The TREAT-NMD DMD global database: Analysis of more than 7,000 duchenne muscular dystrophy mutations

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations)

Protocol for a family-centered behavioral intervention to reduce early childhood caries: the MySmileBuddy program efficacy trial

Background Although largely preventable through diet management and topical fluoride use, early childhood caries (ECC) often progresses to severity that necessitates surgical repair. Yet repair often fails to mitigate caries progression. Needed is an effective behavioral intervention to address underlying behavioral causes. Methods This randomized controlled trial will evaluate the efficacy of a behaviorally focused, family-centered intervention, the MySmileBuddy Program (MSB Program), to reduce ECC progression in high-risk preschoolers in New York City. Recruitment will target 858 children ages 24–71 months with ECC and their parents from primary care medical and dental clinics. The study aims to assess the MSB Program’s efficacy to: (1) decrease ECC progression measured 12-months post-randomization; and (2) enhance adoption of a low cariogenic diet and twice-daily fluoridated toothpaste use compared to control group. Potential causal pathways (mediators and moderators) will be explored. The MSB Program equips community health workers (CHWs) with an app that facilitates multilevel risk assessment and provides motivational interviewing-based counseling to inform parents about the caries process, develop personalized goals, and create family-level action plans to achieve targeted behaviors. Social support from CHWs (4 interactions during the 6-month intervention, supplemented by up to 4 in-person/remote contacts throughout the 12-month study period, based on need) is bolstered by automated text messages. Participants will be randomized to a Control Group (paper-based educational handout plus toothbrushes and fluoridated toothpaste for the child) or Intervention Group (MSB Program, two tooth-brushing observations with feedback and instruction, and toothbrushes and toothpaste for the entire family). All children will receive visual ICDAS dental examinations and parents will complete study measures at baseline and 12-months. An incentive up to $150 plus round-trip transit cards ($5.50 value) will be provided. Discussion This study hypothesizes that the MSB Program can reduce ECC progression in a high-risk population. Sufficient incentives and a focus on establishing rapport between participants and CHWs are anticipated to mitigate recruitment and retention challenges. If successful, this study will advance the long-term goal of reducing pediatric oral health disparities by demonstrating the efficacy of an acceptable and feasible intervention that shifts attention from dental repair to behavioral risk mitigation. Trial registration: Trial registration was completed on 4/13/2021 through the U.S. National Library of Medicine ClinicalTrials.gov website (Identifier: NCT04845594)

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Abstract Background Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. Methods We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. Results We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 × 10−03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten “CNV positive” trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. Conclusions Our findings suggest that rare CNVs may contribute to the etiology of OCD.http://deepblue.lib.umich.edu/bitstream/2027.42/134675/1/11689_2016_Article_9170.pd

Vulnerability pathways to mental health outcomes in children and parents during COVID-19

We examined pathways from pre-existing psychosocial and economic vulnerability to mental health difficulties and stress in families during the COVID-19 pandemic. Data from two time points from a multi-cohort study initiated during the COVID-19 pandemic were used. Parents of children 6–18 years completed questionnaires on pre-COVID-19 socioeconomic and demographic factors in addition to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning. Youth 10 years and older also completed their own measures of mental health and stress. Using structural equation modelling, pathways from pre-existing vulnerability to material deprivation and stress due to COVID-19 restrictions, mental health, and family functioning, including reciprocal pathways, were estimated. Pre-existing psychosocial and economic vulnerability predicted higher material deprivation due to COVID-19 restrictions which in turn was associated with parent and child stress due to restrictions and mental health difficulties. The reciprocal effects between increased child and parent stress and greater mental health difficulties at Time 1 and 2 were significant. Reciprocal effects between parent and child mental health were also significant. Finally, family functioning at Time 2 was negatively impacted by child and parent mental health and stress due to COVID-19 restrictions at Time 1. Psychosocial and economic vulnerability is a risk factor for material deprivation during COVID-19, increasing the risk of mental health difficulties and stress, and their reciprocal effects over time within families. Implications for prevention policy and parent and child mental health services are discussed

Energy dependence of acceptance-corrected dielectron excess mass spectrum at mid-rapidity in Au+Au collisions at sNN=19.6\sqrt{s_{NN}} = 19.6 and 200 GeV

The acceptance-corrected dielectron excess mass spectra, where the known hadronic sources have been subtracted from the inclusive dielectron mass spectra, are reported for the first time at mid-rapidity $|y_{ee}|<1$ in minimum-bias Au+Au collisions at $\sqrt{s_{NN}}$ = 19.6 and 200 GeV. The excess mass spectra are consistently described by a model calculation with a broadened $\rho$ spectral function for $M_{ee}<1.1$ GeV/$c^{2}$. The integrated dielectron excess yield at $\sqrt{s_{NN}}$ = 19.6 GeV for $0.4<M_{ee}<0.75$ GeV/$c^2$, normalized to the charged particle multiplicity at mid-rapidity, has a value similar to that in In+In collisions at $\sqrt{s_{NN}}$ = 17.3 GeV. For $\sqrt{s_{NN}}$ = 200 GeV, the normalized excess yield in central collisions is higher than that at $\sqrt{s_{NN}}$ = 17.3 GeV and increases from peripheral to central collisions. These measurements indicate that the lifetime of the hot, dense medium created in central Au+Au collisions at $\sqrt{s_{NN}}$ = 200 GeV is longer than those in peripheral collisions and at lower energies.Comment: 9 pages, 6 figure

