly diagnosed and established pwNMOSD.

"I Didn't Sign Up for This": Perspectives from Persons Living with Dementia and Care Partners on Challenges, Supports, and Opportunities to Add Geriatric Neuropalliative Care to Dementia Specialty Care.

BACKGROUND: In the United States, dementia specialty centers affiliated with centers of excellence for research hold promise as locations to develop innovative, holistic care in care systems otherwise siloed by discipline or payer. OBJECTIVE: We conducted foundational research to inform development of patient-and family-centered palliative care interventions for dementia specialty centers. METHODS: We interviewed persons living with dementia (PLWD), current, and former care partners (CP) recruited from a specialty dementia clinic and purposively selected for variation across disease syndrome and stage. A framework method of thematic analysis included coding, analytic matrices, and pattern mapping. RESULTS: 40 participants included 9 PLWD, 16 current CPs, and 15 former CPs of decedents; 48% impacted by Alzheimer's disease dementia. While help from family, support groups and adult day centers, paid caregiving, and sensitive clinical care were invaluable to PLWD, CPs, or both, these supports were insufficient to navigate the extensive challenges. Disease-oriented sources of distress included symptoms, functional impairment and falls, uncertainty and loss, and inaccessible care. Social and relational challenges included constrained personal and professional opportunities. The obligation and toll of giving or receiving caregiving were challenging. Clinical care challenges for PLWD and/or CPs included care fragmentation, insufficient guidance to inform planning and need for expert interdisciplinary clinical care at home. CONCLUSION: Findings highlight the breadth and gravity of gaps, which surpass the disciplinary focus of either behavioral neurology or palliative care alone. Results can inform the development of novel interventions to add principles of geriatrics and neuropalliative care to dementia care.

Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids.

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders.

Changes in older adults' life space during lung cancer treatment: A mixed methods cohort study.

BACKGROUND: Maintenance of function during cancer treatment is important to older adults. Characteristics associated with pretreatment life-space mobility and changes during non-small cell lung cancer (NSCLC) treatment remain unknown. METHODS: This mixed methods cohort study recruited adults age ≥65 with advanced NSCLC starting palliative chemotherapy, immunotherapy, and/or targeted therapy from a Comprehensive Cancer Center, Veterans Affairs, and safety-net clinic. Patients completed geriatric assessments including Life-Space Assessment (LSA) pretreatment and at 1, 2, 4, and 6 months after treatment initiation. LSA scores range from 0 to 120 (greater mobility); LSA <60 is considered restricted. We used mixed-effects models to examine pretreatment LSA, change from 0 to 1 month, and change from 1 to 6 months. A subgroup participated in semistructured interviews pretreatment and at 2 and 6 months to understand the patient experience of life-space change. For each interview participant, we created joint displays of longitudinal LSA scores juxtaposed with illustrative quotes. RESULTS: Among 93 patients, median age was 73 (range 65-94). Mean pretreatment LSA score was 67.1. On average, LSA declined 10.1 points from pretreatment to 1 month and remained stable at 6 months. Pretreatment LSA score was associated with several demographic, clinical, geriatric assessment, and symptom characteristics. LSA decline at 1 month was greater among patients with high anxiety (slope = -12.6 vs. -2.3, p = 0.048). Pretreatment body mass index <21 kg/m2 was associated with LSA improvement from 1 to 6 months (slope = 4.1 vs. -0.04, p = 0.003). Joint displays illustrated the impact of different life-space trajectories on patients' lives in their words. CONCLUSION: Older adults with NSCLC have low pretreatment life space with many developing restricted life space during treatment. Incorporating life-space assessments into clinical cancer care may help older adults concretely visualize how treatment might impact their daily function to allow for informed decision making and identify early changes in mobility to implement supportive interventions.

Inducing neuroplasticity through intracranial θ-burst stimulation in the human sensorimotor cortex.

