Delivering integrated child development care in Pakistan: protocol for a clustered randomised trial

Background: Early childhood developmental delay is associated with significant disadvantage in adult life. In Pakistan, high prevalence of developmental delay is associated with poverty, under-nutrition, and maternal depression. Aim: To assess the effectiveness of an early child development counselling intervention delivered at private GP clinics, in poor urban communities. Design & setting: A clustered randomised trial in Pakistan. Method: The intervention was developed following a period of formative research, and in consultation with local experts. A total of 2112 mother–child pairs will be recruited at 32 clinics, from within the locality (cluster); 16 clinics per arm. A primary care counselling intervention (promoting child development, nutrition, and maternal mental health) will be delivered at 6 weeks, 3, 6, and 9 months of the child’s age. Monitoring, assessment, and treatment will also be performed at quarterly visits in intervention clinics. Primary outcome is the developmental delay at 12 months (ASQ-3 scores). Secondary outcomes are stunting rate, and maternal depression (PHQ-9 score). In addition, a process evaluation and costing study will be conducted. Discussion: This trial will be the first to assess an early child development intervention, delivered in private GP clinics for poor urban communities in Pakistan. If found to be effective, this public–private model may offer a more sustainable, and feasible option for populations in poor urban settings, where private GP clinics are the most accessible provider of primary health care. There is scope for scale-up at provincial level, should the intervention be effective. Trial registration: The trial has been registered with the Current Controlled Trials ISRCTN48032200

Locomotion disorders and skin and claw lesions in gestating sows housed in dynamic versus static groups

Lameness and lesions to the skin and claws of sows in group housing are commonly occurring indicators of reduced welfare. Typically, these problems are more common in group housing than in individual housing systems. Group management type (dynamic versus static) and stage of gestation influence the behavior of the animals, which in turn influences the occurrence of these problems. The present study compared prevalence, incidence and mean scores of lameness and skin and claw lesions in static versus dynamic group housed sows at different stages of gestation during three consecutive reproductive cycles. A total of 10 Belgian sow herds were monitored; 5 in which dynamic groups and 5 in which static groups were utilized. All sows were visually assessed for lameness and skin lesions three times per cycle and the claws of the hind limbs were assessed once per cycle. Lameness and claw lesions were assessed using visual analogue scales. Static groups, in comparison with dynamic groups, demonstrated lower lameness scores (P<0.05) and decreased skin lesion prevalence (24.9 vs. 47.3%, P<0.05) at the end of gestation. There was no difference between treatment group regarding claw lesion prevalence with 75.5% of sows demonstrating claw lesions regardless of group management. Prevalences of lameness (22.4 vs. 8.9%, P<0.05) and skin lesions (46.6 vs. 4.4%, P<0.05) were highest during the group-housed phase compared to the individually housed phases. Although the prevalence of lameness and skin lesions did not differ three days after grouping versus at the end of the group-housing phase, their incidence peaked during the first three days after moving from the insemination stalls to the group. In conclusion, the first three days after grouping was the most risky period for lameness incidence, but there was no significant difference between static or dynamic group management

Reduced hospital stay, morphine consumption, and pain intensity with local infiltration analgesia after unicompartmental knee arthroplasty: A randomized double–blind study of 40 patients

Background and purpose The degree of postoperative pain is usually moderate to severe following knee arthroplasty. We investigated the efficacy of local administration of analgesics into the operating area, both intraoperatively and postoperatively

Evaluation of Magnetic Micro- and Nanoparticle Toxicity to Ocular Tissues

Purpose: Magnetic nanoparticles (MNPs) may be used for focal delivery of plasmids, drugs, cells, and other applications. Here we ask whether such particles are toxic to ocular structures. Methods: To evaluate the ocular toxicity of MNPs, we asked if either 50 nm or 4 mm magnetic particles affect intraocular pressure, corneal endothelial cell count, retinal morphology including both cell counts and glial activation, or photoreceptor function at different time points after injection. Sprague-Dawley rats (n = 44) were injected in the left eye with either 50 nm (3 ml, 1.65 mg) or 4 mm(3ml, 1.69 mg) magnetic particles, and an equal volume of PBS into the right eye. Electroretinograms (ERG) were used to determine if MNPs induce functional changes to the photoreceptor layers. Enucleated eyes were sectioned for histology and immunofluorescence. Results: Compared to control-injected eyes, MNPs did not alter IOP measurements. ERG amplitudes for a-waves were in the 100–250 mV range and b-waves were in the 500–600 mV range, with no significant differences between injected and noninjected eyes. Histological sectioning and immunofluorescence staining showed little difference in MNP-injected animals compared to control eyes. In contrast, at 1 week, corneal endothelial cell numbers were significantly lower in the 4 mm magnetic particle-injected eyes compared to either 50 nm MNP- or PBS-injected eyes. Furthermore, iron deposition was detected after 4 mm magnetic particle but not 50 nm MNP injection

