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Background: Family group conferences (FGCs) in child welfare bring immediate and wider family members together to decide on the best way to meet a child's needs. Unlike professionally led meetings, the aim is for decisions to be made by or with family members. Qualitative and mixed-method research with FGC participants tends to show positive experiences: most participants feel their voices are heard; FGCs facilitate family-driven solutions and closer relationships-within families and with social workers. Although there is existing literature on FGCs, there is a paucity of robust comparative UK evaluations, i.e., randomised controlled trials or quasi-experimental studies. Comparative studies internationally have focused on a narrow range of outcomes, not recognised the importance of context, and paid little attention to the quality of delivery. Some qualitative studies have considered process and context but there is scant measurement of these. The aims of this study are, firstly, to establish how FGCs improve outcomes for families and what factors vary their quality, and, secondly, to assess longer-term outcomes in terms of service use and associated costs., Methods: Given the importance of process and context, evaluation informed by realist and complex systems approaches is needed. This multi-method evaluation includes a survey of FGC services in all UK local authorities (n = 212) to map service provision; co-design of programme theory and evaluation measures with family members who have experienced an FGC (n = 16-24) and practitioners (n = 16-24) in two sites; a prospective single-arm study of FGC variability and outcomes after six months; and comparison of service use and costs in FGC participants (n≥300 families) and a control group (n≥1000) after two years using a quasi-experiment., Discussion: This is a pragmatic evaluation of an existing intervention, to identify what mechanisms and contexts influence effective process and longer-term outcomes. The study is registered with Research Registry (ref. 7432)., Competing Interests: Jonathan Scourfield is a trustee of the Family Rights Group, a charity that promotes better family participation in the child welfare process, and family group conferences as one way of achieving this. This non-financial interest does not alter our adherence to PLOS ONE policies on sharing data and materials, with the provisos in the data sharing statement., (Copyright: © 2024 Scourfield et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The apicomplexans Toxoplasma gondii and Plasmodium are intracellular parasites that reside within a host-derived compartment termed the parasitophorous vacuole (PV). During infection, the parasites must acquire critical host resources and transport them across their PV for development. However, the mechanism by which host resources are trafficked to and across the PV remains uncertain. Here, we investigated host ADP ribosylation factors (Arfs), a class of proteins involved in vesicular trafficking that may be exploited by T. gondii and Plasmodium berghei for nutrient acquisition. Using overexpressed Arf proteins coupled with immunofluorescence microscopy, we found that all Arfs were internalized into the T. gondii PV, with most vacuoles containing at least one punctum of Arf protein by the end of the lytic cycle. We further characterized Arf1, the most abundant Arf inside the T. gondii PV, and observed that active recycling between its GDP/GTP-bound state influenced Arf1 internalization independent of host guanine nucleotide exchange factors (GEFs). In addition, Arf1 colocalized with vesicle coat complexes and exogenous sphingolipids, suggesting a role in nutrient acquisition. While Arf1 and Arf4 were not observed inside the PV during P. berghei infection, our gene depletion studies showed that liver stage development and survival depended on the expression of Arf4 and the host GEF, GBF1. Collectively, these observations indicate that apicomplexans use distinct mechanisms to subvert the host vesicular trafficking network and efficiently replicate. The findings also pave the way for future studies to identify parasite proteins critical to host vesicle recruitment and the components of vesicle cargo., Importance: The parasites Toxoplasma gondii and Plasmodium live complex intracellular lifestyles where they must acquire essential host nutrients while avoiding recognition. Although previous work has sought to identify the specific nutrients scavenged by apicomplexans, the mechanisms by which host materials are transported to and across the parasite vacuole membrane are largely unknown. Here, we examined members of the host vesicular trafficking network to identify specific pathways subverted by T. gondii and Plasmodium berghei . Our results indicate that T. gondii selectively internalizes host Arfs, a class of proteins involved in intracellular trafficking. For P. berghei , host Arfs were restricted by the parasite's vacuole membrane, but proteins involved in vesicular trafficking were identified as essential for liver stage development. A greater exploration into how and why apicomplexans subvert host vesicular trafficking could help identify targets for host-directed therapeutics., Competing Interests: The authors declare no conflict of interest.

