Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive ...performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.
Glaucoma can develop following cataract removal in children.
To assess the cumulative incidence of glaucoma-related adverse events (defined as glaucoma or glaucoma suspect) and factors associated ...with risk of these adverse events in the first 5 years after lensectomy prior to 13 years of age.
This cohort study used longitudinal registry data collected at enrollment and annually for 5 years from 45 institutional and 16 community sites. Participants were children aged 12 years or younger with at least 1 office visit after lensectomy from June 2012 to July 2015. Data were analyzed from February through December 2022.
Usual clinical care after lensectomy.
The main outcomes were cumulative incidence of glaucoma-related adverse events and baseline factors associated with risk of these adverse events.
The study included 810 children (1049 eyes); 443 eyes of 321 children (55% female; mean SD age, 0.89 1.97 years) were aphakic after lensectomy, and 606 eyes of 489 children (53% male; mean SD age, 5.65 3.32 years) were pseudophakic. The 5-year cumulative incidence of glaucoma-related adverse events was 29% (95% CI, 25%-34%) in 443 eyes with aphakia and 7% (95% CI, 5%-9%) in 606 eyes with pseudophakia; 7% (95% CI, 5%-10%) of aphakic eyes and 3% (95% CI, 2%-5%) of pseudophakic eyes were diagnosed as glaucoma suspect. Among aphakic eyes, a higher risk for glaucoma-related adverse events was associated with 4 of 8 factors, including age less than 3 months (vs ≥3 months: adjusted hazard ratio aHR, 2.88; 99% CI, 1.57-5.23), abnormal anterior segment (vs normal: aHR, 2.88; 99% CI, 1.56-5.30), intraoperative complications at time of lensectomy (vs none; aHR, 2.25; 99% CI, 1.04-4.87), and bilaterality (vs unilaterality: aHR, 1.88; 99% CI, 1.02-3.48). Neither of the 2 factors evaluated for pseudophakic eyes, laterality and anterior vitrectomy, were associated with risk of glaucoma-related adverse events.
In this cohort study, glaucoma-related adverse events were common after cataract surgery in children; age less than 3 months at surgery was associated with elevated risk of the adverse events in aphakic eyes. Children with pseudophakia, who were older at surgery, less frequently developed a glaucoma-related adverse event within 5 years of lensectomy. The findings suggest that ongoing monitoring for the development of glaucoma is needed after lensectomy at any age.
Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that ...varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.
ABSTRACT
Adrenomedullin is a 52 amino acid peptide that shows a remarkable range of effects on the vasculature that include inter alia, vasodilatation, regulation of permeability, inhibition of ...endothelial cell apoptosis, and promotion of angiogenesis. Recently the G‐protein coupled receptor (GPCR) calcitonin receptor‐like receptor (CRLR), and receptor activity modifying proteins (RAMPs) have become recognized as integral components of the adrenomedullin signaling system. However, mechanisms of regulation of CRLR expression are still largely unknown. This is in part due to lack of information on the gene promoter. In this study we have determined the transcriptional start of human CRLR cDNA by 5′‐RACE and cloned the proximal 5′‐flanking region of the gene by PCR. The 2318 bp genomic fragment contains the basal promoter of human CRLR, including potential TATA‐boxes and several GC boxes. Regulatory elements binding known transcription factors, such as Sp‐1, Pit‐1, glucocorticoid receptor, and hypoxia‐inducible factor‐1 α (HIF‐1α) were also identified. When cloned into reporter gene vectors, the genomic fragment showed significant promoter activity, indicating that the 5′‐flanking region isolated by PCR contains the gene promoter of human CRLR. Of significance is that the cloned promoter fragments were activated by hypoxia when transfected in primary microvascular endothelial cells. Site‐directed mutagenesis of the consensus hypoxia‐response element (HRE) in the 5′‐flanking region abolished such a response. We also demonstrated by semi‐quantitative RT‐PCR that transcription of the gene is activated by hypoxia in microvascular endothelial cells. In contrast, expression of RAMPs 1, 2, and 3 was unaffected by low oxygen tension. We conclude that simultaneous transcriptional up‐regulation of CRLR and its ligand adrenomedullin in endothelial cells could lead to a potent survival loop and therefore might play a significant role in vascular responses to hypoxia and ischemia.
