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Risk and protection of different rare protein-coding variants of complement component C4A in age-related macular degeneration
Get PDFIntroduction: Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. One-third of the genetic contribution to this disease remains unexplained. Methods: We analyzed targeted sequencing data from two independent cohorts (4,245 cases, 1,668 controls) which included genomic regions of known AMD loci in 49 genes. Results: At a false discovery rate of <0.01, we identified 11 low-frequency AMD variants (minor allele frequency <0.05). Two of those variants were present in the complement C4A gene, including the replacement of the residues that contribute to the Rodgers-1/Chido-1 blood group antigens: [VDLL1207-1210ADLR (V1207A)] with discovery odds ratio (OR) = 1.7 (p = 3.2 × 10-5) which was replicated in the UK Biobank dataset (3,294 cases, 200,086 controls, OR = 1.52, p = 0.037). A novel variant associated with reduced risk for AMD in our discovery cohort was P1120T, one of the four C4A-isotypic residues. Gene-based tests yielded aggregate effects of nonsynonymous variants in 10 genes including C4A, which were associated with increased risk of AMD. In human eye tissues, immunostaining demonstrated C4A protein accumulation in and around endothelial cells of retinal and choroidal vasculature, and total C4 in soft drusen. Conclusion: Our results indicate that C4A protein in the complement activation pathways may play a role in the pathogenesis of AMD
Medicaid Accountable Care Organizations and Disparities in Pediatric Asthma Care
No full textImportance: Nearly 6 million children in the US have asthma, and over one-third of US children are insured by Medicaid. Although 23 state Medicaid programs have experimented with accountable care organizations (ACOs), little is known about ACOs' effects on longstanding insurance-based disparities in pediatric asthma care and outcomes.
Objective: To determine associations between Massachusetts Medicaid ACO implementation in March 2018 and changes in care quality and use for children with asthma.
Design, setting, and participants: Using data from the Massachusetts All Payer Claims Database from January 1, 2014, to December 31, 2020, we determined child-years with asthma and used difference-in-differences (DiD) estimates to compare asthma quality of care and emergency department (ED) or hospital use for child-years with Medicaid vs private insurance for 3 year periods before and after ACO implementation for children aged 2 to 17 years. Regression models accounted for demographic and community characteristics and health status. Data analysis was conducted between January 2022 and June 2024.
Exposure: Massachusetts Medicaid ACO implementation.
Main outcomes and measures: Primary outcomes were binary measures in a calendar year of (1) any routine outpatient asthma visit, (2) asthma medication ratio (AMR) greater than 0.5, and (3) any ED or hospital use with asthma. To determine the statistical significance of differences in descriptive statistics between groups, χ2 and t tests were used.
Results: Among 376 509 child-year observations, 268 338 (71.27%) were insured by Medicaid and 73 633 (19.56%) had persistent asthma. There was no significant change in rates of routine asthma visits for Medicaid-insured child-years vs privately insured child-years post-ACO implementation (DiD, -0.4 percentage points [pp]; 95% CI, -1.4 to 0.6 pp). There was an increase in the proportion with AMR greater than 0.5 for Medicaid-insured child-years vs privately insured in the postimplementation period (DiD, 3.7 pp; 95% CI, 2.0-5.4 pp), with absolute declines in both groups postimplementation. There was an increase in any ED or hospital use for Medicaid-insured child-years vs privately insured postimplementation (DiD, 2.1 pp; 95% CI, 1.2-3.0 pp), an 8% increase from the preperiod Medicaid use rate.
