The heterogeneous genetic architectures of orofacial clefts.

Orofacial clefts (OFCs) are common, affecting 1:1000 live births. OFCs occur across a phenotypic spectrum - including cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP) - and can be further subdivided based on laterality, severity, or specific structures affected. Herein we review what is known about the genetic architecture underlying each of these subtypes, considering both shared and subtype-specific risks. While there are more known genetic similarities between CL and CLP than CP, recent research supports both shared and subtype-specific genetic risk factors within and between phenotypic classifications of OFCs. Larger sample sizes and deeper phenotyping data will be of increasing importance for the discovery of novel genetic risk factors for OFCs and various subtypes going forward.

Developing a Global Strategy for strengthening the occupational therapy workforce: a two-phased mixed-methods consultation of country representatives shows the need for clarifying task-sharing strategies.

INTRODUCTION: Occupational therapy has been underdeveloped and often neglected in the global health workforce agenda, contrasting with the global rise of population needs for services. The World Federation of Occupational Therapists (WFOT) is utilizing a research-based, multi-step process for developing a Global Strategy for strengthening the occupational therapist workforce. A multi-pronged scoping review, situational analysis, and expert input process enabled the drafting of a provisional Global Strategy. Here, feedback on that draft from representatives of WFOT member organizations was obtained and analyzed as one key intermediate step toward shaping the in-developing Strategy's content and structure. METHODS: Two-phased, mixed-methods consultation consisting of: (1) online survey with score ratings and comments on the utility of each strategy and (2) four in-person focus groups discussions on low-scoring items involving a total of 76 representatives of WFOT member organizations. The focus group discussions were analyzed using an inductive thematic analysis approach. RESULTS: Strategies involving 'task shifting/task sharing' or the 'harmonization of workforce data-collection requirements' received the lowest scores in the initial survey and were thereby addressed in the focus groups discussions. The overarching theme of the focus groups was the need to: "clarify, specify, and contextualize the strategies", including: (1) "clarify the terminology and specify the application", for example, describe the meaning of task shifting, specify which tasks can (and cannot) be shifted and to whom, to address concerns regarding scope-of-practice, service demand, and safety; and (2) "outline the context of need and the context for the implementation" of the strategies, elucidating why the strategies are needed and how they can be feasibly implemented across the different jurisdictional contexts. CONCLUSION: Within a mixed-methods consultation, WFOT representatives identified challenging topics on the draft workforce strategies and suggested methods to improve the Global Strategy, its acceptability, and implementation. The terms 'task shifting/task sharing' raised the greatest discussion among the profession leaders, when the strategy was not sufficiently clarified, specified, or contextualized.

Sibling adjustment to diabetes and educational needs: A literature review.

ABSTRACT: As cases of type 1 diabetes mellitus (T1DM) increase, so do their impact on sibling relationships. This literature review of four databases from 2010 to 2024 discusses findings from five studies and the themes that emerged: education needs and family functioning. Improvements in family-centered care and education are needed for siblings of children with T1DM.

Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes.

As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to test for genetic modifiers of cleft lip (CL) vs cleft lip and palate (CLP). We found that there was a significantly increased burden of rare variants in SEC24D in CL cases compared to CLP cases (p = 6.86 [Formula: see text] 10-7). Of the 15 variants within SEC24D, 53.3% were synonymous, but overlapped a known craniofacial enhancer. We then tested whether these variants could alter predicted transcription factor binding sites (TFBS), and found that the rare alleles destroyed binding sites for 9 transcription factors (TFs), including Pax1 (p = 0.0009), and created binding sites for 23 TFs, including Pax6 (p = 6.12 [Formula: see text] 10-5) and Pax9 (p = 0.0001), which are known to be involved in normal craniofacial development, suggesting a potential mechanism by which these synonymous variants could have a functional impact. Overall, this study indicates that rare genetic variation may contribute to the phenotypic heterogeneity of OFCs and suggests that regulatory variation may also contribute and warrant further investigation in future studies of genetic variants controlling risk to OFC.

Rare variants found in clinical gene panels illuminate the genetic and allelic architecture of orofacial clefting.

PURPOSE: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls. METHODS: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria. RESULTS: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance. CONCLUSION: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs.

Elimination of PBB-153; findings from a cohort of Michigan adults.