The progress of therapeutic neuromodulation greatly depends on improving stimulation parameters to most efficiently induce neuroplasticity effects. Intermittent θ-burst stimulation (iTBS), a form of electrical stimulation that mimics natural brain activity patterns, has proved to efficiently induce such effects in animal studies and rhythmic transcranial magnetic stimulation studies in humans. However, little is known about the potential neuroplasticity effects of iTBS applied through intracranial electrodes in humans. This study characterizes the physiological effects of intracranial iTBS in humans and compare them with α-frequency stimulation, another frequently used neuromodulatory pattern. We applied these two stimulation patterns to well-defined regions in the sensorimotor cortex, which elicited contralateral hand muscle contractions during clinical mapping, in patients with epilepsy implanted with intracranial electrodes. Treatment effects were evaluated using oscillatory coherence across areas connected to the treatment site, as defined with corticocortical-evoked potentials. Our results show that iTBS increases coherence in the ß-frequency band within the sensorimotor network indicating a potential neuroplasticity effect. The effect is specific to the sensorimotor system, the ß band, and the stimulation pattern and outlasted the stimulation period by ∼3 min. The effect occurred in four out of seven subjects depending on the buildup of the effect during iTBS treatment and other patterns of oscillatory activity related to ceiling effects within the ß band and to preexistent coherence within the α band. By characterizing the neurophysiological effects of iTBS within well-defined cortical networks, we hope to provide an electrophysiological framework that allows clinicians/researchers to optimize brain stimulation protocols which may have translational value.NEW & NOTEWORTHY θ-Burst stimulation (TBS) protocols in transcranial magnetic stimulation studies have shown improved treatment efficacy in a variety of neuropsychiatric disorders. The optimal protocol to induce neuroplasticity in invasive direct electrical stimulation approaches is not known. We report that intracranial TBS applied in human sensorimotor cortex increases local coherence of preexistent ß rhythms. The effect is specific to the stimulation frequency and the stimulated network and outlasts the stimulation period by ∼3 min.

Umbilical cord as an analytical matrix - A technical note.

The umbilical cord (UC) connects the fetal blood supply to the placenta, so is exposed to all systemic endo- and xenobiotics. We have extensive experience using UC as an analytical matrix for detecting and/or quantitating drugs, chemicals and endogenous compounds. This technical note describes advantages (large amount available, ease of collection, small sample needed for use, rapid availability) and challenges (clinical relationships, processing difficulties, matrix effects on analytes and detection technologies) of UC as an analytical matrix in ELISA and LC/MS platforms, and provides guidance for successfully working with this tissue.

A multiplexed in vitro assay system for evaluating human skeletal muscle functionality in response to drug treatment.

In vitro systems that mimic organ functionality have become increasingly important tools in drug development studies. Systems that measure the functional properties of skeletal muscle are beneficial to compound screening studies and also for integration into multiorgan devices. To date, no studies have investigated human skeletal muscle responses to drug treatments at the single myotube level in vitro. This report details a microscale cantilever chip-based assay system for culturing individual human myotubes. The cantilevers, along with a laser and photo-detector system, enable measurement of myotube contractions in response to broad-field electrical stimulation. This system was used to obtain baseline functional parameters for untreated human myotubes, including peak contractile force and time-to-fatigue data. The cultured myotubes were then treated with known myotoxic compounds and the resulting functional changes were compared to baseline measurements as well as known physiological responses in vivo. The collected data demonstrate the system's capacity for screening direct effects of compound action on individual human skeletal myotubes in a reliable, reproducible, and noninvasive manner. Furthermore, it has the potential to be utilized for high-content screening, disease modeling, and exercise studies of human skeletal muscle performance utilizing iPSCs derived from specific patient populations such as the muscular dystrophies.

"Now I Write Songs": Growth and Reciprocity After Long-Term Nursing Home Placement.

BACKGROUND AND OBJECTIVES: Nursing home residents have a need for activities that are meaningful, yet mandated scheduled activities remain poorly characterized. In order to understand how scheduled activities provide meaning for nursing home residents, we conducted a study of daily life in a nursing home with a robust activities program. RESEARCH DESIGN AND METHODS: This 2-year, longitudinal ethnographic study embedded an ethnographer into the activities department of a 430-bed, not-for-profit, faith-based nursing home. Forty-three interviews and more than 250 hr of participant-observation were conducted, with a focus on creative arts and religious activities. Thirty-two residents and 15 activities staff were followed more than 12-23 months. Data were coded concurrently, and emerging themes challenged through purposive recruitment until thematic saturation was reached. RESULTS: Scheduled activities in the nursing home offered opportunities for learning and personal growth regardless of functional or cognitive disability. Three major themes emerged. Artistic development included new self-identification as a musician, painter, or sculptor through arts programming. Intellectual and spiritual growth involved the use of activities to support ongoing practice and study. Reciprocity occurred as residents used the arts to remain contributing members of their institutional society, reciprocating with the institution that housed them. DISCUSSION AND IMPLICATIONS: Nursing home scheduled activities can facilitate the transformation of identity from resident or patient to the normalized social roles of artist, Torah scholar, and productive member of society.

