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Leucine-rich repeat-containing G-protein-coupled receptor (LGR5) and LGR6 mark epithelial stem cells in normal tissues and tumors. They are expressed by stem cells in the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. High-grade serous ovarian cancer is unique in expressing unusually high levels of LGR5 and LGR6 mRNA. R-spondins are the natural ligands for LGR5 and LGR6 to which they bind with nanomolar affinity. To target stem cells in ovarian cancer, we used the sortase reaction to site-specifically conjugate the potent cytotoxin monomethyl auristatin E (MMAE) via a protease sensitive linker to the two furin-like domains of RSPO1 (Fu1-Fu2) that mediate its binding to LGR5 and LGR6 and their co-receptors Zinc And Ring Finger 3 and Ring Finger Protein 43 via a protease-cleavable linker. An immunoglobulin Fc domain added to the N-terminal end served to dimerize the receptor-binding domains so that each molecule carries two MMAE. The resulting molecule, FcF2-MMAE, demonstrated: 1) selective LGR5-dependent low nanomolar cytotoxicity against ovarian cancer cells in vitro; 2) selectivity that was dependent on binding to both the LGR receptors and ubiquitin ligase co-receptors; 3) favorable stability and plasma pharmacokinetic properties when administered intravenously with an elimination half-life of 29.7 hours; 4) selective inhibition of LGR5-rich as opposed to isogenic LGR5-poor tumors in vivo; and, 5) therapeutic efficacy in three aggressive wild-type human ovarian cancer xenograft models. These results demonstrate the successful use of the Fu1-Fu2 domain of RSPO1 as a drug carrier and the ability of FcF2-MMAE to target cells in tumors that express stem cell markers. SIGNIFICANCE STATEMENT: FcF2-MMAE is a novel cancer therapeutic that exploits the high-affinity binding domains of RSPO1 to target monomethyl auristatin E to tumor stem cells that express LGR5. FcF2-MMAE has low nanomolar LGR5-dependent cytotoxicity in vitro, favorable pharmacokinetics, and differential efficacy in an isogenic LGR5-poor versus LGR5-rich ovarian cancer xenograft model when given on a weekly schedule.

The study examined timing of autism spectrum disorder (ASD) identification in education versus health settings for 8-year-old children with ASD identified through records-based surveillance. The study also examined type of ASD symptoms noted within special education evaluations. Results indicated that children with records from only education sources had a median time to identification of ASD over a year later than children with records from health sources. Black children were more likely than White children to have records from only education sources. Restricted and repetitive behaviors were less frequently documented in educational evaluations resulting in developmental delay eligibility compared to specific ASD eligibility among children with ASD. Future research could explore strategies reduce age of identification in educational settings and increase equitable access to health evaluations.

The study examined timing of autism spectrum disorder (ASD) identification in education versus health settings for 8-year-old children with ASD identified through records-based surveillance. The study also examined type of ASD symptoms noted within special education evaluations. Results indicated that children with records from only education sources had a median time to identification of ASD over a year later than children with records from health sources. Black children were more likely than White children to have records from only education sources. Restricted and repetitive behaviors were less frequently documented in educational evaluations resulting in developmental delay eligibility compared to specific ASD eligibility among children with ASD. Future research could explore strategies reduce age of identification in educational settings and increase equitable access to health evaluations., Author(s): Amy N. Esler [sup.1] , Jeannette Sample [sup.2] , Jennifer Hall-Lande [sup.3] , Bryn Harris [sup.4] , Catherine Rice [sup.5] , Jenny Poynter [sup.2] , Russell S. Kirby [sup.6] [...]

National Surveys of Children's Health (NSCH, 2016-2018) data were analyzed to determine if conjoint monitoring and screening showed stronger associations with children under 5 identified with ASD compared to monitoring alone, screening alone or no monitoring or screening; and investigate relationships between monitoring and screening across racial/ethnic subgroups. 86 of 332 children with ASD received their diagnosis in a timeframe suggesting potential monitoring and screening for identification purposes. Analyses showed that conjoint monitoring and screening and monitoring alone, but not screening alone, was associated with early identified ASD cases across race groups. Caution is warranted as interpreting NSCH monitoring and screening items solely for identification purposes is inaccurate in many cases. More research on monitoring with screening is needed.