Introduction: The Kids Guided Personalised Service (KidsGPS) is an integrated model of care coordination for children and young people (CYP) living with medical complexity. After successful implementation in an urban setting, the model of care will be rolled-out at scale to four rural regions in New South Wales, Australia to establish RuralKidsGPS. This paper describes the approach and methods for the outcome and implementation evaluation of RuralKidsGPS., Description: The evaluation aims to assess health, economic and implementation outcomes and processes whilst identifying barriers and enablers to inform future rollouts. Measures of health service utilisation (primary outcome), child health related quality of life and parent/carer experiences will be assessed. The implementation evaluation will occur alongside the outcomes evaluation and is underpinned by the Consolidated Framework for Implementation Research and informed by validated quantitative measures and qualitative interviews with patients, families, healthcare providers and service managers. An economic analysis will determine incremental cost effectiveness ratios for the new model of care using health service utilisation data., Conclusion: RuralKidsGPS, if effective, has the potential to improve equity of access to integrated care for CYP and their families and this protocol may inform other evaluations of similar models of care delivered at scale., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2023 The Author(s).)

Objective: This research uses Australian survey data to identify industries with high rates of psychological distress, and to estimate productivity impacts in the form of work loss and cutback days., Methods: Analyzing cross-sectional data from the 2017/2018 National Health Survey, industry prevalence of psychological distress (Kessler Screening Scale) was compared using ordered logistic regression. Productivity outcomes were distress-related work loss days and work cutback days in the previous 4 weeks. Losses were analyzed using zero-inflated negative binomial regression., Results: The sample consisted of 9073 employed workers [4497 males (49.6%), 4576 females (50.4%)]. Compared to the reference industry, Health, the odds of very high distress for males were highest in Information media and telecommunications (OR 2.4; 95% CI 1.2-4.6) and Administrative and support services (OR 2.5; 95% CI 1.2-5.0), while for females the odds were highest in Accommodation and food services (OR 2.0; 95% CI 1.5-2.8) followed by Retail (OR 1.6; 95% CI 1.2-2.0). Very high distress was associated excess productivity losses. Industry of occupation did not impact on productivity loss over and above distress., Conclusions: Substantial psychological distress was reported which impacted on productivity. High-risk industries included Information media and telecommunications, Accommodation and food services, and Retail., (© 2023 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

In this issue of Cell Chemical Biology, Vijayan and colleagues identify host factors integral for Plasmodium liver-stage infection using a whole-genome CRISPR-Cas9 knockout screen. Their efforts reveal that liver-stage parasites redistribute host microtubules to the parasite membrane in a process dependent on the host Golgi., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Plasmodium parasites extensively alter their host hepatocyte to evade host detection and support an unprecedented replication rate. Host cell manipulation includes association with the host early and late endomembrane systems, where Plasmodium accesses nutrients while suppressing cellular immune processes. Early endomembrane organelles provide an opportunity to sequester an abundance of lipids and proteins, but the association with late endomembrane organelles also risks autophagy-mediated elimination. While not all parasites survive, those that do benefit from a plethora of nutrients provided through this pathway. In this review, we discuss recent advances in our understanding of how Plasmodium parasites balance the need for host nutrients while avoiding elimination during the liver stage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Salmonella enterica is represented by >2,600 serovars that can differ in routes of transmission, host colonization, and in resistance to antimicrobials. S. enterica is the leading bacterial cause of foodborne illness in the United States, with well-established detection methodology. Current surveillance protocols rely on the characterization of a few colonies to represent an entire sample; thus, minority serovars remain undetected. Salmonella contains two CRISPR loci, CRISPR1 and CRISPR2, and the spacer contents of these can be considered serovar specific. We exploited this property to develop an amplicon-based and multiplexed sequencing approach, CRISPR-SeroSeq ( sero typing by seq uencing of the CRISPR loci), to identify multiple serovars present in a single sample. Using mixed genomic DNA from two Salmonella serovars, we were able to confidently detect a serovar that constituted 0.01% of the sample. Poultry is a major reservoir of Salmonella spp., including serovars that are frequently associated with human illness, as well as those that are not. Numerous studies have examined the prevalence and diversity of Salmonella spp. in poultry, though these studies were limited to culture-based approaches and therefore only identified abundant serovars. CRISPR-SeroSeq was used to investigate samples from broiler houses and a processing facility. Ninety-one percent of samples harbored multiple serovars, and there was one sample in which four different serovars were detected. In another sample, reads for the minority serovar comprised 0.003% of the total number of Salmonella spacer reads. The most abundant serovars identified were Salmonella enterica serovars Montevideo, Kentucky, Enteritidis, and Typhimurium. CRISPR-SeroSeq also differentiated between multiple strains of some serovars. This high resolution of serovar populations has the potential to be utilized as a powerful tool in the surveillance of Salmonella species. IMPORTANCE Salmonella enterica is the leading bacterial cause of foodborne illness in the United States and is represented by over 2,600 distinct serovars. Some of these serovars are pathogenic in humans, while others are not. Current surveillance for this pathogen is limited by the detection of only the most abundant serovars, due to the culture-based approaches that are used. Thus, pathogenic serovars that are present in a minority remain undetected. By exploiting serovar-specific differences in the CRISPR arrays of Salmonella spp., we have developed a high-throughput sequencing tool to be able to identify multiple serovars in a single sample and tested this in multiple poultry samples. This novel approach allows differences in the dynamics of individual Salmonella serovars to be measured and can have a significant impact on understanding the ecology of this pathogen with respect to zoonotic risk and public health., (Copyright © 2018 American Society for Microbiology.)

Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox-sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM dimerization. In HeLa cells, ATM dimers were localized to the nucleus and inhibited by the redox regulatory protein thioredoxin 1 (TRX1), suggesting the existence of a ROS-mediated, stress-signaling relay from mitochondria to the nucleus. ATM dimer formation did not affect its association with chromatin in the absence or presence of nuclear DNA damage, consistent with the separation of its redox and DNA damage signaling functions. Comparative analysis of U2OS cells expressing either wild-type ATM or the redox sensing-deficient C2991L mutant revealed that one function of ATM redox sensing is to promote glucose flux through the pentose phosphate pathway (PPP) by increasing the abundance and activity of glucose-6-phosphate dehydrogenase (G6PD), thereby increasing cellular antioxidant capacity. The PPP produces the coenzyme NADPH needed for a robust antioxidant response, including the regeneration of TRX1, indicating the existence of a regulatory feedback loop involving ATM and TRX1. We propose that loss of the mitochondrial ROS-sensing function of ATM may cause cellular ROS accumulation and oxidative stress in A-T., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding., Method: We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis., Results: From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence., Conclusions: This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing., (© The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-unsaturated fatty acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.

Historically, fat was considered detrimental to health and lifespan. However, lipidomics, the quantification of all lipid molecules in a biological sample, and genetic studies in model organisms are revealing specific fats that may promote longevity. These emerging findings provide insight into the complex relationship between lipids and longevity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mitochondrial DNA (mtDNA) exists in multiple copies per cell and is essential for oxidative phosphorylation. Depleted or mutated mtDNA promotes numerous human diseases and may contribute to aging. Reduced TORC1 signaling in the budding yeast, Saccharomyces cerevisiae, extends chronological lifespan (CLS) in part by generating a mitochondrial ROS (mtROS) signal that epigenetically alters nuclear gene expression. To address the potential requirement for mtDNA maintenance in this response, we analyzed strains lacking the mitochondrial base-excision repair enzyme Ntg1p. Extension of CLS by mtROS signaling and reduced TORC1 activity, but not caloric restriction, was abrogated in ntg1Δ strains that exhibited mtDNA depletion without defects in respiration. The DNA damage response (DDR) kinase Rad53p, which transduces pro-longevity mtROS signals, is also activated in ntg1Δ strains. Restoring mtDNA copy number alleviated Rad53p activation and re-established CLS extension following mtROS signaling, indicating that Rad53p senses mtDNA depletion directly. Finally, DDR kinases regulate nucleus-mitochondria localization dynamics of Ntg1p. From these results, we conclude that the DDR pathway senses and may regulate Ntg1p-dependent mtDNA stability. Furthermore, Rad53p senses multiple mitochondrial stresses in a hierarchical manner to elicit specific physiological outcomes, exemplified by mtDNA depletion overriding the ability of Rad53p to transduce an adaptive mtROS longevity signal., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We have explored the role of mitochondrial function in aging by genetically and pharmacologically modifying yeast cellular respiration production during the exponential and/or stationary growth phases and determining how this affects chronological life span (CLS). Our results demonstrate that respiration is essential during both growth phases for standard CLS, but that yeast have a large respiratory capacity, and only deficiencies below a threshold (~40% of wild-type) significantly curtail CLS. Extension of CLS by caloric restriction also required respiration above a similar threshold during exponential growth and completely alleviated the need for respiration in the stationary phase. Finally, we show that supplementation of media with 1% trehalose, a storage carbohydrate, restores wild-type CLS to respiratory-null cells. We conclude that mitochondrial respiratory thresholds regulate yeast CLS and its extension by caloric restriction by increasing stress resistance, an important component of which is the optimal accumulation and mobilization of nutrient stores., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this issue of Cell Metabolism, Ristow and colleagues (Zarse et al., 2012) elucidate a conserved mechanism through which reduced insulin-IGF1 signaling activates an AMP-kinase-driven metabolic shift toward oxidative proline metabolism. This, in turn, produces an adaptive mitochondrial ROS signal that extends worm life span. These findings further bolster the concept of mitohormesis as a critical component of conserved aging and longevity pathways., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Here we show that yeast strains with reduced target of rapamycin (TOR) signaling have greater overall mitochondrial electron transport chain activity during growth that is efficiently coupled to ATP production. This metabolic alteration increases mitochondrial membrane potential and reactive oxygen species (ROS) production, which we propose supplies an adaptive signal during growth that extends chronological life span (CLS). In strong support of this concept, uncoupling respiration during growth or increasing expression of mitochondrial manganese superoxide dismutase significantly curtails CLS extension in tor1Δ strains, and treatment of wild-type strains with either rapamycin (to inhibit TORC1) or menadione (to generate mitochondrial ROS) during growth is sufficient to extend CLS. Finally, extension of CLS by reduced TORC1/Sch9p-mitochondrial signaling occurs independently of Rim15p and is not a function of changes in media acidification/composition. Considering the conservation of TOR-pathway effects on life span, mitochondrial ROS signaling may be an important mechanism of longevity regulation in higher organisms., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The objective of this study was to estimate the economic costs over the first 2 years of life of Group B Streptococcus (GBS) disease occurring in infants less than 90 days of age. A cost analysis was conducted using a prospective cohort of children born between 2000 and 2003 in the Greater London, Oxford, Portsmouth and Bristol areas of England. Unit costs were applied to estimates of the health and social resource use made by 138 infants diagnosed with GBS disease and 305 non-GBS controls matched for birth weight and hospital stay and time of birth. The health and social care costs for infants exposed to GBS disease were analysed in a multiple linear regression model. The mean health and social care cost over the first 2 years of life was estimated at pound11,968.9 for infants with GBS, compared to pound6,260.7 for the non-GBS controls; a mean cost difference of pound5,708.1 (bootstrap 95% CI pound2,977.1, pound8,391.2, P=0.03). After adjusting for gestational age and other potential confounders in a multiple linear regression, mean societal costs was pound6,144.7 higher among GBS cases than among non-GBS controls (P<0.001). This study shows that the health and social care costs for infants with GBS disease is, on average, two-fold higher during the first 2 years of life than for infants without GBS disease. These data should be used to inform policy decisions regarding the cost-effectiveness of prevention and treatment strategies for GBS disease during early childhood.