Rehabbed to Death: Breaking the Cycle.

Many older adults transfer from the hospital to a post-acute care (PAC) facility and back to the hospital in the final phase of life. This phenomenon, which we have dubbed "Rehabbing to death," is emblematic of how our healthcare system does not meet the needs of older adults and their families. Policy has driven practice in this area including seemingly benign habits such as calling PAC facilities "rehab." We advocate for practice changes: (1) calling PAC "after-hospital transitional care," rather than "rehab"; (2) adopting a serious illness communication model when discussing new care needs at the end of a hospitalization; and (3) policies that incentivize comprehensive care planning for older adults across all settings and provide broad support and training for caregivers. In realigning health and social policies to meet the needs of older adults and their caregivers, fewer patients will be rehabbed to death, and more will receive care consistent with their preferences and priorities. J Am Geriatr Soc 67:2398-2401, 2019.

Differential plasma postprandial lipidomic responses to krill oil and fish oil supplementations in women: A randomized crossover study.

OBJECTIVES: There is no convincing evidence that krill oil (KO) consumption results in a higher incorporation of long chain ω-3 polyunsaturated fatty acids into blood lipid fractions than fish oil (FO). This study examined the postprandial plasma lipidomic responses to KO supplementation compared with FO supplementation in healthy women. METHODS: Ten women (aged 18-45 y) consumed a high-fat (15 g of olive oil) breakfast, supplemented with 5 g of KO or FO in a randomized crossover study with a minimum 7-d washout period between the supplementations. Plasma samples collected at the fasting state and at 3 and 5 h postprandially were analyzed using liquid chromatography electrospray ionization-tandem mass spectrometry. RESULTS: After the supplementations, 5 out of 34 lipid classes or subclasses had significantly greater concentrations from KO compared with FO. There were 27 molecular species including 5 ether-phospholipid species, out of a total of 701, which had significant differences between supplementations in the postprandial period. Eicosapentaenoic acid and docosahexaenoic acid from KO were preferentially partitioned toward phospholipid molecular species, whereas eicosapentaenoic acid and docosahexaenoic acid from FO were preferentially partitioned toward neutral lipids.

Serving the Very Sick, Very Frail, and Very Old: Geriatrics, Palliative Care, and Clinical Ethics.

How can we provide the best care for growing numbers of very frail, very sick, or very old people? The disciplines of geriatrics, palliative care, and clinical ethics each have a good deal to offer to improve care for elders, yet each field is saddled with heavy historical baggage. Using a case as a springboard, we address specific strengths and shortcomings of each field, and what these disciplines can learn from each other. Geriatrics is currently largely focused on prevention of disability, cognitive impairment, and death; it should reorganize around a palliative approach to providing care for elders living with multiple chronic conditions, disability, and dementia. Palliative care, while paying some attention to the spectrum of advanced illness, concentrates primarily on cancer; it should expand its central purpose to include providing supportive care to elders with serious illness and their caregivers. Ethics committee members and consultants principally stress individual autonomy; they need to expand their approach and develop longitudinal relationships with patients and family members, routinely incorporating them in deliberations and the crafting of recommendations. However, improving these three disciplines will only go so far toward improving the care of very frail, very sick, or very old people. What is most needed is longitudinal care provided by interdisciplinary primary care teams steeped in the core principles of all three disciplines.

Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties.