National Surveys of Children's Health (NSCH, 2016-2018) data were analyzed to determine if conjoint monitoring and screening showed stronger associations with children under 5 identified with ASD compared to monitoring alone, screening alone or no monitoring or screening; and investigate relationships between monitoring and screening across racial/ethnic subgroups. 86 of 332 children with ASD received their diagnosis in a timeframe suggesting potential monitoring and screening for identification purposes. Analyses showed that conjoint monitoring and screening and monitoring alone, but not screening alone, was associated with early identified ASD cases across race groups. Caution is warranted as interpreting NSCH monitoring and screening items solely for identification purposes is inaccurate in many cases. More research on monitoring with screening is needed., Author(s): Brian Barger [sup.1] [sup.2] , Catherine Rice [sup.3] , Teal Benevides [sup.4] , Ashley Salmon [sup.1] , Sonia Sanchez-Alvarez [sup.1] , Daniel Crimmins [sup.1] Author Affiliations: (1) grid.256304.6, 0000 [...]

Adults with disabilities are at increased risk for severe coronavirus disease 2019 (COVID-19). Using data across 9 states during Delta- and Omicron-predominant periods (June 2021–September 2022), we evaluated the effectiveness of the original monovalent COVID-19 messenger RNA vaccines among 521 206 emergency department/urgent care encounters (11 471 [2%] in patients with a documented disability) and 139 548 hospitalizations (16 569 [12%] in patients with a disability) for laboratory-confirmed COVID-19 illness in adults (aged ≥18 years). Across variant periods and for the primary series or booster doses, vaccine effectiveness was similar in those with and those without a disability. These findings highlight the importance of adults with disabilities staying up to date with COVID-19 vaccinations. [ABSTRACT FROM AUTHOR]

Approximately 27% of adults in the United States live with a disability,* some of whom qualify for Medicare benefits. Persons with disabilities are at increased risk for severe COVID-19-associated outcomes compared with the general population (1); however, existing studies have limited generalizability† or only pertain to a specific disability (e.g., intellectual) (2). Older age is also associated with COVID-19-associated hospitalization and death, but the extent to which age might contribute to increased risk for severe COVID-19-associated outcomes among persons with disabilities is unknown (3). To describe the impact of COVID-19 on persons with disabilities and whether and how age contributes to disease rates, CDC assessed COVID-19 cases and hospitalizations during January 2020-November 2021, among Centers for Medicare & Medicaid Services (CMS) Medicare beneficiaries aged ≥18 years who were either eligible because of a disability (disability-eligible§) or only eligible because of age ≥65 years (age-eligible). COVID-19 incidence and hospitalization rates were higher in the disability-eligible group (10,978 and 3,148 per 100,000 population, respectively) throughout the study period compared with the age-eligible group (8,102 and 2,129 per 100,000 population, respectively). Both COVID-19 incidence and hospitalization rates increased with age in both disability- and age-eligible beneficiaries. American Indian or Alaska Native (AI/AN) persons had the highest disability-eligible (4,962 per 100,000) and age-eligible (5,024 per 100,000) hospitalization rates. Among all other racial and ethnic groups, hospitalization rates were higher among disability-eligible than among age-eligible patients. COVID-19 incidence and hospitalization rates among disability-eligible Medicare beneficiaries were disproportionally higher than rates among age-eligible beneficiaries. Collection of disability status as a core demographic variable in public health surveillance data and identification, as well as the addition of disability questions in other existing data sources can guide research and development of interventions for persons with disabilities. Efforts to increase access to and use of COVID-19 prevention and treatment strategies, including activities that support equitable vaccine access regardless of the substantial challenges that older adults and persons with disability face, are critical to reducing severe COVID-19-associated outcomes among these groups. [ABSTRACT FROM AUTHOR]

