Parents' Experiences of Having a Child with Down Syndrome and Sleep Difficulties.

OBJECTIVES: Sleep disorders are prevalent in children with Down Syndrome (DS). However, sleep treatment is not always readily accessed by this group. This study aims to understand families' experiences of having a child with DS and sleep difficulties, and in particular, their healthcare experiences, with the goal of informing practice improvements. METHODS: We conducted semi-structured interviews with 34 parents (fathers n = 4 and mothers n = 30) with open-ended questions about parents' experiences of sleep, family dynamics, and healthcare. We operationalized a reflexive Thematic Analysis. RESULTS: Parents normalized their experiences of having a child with DS and sleep problems. Parents acknowledged that sleep disruption has adverse and pervasive impacts on their wellbeing and family dynamics, but also found this difficult to identify as a health problem. They accepted sleep difficulties as a regular part of bringing up any child, particularly one with a disability. When they did seek treatment for their child's sleep difficulties, parents often reported encountering insensitive and inadequate care and described that, at times, healthcare professionals also normalized children's sleep difficulties, resulting in sub-optimal treatment. This included at times failure to refer to tertiary sleep medicine services when required. CONCLUSIONS: Parents' and healthcare professionals' normalization of sleeping difficulties denies that they are both deleterious and modifiable. Practice implications include raising healthcare professionals' awareness of the importance of proactively addressing sleep, with sensitivity to families' normalization strategies, recognizing that families may require prompting to report concerns.

Ethical challenges and moral distress among field epidemiologists.

BACKGROUND: As 'disease detectives' and directors of public health programs, field epidemiologists play essential roles in protecting public health. Although ethical issues receive considerable attention in medical and research settings, less is known about ethical challenges faced by field epidemiologists in public health programs. Similarly, little is known about moral distress among field epidemiologists, i.e., situations in which they are constrained from acting on what they know to be morally right. Moral distress is strongly associated with empathy fatigue, burnout, reduced job retention, and disengagement. To better understand ethics training needs for field epidemiologists, in February 2019, members of TEPHIConnect, an online and mobile networking platform for Field Epidemiology Training Program (FETP) alumni, were invited to participate in an anonymous survey about ethical challenges and moral distress. RESULTS: Among 126 respondents from 54 countries, leading causes of ethical dilemmas included inadequate informed consent (61%), inequitable allocation of resources (49%), and conflicts of interest (43%). These occur primarily in settings of disease outbreaks (60%); research (55%); and public health programs at the state, province, or national level (45%) or community level (43%). Work-related moral distress was reported by 91% of respondents, including 26% who experience it "frequently" or "almost always." Field epidemiologists working in low- and low-middle income countries were more likely to report moral distress "frequently" or "almost always" than those in higher-income countries (33.0% vs 9.1%, P = 0.006). The most common perceived contributors to moral distress included excessive stress and work demands (30%) and inadequate support from leaders (25%). CONCLUSIONS: Field epidemiologists face significant work-related ethical challenges, which are endemic to public health and political systems. A substantial proportion of field epidemiologists also experience some degree of moral distress, often in association with these challenges. These findings indicate an unmet need among field epidemiologists for support in navigating ethical challenges, as well as for resources to address the human and professional consequences of moral distress.

Parents' experiences of accessing respite care for children with Autism Spectrum Disorder (ASD) at the acute and primary care interface: a systematic review.

BACKGROUND: Population prevalence estimates by the World Health Organisation suggest that 1 in 160 children worldwide has an Autism Spectrum Disorder (ASD). Accessing respite care services for children with an ASD can often be a daunting and exhaustive process, with parents sometimes forced to access acute hospital services as an initial point of contact for respite care or in a crisis situation. To gain an in-depth understanding of accessing respite care for children with an ASD, from the perspectives of parents, a systematic review of the evidence on parent's experiences and views of respite care for children with an ASD at the acute and primary interface was undertaken. METHODS: Pubmed, Embase, CINAHL and PsycINFO were systematically searched. Studies identified as relevant based on predetermined eligibility criteria were selected for inclusion. The search strategy also targeted unpublished studies and grey literature. Qualitative data and qualitative components of mixed method studies that represented the experiences of parents accessing respite care for children with an ASD were eligible for inclusion. A meta-aggregative approach was used during data synthesis. RESULTS: Database searching elicited 430 records of which 291 studies remained after removal of duplicates. These 291 studies were screened for title and abstract by two reviewers resulting in 31 studies to be screened at full text and assessed for eligibility. Six studies met the inclusion criteria and a further additional study also met the inclusion criteria during a manual search. As a result, 7 studies were selected for the review as set out in Fig. 1. CONCLUSION: In the absence of appropriate services and defined pathways to support services such as respite care, overwhelmed parents and community providers of mental health resources may not be in a position to meet the specific needs of children with an ASD and their families which may be contributing to a direct increase in hospitalizations. This systematic review identified a number of barriers to respite care, of which the findings can be used to inform future service development and further research. Knowledge of parental experiences in caring for a child with an ASD is vital in addressing the need and type of respite care required for children with an ASD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106629.