BACKGROUND: An industrial accident led to the widespread contamination of polybrominated biphenyl (PBB), a flame retardant, into the food system in Michigan in the 1970's. PBB continues to be detected in Michiganders' blood some forty years later. It is necessary to understand the elimination rate and half-life of PBB because it may provide clues on how to hasten the elimination of it from the human body. METHODS: Serum samples were taken from young adult and adult participants of the Michigan PBB registry from 1974 to 2019. A single compartment model was assumed for the elimination rate for PBB-153 in young adults and adults (≥16 years). Generalized linear mixed models were used to estimate the average elimination rate of PBB-153 and allowed for a random intercept and slope for the time between measurements. Models were adjusted for age at exposure, body mass index (BMI) at initial measurement, and smoking. Models were also stratified by demographic characteristics. RESULTS: In total, 1974 participants contributed 4768 samples over a forty-year span. The median initial PBB-153 level was 1.542 parts per billion (ppb) (Range: 0.001-1442.48 ppb). The adjusted median participant-specific half-life for PBB-153 was 12.23 years. The half-life of PBB-153 was lengthened by higher initial PBB level (∼1.5 years), younger age at exposure (∼5.4 years), higher BMI (∼1.0 years), and increased gravidity (∼7.3 years). Additionally, the half-life of PBB-153 was shortened by smoking status (∼-2.8 years) and breastfeeding (∼-3.5 years). CONCLUSIONS: Consistent with previous studies, PBB-153 has been demonstrated to have a long half-life in the human body and may be modified by some demographic characteristics. These updated estimates of half-life will further support evaluation of health effects associated with PBB exposure. Investigations into mechanisms to accelerate elimination and reduce body burdens of PBB-153, especially those related to body weight, are needed.

Engineered Chimeras Unveil Swappable Modular Features of Fatty Acid and Polyketide Synthase Acyl Carrier Proteins.

The strategic redesign of microbial biosynthetic pathways is a compelling route to access molecules of diverse structure and function in a potentially environmentally sustainable fashion. The promise of this approach hinges on an improved understanding of acyl carrier proteins (ACPs), which serve as central hubs in biosynthetic pathways. These small, flexible proteins mediate the transport of molecular building blocks and intermediates to enzymatic partners that extend and tailor the growing natural products. Past combinatorial biosynthesis efforts have failed due to incompatible ACP-enzyme pairings. Herein, we report the design of chimeric ACPs with features of the actinorhodin polyketide synthase ACP (ACT) and of the Escherichia coli fatty acid synthase (FAS) ACP (AcpP). We evaluate the ability of the chimeric ACPs to interact with the E. coli FAS ketosynthase FabF, which represents an interaction essential to building the carbon backbone of the synthase molecular output. Given that AcpP interacts with FabF but ACT does not, we sought to exchange modular features of ACT with AcpP to confer functionality with FabF. The interactions of chimeric ACPs with FabF were interrogated using sedimentation velocity experiments, surface plasmon resonance analyses, mechanism-based cross-linking assays, and molecular dynamics simulations. Results suggest that the residues guiding AcpP-FabF compatibility and ACT-FabF incompatibility may reside in the loop I, α-helix II region. These findings can inform the development of strategic secondary element swaps that expand the enzyme compatibility of ACPs across systems and therefore represent a critical step toward the strategic engineering of "un-natural" natural products.

FAT4 identified as a potential modifier of orofacial cleft laterality.

Orofacial clefts (OFCs) are common (1 in 700 births) congenital malformations that include a cleft lip (CL) and cleft lip and palate (CLP). These OFC subtypes are also heterogeneous themselves, with the CL occurring on the left, right, or both sides of the upper lip. Unilateral CL and CLP have a 2:1 bias towards left-sided clefts, suggesting a nonrandom process. Here, we performed a study of left- and right-sided clefts within the CL and CLP subtypes to better understand the genetic factors controlling cleft laterality. We conducted genome-wide modifier analyses by comparing cases that had right unilateral CL (RCL; N = 130), left unilateral CL (LCL; N = 216), right unilateral CLP (RCLP; N = 416), or left unilateral CLP (LCLP; N = 638), and identified a candidate region on 4q28, 400 kb downstream from FAT4, that approached genome-wide significance for LCL versus RCL (p = 8.4 × 10-8 ). Consistent with its potential involvement as a genetic modifier of CL, we found that Fat4 exhibits a specific domain of expression in the mesenchyme of the medial nasal processes that form the median upper lip. Overall, these results suggest that the epidemiological similarities in left- to right-sided clefts in CL and CLP are not reflected in the genetic association results.