Observation of charge asymmetry dependence of pion elliptic flow and the possible chiral magnetic wave in heavy-ion collisions

We present measurements of $\pi^-$ and $\pi^+$ elliptic flow, $v_2$, at midrapidity in Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200, 62.4, 39, 27, 19.6, 11.5 and 7.7 GeV, as a function of event-by-event charge asymmetry, $A_{ch}$, based on data from the STAR experiment at RHIC. We find that $\pi^-$ ($\pi^+$) elliptic flow linearly increases (decreases) with charge asymmetry for most centrality bins at $\sqrt{s_{_{\rm NN}}} = \text{27 GeV}$ and higher. At $\sqrt{s_{_{\rm NN}}} = \text{200 GeV}$, the slope of the difference of $v_2$ between $\pi^-$ and $\pi^+$ as a function of $A_{ch}$ exhibits a centrality dependence, which is qualitatively similar to calculations that incorporate a chiral magnetic wave effect. Similar centrality dependence is also observed at lower energies.Comment: 6 pages, 4 figure

Long-range pseudorapidity dihadron correlations in dd+Au collisions at sNN=200\sqrt{s_{\rm NN}}=200 GeV

Dihadron angular correlations in $d$+Au collisions at $\sqrt{s_{\rm NN}}=200$ GeV are reported as a function of the measured zero-degree calorimeter neutral energy and the forward charged hadron multiplicity in the Au-beam direction. A finite correlated yield is observed at large relative pseudorapidity ($\Delta\eta$) on the near side (i.e. relative azimuth $\Delta\phi\sim0$). This correlated yield as a function of $\Delta\eta$ appears to scale with the dominant, primarily jet-related, away-side ($\Delta\phi\sim\pi$) yield. The Fourier coefficients of the $\Delta\phi$ correlation, $V_{n}=\langle\cos n\Delta\phi\rangle$, have a strong $\Delta\eta$ dependence. In addition, it is found that $V_{1}$ is approximately inversely proportional to the mid-rapidity event multiplicity, while $V_{2}$ is independent of it with similar magnitude in the forward ($d$-going) and backward (Au-going) directions.Comment: 8 pages, 4 figure

Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in sNN=\sqrt{s_{_{\rm NN}}} = 200 GeV Au+Au Collisions

A data-driven method was applied to measurements of Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance $\Delta\eta$-dependent and $\Delta\eta$-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a component of the correlation that is $\Delta\eta$-independent, which is likely dominated by anisotropic flow and flow fluctuations. It was also found to be independent of $\eta$ within the measured range of pseudorapidity $|\eta|<1$. The relative flow fluctuation was found to be $34\% \pm 2\% (stat.) \pm 3\% (sys.)$ for particles of transverse momentum $p_{T}$ less than $2$ GeV/$c$. The $\Delta\eta$-dependent part may be attributed to nonflow correlations, and is found to be $5\% \pm 2\% (sys.)$ relative to the flow of the measured second harmonic cumulant at $|\Delta\eta| > 0.7$

System size and energy dependence of near-side di-hadron correlations

Two-particle azimuthal ($\Delta\phi$) and pseudorapidity ($\Delta\eta$) correlations using a trigger particle with large transverse momentum ($p_T$) in $d$+Au, Cu+Cu and Au+Au collisions at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV and 200~GeV from the STAR experiment at RHIC are presented. The \ns correlation is separated into a jet-like component, narrow in both $\Delta\phi$ and $\Delta\eta$, and the ridge, narrow in $\Delta\phi$ but broad in $\Delta\eta$. Both components are studied as a function of collision centrality, and the jet-like correlation is studied as a function of the trigger and associated $p_T$. The behavior of the jet-like component is remarkably consistent for different collision systems, suggesting it is produced by fragmentation. The width of the jet-like correlation is found to increase with the system size. The ridge, previously observed in Au+Au collisions at $\sqrt{s_{{NN}}}$ = 200 GeV, is also found in Cu+Cu collisions and in collisions at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV, but is found to be substantially smaller at $\sqrt{s_{{NN}}}$ =\xspace 62.4 GeV than at $\sqrt{s_{{NN}}}$ = 200 GeV for the same average number of participants ($\langle N_{\mathrm{part}}\rangle$). Measurements of the ridge are compared to models.Comment: 17 pages, 14 figures, submitted to Phys. Rev.