The field of global autism research lost a pioneer, champion, and innovator with the passing of Dr Li-Ching Lee in May 2021. Dr Lee served as the editor for a special issue in Autism on global autism research (2017, Volume 21, Issue 5) and her substantial impact on autism research and autistic individuals and their families in low- and middle-income countries warrants a place in this special issue. While a giant in the professional arena, her large impact on science is minor compared to the compassion, kindness, and love she brought to her family, friends, and her professional communities at Johns Hopkins, across institutions, her native Taiwan, and the areas in which she conducted her research. Dr Lee was immensely humble and intensely focused on harnessing epidemiology to positively impact the lives of people with autism and developmental disabilities. Her humility and professional dedication was coupled with a desire to keep her own challenges and triumphs private including her courageous efforts to stave off cancer while accomplishing so much in support of others. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat-containing G-protein-coupled receptor (LGR5) and LGR6 mark epithelial stem cells in normal tissues and tumors. They are expressed by stem cells in the ovarian surface and fallopian tube epithelia from which ovarian cancer arises. High-grade serous ovarian cancer is unique in expressing unusually high levels of LGR5 and LGR6 mRNA. R-spondins are the natural ligands for LGR5 and LGR6 to which they bind with nanomolar affinity. To target stem cells in ovarian cancer, we used the sortase reaction to site-specifically conjugate the potent cytotoxin monomethyl auristatin E (MMAE) via a protease sensitive linker to the two furin-like domains of RSPO1 (Fu 1 -Fu 2 ) that mediate its binding to LGR5 and LGR6 and their co-receptors Zinc And Ring Finger 3 and Ring Finger Protein 43 via a protease-cleavable linker. An immunoglobulin Fc domain added to the N-terminal end served to dimerize the receptor-binding domains so that each molecule carries two MMAE. The resulting molecule, FcF2-MMAE, demonstrated: 1) selective LGR5-dependent low nanomolar cytotoxicity against ovarian cancer cells in vitro; 2) selectivity that was dependent on binding to both the LGR receptors and ubiquitin ligase co-receptors; 3) favorable stability and plasma pharmacokinetic properties when administered intravenously with an elimination half-life of 29.7 hours; 4) selective inhibition of LGR5-rich as opposed to isogenic LGR5-poor tumors in vivo; and, 5) therapeutic efficacy in three aggressive wild-type human ovarian cancer xenograft models. These results demonstrate the successful use of the Fu 1 -Fu 2 domain of RSPO1 as a drug carrier and the ability of FcF2-MMAE to target cells in tumors that express stem cell markers. SIGNIFICANCE STATEMENT: FcF2-MMAE is a novel cancer therapeutic that exploits the high-affinity binding domains of RSPO1 to target monomethyl auristatin E to tumor stem cells that express LGR5. FcF2-MMAE has low nanomolar LGR5-dependent cytotoxicity in vitro, favorable pharmacokinetics, and differential efficacy in an isogenic LGR5-poor versus LGR5-rich ovarian cancer xenograft model when given on a weekly schedule., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Approximately 27% of adults in the United States live with a disability,* some of whom qualify for Medicare benefits. Persons with disabilities are at increased risk for severe COVID-19-associated outcomes compared with the general population (1); however, existing studies have limited generalizability † or only pertain to a specific disability (e.g., intellectual) (2). Older age is also associated with COVID-19-associated hospitalization and death, but the extent to which age might contribute to increased risk for severe COVID-19-associated outcomes among persons with disabilities is unknown (3). To describe the impact of COVID-19 on persons with disabilities and whether and how age contributes to disease rates, CDC assessed COVID-19 cases and hospitalizations during January 2020-November 2021, among Centers for Medicare & Medicaid Services (CMS) Medicare beneficiaries aged ≥18 years who were either eligible because of a disability (disability-eligible § ) or only eligible because of age ≥65 years (age-eligible). COVID-19 incidence and hospitalization rates were higher in the disability-eligible group (10,978 and 3,148 per 100,000 population, respectively) throughout the study period compared with the age-eligible group (8,102 and 2,129 per 100,000 population, respectively). Both COVID-19 incidence and hospitalization rates increased with age in both disability- and age-eligible beneficiaries. American Indian or Alaska Native (AI/AN) persons had the highest disability-eligible (4,962 per 100,000) and age-eligible (5,024 per 100,000) hospitalization rates. Among all other racial and ethnic groups, hospitalization rates were higher among disability-eligible than among age-eligible patients. COVID-19 incidence and hospitalization rates among disability-eligible Medicare beneficiaries were disproportionally higher than rates among age-eligible beneficiaries. Collection of disability status as a core demographic variable in public health surveillance data and identification, as well as the addition of disability questions in other existing data sources can guide research and development of interventions for persons with disabilities. Efforts to increase access to and use of COVID-19 prevention and treatment strategies, including activities that support equitable vaccine access regardless of the substantial challenges that older adults and persons with disability face, are critical to reducing severe COVID-19-associated outcomes among these groups., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Developmental delays, disorders, or disabilities (DDs) manifest in infancy and childhood and can limit a person's function throughout life* (1-3). To guide strategies to optimize health for U.S. children with DDs, CDC analyzed data from 44,299 participants in the 2014-2018 National Health Interview Survey (NHIS). Parents reported on 10 DDs, † functional abilities, health needs, and use of services. Among the approximately one in six (17.3%) U.S. children and adolescents aged 3-17 years (hereafter children) with one or more DDs, 5.7% had limited ability to move or play, 4.7% needed help with personal care, 4.6% needed special equipment, and 2.4% received home health care, compared with ≤1% for each of these measures among children without DDs. Children with DDs were two to seven times as likely as those without DDs to have taken prescription medication for ≥3 months (41.6% versus 8.4%), seen a mental health professional (30.6% versus 4.5%), a medical specialist (26.0% versus 12.4%), or a special therapist, such as a physical, occupational, or speech therapist, (25.0% versus 4.5%) during the past year, and 18 times as likely to have received special education or early intervention services (EIS) (41.9% versus 2.4%). These percentages varied by type of disability and by sociodemographic subgroup. DDs are common, and children with DDs often need substantial health care and services. Policies and programs that promote early identification of children with developmental delays and facilitate increased access to intervention services can improve health and reduce the need for services later in life. § Sociodemographic inequities merit further investigation to guide public health action and ensure early and equitable access to needed care and services., Competing Interests: Catherine E. Rice reports compensation for professional training workshops on the diagnostic assessment of autism; uncompensated educational and clinical work related to licensure as a psychologist in Georgia; and uncompensated service on advisory boards for the Atlanta Autism Consortium, New Jersey State Scientific Advisory Panel for Autism, and HANDS in Autism Program during the last 36 months. No other potential conflicts of interest were disclosed.