Support Vector Machine Implementations for Classification & Clustering

BACKGROUND: We describe Support Vector Machine (SVM) applications to classification and clustering of channel current data. SVMs are variational-calculus based methods that are constrained to have structural risk minimization (SRM), i.e., they provide noise tolerant solutions for pattern recognition. The SVM approach encapsulates a significant amount of model-fitting information in the choice of its kernel. In work thus far, novel, information-theoretic, kernels have been successfully employed for notably better performance over standard kernels. Currently there are two approaches for implementing multiclass SVMs. One is called external multi-class that arranges several binary classifiers as a decision tree such that they perform a single-class decision making function, with each leaf corresponding to a unique class. The second approach, namely internal-multiclass, involves solving a single optimization problem corresponding to the entire data set (with multiple hyperplanes). RESULTS: Each SVM approach encapsulates a significant amount of model-fitting information in its choice of kernel. In work thus far, novel, information-theoretic, kernels were successfully employed for notably better performance over standard kernels. Two SVM approaches to multiclass discrimination are described: (1) internal multiclass (with a single optimization), and (2) external multiclass (using an optimized decision tree). We describe benefits of the internal-SVM approach, along with further refinements to the internal-multiclass SVM algorithms that offer significant improvement in training time without sacrificing accuracy. In situations where the data isn't clearly separable, making for poor discrimination, signal clustering is used to provide robust and useful information – to this end, novel, SVM-based clustering methods are also described. As with the classification, there are Internal and External SVM Clustering algorithms, both of which are briefly described

Latency Antigen α-Crystallin Based Vaccination Imparts a Robust Protection against TB by Modulating the Dynamics of Pulmonary Cytokines

BACKGROUND: Efficient control of tuberculosis (TB) requires development of strategies that can enhance efficacy of the existing vaccine Mycobacterium bovis Bacille Calmette Guerin (BCG). To date only a few studies have explored the potential of latency-associated antigens to augment the immunogenicity of BCG. METHODS/PRINCIPAL FINDINGS: We evaluated the protective efficacy of a heterologous prime boost approach based on recombinant BCG and DNA vaccines targeting α-crystallin, a prominent latency antigen. We show that "rBCG prime-DNA boost" strategy (R/D) confers a markedly superior protection along with reduced pathology in comparison to BCG vaccination in guinea pigs (565 fold and 45 fold reduced CFU in lungs and spleen, respectively, in comparison to BCG vaccination). In addition, R/D regimen also confers enhanced protection in mice. Our results in guinea pig model show a distinct association of enhanced protection with an increased level of interleukin (IL)12 and a simultaneous increase in immuno-regulatory cytokines such as transforming growth factor (TGF)β and IL10 in lungs. The T cell effector functions, which could not be measured in guinea pigs due to technical limitations, were characterized in mice by multi-parameter flow cytometry. We show that R/D regimen elicits a heightened multi-functional CD4 Th1 cell response leading to enhanced protection. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of α-crystallin based R/D regimen over BCG. Our observations from guinea pig studies indicate a crucial role of IL12, IL10 and TGFβ in vaccine-induced protection. Further, characterization of T cell responses in mice demonstrates that protection against TB is predictable by the frequency of CD4 T cells simultaneously producing interferon (IFN)γ, tumor necrosis factor (TNF)α and IL2. We anticipate that this study will not only contribute toward the development of a superior alternative to BCG, but will also stimulate designing of TB vaccines based on latency antigens

Screen or not to screen for peripheral arterial disease: Guidance from a decision model

__Abstract__ Background: Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. Methods. A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. Results: For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Ye

CD8+ DC, but Not CD8−DC, Isolated from BCG-Infected Mice Reduces Pathological Reactions Induced by Mycobacterial Challenge Infection

Tuberculosis is a mycobacterial infection causing worldwide public health problems but the available vaccine is far from ideal. Type-1 T cell immunity has been shown to be critical for host defence against tuberculosis infection, but the role of dendritic cell (DC) subsets in pathogenesis of mycobacterial infection remains unclear.We examined the effectiveness of dendritic cell (DC) subsets in BCG-infected mice in generating immune responses beneficial for pathogen clearance and reduction of pathological reactions in the tissues following challenge infection. Our data showed that only the adoptive transfer of the subset of CD8alpha+ DC isolated from infected mice (iCD8+ DC) generated significant protection, demonstrated by less mycobacterial growth and pathological changes in the lung and liver tissues in iCD8+ DC recipients than sham-treated control mice. The adoptive transfer of the CD8alpha(-)DC from the infected mice (iCD8(-) DC) not only failed to reduce bacterial growth, but enhanced inflammation characterized by diffuse heavy cellular infiltration. Notably, iCD8(-) DC produced significantly higher levels of IL-10 than iCD8+ DC and promoted more Th2 cytokine responses in in vitro DC-T cell co-culture and in vivo adoptive transfer experiments.The data indicate that in vivo BCG-primed CD8+ DC is the dominant DC subset in inducing protective immunity especially for reducing pathological reactions in infected tissues. The finding has implications for the rational improvement of the prophylactic and therapeutic approaches for controlling tuberculosis infection and related diseases

Inhibition of MLC Phosphorylation Restricts Replication of Influenza Virus—A Mechanism of Action for Anti-Influenza Agents

Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds