•Vaccine acceptance in the Amish decreased in the last decade, similar to the general population.•More conservative Amish sects were less likely to accept vaccines.•Parents of special needs children ...were more likely to vaccinate than parents of healthy children.•Fathers and bishops are potential key targets for vaccine education in the Amish.•The Amish are less likely to accept a COVID-19 vaccine than the general population.
The Holmes County Amish have low vaccination rates, an increasingly diverse population, and have an increased incidence of certain inherited diseases. The objectives were to evaluate; the rate and influences of vaccine hesitancy compared to a decade ago, vaccination patterns between Amish affiliations, vaccine practices of Amish special needs children, and the Amish’s acceptance of a COVID-19 vaccine.
Study design.
In April of 2020, a survey assessing vaccination patterns and beliefs were mailed to 1000 Amish families, including ultra-conservative Amish sects and special needs families.
The response rate was 39%. Among 391 respondents, 59% did not vaccinate their children, compared to only 14% that refused all vaccinations reported by Wenger et al in the same community only a decade ago. The ultra-conservative Amish rejected vaccines more often. Amish special needs children were more likely to receive vaccines than healthy Amish children. 75% responded they would reject a COVID-19 vaccine. Fear of adverse effects was the most common reason to reject vaccines. Families that accepted vaccines were more likely to cite a healthcare worker as the primary influence to vaccinate. Wives were more likely to cite their spouse as the primary influence to vaccinate. Families that rejected vaccines were more likely to state their bishop was the most influential person on vaccination.
The Holmes County Amish have decreasing vaccine acceptance. Efforts to improve vaccination will require a targeted focus on the primary influences and beliefs of sub-populations within the Amish. Physician advocacy, peer mentorship, father-directed education, and close partnership with Church leadership will be needed to limit vaccine-preventable disease. The Amish may be at risk for low uptake of a COVID-19 vaccine.
Background
Aortopathy is common with bicuspid aortic valve (BAV), and underlying intrinsic tissue abnormalities are believed causative. Valve‐mediated hemodynamics are altered in BAV and may ...contribute to aortopathy and its progression. The contribution of intrinsic tissue defects versus altered hemodynamics to aortopathy progression is not known.
Purpose
To investigate relative contributions of tissue‐innate versus hemodynamics in progression of BAV aortopathy.
Study Type
Retrospective.
Subjects
Four hundred seventy‐three patients with aortic dilatation (diameter ≥40 mm; comprised of 281 BAV with varied AS severity, 192 tricuspid aortic valve TAV without AS) and 124 healthy controls. Subjects were 19–91 years (141/24% female).
Field Strength/Sequence
1.5T, 3T; time‐resolved gradient‐echo 3D phase‐contrast (4D flow) MRI.
Assessment
A surrogate measure for global aortic wall stiffness, pulse wave velocity (PWV), was quantified from MRI by standardized, automated technique based on through‐plane flow cross‐correlation maximization. Comparisons were made between BAV patients with aortic dilatation and varying aortic valve stenosis (AS) severity and healthy subjects and aortopathy patients with normal TAV.
Statistical Tests
Multivariable regression, analysis of covariance (ANCOVA), Tukey's, student's (t), Mann–Whitney (U) tests, were used with significance levels P < 0.05 or P < 0.01 for post‐hoc Bonferroni‐corrected t/U tests. Bland–Altman and ICC calculations were performed.
Results
Multivariable regression showed age with the most significant association for increased PWV in all groups (increase 0.073–0.156 m/sec/year, R2 = 0.30–48). No significant differences in aortic PWV were observed between groups without AS (P = 0.20–0.99), nor were associations between PWV and regurgitation or Sievers type observed (P = 0.60, 0.31 respectively). In contrast, BAV AS patients demonstrated elevated PWV and a significant relationship for AS severity with increased PWV (covariate: age, R2 = 0.48). BAV and TAV patients showed no association between aortic diameter and PWV (P = 0.73).
Data Conclusion
No significant PWV differences were observed between BAV patients with normal valve function and control groups. However, AS severity and age in BAV patients were directly associated with PWV increases.
Evidence Level
3
Technical Efficacy
Stage 3
Residents of long-term care facilities are at risk for coronavirus disease. We report a surveillance exercise at such a facility in Pennsylvania, USA. After introduction of a testing strategy and ...other measures, this facility had a 17-fold lower coronavirus disease case rate than neighboring facilities.