Estimates from the 2019 American Community Survey (ACS) indicated that 15.2% of adults aged ≥18 years had at least one reported functional disability (1). Persons with disabilities are more likely than are those without disabilities to have chronic health conditions (2) and also face barriers to accessing health care (3). These and other health and social inequities have placed persons with disabilities at increased risk for COVID-19-related illness and death, yet they face unique barriers to receipt of vaccination (4,5). Although CDC encourages that considerations be made when expanding vaccine access to persons with disabilities,* few public health surveillance systems measure disability status. To describe COVID-19 vaccination status and intent, as well as perceived vaccine access among adults by disability status, data from the National Immunization Survey Adult COVID Module (NIS-ACM) were analyzed. Adults with a disability were less likely than were those without a disability to report having received ≥1 dose of COVID-19 vaccine (age-adjusted prevalence ratio [aPR] = 0.88; 95% confidence interval [CI] = 0.84-0.93) but more likely to report they would definitely get vaccinated (aPR = 1.86; 95% CI = 1.43-2.42). Among unvaccinated adults, those with a disability were more likely to report higher endorsement of vaccine as protection (aPR = 1.29; 95% CI = 1.16-1.44), yet more likely to report it would be or was difficult to get vaccinated than did adults without a disability (aPR = 2.69; 95% CI = 2.16-3.34). Reducing barriers to vaccine scheduling and making vaccination sites more accessible might improve vaccination rates among persons with disabilities., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Catherine E. Rice reports institutional support to Emory University from the Georgia Department of Public Health, the Georgia Department of Behavioral Health and Developmental Disabilities, NEXT for Autism, National Institute of Mental Health, National Institutes of Health (NIH), and National Institute of Environmental Health Sciences, NIH, outside the submitted work; personal fees for professional training workshops on the diagnostic assessment of autism, outside the submitted work; and participation on advisory boards for the Atlanta Autism Consortium, New Jersey State Scientific Advisory Panel for Autism, HANDS in Autism program. No other potential conflicts of interest were disclosed.