Family caregivers are an important component of the long-term services and supports (LTSS) system. However, caregiving may have negative consequences for caregiver physical and emotional health. ...Connecting caregivers to formal short-term home- and community-based services (HCBS), through information resources and referrals, might alleviate family caregiver burden and delay nursing home entry for the patient. The aim of this study was to evaluate the early impact of the Program of Comprehensive Assistance for Family Caregivers (PCAFC) (established by P.L. 111-163 for family caregivers of seriously injured post-9/11 Veterans) on Veteran use of LTSS. A two-cohort pre-post design with a nonequivalent comparison group (treated n = 15 650; comparison n = 8339) was used to (1) examine the association between caregiver enrollment in PCAFC and any VA-purchased or VA-provided LTSS use among Veterans and (2) describe program-related trends in HCBS and institutional LTSS use. The comparison group was an inverse-propensity-score weighted sample of Veterans whose caregivers applied for, but were not accepted into, the program. From baseline through 24 months post application, use of any LTSS ranged from 13.1% to 17.8% for Veterans whose caregivers were enrolled in PCAFC versus from 3.8% to 5.3% for Veterans in the comparison group. Participation in PCAFC was associated with a statistically significant increased use of any LTSS from 1 to 24 months post application (over time odds ratios ranged from 2.71 95% confidence interval: 2.31-3.17 to 4.86 3.93-6.02). Support for family caregivers may enhance utilization of LTSS for Veterans with physical, emotional, and/or cognitive conditions.
Glaucoma is an age-related neurodegenerative disorder involving the loss of retinal ganglion cells (RGCs), which results in blindness. Studies in animal models have shown that activation of ...inflammatory processes occurs early in the disease. In particular, the complement cascade is activated very early in DBA/2J mice, a widely used mouse model of glaucoma. A comprehensive analysis of the role of the complement cascade in DBA/2J glaucoma has not been possible because DBA/2J mice are naturally deficient in complement component 5 (C5, also known as hemolytic complement, Hc), a key mediator of the downstream processes of the complement cascade, including the formation of the membrane attack complex.
To assess the role of C5 in DBA/2J glaucoma, we backcrossed a functional C5 gene from strain C57BL/6J to strain DBA/2J for at least 10 generations. The prevalence and severity of glaucoma was evaluated using ocular examinations, IOP measurements, and assessments of optic nerve damage and RGC degeneration. To understand how C5 affects glaucoma, C5 expression was assessed in the retinas and optic nerves of C5-sufficient DBA/2J mice, using immunofluorescence.
C5-sufficient DBA/2J mice developed a more severe glaucoma at an earlier age than standard DBA/2J mice, which are therefore protected by C5 deficiency. Components of the membrane attack complex were found to be deposited at sites of axonal injury in the optic nerve head and associated with RGC soma in the retina.
C5 plays an important role in glaucoma, with its deficiency lessening disease severity. These results highlight the importance of fully understanding the role of the complement cascade in neurodegenerative diseases. Inhibiting C5 may be beneficial as a therapy for human glaucoma.
The Cornea Donor Study (CDS) showed that donor age is not a factor in survival of most penetrating keratoplasties for endothelial disease. Secondary analyses confirm the importance of surgical ...indication and presence of glaucoma in outcomes at 10 years.
To assess the relationship between donor and recipient factors and corneal graft survival in the CDS.
Multicenter prospective, double-masked, controlled clinical trial conducted at 80 clinical sites. One hundred five surgeons enrolled 1090 participants undergoing corneal transplant for a moderate-risk condition, principally Fuchs dystrophy or pseudophakic or aphakic corneal edema (PACE). Forty-three eye banks provided corneas.
Corneas from donors younger than 66 years and donors 66 years or older were assigned, masked to donor age. Surgery and postoperative care were performed according to the surgeons' usual routines. Participants were followed up for as long as 12 years.