Leukemias exhibit a dysregulated developmental program mediated through both genetic and epigenetic mechanisms. Although IKZF2 is expressed in hematopoietic stem cells (HSCs), we found that it is ...dispensable for mouse and human HSC function. In contrast to its role as a tumor suppressor in hypodiploid B-acute lymphoblastic leukemia, we found that IKZF2 is required for myeloid leukemia. IKZF2 is highly expressed in leukemic stem cells (LSCs), and its deficiency results in defective LSC function. IKZF2 depletion in acute myeloid leukemia (AML) cells reduced colony formation, increased differentiation and apoptosis, and delayed leukemogenesis. Gene expression, chromatin accessibility, and direct IKZF2 binding in MLL-AF9 LSCs demonstrate that IKZF2 regulates a HOXA9 self-renewal gene expression program and inhibits a C/EBP-driven differentiation program. Ectopic HOXA9 expression and CEBPE depletion rescued the effects of IKZF2 depletion. Thus, our study shows that IKZF2 regulates the AML LSC program and provides a rationale to therapeutically target IKZF2 in myeloid leukemia.
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•IKZF2 is a chromatin remodeler, highly expressed in leukemic stem cells•IKZF2 maintains self-renewal and inhibits differentiation in leukemic stem cells•CUT&RUN assay shows that IKZF2 binds to IKZF2 motifs adjacent to HOXA9 and CEBPD/E motifs•IKZF2 regulates accessibility of HOXA9 and CEBPD/E motifs, modulating gene expression
Park et al. find that IKZF2 regulates chromatin accessibility of self-renewal and differentiation genes in leukemic stem cells. Depletion of IKZF2 has preferential effect in leukemic stem cells compared to normal hematopoietic stem cells, providing a new strategy for targeting leukemic stem cells.
Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug ...antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3+ Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.
•Generation and function of specific human Tregs.•Specific regulation of FVIII responses by engineered human Tregs.
The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy ...for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.
Treatment of de-epithelialized human corneas with riboflavin (RF) + long-wavelength ultraviolet light (UVA; RFUVA) increases corneal stroma tensile strength significantly. RFUVA treatment retards the ...progression of keratoconus, perhaps by cross-linking of collagen molecules, but exact molecular mechanisms remain unknown. Research described here tested possible chemical mechanisms of cross-linking.
Corneas of rabbits and spiny dogfish sharks were de-epithelialized mechanically, subjected to various chemical pretreatments, exposed to RFUVA, and then subjected to destructive tensile stress measurements. Tensile strength was quantified with a digital force gauge to measure degree of tissue cross-linking.
For both rabbit and shark corneas, RFUVA treatment causes significant cross-linking by mechanism(s) that can be blocked by the presence of sodium azide. Conversely, such cross-linking is greatly enhanced in the presence of deuterium oxide (D(2)O), even when RF is present at only one tenth the currently used clinical concentrations. Blocking carbonyl groups preexisting in the stroma with 2,4-dinitrophenylhydrazide or hydroxylamine blocks essentially all corneal cross-linking. In contrast, blocking free amine groups preexisting in the stroma with acetic anhydride or ethyl acetimidate does not affect RFUVA corneal cross-linking. When both carbonyl groups are blocked and singlet oxygen is quenched, no RFUVA cross-linking occurs, indicating the absence of other cross-linking mechanisms.
RFUVA catalyzes cross-linking reactions that require production of singlet oxygen ((1)O(2)), whose half-life is extended by D(2)O. Carbonyl-based cross-linking reactions dominate in the corneal stroma, but other possible reaction schemes are proposed. The use of D(2)O as solution media for RF would enable concentration decreases or significant strength enhancement in treated corneas.
GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a ...pathogenic ST3GAL5 c.862C>T founder allele (median age 8.1, range 0.7–30.5 years). GM3 and its derivatives were undetectable in plasma. Weight and head circumference were normal at birth and mean Apgar scores were 7.7 ± 2.0 (1 min) and 8.9 ± 0.5 (5 min). Somatic growth failure, progressive microcephaly, global developmental delay, visual inattentiveness, and dyskinetic movements developed within a few months of life. Infantile-onset epileptic encephalopathy was characterized by a slow, disorganized, high-voltage background, poor state transitions, absent posterior rhythm, and spike trains from multiple independent cortical foci; >90% of electrographic seizures were clinically silent. Hearing loss affected cochlea and central auditory pathways and 76% of children tested failed the newborn hearing screen. Development stagnated early in life; only 13 (26%) patients sat independently (median age 30 months), three (6%) learned to crawl, and none achieved reciprocal communication. Incessant irritability, often accompanied by insomnia, began during infancy and contributed to high parental stress. Despite catastrophic neurological dysfunction, neuroimaging showed only subtle or no destructive changes into late childhood and hospitalizations were surprisingly rare (0.2 per patient per year). Median survival was 23.5 years. Our observations corroborate findings from transgenic mice which indicate that gangliosides might have a limited role in embryonic neurodevelopment but become vital for postnatal brain growth and function. These results have critical implications for the design and implementation of ganglioside restitution therapies.
Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide ...association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.
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