Efficient estimation of indirect effects in case-control studies using a unified likelihood framework.

Mediation models are a set of statistical techniques that investigate the mechanisms that produce an observed relationship between an exposure variable and an outcome variable in order to deduce the extent to which the relationship is influenced by intermediate mediator variables. For a case-control study, the most common mediation analysis strategy employs a counterfactual framework that permits estimation of indirect and direct effects on the odds ratio scale for dichotomous outcomes, assuming either binary or continuous mediators. While this framework has become an important tool for mediation analysis, we demonstrate that we can embed this approach in a unified likelihood framework for mediation analysis in case-control studies that leverages more features of the data (in particular, the relationship between exposure and mediator) to improve efficiency of indirect effect estimates. One important feature of our likelihood approach is that it naturally incorporates cases within the exposure-mediator model to improve efficiency. Our approach does not require knowledge of disease prevalence and can model confounders and exposure-mediator interactions, and is straightforward to implement in standard statistical software. We illustrate our approach using both simulated data and real data from a case-control genetic study of lung cancer.

A data linkage study of the effects of the Great Recession and austerity on antidepressant prescription usage.

BACKGROUND: International literature shows unemployment and income loss during the Great Recession worsened population mental health. This individual-level longitudinal study examines how regional economic trends and austerity related to depression using administrative prescription data for a large and representative population sample. METHODS: Records from a sample of the Scottish Longitudinal Study (N=86 500) were linked to monthly primary care antidepressant prescriptions (2009-15). Regional economic trends were characterized by annual full-time employment data (2004-14). Economic impact of austerity was measured via annual income lost per working age adult due to welfare reforms (2010-15). Sequence analysis identified new cases of antidepressant use, and group-based trajectory modelling classified regions into similar economic trajectories. Multi-level logistic regression examined relationships between regional economic trends and new antidepressant prescriptions. Structural equation mediation analysis assessed the contributory role of welfare reforms. RESULTS: Employed individuals living in regions not recovering post-recession had the highest risk of beginning a new course of antidepressants (AOR 1.23; 95% CI 1.08-1.38). Individuals living in areas with better recovery trajectories had the lowest risk. Mediation analyses showed that 50% (95% CI 7-61%) of this association was explained by the impact of welfare benefit reforms on average incomes. CONCLUSIONS: Following the Great Recession, local labour market decline and austerity measures were associated with growing antidepressant usage, increasing regional inequalities in mental health. The study evidences the impact of austerity on health inequalities and suggests that economic conditions and welfare policies impact on population health. Reducing the burden of mental ill-health primarily requires action on the social determinants.

Test Characteristics of Cerebrospinal Fluid Gram Stain to Identify Bacterial Meningitis in Infants Younger Than 60 Days.

ABSTRACT: In our cohort of 20,947 infants aged 60 days or younger, cerebrospinal fluid Gram stain had a sensitivity of 34.3% (95% confidence interval, 28.1%-41.1%) and a positive predictive value of 61.4% (95% confidence interval, 52.2%-69.8%) for positive cerebrospinal fluid culture, suggesting that Gram stain alone may lead to both underdiagnosis and overdiagnosis of bacterial meningitis.

A randomized trial of iPad distraction to reduce children's pain and distress during intravenous cannulation in the paediatric emergency department.