Conclusions and relevance: Introduction of Massachusetts Medicaid ACOs was associated with persistent insurance-based disparities in routine asthma visit rates; a narrowing in disparities in appropriate AMR rates due to reductions in appropriate rates among those with private insurance; and worsening disparities in any ED or hospital use for Medicaid-insured children with asthma compared to children with private insurance. Continued study of changes in pediatric asthma care delivery is warranted in relation to major Medicaid financing and delivery system reforms
The Center for Accelerating Practices to End Suicide (CAPES) Impact Report Year 1: 4/1/2023-3/1/2024
Get PDFCAPES Evaluation Core is excited to share our Year 1 Impact Report which highlights our Center’s work to prevent suicide and accelerate delivery of evidence-based, compassionate suicide care
Practice Site Heterogeneity within and between Medicaid Accountable Care Organizations
Get PDFThe existing literature has considered accountable care organizations (ACOs) as whole entities, neglecting potentially important variations in the characteristics and experiences of the individual practice sites that comprise them. In this observational cross-sectional study, our aim is to characterize the experience, capacity, and process heterogeneity at the practice site level within and between Medicaid ACOs, drawing on the Massachusetts Medicaid and Children's Health Insurance Program (MassHealth), which launched an ACO reform effort in 2018. We used a 2019 survey of a representative sample of administrators from practice sites participating in Medicaid ACOs in Massachusetts (n = 225). We quantified the clustering of responses by practice site within all 17 Medicaid ACOs in Massachusetts for measures of process change, previous experience with alternative payment models, and changes in the practices' ability to deliver high-quality care. Using multilevel logistic models, we calculated median odds ratios (MORs) and intraclass correlation coefficients (ICCs) to quantify the variation within and between ACOs for each measure. We found greater heterogeneity within the ACOs than between them for all measures, regardless of practice site and ACO characteristics (all ICCs ≤ 0.26). Our research indicates diverse experience with, and capacity for, implementing ACO initiatives across practice sites in Medicaid ACOs. Future research and program design should account for characteristics of practice sites within ACOs
Appropriate Use of Medical Interpreters in the Breast Imaging Clinic
No full textMore than 25 million Americans have limited English-language proficiency (LEP) according to the U.S. Census Bureau. This population experiences challenges accessing health care and is least likely to receive preventive health care, including screening mammogram. In a setting where the breast radiologist does not speak the language of their patient, using certified medical interpreter services is fundamental. Medical interpreter use is associated with improved clinical care and patient satisfaction and can potentially increase adherence to screening mammograms and follow-up in patients with LEP. Title VI of the Civil Rights Act requires interpreter services for patients with LEP who are receiving federal financial assistance. Failure to provide interpretative services when necessary is considered discriminatory and illegal. The use of untrained medical interpreters, including ad hoc interpreters (eg, family, friends, or untrained staff), is associated with more medical errors, violation of confidentiality, and poor health outcomes. Types of medical interpretation services available to address language barriers include in-person interpretation, telephone and video remote interpretation, and qualified bilingual staff. Proper training and certification of medical interpreters is essential to prevent misinterpretations and ensure patient safety. When using an interpreter service, speak to and maintain eye contact with the patient, address the patient directly and seat the interpreter next to or slightly behind the patient, use visual aids whenever possible, and have the patient repeat the information to verify comprehension. Breast radiologists can address disparities in breast cancer screening and treatment by promoting effective communication
Relationship Between Patient Portal Tool Use and Medication Adherence and Viral Load Among Patients Living with HIV
Get PDFBACKGROUND: Patient portals play an increasingly critical role in engaging patients in their health care. They have the potential to significantly impact the health of those living with chronic diseases, such as HIV, for whom consistent care engagement is both critical and complex.
OBJECTIVE: The primary aim was to examine the longitudinal relationships between individual portal tool use and health-related outcomes in patients living with HIV.
DESIGN: Retrospective cohort study using electronic health record data to examine the relationship between patient portal tool use and key HIV-specific, health-related outcomes in patients engaged in care in the Veterans Health Administration (VA) through the application of marginal structural models.
PARTICIPANTS: A national sample of patients living with HIV (PLWH) active in VA care who were registered to use the VA's patient portal, My HealtheVet (MHV; n = 18,390) between 10/1/2012 and 4/1/2017.
MAIN MEASURES: The MHV tools examined were prescription refill (including prescription refill of an antiretroviral (ART) medication and any medication), secure messaging, view appointments, and view labs. Primary outcomes were viral load test receipt, viral load suppression, and ART medication adherence (measured as proportion of days covered).