In the recent years, PI3Kδ has emerged as a promising target for the treatment of B- and T-cell mediated inflammatory diseases. We present a cellular assay activity analysis for our previously reported 4,6-diaryl quinazoline PI3Kδ inhibitor series that suggests an optimal logP range between 2 and 3. We discovered novel analogues in this lipophilicity space that feature a chiral pyrrolidineoxy-group as a replacement for the position-4 aromatic ring of 4,6-diaryl quinazolines. These Fsp3 enriched derivatives retain potency and selectivity towards PI3Kδ. Compared to 4,6-diaryl quinazolines, their permeability profile is improved and molecular weight as well as PSA are reduced. These modifications offer additional possibilities for derivative generation in a favorable physicochemical property space and thus increase the chances to identify a clinical candidate.

A Multicenter, Randomized, Observer-blinded, Active-controlled Study to Evaluate the Safety and Efficacy of Ceftaroline Versus Comparator in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infection.

BACKGROUND: Ceftaroline has in vitro activity against bacterial isolates, including methicillin-resistant Staphylococcus aureus. This is the first study to investigate ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs). METHODS: A multicenter, observer-blinded study (NCT01400867) in pediatric patients (2 months-17 years of age) with ABSSSIs. Patients were randomized 2:1 to receive intravenous (IV) ceftaroline fosamil or IV comparator (vancomycin or cefazolin, plus optional aztreonam) with optional switch to oral antibacterials from Day 4. Safety and clinical outcomes were assessed. RESULTS: Of 163 enrolled patients, 159 received treatment. Treatment groups were comparable for baseline characteristics. Rates of study drug-related treatment-emergent adverse events were similar for ceftaroline fosamil [22% (23/106)] and comparator [23% (12/53)]. One serious adverse event, considered to be related to IV study drug, occurred in the ceftaroline fosamil group (hypersensitivity). In both the treatment groups, 85% (ceftaroline fosamil, 91/107 and comparator, 44/52) of the modified intent-to-treat population achieved early clinical response (≥20% reduction in infection area from baseline). Clinical cure rates at test-of-cure were high [ceftaroline fosamil, 94% (101/107) and comparator, 87% (45/52)]. For patients evaluated 8 to 15 days after the last dose of any antibiotic (IV or oral), from whom methicillin-resistant Staphylococcus aureus was initially isolated, a favorable microbiologic response (reflecting the efficacy of oral/IV therapy and capturing a relapse or reinfection) was achieved with ceftaroline fosamil [89% (16/18)] and comparator [57% (4/7)]. CONCLUSIONS: Ceftaroline fosamil, with optional oral switch, was as well-tolerated and effective in pediatric patients with ABSSSIs as comparator therapy.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND: Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS: We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS: Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS: Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Observer rating of recreational use in wadeable streams of New York State, USA: implications for nutrient criteria development.

Like most other States and Tribes in the United States, New York State has been working with the United States Environmental Protection Agency to develop numeric nutrient criteria. These criteria are to protect water use such as drinking water supply, aquatic life, and recreation. Although extensive research exists related to the effects of eutrophication on human health and aquatic life, limited information is available on perceived impairment of recreational opportunities in rivers and streams. We present an approach to assess impacts to recreation using information collected by New York State's (NYS) monitoring program. This approach involved a questionnaire adapted from lake management surveys in which field crews rated their perceptions of recreational ability at each site. The ratings were then used to assess the relationship between perceived impact to recreational use and water quality. We include in our analyses the primary nutrient criteria variables total phosphorus (TP), total nitrogen (TN), suspended chlorophyll-a (SChl-a), and turbidity (Tb), as well as biological condition (benthic macroinvertebrate community assessment). We sampled 203 wadeable stream locations throughout NYS between July and September 2008-2012. Field crews ranked most locations as having "Minor aesthetic problems," but still considered them excellent for both primary (34%) and secondary (37%) contact recreation. Field crew rankings of recreational ability coincided with a gradient of nutrients (TP and TN), SChl-a, and Tb concentration. Logistic regression models were developed that identified significant predictors affecting field crew decisions about recreation. These included water clarity, periphyton cover, and odor. Analysis of variance using NYS's multimetric assessment of biological condition and a nutrient specific community metric suggest significant differences in metric scores among recreational use categories. These results indicate correlation of impairment of recreational use with impairment of aquatic life use from nutrient enrichment. The results of this investigation will be used to help establish nutrient endpoints for the protection of recreation in NYS streams and rivers.

Contemporary use of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia: CAPTURE study experience.

The Clinical Assessment Program and Teflaro(®) Utilization Registry (CAPTURE) is a multicenter cohort study designed to collect information on the contemporary use of ceftaroline fosamil in the US. Data collected from 398 evaluable patients with community-acquired bacterial pneumonia (CABP) (mean age 64 years) during the first 18 months of the study are presented. Most patients had co-morbidities (76%; primarily structural lung disease), and ≧2 signs and symptoms of CABP (76%). Overall clinical success was 79% which varied little with ceftaroline fosamil usage (monotherapy vs concurrent therapy; first-line vs second-line therapy). Most patients were discharged home (60%) or to another healthcare facility (35%). These data suggest that ceftaroline, in contemporary clinical use, is an effective antibiotic for the treatment of patients with CABP, including those with significant co-morbidities or who required a change of their prior antibiotic therapy.

The diverse landscape of palliative care clinics.

BACKGROUND: Many health care organizations are interested in instituting a palliative care clinic. However, there are insufficient published data regarding existing practices to inform the development of new programs. OBJECTIVE: Our objective was to obtain in-depth information about palliative care clinics. METHODS: We conducted a cross-sectional survey of 20 outpatient palliative care practices in diverse care settings. The survey included both closed- and open-ended questions regarding practice size, utilization of services, staffing, referrals, services offered, funding, impetus for starting, and challenges. RESULTS: Twenty of 21 (95%) practices responded. Practices self-identified as: hospital-based (n=7), within an oncology division/cancer center (n=5), part of an integrated health system (n=6), and hospice-based (n=2). The majority of referred patients had a cancer diagnosis. Additional common diagnoses included chronic obstructive pulmonary disease, neurologic disorders, and congestive heart failure. All practices ranked "pain management" and "determining goals of care" as the most common reasons for referrals. Twelve practices staffed fewer than 5 half-days of clinic per week, with 7 operating only one half-day per week. Practices were staffed by a mixture of physicians, advanced practice nurses or nurse practitioners, nurses, or social workers. Eighteen practices expected their practice to grow within the next year. Eleven practices noted a staffing shortage and 8 had a wait time of a week or more for a new patient appointment. Only 12 practices provide 24/7 coverage. Billing and institutional support were the most common funding sources. Most practices described starting because inpatient palliative providers perceived poor quality outpatient care in the outpatient setting. The most common challenges included: funding for staffing (11) and being overwhelmed with referrals (8). CONCLUSIONS: Once established, outpatient palliative care practices anticipate rapid growth. In this context, outpatient practices must plan for increased staffing and develop a sustainable financial model.

Subretinal delivery of adeno-associated virus serotype 2 results in minimal immune responses that allow repeat vector administration in immunocompetent mice.

BACKGROUND: Adeno-associated virus serotype 2 (AAV2) vectors show considerable promise for ocular gene transfer. However, one potential barrier to efficacious long-term therapy is the development of immune responses against the vector or transgene product. METHODS: We evaluated cellular and humoral responses in mice following both single and repeated subretinal administration of AAV2, and examined their effects on RPE65 and green fluorescent protein transgene expression. RESULTS: Following subretinal administration of vector, splenocytes and T-cells from draining lymph nodes showed minimal activation following stimulation by co-culture with AAV2. Neutralizing antibodies (NAbs) were not detected in the ocular fluids of any mice receiving AAV2 or in the serum of mice receiving a lower dose. NAbs were present in the serum of a proportion of mice receiving a higher dose of the vector. Furthermore, no differences in immunoglobulin titre in serum or ocular fluids against RPE65 protein or AAV2 capsid between treated and control mice were detected. Histological examination showed no evidence of retinal toxicity or leukocyte infiltration compared to uninjected eyes. Repeat administration of low-dose AAV.hRPE65.hRPE65 to both eyes of RPE65(-/-) mice resulted in transgene expression and functional rescue, but re-administration of high-dose AAV2 resulted in boosted NAb titres and variable transgene expression in the second injected eye. CONCLUSIONS: These data, which were obtained in mice, suggest that, following subretinal injection, immune responses to AAV2 are dose-dependent. Low-dose AAV2 is well tolerated in the eye, with minimal immune responses, and transgene expression after repeat administration of vector is achievable. Higher doses lead to the expression of NAbs that reduce the efficacy of repeated vector administration.