OBJECTIVES: We compared the addition of iPad distraction to standard care, versus standard care alone, to manage the pain and distress of intravenous (IV) cannulation. METHODS: Eighty-five children aged 6 to 11 years requiring IV cannulation (without child life services present) were recruited for a randomized controlled trial from a paediatric emergency department. Primary outcomes were self-reported pain (Faces Pain Scale-Revised [FPS-R]) and distress (Observational Scale of Behavioral Distress-Revised [OSBD-R]), analyzed with two-sample t-tests, Mann-Whitney U-tests, and regression analysis. RESULTS: Forty-two children received iPad distraction and 43 standard care; forty (95%) and 35 (81%) received topical anesthesia, respectively (P=0.09). There was no significant difference in procedural pain using an iPad (median [interquartile range]: 2.0 [0.0, 6.0]) in addition to standard care (2.0 [2.0, 6.0]) (P=0.35). There was no significant change from baseline behavioural distress using an iPad (mean ± SD: 0.53 ± 1.19) in addition to standard care (0.43 ± 1.56) (P=0.44). Less total behavioural distress was associated with having prior emergency department visits (odds ratio [95% confidence interval]: -1.90 [-3.37, -0.43]) or being discharged home (-1.78 [-3.04, -0.52]); prior hospitalization was associated with greater distress (1.29 [0.09, 2.49]). Significantly more parents wished to have the same approach in the future in the iPad arm (41 of 41, 100%) compared to standard care (36 of 42, 86%) (P=0.03). CONCLUSIONS: iPad distraction during IV cannulation in school-aged children was not associated with less pain or distress than standard care alone. The effects of iPad distraction may have been blunted by topical anesthetic cream usage. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: NCT02326623.

Screening for chronic kidney disease: moving toward more sustainable health care.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is a pervasive and growing health concern that has a significant impact on mortality and morbidity, putting stress on global healthcare systems. CKD affects ∼14% of general populations and ∼36% of high-risk populations and is projected to rise in the coming decade due to increasing rates of diabetes and hypertension. RECENT FINDINGS: Screen, triage, and treat programs aim to detect early stage disease with the intention of promoting medical and lifestyle interventions in line with a patient's level of risk that may slow disease progression and reduce morbidity and mortality. Early detection facilitates appropriate risk stratification and coordination of care among patients, primary care and nephrology ensuring resources are utilized appropriately. SUMMARY: By using readily available laboratory measures, screening for CKD in high-risk populations is cost effective and beneficial to both individuals and healthcare systems. Program models such as Kidney Early Evaluation Program and First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis have proven the efficacy of screening initiatives in these groups, but improvements are required to maximize the benefits of early CKD detection.

Predictors of moving on from mental health supported accommodation in England: national cohort study.

BACKGROUND: Around 60 000 people in England live in mental health supported accommodation. There are three main types: residential care, supported housing and floating outreach. Supported housing and floating outreach aim to support service users in moving on to more independent accommodation within 2 years, but there has been little research investigating their effectiveness. AIMS: A 30-month prospective cohort study investigating outcomes for users of mental health supported accommodation. METHOD: We used random sampling, accounting for relevant geographical variation factors, to recruit 87 services (22 residential care, 35 supported housing and 30 floating outreach) and 619 service users (residential care 159, supported housing 251, floating outreach 209) across England. We contacted services every 3 months to investigate the proportion of service users who successfully moved on to more independent accommodation. Multilevel modelling was used to estimate how much of the outcome and cost variations were due to service type and quality, after accounting for service-user characteristics. RESULTS: Overall 243/586 participants successfully moved on (residential care 15/146, supported housing 96/244, floating outreach 132/196). This was most likely for floating outreach service users (versus residential care: odds ratio 7.96, 95% CI 2.92-21.69, P < 0.001; versus supported housing: odds ratio 2.74, 95% CI 1.01-7.41, P < 0.001) and was associated with reduced costs of care and two aspects of service quality: promotion of human rights and recovery-based practice. CONCLUSIONS: Most people do not move on from supported accommodation within the expected time frame. Greater focus on human rights and recovery-based practice may increase service effectiveness.

Development of a Kribbella-specific isolation medium and description of Kribbella capetownensis sp. nov. and Kribbella speibonae sp. nov., isolated from soil.

