Readings in Targeted Maximum Likelihood Estimation

This is a compilation of current and past work on targeted maximum likelihood estimation. It features the original targeted maximum likelihood learning paper as well as chapters on super (machine) learning using cross validation, randomized controlled trials, realistic individualized treatment rules in observational studies, biomarker discovery, case-control studies, and time-to-event outcomes with censored data, among others. We hope this collection is helpful to the interested reader and stimulates additional research in this important area

How do you spell bird? Effective parent programs to enhance 4-6 year old children's literacy development

This research examined the effectiveness of parent programs designed for families to support the literacy learning of their 4-6 year old children. The project began with a literature review analysing six established, effective parent programs that have been reported in the international and national research literature. An analysis of what made each of the programs effective entailed an analysis of the program's target population, the project inputs and activities and the initial, immediate and long term outcomes. To explore further what local parents and families view as effective parent programs for 4-6 year old children the research explored individual site-specific parent programs in operation in South Australian childcare centres, preschools and schools in a range of diverse socioeconomic and geographic sites. Parents and teachers engaged in focus groups to describe ways the schools and centres sustain links between home and school learning. To assess the elements of two existing parent programs to support children's early literacy development, parents and teachers participated in several focus groups. The two programs were the parent component of The Abecedarian Program (2001, 1979) developed in the United States and the South Australian Early Childhood Literacy Includes Parents Staff and Education ECLIPSE program (1997) developed by the South Australian Department of Education and Children's Services (DECS)

Postmenopausal Women With Greater Paracardial Fat Have More Coronary Artery Calcification Than Premenopausal Women: The Study of Women's Health Across the Nation (SWAN) Cardiovascular Fat Ancillary Study.

BackgroundVolumes of paracardial adipose tissue (PAT) and epicardial adipose tissue (EAT) are greater after menopause. Interestingly, PAT but not EAT is associated with estradiol decline, suggesting a potential role of menopause in PAT accumulation. We assessed whether volumes of heart fat depot (EAT and PAT) were associated with coronary artery calcification (CAC) in women at midlife and whether these associations were modified by menopausal status and estradiol levels.Methods and resultsEAT and PAT volumes and CAC were measured using electron beam computed tomography scans. CAC was evaluated as (1) the presence of CAC (CAC Agatston score ≥10) and (2) the extent of any CAC (log CAC Agatston score >0). The study included 478 women aged 50.9 years (58% pre- or early perimenopausal, 10% late perimenopausal, and 32% postmenopausal). EAT was significantly associated with CAC measures, and these associations were not modified by menopausal status or estradiol. In contrast, associations between PAT and CAC measures were modified by menopausal status (interaction-P≤0.01). Independent of study covariates including other adiposity measures, each 1-SD unit increase in log PAT was associated with 102% higher risk of CAC presence (P=0.04) and an 80% increase in CAC extent (P=0.008) in postmenopausal women compared with pre- or early perimenopausal women. Additional adjustment for estradiol and hormone therapy attenuated these differences. Moreover, the association between PAT and CAC extent was stronger in women with lower estradiol levels (interaction P=0.004).ConclusionsThe findings suggest that PAT is a potential menopause-specific coronary artery disease risk marker, supporting the need to monitor and target this fat depot for intervention in women at midlife

Headloop suppression PCR and its application to selective amplification of methylated DNA sequences

Selective amplification in PCR is principally determined by the sequence of the primers and the temperature of the annealing step. We have developed a new PCR technique for distinguishing related sequences in which additional selectivity is dependent on sequences within the amplicon. A 5′ extension is included in one (or both) primer(s) that corresponds to sequences within one of the related amplicons. After copying and incorporation into the PCR product this sequence is then able to loop back, anneal to the internal sequences and prime to form a hairpin structure—this structure is then refractory to further amplification. Thus, amplification of sequences containing a perfect match to the 5′ extension is suppressed while amplification of sequences containing mismatches or lacking the sequence is unaffected. We have applied Headloop PCR to DNA that had been bisulphite-treated for the selective amplification of methylated sequences of the human GSTP1 gene in the presence of up to a 10(5)-fold excess of unmethylated sequences. Headloop PCR has a potential for clinical application in the detection of differently methylated DNAs following bisulphite treatment as well as for selective amplification of sequence variants or mutants in the presence of an excess of closely related DNA sequences

Corrupción y gobierno: causas, consecuencias y reformas

- Divulgação dos SUMÁRIOS das obras recentemente incorporadas ao acervo da Biblioteca Ministro Oscar Saraiva do STJ. Em respeito à Lei de Direitos Autorais, não disponibilizamos a obra na íntegra.- Localização na estante: 343.352 R795c 2.ed

Loss of KLP-19 polar ejection force causes misorientation and missegregation of holocentric chromosomes

Holocentric chromosomes assemble kinetochores along their length instead of at a focused spot. The elongated expanse of an individual holocentric kinetochore and its potential flexibility heighten the risk of stable attachment to microtubules from both poles of the mitotic spindle (merotelic attachment), and hence aberrant segregation of chromosomes. Little is known about the mechanisms that holocentric species have evolved to avoid this type of error. Our studies of the influence of KLP-19, an essential microtubule motor, on the behavior of holocentric Caenorhabditis elegans chromosomes suggest that it has a major role in combating merotelic attachments. Depletion of KLP-19, which associates with nonkinetochore chromatin, allows aberrant poleward chromosome motion during prometaphase, misalignment of holocentric kinetochores, and multiple anaphase chromosome bridges in all mitotic divisions. Time-lapse movies of GFP-labeled mono- and bipolar spindles demonstrate that KLP-19 generates a force on relatively stiff holocentric chromosomes that pushes them away from poles. We hypothesize that this polar ejection force minimizes merotelic misattachment by maintaining a constant tension on pole–kinetochore connections throughout prometaphase, tension that compels sister kinetochores to face directly toward opposite poles

