Field efficacy evaluation and post-treatment contamination risk assessment of an ultraviolet disinfection and safe storage system.

Inconsistent use of household water treatment and safe storage (HWTS) systems reduces their potential health benefits. Ultraviolet (UV) disinfection is more convenient than some existing HWTS systems, but it does not provide post-treatment residual disinfectant, which could leave drinking water vulnerable to recontamination. In this paper, using as-treated analyses, we report on the field efficacy of a UV disinfection system at improving household drinking water quality in rural Mexico. We further assess the risk of post-treatment contamination from the UV system, and develop a process-based model to better understand household risk factors for recontamination. This study was part of a larger cluster-randomized stepped wedge trial, and the results complement previously published population-level results of the intervention on diarrheal prevalence and water quality. Based on the presence of Escherichia coli (proportion of households with ≥ 1 E. coli/100 mL), we estimated a risk difference of -28.0% (95% confidence interval (CI): -33.9%, -22.1%) when comparing intervention to control households; -38.6% (CI: -48.9%, -28.2%) when comparing post- and pre-intervention results; and -37.1% (CI: -45.2%, -28.9%) when comparing UV disinfected water to alternatives within the household. We found substantial increases in post-treatment E. coli contamination when comparing samples from the UV system effluent (5.0%) to samples taken from the storage container (21.1%) and drinking glasses (26.0%). We found that improved household infrastructure, additional extractions from the storage container, additional time from when the storage container was filled, and increased experience of the UV system operator were associated with reductions in post-treatment contamination. Our results suggest that the UV system is efficacious at improving household water quality when used as intended. Promoting safe storage habits is essential for an effective UV system dissemination. The drinking glass appears to represent a small but significant source of recontamination that is likely to impact all HWTS systems

True happiness: The role of morality in the folk concept of happiness

Recent scientific research has settled on a purely descriptive definition of happiness that is focused solely on agents’ psychological states (high positive affect, low negative affect, high life satisfaction). In contrast to this understanding, recent research has suggested that the ordinary concept of happiness is also sensitive to the moral value of agents’ lives. Five studies systematically investigate and explain the impact of morality on ordinary assessments of happiness. Study 1 demonstrates that moral judgments influence assessments of happiness not only for untrained participants, but also for academic researchers and even in those who study happiness specifically. Studies 2 and 3 then respectively ask whether this effect may be explained by general motivational biases or beliefs in a just world. In both cases, we find evidence against these explanations. Study 4 shows that the impact of moral judgments cannot be explained by changes in the perception of descriptive psychological states. Finally, Study 5 compares the impact of moral and non-moral value, and provides evidence that unlike non-moral value, moral value is part of the criteria that govern the ordinary concept of happiness. Taken together, these studies provide a specific explanation of how and why the ordinary concept of happiness deviates from the definition used by researchers studying happiness

Targeted Maximum Likelihood Estimation for Dynamic and Static Longitudinal Marginal Structural Working Models

This paper describes a targeted maximum likelihood estimator (TMLE) for the parameters of longitudinal static and dynamic marginal structural models. We consider a longitudinal data structure consisting of baseline covariates, time-dependent intervention nodes, intermediate time-dependent covariates, and a possibly time-dependent outcome. The intervention nodes at each time point can include a binary treatment as well as a right-censoring indicator. Given a class of dynamic or static interventions, a marginal structural model is used to model the mean of the intervention-specific counterfactual outcome as a function of the intervention, time point, and possibly a subset of baseline covariates. Because the true shape of this function is rarely known, the marginal structural model is used as a working model. The causal quantity of interest is defined as the projection of the true function onto this working model. Iterated conditional expectation double robust estimators for marginal structural model parameters were previously proposed by Robins (2000, 2002) and Bang and Robins (2005). Here we build on this work and present a pooled TMLE for the parameters of marginal structural working models. We compare this pooled estimator to a stratified TMLE (Schnitzer et al. 2014) that is based on estimating the intervention-specific mean separately for each intervention of interest. The performance of the pooled TMLE is compared to the performance of the stratified TMLE and the performance of inverse probability weighted (IPW) estimators using simulations. Concepts are illustrated using an example in which the aim is to estimate the causal effect of delayed switch following immunological failure of first line antiretroviral therapy among HIV-infected patients. Data from the International Epidemiological Databases to Evaluate AIDS, Southern Africa are analyzed to investigate this question using both TML and IPW estimators. Our results demonstrate practical advantages of the pooled TMLE over an IPW estimator for working marginal structural models for survival, as well as cases in which the pooled TMLE is superior to its stratified counterpar

Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid.