Two actinobacterial strains were isolated from samples collected from the University of Cape Town, South Africa. A third actinobacterial strain was isolated from soil collected in the town of Stellenbosch, South Africa, using a newly-developed Kribbella-selective medium. Analysis of the 16S rRNA genes showed that the three strains belonged to the genus Kribbella. A multilocus sequence analysis using the concatenated gene sequences of the gyrB, rpoB, relA, recA and atpD genes showed that strains YM55T and SK5 were most closely related to the type strains of Kribbella sindirgiensis and Kribbella soli, while strain YM53T was most closely related to the type strain of Kribbella pittospori. Digital DNA-DNA hybridisation and Average Nucleotide Identity (ANI) analyses showed that strains YM55T and SK5 belong to the same genomic species (OrthoANI value = 98.4%), but are distinct from the genomic species represented by the type strains of K. sindirgiensis (OrthoANI values < 95.6%) and K. soli (OrthoANI values < 91.4%). Strain YM53T is distinct from the genomic species represented by the type strain of K. pittospori (OrthoANI value = 94.0%). Phenotypic comparisons showed that strains YM55T and SK5 are distinct from the type strains of K. sindirgiensis and K. soli and that strain YM53T is distinct from the type strain of K. pittospori. Strains YM53T and YM55T are thus presented as the type strains of novel species, for which the names Kribbella capetownensis sp. nov. (= DSM 29426T = NRRL B-65062T) and Kribbella speibonae sp. nov. (= DSM 29425T = NRRL B-59161T), respectively, are proposed.

Use of sequence analysis for classifying individual antidepressant trajectories to monitor population mental health.

BACKGROUND: Over the past decade, antidepressant prescriptions have increased in European countries and the United States, partly due to an increase in the number of new cases of mental illness. This paper demonstrates an innovative approach to the classification of population level change in mental health status, using administrative data for a large sample of the Scottish population. We aimed to identify groups of individuals with similar patterns of change in pattern of prescribing, validate these groups by comparison with other indicators of mental illness, and characterise the population most at risk of increasing mental ill health. METHODS: National Health Service (NHS) prescription data were linked to the Scottish Longitudinal Study (SLS), a 5.3% sample of the Scottish population (N = 151,418). Antidepressant prescription status over the previous 6 months was recorded for every month for which data were available (January 2009-December 2014), and sequence dissimilarity was computed by optimal matching. Hierarchical clustering was used to create groups of participants who had similar patterns of change, with multi-level logistic regression used to understand group membership. RESULTS: Five distinct prescription pattern groups were observed, indicating: no prescriptions (76%), occasional prescriptions (10%), continuation of prior use of prescriptions (8%), a new course of prescriptions started (4%) or ceased taking prescriptions (3%). Young, white, female participants, of low social grade, residing in socially deprived neighbourhoods, living alone, being separated/divorced or out of the labour force, were more likely to be in the group that started a new course of antidepressant prescriptions. CONCLUSIONS: The use of sequence analysis for classifying individual antidepressant trajectories offers a novel approach for capturing population-level changes in mental health risk. By classifying individuals into groups based on their anti-depressant medication use we can better identify how over time, mental health is associated with individual risk factors and contextual factors at the local level and the macro political and economic scale.

Assay in serum of exchangeable copper and total copper using inductively coupled plasma mass spectrometry (ICP-MS): development, optimisation and evaluation of a routine procedure.

The assay in serum of non-caeruloplasmin copper, as exchangeable copper after complexation with EDTA (ExCu) and total copper has been evaluated and compared in patients with varying c-reactive protein(CRP). Measurement of ExCu and total copper, range 0.2-47.2 µmol/L, was developed using ICP-MS. The chelating agents EDTA and TEPA were compared over 0.0-10 g/L after incubation with serum for 60 mins followed by ultrafiltration with Amicon 10 kDa filter. The assay for ExCu was optimised with EDTA 3 g/L (8.1 mmol/L) maintained at pH 7.0-8.0 before ultrafiltration. TEPA was not as selective in chelation of copper. Patients n = 82 were studied in relation to changes in inflammatory marker CRP and a group of patients n = 37 with normal CRP. The ExCu assay gave excellent recoveries (94-102 % but poor recovery for free uncomplexed copper), good repeatability, limit of quantitation 0.19 µmol/l with a provisional reference range 0.48 to 1.63 µmol/L (n = 37 patients). The range for relative exchangeable copper (exchangeable copper divided by total serum copper) was 2.49 to 9.96 %. ExCu was elevated in conditions with increased CRP greater than 100 mg/L suggesting an effect of inflammation on the free copper fraction. A reliable and reproducible assay for ExCu and total copper has been developed. The upregulated inflammatory state increases the ExCu suggesting excess free copper.

Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis.

PURPOSE: Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS: Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the ß value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS: In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. CONCLUSION: We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).