Discovery of 2,6-disubstituted pyrazine derivatives as inhibitors of CK2 and PIM kinases.

The design and synthesis of a novel series of 2,6-disubstituted pyrazine derivatives as CK2 kinase inhibitors is described. Structure-guided optimization of a 5-substituted-3-thiophene carboxylic acid screening hit (3a) led to the development of a lead compound (12b), which shows inhibition in both enzymatic and cellular assays. Subsequent design and hybridization efforts also led to the unexpected identification of analogs with potent PIM kinase activity (14f).

Arabidopsis defense against Botrytis cinerea: chronology and regulation deciphered by high-resolution temporal transcriptomic analysis.

Transcriptional reprogramming forms a major part of a plant's response to pathogen infection. Many individual components and pathways operating during plant defense have been identified, but our knowledge of how these different components interact is still rudimentary. We generated a high-resolution time series of gene expression profiles from a single Arabidopsis thaliana leaf during infection by the necrotrophic fungal pathogen Botrytis cinerea. Approximately one-third of the Arabidopsis genome is differentially expressed during the first 48 h after infection, with the majority of changes in gene expression occurring before significant lesion development. We used computational tools to obtain a detailed chronology of the defense response against B. cinerea, highlighting the times at which signaling and metabolic processes change, and identify transcription factor families operating at different times after infection. Motif enrichment and network inference predicted regulatory interactions, and testing of one such prediction identified a role for TGA3 in defense against necrotrophic pathogens. These data provide an unprecedented level of detail about transcriptional changes during a defense response and are suited to systems biology analyses to generate predictive models of the gene regulatory networks mediating the Arabidopsis response to B. cinerea.

A local regulatory network around three NAC transcription factors in stress responses and senescence in Arabidopsis leaves.

A model is presented describing the gene regulatory network surrounding three similar NAC transcription factors that have roles in Arabidopsis leaf senescence and stress responses. ANAC019, ANAC055 and ANAC072 belong to the same clade of NAC domain genes and have overlapping expression patterns. A combination of promoter DNA/protein interactions identified using yeast 1-hybrid analysis and modelling using gene expression time course data has been applied to predict the regulatory network upstream of these genes. Similarities and divergence in regulation during a variety of stress responses are predicted by different combinations of upstream transcription factors binding and also by the modelling. Mutant analysis with potential upstream genes was used to test and confirm some of the predicted interactions. Gene expression analysis in mutants of ANAC019 and ANAC055 at different times during leaf senescence has revealed a distinctly different role for each of these genes. Yeast 1-hybrid analysis is shown to be a valuable tool that can distinguish clades of binding proteins and be used to test and quantify protein binding to predicted promoter motifs.

How Should Technology-Dependent Patients' Care Be Managed Collaboratively to Avoid Turfing?

Technology-dependent patients require interventions (eg, tracheostomies, gastrostomy tubes, or total parenteral nutrition) to survive. Such patients are commonly "turfed" between general services or from subspecialty to general services within the hospital. This case commentary proposes several explanations for why technology-dependent patients are particularly susceptible to turfing, including clinicians' lack of familiarity with managing patients' technology, bias and ableism, and quality-of-life quandaries. It also addresses ways to combat turfing of technology-dependent patients and proposes educational strategies for managing common problems in the care of technology-dependent patients.

Communicating the complex lives of families that include a child with Down syndrome.

Families of children with Down syndrome experience complex lives and needs, yet the few existing studies on these families are written in conventional academic prose that is not optimal for knowledge translation beyond academia, particularly for busy healthcare professionals. In this paper, we Depart Radically in Academic Writing (DRAW) (Mackinlay, 2022) and present data poetry and two case studies that draw upon semi-structured interviews with mothers, fathers, and siblings, who were interviewed separately about their experiences of having a child/sibling with Down syndrome. We introduce our interdisciplinary team that includes academics and clinicians to contextualise our focus on research translation. We demonstrate that writing with creative criticality (i.e. 'DRAWing') contributes an embodied and affective understanding of research participants' stories, which is largely lacking in the academic literature on families of children with Down syndrome and the sociology of health and illness field more broadly. Moreover, DRAWing can impact audiences emotionally as well as intellectually (Richardson, 2003, p. 924), which has important knowledge translation implications for both healthcare professionals and these families. DRAWing can capture healthcare professionals' attention, prompting them to critically reflect on their practices and opportunities for improving care and treatment for these families.