KEY RESULTS: The use of prescription refill for any medication or for ART was positively associated with ART adherence. Secure messaging was positively associated with ART adherence but not with viral load test receipt or viral load suppression. The use of view appointments was positively associated with ART adherence and viral load test receipt but not viral load suppression. The use of view labs was positively associated with viral load suppression but not ART adherence or viral load test receipt.
CONCLUSIONS: These findings highlight the valuable role patient portals may play in improving health-related outcomes among PLWH and have implications for patients living with other types of chronic disease.No embarg
Thalamocortical mGlu8 Modulates Dorsal Thalamus Excitatory Transmission and Sensorimotor Activity
No full textMetabotropic glutamate receptor 8 (mGlu8) is a heterogeneously expressed and poorly understood glutamate receptor with potential pharmacological significance. The thalamic reticular nucleus (TRN) is a critical inhibitory modulator of the thalamocortical-corticothalamic (TC-CT) network and plays a crucial role in information processing throughout the brain, is implicated in a variety of psychiatric conditions, and is also a site of significant mGlu8 expression. Using both male and female mice, we determined via fluorescent in situ hybridization that parvalbumin-expressing cells in the TRN core and shell matrices (identified by spp1+ and ecel1+ expression, respectively) as well as the cortical layers involved in corticothalamic signaling, express grm8 mRNA. We then assayed the physiological and behavioral impacts of perturbing grm8 signaling in the TC circuit through conditional (AAV-CRE mediated) and cell type-specific constitutive deletion strategies. We show that constitutive parvalbumin grm8 knockout (PV grm8 KO) mice exhibited 1) increased spontaneous excitatory drive onto dorsal thalamus relay cells and 2) impaired sensorimotor gating, measured via paired-pulse inhibition, but observed no differences in locomotion and thigmotaxis in repeated bouts of open field testing. Conversely, we observed hyperlocomotive phenotypes and anxiolytic effects of AAV-mediated conditional knockdown of grm8 in the TRN (TRN grm8 KD) in repeated open field testing. Our findings underscore a role for mGlu8 in regulating excitatory neurotransmission as well as anxiety-related locomotor behavior and sensorimotor gating, revealing potential therapeutic applications for various neuropsychiatric disorders and guiding future research endeavors into mGlu8 signaling and TRN function.Significance statement Group III mGlu receptors and the Thalamic Reticular Nucleus (TRN) are critical modulators of reciprocal cortico-thalamic neurotransmission and are implicated in anxiety and locomotor behaviors. The present study demonstrates a specific enrichment of grm8 mRNA within the TRN and thalamus-projecting cortical layers and characterizes the role of mGlu8 receptors in controlling spontaneous excitatory neurotransmission onto cells located within the dorsal thalamus and regulating sensorimotor behaviors from open field and PPI testing. These findings add to growing bodies of literature regarding both TRN and grm8 regulation of thalamocortical activity and related behaviors implicated in neurological and neuropsychiatric disorders
SLIGHT shield dataset on effect of chest shielding during phototherapy in premature infants on the incidence of patent ductus arteriosus
No full textThe SLIGHT shield dataset reflects the results from a double blind randomized trial on the effect of chest shielding during phototherapy in premature infants on the incidence of patent ductus arteriosus. All preterm infants ≤ 29 weeks GA or weighing ≤1000 grams at birth admitted to our neonatal intensive care unit (NICU) within the first 24 hours of life were eligible for the study and randomized to chest shield placement or sham shield placement during phototherapy treatment. Enrollment occurred from August 1, 2015 to April 13, 2018. The primary outcome was the incidence of sPDA diagnosed via clinical parameters by the investigator team during the period from 24 hours after initiating phototherapy to 3 days after stopping phototherapy. Secondary outcomes consistent of echo based parameters : 1) ductal diameter with a left to right or bidirectional shunt across the PDA 2) left atrium (LA) to aortic root (AO) diameter ratio (LA/AO) and 3) LA volume. Additional secondary outcomes included the following: 1) surgical ligation of PDA, 2) chronic lung disease (CLD), 3) retinopathy of prematurity (ROP), 4) intraventricular hemorrhage (IVH), 5) peak levels of total serum bilirubin and 6) duration of phototherapy. Baseline/demographc data as well as clinical data were also obtained.