Effect of Nebulized Magnesium vs Placebo Added to Albuterol on Hospitalization Among Children With Refractory Acute Asthma Treated in the Emergency Department: A Randomized Clinical Trial.

Importance: While intravenous magnesium decreases hospitalizations in refractory pediatric acute asthma, it is variably used because of invasiveness and safety concerns. The benefit of nebulized magnesium to prevent hospitalization is unknown. Objective: To evaluate the effectiveness of nebulized magnesium in children with acute asthma remaining in moderate or severe respiratory distress after initial therapy. Design, Setting, and Participants: A randomized double-blind parallel-group clinical trial from September 26, 2011, to November 19, 2019, in 7 tertiary-care pediatric emergency departments in Canada. The participants were otherwise healthy children aged 2 to 17 years with moderate to severe asthma defined by a Pediatric Respiratory Assessment Measure (PRAM) score of 5 or greater (on a 12-point scale) after a 1-hour treatment with an oral corticosteroid and 3 inhaled albuterol and ipratropium treatments. Of 5846 screened patients, 4332 were excluded for criteria, 273 declined participation, 423 otherwise excluded, 818 randomized, and 816 analyzed. Interventions: Participants were randomized to 3 nebulized albuterol treatments with either magnesium sulfate (n = 410) or 5.5% saline placebo (n = 408). Main Outcomes and Measures: The primary outcome was hospitalization for asthma within 24 hours. Secondary outcomes included PRAM score; respiratory rate; oxygen saturation at 60, 120, 180, and 240 minutes; blood pressure at 20, 40, 60, 120, 180, and 240 minutes; and albuterol treatments within 240 minutes. Results: Among 818 randomized patients (median age, 5 years; 63% males), 816 completed the trial (409 received magnesium; 407, placebo). A total of 178 of the 409 children who received magnesium (43.5%) were hospitalized vs 194 of the 407 who received placebo (47.7%) (difference, -4.2%; absolute risk difference 95% [exact] CI, -11% to 2.8%]; P = .26). There were no significant between-group differences in changes from baseline to 240 minutes in PRAM score (difference of changes, 0.14 points [95% CI, -0.23 to 0.50]; P = .46); respiratory rate (0.17 breaths/min [95% CI, -1.32 to 1.67]; P = .82); oxygen saturation (-0.04% [95% CI, -0.53% to 0.46%]; P = .88); systolic blood pressure (0.78 mm Hg [95% CI, -1.48 to 3.03]; P = .50); or mean number of additional albuterol treatments (magnesium: 1.49, placebo: 1.59; risk ratio, 0.94 [95% CI, 0.79 to 1.11]; P = .47). Nausea/vomiting or sore throat/nose occurred in 17 of the 409 children who received magnesium (4%) and 5 of the 407 who received placebo (1%). Conclusions and Relevance: Among children with refractory acute asthma in the emergency department, nebulized magnesium with albuterol, compared with placebo with albuterol, did not significantly decrease the hospitalization rate for asthma within 24 hours. The findings do not support use of nebulized magnesium with albuterol among children with refractory acute asthma. Trial Registration: ClinicalTrials.gov Identifier: NCT01429415.

Being Well Together: Individual Subjective and Community Wellbeing.

This paper explores the ways in which community wellbeing is, and could be, related to individual subjective wellbeing by mapping current practice, teasing out the assumptions underlying a dominant approach and flagging neglected issues. The notion of community is widely understood as about something more than the sum of the parts. Capturing subjective aspects of local life that are not simply individual but reflect the ways in which people feel and are well together is a challenging undertaking. Most existing frameworks for assessing community wellbeing are premised on a theory of the self as an autonomous, rational and independently acting or feeling individual, and the primary interest is on how community aspects of life impact on individual subjective wellbeing. This dominant approach consistently neglects spatial and social inequalities, multiple settings and scales and temporal choices and legacies, all of which constitute important political dimensions to community wellbeing. Social theories of the self as relational put relations as prior to subjectivity and as such afford ways to conceptualise community wellbeing in terms of being well together. A relational approach can also offer routes to tackling the complex interactions of inequality, scale and time. Such an approach is not, however, easily translated into quantitative measures or simple policy interventions. The approach taken to community wellbeing is not a technological issue but a political choice.