Myosin Binding Protein C Mutation Locus and Type Affect Hypertrophic Cardiomyopathy Disease Mechanism

Honors (Bachelor's)Cell and Molecular Biology (CMB)University of Michiganhttps://deepblue.lib.umich.edu/bitstream/2027.42/147361/1/nhafeez.pd

Effect of the SPRING home visits intervention on early child development and growth in rural India and Pakistan: parallel cluster randomised controlled trials

INTRODUCTION: Almost 250 million children fail to achieve their full growth or developmental potential, trapping them in a cycle of continuing disadvantage. Strong evidence exists that parent-focussed face to face interventions can improve developmental outcomes; the challenge is delivering these on a wide scale. SPRING (Sustainable Programme Incorporating Nutrition and Games) aimed to address this by developing a feasible affordable programme of monthly home visits by community-based workers (CWs) and testing two different delivery models at scale in a programmatic setting. In Pakistan, SPRING was embedded into existing monthly home visits of Lady Health Workers (LHWs). In India, it was delivered by a civil society/non-governmental organisation (CSO/NGO) that trained a new cadre of CWs. METHODS: The SPRING interventions were evaluated through parallel cluster randomised trials. In Pakistan, clusters were 20 Union Councils (UCs), and in India, the catchment areas of 24 health sub-centres. Trial participants were mother-baby dyads of live born babies recruited through surveillance systems of 2 monthly home visits. Primary outcomes were BSID-III composite scores for psychomotor, cognitive and language development plus height for age z-score (HAZ), assessed at 18 months of age. Analyses were by intention to treat. RESULTS: 1,443 children in India were assessed at age 18 months and 1,016 in Pakistan. There was no impact in either setting on ECD outcomes or growth. The percentage of children in the SPRING intervention group who were receiving diets at 12 months of age that met the WHO minimum acceptable criteria was 35% higher in India (95% CI: 4-75%, p = 0.023) and 45% higher in Pakistan (95% CI: 15-83%, p = 0.002) compared to children in the control groups. DISCUSSION: The lack of impact is explained by shortcomings in implementation factors. Important lessons were learnt. Integrating additional tasks into the already overloaded workload of CWs is unlikely to be successful without additional resources and re-organisation of their goals to include the new tasks. The NGO model is the most likely for scale-up as few countries have established infrastructures like the LHW programme. It will require careful attention to the establishment of strong administrative and management systems to support its implementation

Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients with Hypertrophic Cardiomyopathy

Background - Pathogenic variants in MYBPC3, encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations. Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant types and locations were analyzed, morphologic severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, LVAD/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro. Results - Among 4,756 genotyped HCM patients in SHaRe, 1,316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or non-truncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5' - 3' quartiles or by founder variant subgroup). Non-truncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, p<0.001 vs. gnomAD common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ~90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. Conclusions - Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Non-truncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss-of-function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating vs. non-truncating variants

Effect of the SPRING home visits intervention on early child development and growth in rural India and Pakistan: parallel cluster randomised controlled trials

IntroductionAlmost 250 million children fail to achieve their full growth or developmental potential, trapping them in a cycle of continuing disadvantage. Strong evidence exists that parent-focussed face to face interventions can improve developmental outcomes; the challenge is delivering these on a wide scale. SPRING (Sustainable Programme Incorporating Nutrition and Games) aimed to address this by developing a feasible affordable programme of monthly home visits by community-based workers (CWs) and testing two different delivery models at scale in a programmatic setting. In Pakistan, SPRING was embedded into existing monthly home visits of Lady Health Workers (LHWs). In India, it was delivered by a civil society/non-governmental organisation (CSO/NGO) that trained a new cadre of CWs.MethodsThe SPRING interventions were evaluated through parallel cluster randomised trials. In Pakistan, clusters were 20 Union Councils (UCs), and in India, the catchment areas of 24 health sub-centres. Trial participants were mother-baby dyads of live born babies recruited through surveillance systems of 2 monthly home visits. Primary outcomes were BSID-III composite scores for psychomotor, cognitive and language development plus height for age z-score (HAZ), assessed at 18 months of age. Analyses were by intention to treat.Results1,443 children in India were assessed at age 18 months and 1,016 in Pakistan. There was no impact in either setting on ECD outcomes or growth. The percentage of children in the SPRING intervention group who were receiving diets at 12 months of age that met the WHO minimum acceptable criteria was 35% higher in India (95% CI: 4–75%, p = 0.023) and 45% higher in Pakistan (95% CI: 15–83%, p = 0.002) compared to children in the control groups.DiscussionThe lack of impact is explained by shortcomings in implementation factors. Important lessons were learnt. Integrating additional tasks into the already overloaded workload of CWs is unlikely to be successful without additional resources and re-organisation of their goals to include the new tasks. The NGO model is the most likely for scale-up as few countries have established infrastructures like the LHW programme. It will require careful attention to the establishment of strong administrative and management systems to support its implementation

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Probing effective field theory operators in the associated production of top quarks with a Z boson in multilepton final states at root s=13 TeV

Peer reviewe

Observation of tW production in the single-lepton channel in pp collisions at root s=13 TeV

A measurement of the cross section of the associated production of a single top quark and a W boson in final states with a muon or electron and jets in proton-proton collisions at root s = 13 TeV is presented. The data correspond to an integrated luminosity of 36 fb(-1) collected with the CMS detector at the CERN LHC in 2016. A boosted decision tree is used to separate the tW signal from the dominant t (t) over bar background, whilst the subleading W+jets and multijet backgrounds are constrained using data-based estimates. This result is the first observation of the tW process in final states containing a muon or electron and jets, with a significance exceeding 5 standard deviations. The cross section is determined to be 89 +/- 4 (stat) +/- 12 (syst) pb, consistent with the standard model.Peer reviewe

Measurements of the Electroweak Diboson Production Cross Sections in Proton-Proton Collisions at root s=5.02 TeV Using Leptonic Decays

The first measurements of diboson production cross sections in proton-proton interactions at a center-of-mass energy of 5.02 TeV are reported. They are based on data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 302 pb(-1). Events with two, three, or four charged light leptons (electrons or muons) in the final state are analyzed. The WW, WZ, and ZZ total cross sections are measured as sigma(WW) = 37:0(-5.2)(+5.5) (stat)(-2.6)(+2.7) (syst) pb, sigma(WZ) = 6.4(-2.1)(+2.5) (stat)(-0.3)(+0.5)(syst) pb, and sigma(ZZ) = 5.3(-2.1)(+2.5)(stat)(-0.4)(+0.5) (syst) pb. All measurements are in good agreement with theoretical calculations at combined next-to-next-to-leading order quantum chromodynamics and next-to-leading order electroweak accuracy

Search for lepton-flavor violating decays of the Higgs boson in the mu tau and e tau final states in proton-proton collisions at root s=13 TeV

A search is presented for lepton-flavor violating decays of the Higgs boson to mu t and et. The dataset corresponds to an integrated luminosity of 137 fb(-1) collected at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV. No significant excess has been found, and the results are interpreted in terms of upper limits on lepton-flavor violating branching fractions of the Higgs boson. The observed (expected) upper limits on the branching fractions are, respectively, B(H -> mu t) e tau) < 0.22(0.16)% at 95% confidence level.Peer reviewe