Study participants self-reported three items assessing religiosity: strength/comfort from religion, petition prayers for health, and awareness of intercessory prayers by others. All cause-mortality within 2-years of hospital discharge was ascertained by review of medical records at participating study hospitals and from death certificates. Cox proportional hazards models were used to estimate the multivariable adjusted risk of 2-year all-cause mortality.This trial was funded by Gerber Grant 4156. The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
mRNA initiation and termination are spatially coordinated [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.The expression of a precise mRNA transcriptome is crucial for establishing cell identity and function, with dozens of alternative isoforms produced for a single gene sequence. The regulation of mRNA isoform usage occurs by the coordination of co-transcriptional mRNA processing mechanisms across a gene. Decisions involved in mRNA initiation and termination underlie the largest extent of mRNA isoform diversity, but little is known about any relationships between decisions at both ends of mRNA molecules. Here, we systematically profile the joint usage of mRNA transcription start sites (TSSs) and polyadenylation sites (PASs) across tissues and species. Using both short and long read RNA-seq data, we observe that mRNAs preferentially using upstream TSSs also tend to use upstream PASs, and congruently, the usage of downstream sites is similarly paired. This observation suggests that mRNA 5' end choice may directly influence mRNA 3' ends. Our results suggest a novel "Positional Initiation-Termination Axis" (PITA), in which the usage of alternative terminal sites are coupled based on the order in which they appear in the genome. PITA isoforms are more likely to encode alternative protein domains and use conserved sites. PITA is strongly associated with the length of genomic features, such that PITA is enriched in longer genes with more area devoted to regions that regulate alternative 5' or 3' ends. Strikingly, we found that PITA genes are more likely than non-PITA genes to have multiple, overlapping chromatin structural domains related to pairing of ordinally coupled start and end sites. In turn, PITA coupling is also associated with fast RNA Polymerase II (RNAPII) trafficking across these long gene regions. Our findings indicate that a combination of spatial and kinetic mechanisms couple transcription initiation and mRNA 3' end decisions based on ordinal position to define the expression mRNA isoforms
Social engagement and cognitive impairment among nursing home residents: The role of sensory impairment
No full textBackground and objectives: Using US national nursing home data, this cross-sectional study sought to evaluate 1) the association between lack of social engagement and level of cognitive impairment; and 2) the extent to which this association differs by hearing and visual impairment.
Research design and methods: Our sample included 793,846 nursing home residents aged ≥ 50 years. The Index of Social Engagement was categorized as none/lower (0, 1, 2) or higher levels (3 through 6). Cognitive Performance Scale was grouped as intact/mild (0, 1, 2), moderate (3, 4), or severe (5, 6). Multinomial models provided adjusted odds ratio (aOR) and 95 % confidence intervals (CI) between none/lower social engagement and cognitive impairment. We estimated relative excess risk due to interaction (RERI) to quantify the joint effects of social engagement and sensory impairment types.
Results: Overall, 12.6 % had lower social engagement, 30.3 % had hearing impairment, and 40.3 % had visual impairment. Compared to residents with high social engagement, those with lower social engagement were more likely to have moderate/severe cognitive impairment (aORmoderate = 2.21, 95 % CI 2.17-2.26; aORsevere = 6.49, 95 % CI 6.24-6.74). The impact of low social engagement on cognitive impairment was more profound among residents with hearing impairment and/or visual impairment (RERIhearing = 3.89, 95 % CI 3.62-4.17; RERIvisual = 25.2, 95 % CI 23.9-26.6)).
Discussion and implications: Residents with lower social engagement had higher levels of cognitive impairment. Residents with sensory impairments are potentially more susceptible to the negative impact of lower levels of social engagement on level of cognitive impairment