Siblings' experiences of sleep disruption in families with a child with Down syndrome.

OBJECTIVE: Adverse effects of sleep disruption are identified in parents who live with a child with Down Syndrome (DS), yet there is no research on siblings' experiences. This study addresses this knowledge gap. DESIGN: A qualitative research study using semi-structured interviews to understand the experiences of siblings of a child with DS and sleep difficulties from the perspectives of parents and siblings. PARTICIPANTS: Eleven siblings aged 5-15 years old, and 11 parents, from 8 families with a child with DS in Australia. METHODS: Semi-structured sibling interviews explored what it was like to have a sibling with DS and sleep difficulties; the participant's own sleep; how their sleep affected how they felt during the day; how sleep impacted their family; and advice that they would give to other siblings. Parent interviews included similar topics; here we report on excerpts in which parents reference siblings. Interviews were audio recorded, transcribed verbatim, and analyzed using a reflexive thematic analysis. RESULTS: Siblings and parents acknowledge sleep disruption for siblings; yet sleep disruption is normalized, viewed with acceptance and inevitability. Siblings report adverse effects from sleep disruption, view sleep in a relational way, and cope with sleep disruption. Parents can underestimate siblings' sleep disruption and are uncertain whether siblings' symptoms result from sleep disruption or other causes. CONCLUSIONS: Siblings of a child with DS experience sleep disruption and may be at risk of developing long-term health problems without focused support.

Ethics of Health Information Sharing and Social Relationships at End of Life in Assisted Living.

Given an observed tension between perceived privacy restrictions and meaningful social connection in assisted living (AL) and using a relational perspective, we conducted a secondary thematic analysis of health information sharing practices among residents and their care partners in one large urban AL community in metropolitan Atlanta. Data included in-depth interviews with residents (n = 26), family members (n = 20), AL staff (n = 11), and external care workers (n = 4) as well as ethnographic data from observations and informal conversations conducted with these participants and others. Findings showed that health information sharing among residents was helpful in building social relationships; barriers to this communication contributed to isolation. Inappropriate public exchange of residents' healthcare information hindered building these relationships. Negotiating privacy boundaries for health information sharing was an ongoing confusing process across the community. Based on the findings, we propose new guidelines for health information sharing and additional privacy training for residents and care partners.

Safety of integrated preventive chemotherapy for neglected tropical diseases.

BACKGROUND: Preventive chemotherapy (PC) is a central strategy for control and elimination of neglected tropical diseases (NTDs). Increased emphasis has been given to "integration" of NTD programs within health systems and coadministration of NTD drugs offers significant programmatic benefits. Guidance from the World Health Organization (WHO) reflects current evidence for safe drug coadministration and highlights measures to prevent choking of young children during PC. METHODOLOGY: To understand how coadministration of NTD drugs might affect PC safety, we reviewed literature on choking risk in young children and safety of coadministered NTD drugs. To understand current practices of drug coadministration, we surveyed 15 NTD program managers and implementing partners. PRINCIPAL FINDINGS: In high-income countries, choking on medication is an infrequent cause of death in young children. In low-resource settings, data are limited, but age-appropriate drug formulations are less available. During PC, fatal choking, although infrequent, occurs primarily in young children; forcing them to swallow tablets appears to be the major risk factor. The WHO currently recommends 6 drugs and 5 possible drug combinations for use in PC. Of 105 nations endemic for the 5 PC-NTDs, 72 (68.6%) are co-endemic for 2 or more diseases and could benefit from drug coadministration during PC. All 15 survey respondents reported coadministering medications during PC. Reported responses to a child refusing to take medicine included: not forcing the child to do so (60.0%), encouraging the child (46.7%), bringing the child back later (26.7%), offering powder for oral suspension (POS) for azithromycin (13.3%), and having parents or community members intervene to calm the child (6.7%). CONCLUSIONS: Coadministration of NTD drugs during PC appears to be increasingly common. Safety of coadministered PC drugs requires attention to choking prevention, use of approved drug combinations, and increased access to age-appropriate drug formulations.

Bayesian hierarchical clustering for microarray time series data with replicates and outlier measurements.