‘Hygienic’ Lymphocytes Convey Increased Cancer Risk

Risk of developing inflammation-associated cancers has increased in industrialized countries during the past 30 years. One possible explanation is societal hygiene practices with use of antibiotics and Caesarian births that provide too few early life exposures of beneficial microbes. Building upon a ‘hygiene hypothesis’ model whereby prior microbial exposures lead to beneficial changes in CD4+ lymphocytes, here we use an adoptive cell transfer model and find that too few prior microbe exposures alternatively result in increased inflammation-associated cancer growth in susceptible recipient mice. Specifically, purified CD4+ lymphocytes collected from ‘restricted flora’ donors increases multiplicity and features of malignancy in intestinal polyps of recipient Apc[superscript Min/+] mice, coincident with increased inflammatory cell infiltrates and instability of the intestinal microbiota. We conclude that while a competent immune system serves to maintain intestinal homeostasis and good health, under hygienic rearing conditions CD4+ lymphocytes instead exacerbate inflammation-associated tumorigenesis, subsequently contributing to more frequent cancers in industrialized societies.National Institutes of Health (U.S.) (Grant P30-ES002109)National Institutes of Health (U.S.) (Grant U01 CA164337)National Institutes of Health (U.S.) (Grant RO1CA108854

Exploiting parallels between livestock and wildlife: Predicting the impact of climate change on gastrointestinal nematodes in ruminants.

Global change, including climate, policy, land use and other associated environmental changes, is likely to have a major impact on parasitic disease in wildlife, altering the spatio-temporal patterns of transmission, with wide-ranging implications for wildlife, domestic animals, humans and ecosystem health. Predicting the potential impact of climate change on parasites infecting wildlife will become increasingly important in the management of species of conservation concern and control of disease at the wildlife-livestock and wildlife-human interface, but is confounded by incomplete knowledge of host-parasite interactions, logistical difficulties, small sample sizes and limited opportunities to manipulate the system. By exploiting parallels between livestock and wildlife, existing theoretical frameworks and research on livestock and their gastrointestinal nematodes can be adapted to wildlife systems. Similarities in the gastrointestinal nematodes and the life-histories of wild and domestic ruminants, coupled with a detailed knowledge of the ecology and life-cycle of the parasites, render the ruminant-GIN host-parasite system particularly amenable to a cross-disciplinary approach

Sustained Attention in the Face of Distractors: A Study of Children with Rett Syndrome

Objective. The object of the present study is to advance our understanding of the cognitive profile of Rett Syndrome (RTT), an x-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. We focus on sustained attention, which plays a critical role in driving cognitive growth, and use an innovative, gaze-based task that minimizes demands on the limited verbal and motor abilities associated with RTT. Method. The task required the ability to sustain attention on a visual target (a butterfly) whilst inhibiting a prepotent response to look to moving distractors (trees and clouds) presented in the peripheral visual field. The sample included children with RTT (N = 32) and their typically developing (TD) counterparts (N = 32), aged 2-12 years. Results. Our findings revealed that children with RTT had more difficulty sustaining attention (with the TD group averaging 60% looking at the butterfly vs only 25% for the RTT group). Furthermore, they showed that RTT was associated with difficulties in three fundamental factors influencing sustained attention: engagement, distractibility, and re-engagement. The RTT group was slower to engage, more distractible, and slower to re-engage. Conclusion. Our findings suggest there may be a fundamental disruption to sustained attention in RTT, identifies factors related to this impairment, and points to cognitive areas that could be assessed in evaluating the usefulness of interventions. Public Statement. Rett syndrome is an x-linked neurodevelopmental disorder characterized by a developmental regression that typically begins between 6 and 18 months, robs the child of purposeful hand use and expressive language, and results in the development of numerous medical problems. These deficits make standard neuropsychological testing becomes all but impossible, and thus little is known about their cognitive abilities. We were able to by-pass the motoric and language problems using eye-tracking technology. Here we used an innovative gaze-based task to assess sustain attention, a core driver of cognitive growth. We found that children with Rett Syndrome showed impairments in sustained attention, and on three fundamental factors influencing sustained attention: engagement, distractibility, and re-engagement. Children with Rett Syndrome were slower to engage, more distractible, and slower to re-engage than their age-matched peers. This work not only begins to elucidate the nature of the cognitive problems associated with Rett syndrome, but is essential for designing markers to assess the effects of pharmacological interventions

Impaired Visual Search in Children with Rett Syndrome

Aim This study aims to investigate selective attention in Rett syndrome, a severely disabling neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Method The sample included 28 females with Rett syndrome (RTT) and 32 age-matched typically developing controls. We used a classic search task, in conjunction with eye-tracking technology. Each trial included the target and several distractors. The distractors varied in number and differed from targets in either a ‘single feature’ (color or shape), creating a pop-out effect, or in a ‘conjunction of features’ (color and shape), requiring serial search. Children searched for the target in arrays containing 5 or 9 objects; trials ended when the target was fixated (or 4000 ms elapsed). Results Children with Rett syndrome had more difficulty finding the target than typically developing children in both conditions (success rates <50% vs 80%) and their success rates were little influenced by display size or age. Even when successful, children with RTT took significantly longer to respond (392--574 ms), although saccadic latency differences were observed only in the single feature condition. Both groups showed the expected slowing of saccadic reaction times for larger arrays in the conjunction feature condition. Search failures in RTT were not related to symptom severity. Conclusion Our findings provide the first evidence that selective attention, the ability to focus on or select a particular element or object in the environment, is compromised by Rett syndrome. They reinforce the notion that gaze-based tasks hold promise for quantifying the cognitive phenotype of RTT