Early Intervention for Children at High Risk of Developmental Disability in Low- and Middle-Income Countries:A Narrative Review

In low- and middle-income countries (LMICs), while neonatal mortality has fallen, the number of children under five with developmental disability remains unchanged. The first thousand days are a critical window for brain development, when interventions are particularly effective. Early Childhood Interventions (ECI) are supported by scientific, human rights, human capital and programmatic rationales. In high-income countries, it is recommended that ECI for high-risk infants start in the neonatal period, and specialised interventions for children with developmental disabilities as early as three months of age; more data is needed on the timing of ECI in LMICs. Emerging evidence supports community-based ECI which focus on peer support, responsive caregiving and preventing secondary morbidities. A combination of individual home visits and community-based groups are likely the best strategy for the delivery of ECI, but more evidence is needed to form strong recommendations, particularly on the dosage of interventions. More data on content, impact and implementation of ECI in LMICs for high-risk infants are urgently needed. The development of ECI for high-risk groups will build on universal early child development best practice but will likely require tailoring to local contexts

Spike-in validation of an Illumina-specific variance-stabilizing transformation

BACKGROUND: Variance-stabilizing techniques have been used for some time in the analysis of gene expression microarray data. A new adaptation, the variance-stabilizing transformation (VST), has recently been developed to take advantage of the unique features of Illumina BeadArrays. VST has been shown to perform well in comparison with the widely-used approach of taking a log2 transformation, but has not been validated on a spike-in experiment. We apply VST to the data from a recently published spike-in experiment and compare it both to a regular log2 analysis and a recently recommended analysis that can be applied if all raw data are available. FINDINGS: VST provides more power to detect differentially expressed genes than a log2 transformation. However, the gain in power is roughly the same as utilizing the raw data from an experiment and weighting observations accordingly. VST is still advantageous when large changes in expression are anticipated, while a weighted log2 approach performs better for smaller changes. CONCLUSION: VST can be recommended for summarized Illumina data regardless of which Illumina pre-processing options have been used. However, using the raw data is still encouraged whenever possible

A new reference genome assembly for the microcrustacean Daphnia pulex

Comparing genomes of closely related genotypes from populations with distinct demographic histories can help reveal the impact of effective population size on genome evolution. For this purpose, we present a high quality genome assembly of Daphnia pulex (PA42), and compare this with the first sequenced genome of this species (TCO), which was derived from an isolate from a population with >90% reduction in nucleotide diversity. PA42 has numerous similarities to TCO at the gene level, with an average amino acid sequence identity of 98.8 and >60% of orthologous proteins identical. Nonetheless, there is a highly elevated number of genes in the TCO genome annotation, with similar to 7000 excess genes appearing to be false positives. This view is supported by the high GC content, lack of introns, and short length of these suspicious gene annotations. Consistent with the view that reduced effective population size can facilitate the accumulation of slightly deleterious genomic features, we observe more proliferation of transposable elements (TEs) and a higher frequency of gained introns in the TCO genome

Viewpoint: Evaluating the impact of malaria control efforts on mortality in sub-Saharan Africa

OBJECTIVE To describe an approach for evaluating the impact of malaria control efforts on malaria-associated mortality in sub-Saharan Africa, where disease-specific mortality trends usually cannot be measured directly and most malaria deaths occur among young children. METHODS Methods for evaluating changes in malaria-associated mortality are examined; advantages and disadvantages are presented. RESULTS All methods require a plausibility argument - i.e., an assumption that mortality reductions can be attributed to programmatic efforts if improvements are found in steps of the causal pathway between intervention scale-up and mortality trends. As different methods provide complementary information, they can be used together. We recommend following trends in the coverage of malaria control interventions, other factors influencing childhood mortality, malaria-associated morbidity (especially anaemia), and all-cause childhood mortality. This approach reflects decreases in malaria's direct and indirect mortality burden and can be examined in nearly all countries. Adding other information can strengthen the plausibility argument: trends in indicators of malaria transmission, information from demographic surveillance systems and sentinel sites where malaria diagnostics are systematically used, and verbal autopsies linked to representative household surveys. Health facility data on malaria deaths have well-recognized limitations; however, in specific circumstances, they could produce reliable trends. Model-based predictions can help describe changes in malaria-specific burden and assist with program management and advocacy. CONCLUSIONS Despite challenges, efforts to reduce malaria-associated mortality in Africa can be evaluated with trends in malaria intervention coverage and all-cause childhood mortality. Where there are resources and interest, complementary data on malaria morbidity and malaria-specific mortality could be added