BACKGROUND: Post-genomic molecular biology has resulted in an explosion of data, providing measurements for large numbers of genes, proteins and metabolites. Time series experiments have become increasingly common, necessitating the development of novel analysis tools that capture the resulting data structure. Outlier measurements at one or more time points present a significant challenge, while potentially valuable replicate information is often ignored by existing techniques. RESULTS: We present a generative model-based Bayesian hierarchical clustering algorithm for microarray time series that employs Gaussian process regression to capture the structure of the data. By using a mixture model likelihood, our method permits a small proportion of the data to be modelled as outlier measurements, and adopts an empirical Bayes approach which uses replicate observations to inform a prior distribution of the noise variance. The method automatically learns the optimum number of clusters and can incorporate non-uniformly sampled time points. Using a wide variety of experimental data sets, we show that our algorithm consistently yields higher quality and more biologically meaningful clusters than current state-of-the-art methodologies. We highlight the importance of modelling outlier values by demonstrating that noisy genes can be grouped with other genes of similar biological function. We demonstrate the importance of including replicate information, which we find enables the discrimination of additional distinct expression profiles. CONCLUSIONS: By incorporating outlier measurements and replicate values, this clustering algorithm for time series microarray data provides a step towards a better treatment of the noise inherent in measurements from high-throughput genomic technologies. Timeseries BHC is available as part of the R package 'BHC' (version 1.5), which is available for download from Bioconductor (version 2.9 and above) via http://www.bioconductor.org/packages/release/bioc/html/BHC.html?pagewanted=all.

Computational approaches to the integration of gene expression, ChIP-chip and sequence data in the inference of gene regulatory networks.

A major challenge in systems biology is the ability to model complex regulatory interactions, such as gene regulatory networks, and a number of computational approaches have been developed over recent years to address this challenge. This paper reviews a number of these approaches, with a focus on probabilistic graphical models and the integration of diverse data sets, such as gene expression and transcription factor binding site location and activity.

The effects of increased dose of exercise-based therapies to enhance motor recovery after stroke: a systematic review and meta-analysis.

BACKGROUND: Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. To determine the strength of current evidence for provision of a higher dose of the same types of exercise-based therapy to enhance motor recovery after stroke. METHODS: An electronic search of: MEDLINE, EMBASE, CINHAL, AMED, and CENTRAL was undertaken. Two independent reviewers selected studies using predetermined inclusion criteria: randomised or quasi randomised controlled trials with or without blinding of assessors; adults, 18+ years, with a clinical diagnosis of stroke; experimental and control group interventions identical except for dose; exercise-based interventions investigated; and outcome measures of motor impairment, movement control or functional activity. Two reviewers independently extracted outcome and follow-up data. Effect sizes and 95% confidence intervals were interpreted with reference to risk of bias in included studies. RESULTS: 9 papers reporting 7 studies were included. Only 3 of the 7 included studies had all design elements assessed as low risk of bias. Intensity of the control intervention ranged from a mean of 9 to 28 hours over a maximum of 20 weeks. Experimental groups received between 14 and 92 hours of therapy over a maximum of 20 weeks. The included studies were heterogeneous with respect to types of therapy, outcome measures and time-points for outcome and follow-up. Consequently, most effect sizes relate to one study only. Single study effect sizes suggest a trend for better recovery with increased dose at the end of therapy but this trend was less evident at follow-up Meta-analysis was possible at outcome for: hand-grip strength, -10.1 [-19.1,-1.2] (2 studies, 97 participants); Action Research Arm Test (ARAT), 0.1 [-5.7,6.0] (3 studies, 126 participants); and comfortable walking speed, 0.3 [0.1,0.5] (2 studies, 58 participants). At follow-up, between 12 and 26 weeks after start of therapy, meta-analysis findings were: Motricity Arm, 10.7 [1.7,19.8] (2 studies, 83 participants); ARAT, 2.2 [-6.0,10.4] (2 studies, 83 participants); Rivermead Mobility, 1.0 [-0.6, 2.5] (2 studies, 83 participants); and comfortable walking speed, 0.2 [0.0,0.4] (2 studies, 60 participants). CONCLUSIONS: Current evidence provides some, but limited, support for the hypothesis that a higher dose of the same type of exercised-based therapy enhances motor recovery after stroke. Prospective dose-finding studies are required.

Spatial variation of mercury bioaccumulation in bats of Canada linked to atmospheric mercury deposition.