13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy

A review of chronic pectoralis major tears: what options are available?

Rupture of the pectoralis major muscle typically occurs in the young, active male. Acute management of these injuries is recommended; however, what if the patient presents with a chronic tear of the pectoralis major? Physical exams and magnetic resonance imaging can help identify the injury and guide the physician with a plan for management. Nonoperative management is feasible, but is recommended for elderly, low-demand patients whose functional goals are minimal. Repair of chronic tears should be reserved for younger, healthier patients with high functional demands. Although operative management provides better functional outcomes, operative treatment of chronic pectoralis tears can be challenging. Tendon retraction, poor tendinous substance and quality of tissue, muscle atrophy, scar formation, and altered anatomy make direct repairs complicated, often necessitating auto- or allograft use. We review the various graft options and fixation methods that can be used when treating patients with chronic pectoralis major tears

Ars2 Links the Nuclear Cap-Binding Complex to RNA Interference and Cell Proliferation

SummaryHere we identify a component of the nuclear RNA cap-binding complex (CBC), Ars2, that is important for miRNA biogenesis and critical for cell proliferation. Unlike other components of the CBC, Ars2 expression is linked to the proliferative state of the cell. Deletion of Ars2 is developmentally lethal, and deletion in adult mice led to bone marrow failure whereas parenchymal organs composed of nonproliferating cells were unaffected. Depletion of Ars2 or CBP80 from proliferating cells impaired miRNA-mediated repression and led to alterations in primary miRNA processing in the nucleus. Ars2 depletion also reduced the levels of several miRNAs, including miR-21, let-7, and miR-155, that are implicated in cellular transformation. These findings provide evidence for a role for Ars2 in RNA interference regulation during cell proliferation

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Evidence for dust destruction from the early-time colour change of GRB 120119A

We present broad-band observations and analysis of Swift gamma-ray burst (GRB) 120119A. Our early-time afterglow detections began under 15 s after the burst in the host frame (redshift z = 1.73), and they yield constraints on the burst energetics and local environment. Late-time afterglow observations of the burst show evidence for a moderate column of dust (AV ≈ 1.1 mag) similar to, but statistically distinct from, dust seen along Small Magellanic Cloud sightlines. Deep late-time observations reveal a dusty, rapidly star-forming host galaxy. Most notably, our early-time observations exhibit a significant red-to-blue colour change in the first ∼200 s after the trigger at levels heretofore unseen in GRB afterglows. This colour change, which is coincident with the final phases of the prompt emission, is a hallmark prediction of the photodestruction of dust in GRB afterglows. We test whether dust-destruction signatures are significantly distinct from other sources of colour change, namely a change in the intrinsic spectral index β. We find that a time-varying power-law spectrum alone cannot adequately describe the observed colour change, and allowing for dust destruction (via a time-varying AV) significantly improves the fit. While not definitively ruling out other possibilities, this event provides the best support yet for the direct detection of dust destruction in the local environment of a GRB

Acetate Kinase Isozymes Confer Robustness in Acetate Metabolism

Acetate kinase (ACK) (EC no: 2.7.2.1) interconverts acetyl-phosphate and acetate to either catabolize or synthesize acetyl-CoA dependent on the metabolic requirement. Among all ACK entries available in UniProt, we found that around 45% are multiple ACKs in some organisms including more than 300 species but surprisingly, little work has been done to clarify whether this has any significance. In an attempt to gain further insight we have studied the two ACKs (AckA1, AckA2) encoded by two neighboring genes conserved in Lactococcus lactis (L. lactis) by analyzing protein sequences, characterizing transcription structure, determining enzyme characteristics and effect on growth physiology. The results show that the two ACKs are most likely individually transcribed. AckA1 has a much higher turnover number and AckA2 has a much higher affinity for acetate in vitro. Consistently, growth experiments of mutant strains reveal that AckA1 has a higher capacity for acetate production which allows faster growth in an environment with high acetate concentration. Meanwhile, AckA2 is important for fast acetate-dependent growth at low concentration of acetate. The results demonstrate that the two ACKs have complementary physiological roles in L. lactis to maintain a robust acetate metabolism for fast growth at different extracellular acetate concentrations. The existence of ACK isozymes may reflect a common evolutionary strategy in bacteria in an environment with varying concentrations of acetate