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Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATVCD98hc) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATVCD98hc demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATVCD98hc that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TVCD98hc as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms.
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Barrera Hematoencefálica , Encéfalo , Animales , Ratones , Distribución Tisular , Anticuerpos , Ingeniería , Macaca fascicularisAsunto(s)
Anestesia Epidural , Anestesia Obstétrica , Escabiosis , Femenino , Embarazo , Humanos , Escabiosis/complicaciones , Mujeres EmbarazadasRESUMEN
Introduction: The coronavirus disease 2019 (COVID-19) pandemic has exacerbated longstanding inequities throughout the United States, disproportionately concentrating adverse social, economic, and health-related outcomes among low-income communities and communities of color. Inequitable distribution, prioritization, and uptake of COVID-19 vaccines due to systemic and organizational barriers add to these disproportionate impacts across the United States. Similar patterns have been observed within Orange County, California (OC). Methods: In response to COVID-19 vaccine inequities unfolding locally, the Orange County Health Equity COVID-19 community-academic partnership generated a tool to guide a more equitable vaccine approach. Contents of the OC vaccine equity best practices checklist emerged through synthesis of community-level knowledge about vaccine inequities, literature regarding equitable vaccination considerations, and practice-based health equity guides. We combined into a memo: the checklist, a written explanation of its goals and origins, and three specific action steps meant to further strengthen the focus on vaccine equity. The memo was endorsed by partnership members and distributed to county officials. Discussion: Since the initial composition of the checklist, the local vaccine distribution approach has shifted, suggesting that equitable pandemic responses require continual re-evaluation of local needs and adjustments to recommendations as new information emerges. To understand and address structural changes needed to reduce racial and socioeconomic inequities exacerbated by the pandemic, authentic partnerships between community, academic, and public health practice partners are necessary. Conclusion: As we face continued COVID-19 vaccine rollout, booster vaccination, and future pandemic challenges, community knowledge and public health literature should be integrated to inform similar equity-driven strategic actions.
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OBJECTIVE: To establish what proportion of hypertensive patients being treated in the primary care health centres of Spain have diminished renal function, and to ascertain their level of blood pressure (BP) control. DESIGN: Descriptive, cross-sectional study, based on an external audit of clinical charts. SETTING: Primary care health centres in 14 autonomous regions. PARTICIPANTS: A total of 6,113 charts of hypertensive patients from 107 primary care health centres were checked. The selection of primary care health centres and charts was randomized. MAIN MEASUREMENTS: Creatinine and BP figures of the patients included were analyzed. Chronic kidney disease was defined as a glomerular filtration rate (GFR), as calculated by the equation developed by the Modification of Diet in Renal Disease (MDRD) Study, at under 60 mL/min per 1.73 m(2) of body surface area. A good level of BP control was defined as having figures lower than 130/80 mm Hg. RESULTS: Of all patients, 25.7% (95% CI, 24.3-27.2) had a diminished GFR. Of these, 19.1% (95% CI, 16.6-21.9) had a good level of control of systolic BP, 49.9% (95% CI, 46.6-53.2) had a good level of control of diastolic BP, and 15.2% (95% CI, 12.9-17.8) had a good level of control of both. CONCLUSIONS: A considerable proportion of hypertensive patients under treatment in the primary care health centres of Spain have a diminished GFR. Only 1 in 6 of these have their BP under control.