Wildlife are exposed to neurotoxic mercury at locations distant from anthropogenic emission sources because of long-range atmospheric transport of this metal. In this study, mercury bioaccumulation in insectivorous bat species (Mammalia: Chiroptera) was investigated on a broad geographic scale in Canada. Fur was analyzed (n=1178) for total mercury from 43 locations spanning 20° latitude and 77° longitude. Total mercury and methylmercury concentrations in fur were positively correlated with concentrations in internal tissues (brain, liver, kidney) for a small subset (n=21) of little brown bats (Myotis lucifugus) and big brown bats (Eptesicus fuscus), validating the use of fur to indicate internal mercury exposure. Brain methylmercury concentrations were approximately 10% of total mercury concentrations in fur. Three bat species were mainly collected (little brown bats, big brown bats, and northern long-eared bats [M. septentrionalis]), with little brown bats having lower total mercury concentrations in their fur than the other two species at sites where both species were sampled. On average, juvenile bats had lower total mercury concentrations than adults but no differences were found between males and females of a species. Combining our dataset with previously published data for eastern Canada, median total mercury concentrations in fur of little brown bats ranged from 0.88-12.78µg/g among 11 provinces and territories. Highest concentrations were found in eastern Canada where bats are most endangered from introduced disease. Model estimates of atmospheric mercury deposition indicated that eastern Canada was exposed to greater mercury deposition than central and western sites. Further, mean total mercury concentrations in fur of adult little brown bats were positively correlated with site-specific estimates of atmospheric mercury deposition. This study provides the largest geographic coverage of mercury measurements in bats to date and indicates that atmospheric mercury deposition is important in determining spatial patterns of mercury accumulation in a mammalian species.

Transitional care for young people with diabetes: policy and practice.

Young people with diabetes inevitably require transfer to adult services. Adult clinics differ from paediatric clinics and therefore a smooth, planned process of transition is required. Adolescence can be especially difficult for young people with diabetes and research evidence highlights the need for individualised approaches to this transition. Health policy related to diabetes services emphasises the importance of good transition and guidelines are available to inform service development and improvement. Local services in one district in England appear to reflect policy, guidelines and evidence but there a number of actions that could be taken to further improve transitional care both locally and nationally.

Alcohol marketing and young people's drinking: a review of the research.

The influence of alcohol advertising on young people continues to be the subject of much debate. This paper presents a review of the literature showing that, while many econometric studies suggest little effect, more focused consumer studies, especially recent ones with sophisticated designs, do show clear links between advertising and behaviour. Furthermore, these effects have to be viewed in combination with the possible impact of other marketing activities such as price promotions, distribution, point of sale activity and new product development. Here, the evidence base is less well developed, but there are indications of effects. It must be acknowledged that categorical statements of cause and effect are always difficult in the social sciences; marketing is a complex phenomenon involving the active participation of consumers as well as marketers and more research is needed on its cumulative impact. Nonetheless, the literature presents an increasingly compelling picture that alcohol marketing is having an effect on young people's drinking.

Accelerating Bayesian hierarchical clustering of time series data with a randomised algorithm.

We live in an era of abundant data. This has necessitated the development of new and innovative statistical algorithms to get the most from experimental data. For example, faster algorithms make practical the analysis of larger genomic data sets, allowing us to extend the utility of cutting-edge statistical methods. We present a randomised algorithm that accelerates the clustering of time series data using the Bayesian Hierarchical Clustering (BHC) statistical method. BHC is a general method for clustering any discretely sampled time series data. In this paper we focus on a particular application to microarray gene expression data. We define and analyse the randomised algorithm, before presenting results on both synthetic and real biological data sets. We show that the randomised algorithm leads to substantial gains in speed with minimal loss in clustering quality. The randomised time series BHC algorithm is available as part of the R package BHC, which is available for download from Bioconductor (version 2.10 and above) via http://bioconductor.org/packages/2.10/bioc/html/BHC.html. We have also made available a set of R scripts which can be used to reproduce the analyses carried out in this paper. These are available from the following URL. https://sites.google.com/site/randomisedbhc/.

Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo.

In this letter, we describe the design, synthesis, and structure-activity relationship of 5-anilinopyrazolo[1,5-a]pyrimidine inhibitors of CK2 kinase. Property-based optimization of early leads using the 7-oxetan-3-yl amino group led to a series of matched molecular pairs with lower lipophilicity, decreased affinity for human plasma proteins, and reduced binding to the hERG ion channel. Agents in this study were shown to modulate pAKT(S129), a direct substrate of CK2, in vitro and in vivo, and exhibited tumor growth inhibition when administered orally in a murine DLD-1 xenograft.

Potent and Selective Inhibitors of CK2 Kinase Identified through Structure-Guided Hybridization.

In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.