Normative Alethic Pluralism

Some philosophers have argued that truth is a norm of judgement and have provided a variety of formulations of this general thesis. In this paper, I shall side with these philosophers and assume that truth is a norm of judgement. What I am primarily interested in here are two core questions concerning the judgement-truth norm: (i) what are the normative relationships between truth and judgement? And (ii) do these relationships vary or are they constant? I argue for a pluralist picture—what I call Normative Alethic Pluralism (NAP)—according to which (i) there is more than one correct judgement-truth norm and (ii) the normative relationships between truth and judgement vary in relation to the subject matter of the judgement. By means of a comparative analysis of disagreement in three areas of the evaluative domain—refined aesthetics, basic taste and morality—I show that there is an important variability in the normative significance of disagreement—I call this the variability conjecture. By presenting a variation of Lynch’s scope problem for alethic monism, I argue that a monistic approach to the normative function of truth is unable to vindicate the conjecture. I then argue that normative alethic pluralism provides us with a promising model to account for it

Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing remitting multiple sclerosis subjects

T cells are important mediators of autoimmune inflammation in relapsing remitting multiple sclerosis (RRMS). Previous studies found that deferiprone, an iron chelator, suppressed disease activity in a mouse model of multiple sclerosis, and inhibition of T cell proliferation was implicated as a putative mechanism. The objective of the present study was to examine the effects of deferiprone on suppressing in vitro responses of T cells from control and RRMS subjects. Peripheral blood T cells were co-stimulated with anti-CD3 + anti-CD28 and cultured with or without interleukin 2 (IL-2). Proliferating CD4+ T cells from control and RRMS subjects, cultured with or without IL-2, decreased in response to 75 μM deferiprone, although the extent of decreased proliferation of CD4+ T cells from RRMS subjects was less than for control subjects. Proliferating CD8+ T cells from control subjects, cultured with or without IL-2, also decreased in response to 75 μM deferiprone, and this decrease was seen in proliferating CD8+ T cells from RRMS cultured with IL-2. CD4+CD25+ and CD8+CD25+ cells from control subjects, cultured with or without IL-2, declined in 75 M deferiprone, but the decrease was smaller than for the CD4+ and CD8+ proliferative responses. CD4+CD25+ and CD8+CD25+ cells from RRMS subjects showed more variability than for control subjects, but CD4+CD25+ cultured with IL-2 and CD8+CD25+ cells cultured without IL-2 significantly declined in 75 μM deferiprone. CD4+FoxP3+ and CD4+CD25+FoxP3+ cells tended to remain constant or increase. In summary, deferiprone induced declines in proliferative responses at a dosage that is within peak serum pharmacological concentrations

A re-annotation pipeline for Illumina BeadArrays: improving the interpretation of gene expression data.

Illumina BeadArrays are among the most popular and reliable platforms for gene expression profiling. However, little external scrutiny has been given to the design, selection and annotation of BeadArray probes, which is a fundamental issue in data quality and interpretation. Here we present a pipeline for the complete genomic and transcriptomic re-annotation of Illumina probe sequences, also applicable to other platforms, with its output available through a Web interface and incorporated into Bioconductor packages. We have identified several problems with the design of individual probes and we show the benefits of probe re-annotation on the analysis of BeadArray gene expression data sets. We discuss the importance of aspects such as probe coverage of individual transcripts, alternative messenger RNA splicing, single-nucleotide polymorphisms, repeat sequences, RNA degradation biases and probes targeting genomic regions with no known transcription. We conclude that many of the Illumina probes have unreliable original annotation and that our re-annotation allows analyses to focus on the good quality probes, which form the majority, and also to expand the scope of biological information that can be extracted