Graft failure, defined as a regrafting procedure or a cloudy cornea for 3 consecutive months.
The 10-year cumulative probability of graft failure was higher in participants with PACE than in those with Fuchs dystrophy (37% vs 20%; hazard ratio HR, 2.1 99% CI, 1.4-3.0; P < .001) and in participants with a history of glaucoma before penetrating keratoplasty, particularly with prior glaucoma surgery (58% with prior glaucoma surgery and use of medications to lower intraocular pressure at the time of surgery vs 22% with no history of glaucoma surgery or medication use; HR, 4.1 99% CI, 2.2-7.5; P < .001). We found trends toward increased graft failure in recipients who were 70 years or older compared with those younger than 60 years (29% vs 19%; HR, 1.2 99% CI, 0.7-2.1; P = .04) or were African American (HR, 1.5; P = .11) or who had a history of smoking (35% vs 24%; HR, 1.6 99% CI, 0.9-2.8; P = .02). Lower endothelial cell density (ECD) and higher corneal thickness (CT) at 6 months (6% vs 41% for ECD ≥2700 vs <1700 cells/mm2 P < .001; 14% vs 36% for CT <500 vs ≥600 μm P = .001), 1 year (4% vs 39% for ECD ≥2700 vs <1700 cells/mm2 P < .001; 18% vs 28% for CT <500 vs ≥600 μm P = .04), and 5 years (2% vs 29% for ECD ≥1500 vs <500 cells/mm2 P < .001; 7% vs 34% for CT <550 vs ≥650 μm P < .001) were associated with subsequent graft failure.
Most penetrating corneal grafts for Fuchs dystrophy or PACE remain clear at 10 years. The risk for failure is greater for graft recipients with PACE and those with a history of glaucoma. Measurements of ECD and CT during the course of postkeratoplasty follow-up are associated with a risk for failure. However, even with very low ECD and high CT at 5 years, most corneas remain clear at 10 years.
Background
Cytomegalovirus (CMV) infection in kidney transplant recipients has been anecdotally observed with concomitant or subsequent opportunistic infections (OI), but this association has yet to ...be defined or quantified.
Methods
Patients who received a renal transplant between 1/1/2005 and 6/30/2014 and developed CMV infection were matched to controls in a ratio of 1:2 and the rates of opportunistic co‐infection were calculated within pre‐specified time frames (−30 days to +90 days and −30 days to +180 days). The primary outcome was composite OI rate, and secondary outcomes included time to OI and patient and graft outcomes. CMV‐OI association rates were estimated via conditional logistic regression.
Results
There were 2405 patients who received a renal transplant during the study period; 394 cases of CMV infection were identified. These cases were matched to 783 controls for a total of 805 participants. OI occurred in 14 patients in the CMV case group (CMV+) and in 5 patients in the control group (CMV‐) in the −30 to +90 day time period (3.55% vs 0.64%, OR = 5.60, 95% CI: 2.02‐12.55). When considering 180‐day follow‐up, OI occurred in 17 CMV+ patients and 8 CMV‐ patients (4.3% vs 1%, OR = 4.25, 95% CI: 1.83‐9.85). Mean time from CMV diagnosis to OI was 33 ± 64 days (median 7 days). Mortality was 3 times more likely in the group with concomitant OI (CMV+/OI+) as compared to a matched cohort of patients with CMV infection without OI (CMV+/OI‐) (unadjusted HR 3.02, 1.64‐5.55, Tables 6 and 7). Cumulative survival for CMV+/OI+ patients was significantly worse than CMV+/OI‐ patients (P < 0.01).
Conclusions
CMV is associated with a significantly increased risk of co‐infection with OI, particularly fungal infections. Clinical suspicion for concomitant OI should drive further workup after a CMV diagnosis. Future studies are needed to better define those patients at highest risk to elucidate subpopulations where the benefits of prophylaxis outweigh the potential risks associated with these therapies.
In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 ...(SARS-CoV-2)-related complications.
To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021.
Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis.
SARS-CoV-2 infection.
Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits).
Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 22% vs 240 of 1692 14%). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated.
SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.
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