The effect of orally administered IGF-I on intestinal development was assessed in piglets. Cesarean-derived, colostrum-deprived piglets received formula alone or formula containing 65 nM (500 microg/L) of recombinant human IGF-I. IGF-I intake averaged 200 microg/kg/d. On d 7 and 14 postpartum, piglets were killed, organs were removed and weighed, and tissue and blood samples were collected. The small intestine was divided into 13 segments that were weighed and measured. A sample of each segment was fixed in formalin, and the mucosa was scraped for enzyme analyses. Food intake, body and organ weights, intestinal weight, length, protein, DNA and RNA content did not differ between the treatment groups. Serum IGF-I, IGF-II, and IGF-binding protein profiles and tissue IGF-binding protein mRNA expression were also comparable between the treatment groups. In contrast, intestinal enzymes and villus height were increased by oral IGF-I. Lactase was approximately 2-fold higher (p < or = 0.05) in the jejunum and proximal ileum, and sucrase was approximately 50% higher (p < or = 0.05) in the jejunum of IGF-I-treated animals than in controls. Villus height in the terminal ileum was approximately 50% greater in IGF-I-treated animals than in controls (p = 0.03). In conclusion, orally administered IGF-I at 200 microg/kg did not affect whole body or organ growth or serum IGF-I concentrations; however, intestinal disaccharidase activity and ileal villus growth were responsive to orally administered IGF-I, supporting a potential role for milk-borne IGF-I in neonatal intestinal development.

The in vivo biosynthesis of hepatic glycerolipids was examined by studying the incorporation of [2-3H] glycerol into triacylglycerol in the mouse. The isotope was administered by rapid injection into the portal vein. The incorporation of glycerol was linear for about 1 min and maximal rates were seen in the presence of additional oleic acid. At 20 mumol of oleic acid bound to 1 mumol of bovine serum albumin, the highest level tested, glycerol incorporation was still increasing linearly, whereas a plateau was reached at 4 mumol of glycerol. The liver incorporated 200-300 nmol of [2-3H] glycerol into triacyglycerol per min when 20 mumol of albumin-bound oleic acid plus 4 mumol of glycerol were injected in a 0.2 ml volume. Studies on the uptake by the liver after intraportal injection revealed that at 0.5 min the liver retained 2 mumol of glycerol and 5 mumol of oleic acid, indicating that the uptake of substrate was not rate-limiting. The results suggest that the availability of substrate is a major factor in the regulation of triacyglycerol biosynthesis by the liver.