Third-Party Allogeneic Mesenchymal Stromal Cells Prevent Rejection in a Pre-sensitized High-Risk Model of Corneal Transplantation

High-risk cornea transplant recipients represent a patient population with significant un-met medical need for more effective therapies to prevent immunological graft rejection due to heightened anti-donor immune response. In this study, a rat model of pre-existing anti-donor immunity was developed in which corneal allografts were rejected earlier than in non-pre-sensitized recipients. In this model, third-party (non-donor, non-recipient strain) allogeneic mesenchymal stromal cells (allo-MSC) were administered intravenously 7 and 1 days prior to transplantation. Rejection-free graft survival to 30 days post-transplant improved from 0 to 63.6% in MSC-treated compared to vehicle-treated control animals (p = < 0.0001). Pre-sensitized animals that received third-party allo-MSC prior to transplantation had significantly higher proportions of CD45+CD11b+ B220+ monocytes in the lungs 24 h after the second MSC injection and significantly higher proportions of CD4+ FoxP3+ regulatory T cells in the graft-draining lymph nodes at the average day of rejection of control animals. In in vitro experiments, third-party allo-MSC polarized primary lung-derived CD11b/c+ myeloid cells to a more anti-inflammatory phenotype, as determined by cytokine profile and conferred them with the capacity to suppress T cell activation via prostaglandin E2 and TGFβ1. In experiments designed to further validate the clinical potential of the protocol, thawed cryopreserved, third-party allo-MSC were shown to be similarly potent at prolonging rejection-free corneal allograft survival as their freshly-cultured counterparts in the pre-sensitized high-risk model. Furthermore, thawed cryopreserved third-party allo-MSC could be co-administered with mycophenolate mofetil without adversely affecting their immunomodulatory function. In conclusion, a clinically-relevant protocol consisting of two intravenous infusions of third-party allo-MSC during the week prior to transplantation, exerts a potent anti-rejection effect in a pre-sensitized rat model of high-risk corneal allo-transplantation. This immune regulatory effect is likely to be mediated in the immediate post-transplant period through the promotion, by allo-MSC, of alternatively-activated macrophages in the lung and, later, by enhanced regulatory T-cell numbers

The effect of hyperbaric oxygen and blood platelet injection therapy on the healing of hamstring injuries in rugby players

There are a number of ultra-structural and immuno-histochemical studies involving hyperbaric oxygen treatment in skeletal muscle, as well as soft tissue healing. Hyperbaric oxygen therapy, in conjunction with blood platelet injection therapy, serves as a valuable addition to previously known and trusted rehabilitation techniques and protocols for the healing of musculoskeletal or soft tissue injuries. The primary aim of this case report is to describe the effect on the recovery time of hamstring injuries when combining hyperbaric oxygen therapy (HBOT) and platelet rich plasma (PRP) injection therapy with exercise rehabilitation. A retrospective, post-intervention data analysis was used in this case series report. Data, obtained through collaboration with a professional rugby union and an accredited Hyperbaric Medicine (HBOT) Centre, were analysed using the Statistical Programme for the Social Sciences (SPSS) software. The significance value was set at 5%. A significant decrease in the injury time of the hamstring injuries in rugby players was noted, with a 38% reduction in injury time in players with a grade-one injury, and 45.7% reduction in players with a grade-two injury. In terms of recurrent injuries, 62% of players with grade-one injuries remained uninjured after treatment, and the percentage of re-injured players with grade-two injuries was 0% after HBOT, PRP and physical therapy treatment. The notion that the healing time of hamstring injuries will decrease when HBOT and PRP are administered in conjunction with traditional rehabilitation therapy is indicated by the data of this report.http://www.ajol.info/journal_index.php?jid=153&ab=ajpherd2017-11-30am201