Feasibility and acceptability of a timeline follow-back method to assess opioid use, non-fatal overdose, and substance use disorder treatment.

BACKGROUND: Non-fatal overdoses are underreported and there is no accepted and feasible self-report research measure of non-fatal opioid overdose. Timeline follow-back (TLFB) calendar-based questionnaires assess self-reported risk behaviors. We assessed feasibility and acceptability of a new TLFB research measure for opioid use, non-fatal opioid overdose, and substance use disorder treatment among opioid overdose survivors. METHODS: For the Repeated-dose Behavioral Intervention to Reduce Opioid Overdose Trial (REBOOT) study among opioid overdose survivors, we developed a TLFB questionnaire to assess daily non-prescribed opioid use, opioid overdose, facility stays, medications/behavioral treatment for opioid use disorder, and COVID-19 history during the previous 120 days. Staff assessors administered TLFB at four-monthly visits over the 16-month study participation period. To measure feasibility, we estimated TLFB completion time using an electronic timestamp tool. To measure acceptability, we administered a satisfaction survey to 103 participants who completed REBOOT. RESULTS: Among 525 TLFB assessments conducted in 174 participants from January 2021-January 2023, opioid use was reported in 510 assessments, medication for opioid use disorder (MOUD) in 331 assessments, and ≥ 1 overdose in 107 assessments. Median TLFB completion time was 11 (IQR: 6-17) minutes for sections administered to all participants; detailed overdose questions administered to those reporting overdose took an additional 3 (IQR: 2-6) minutes. Report of ≥ 1 overdose and MOUD use were significantly associated with increased TLFB completion time. 88 % of participants reported that TLFB was very/somewhat acceptable. CONCLUSIONS: Among opioid overdose survivors, REBOOT TLFB was a feasible and acceptable research measure, with similar completion time as other TLFB assessments of substance use.

A qualitative exploration of the lived experiences of Body Dysmorphic Disorder.

Body Dysmorphic Disorder (BDD) is characterized by an intense preoccupation with one or more perceived "defects" in physical appearance. Despite the distress and impairment associated with BDD, the disorder remains understudied and poorly understood. In particular, there are limited studies available which give voice to those with firsthand experiences of the disorder. A qualitative approach was employed to study lived experience of BDD. In-depth semi-structured interviews were conducted with 12 participants with BDD, aiming to understand their subjective experiences of the disorder. Data was analyzed using Interpretative Phenomenological Analysis (IPA). The results identified three superordinate themes; (1) consumed by the disorder, (2) the flawed self, and (3) intolerance of uncertainty about appearance. The qualitative findings of this study are discussed in relation to current conceptual understandings of BDD, including the cognitive behavioral model.

Capturing the whole-school food environment in primary schools.

OBJECTIVE: The school food environment (SFE) is an ideal setting for encouraging healthy dietary behaviour. We aimed to develop an instrument to assess whole-SFE, test the instrument in the school setting and demonstrate its use to make food environment recommendations. DESIGN: SFE literature and UK school food guidance were searched to inform instrument items. The instrument consisted of (i) an observation proforma capturing canteen areas systems, food presentation and monitoring of food intake and (ii) a questionnaire assessing food policies, provision and activities. The instrument was tested in schools and used to develop SFE recommendations. Descriptive analyses enabled narrative discussion. SETTING: Primary schools. PARTICIPANTS: An observation was undertaken at schools in urban and rural geographical regions of Northern Ireland of varying socio-economic status (n 18). School senior management completed the questionnaire with input from school caterers (n 16). RESULTS: The instrument captured desired detail and potential instrument modifications were identified. SFE varied. Differences existed between food policies and how policies were implemented and monitored. At many schools, there was scope to enhance physical eating environments (n 12, 67 %) and food presentation (n 15, 83 %); emphasise healthy eating through food activities (n 7, 78 %) and increase parental engagement in school food (n 9, 56 %). CONCLUSIONS: The developed instrument can measure whole-SFE in primary schools and also enabled identification of recommendations to enhance SFE. Further assessment and adaptation of the instrument are required to enable future use as a research tool or for self-assessment use by schools.

Temperature sensing by the calcium-sensing receptor.

Whether GPCRs support the sensing of temperature as well as other chemical and physical modalities is not well understood. Introduction: Extracellular Ca2+ concentration (Ca2+ o) modulates core body temperature and the firing rates of temperature-sensitive CNS neurons, and hypocalcemia provokes childhood seizures. However, it is not known whether these phenomena are mediated by Ca2+ o-sensing GPCRs, including the calcium-sensing receptor (CaSR). In favor of the hypothesis, CaSRs are expressed in hypothalamic regions that support core temperature regulation, and autosomal dominant hypocalcemia, due to CaSR activating mutations, is associated with childhood seizures. Methods: Herein, we tested whether CaSR-dependent signaling is temperature sensitive using an established model system, CaSR-expressing HEK-293 cells. Results: We found that the frequency of Ca2+ o-induced Ca2+ i oscillations but not the integrated response was linearly dependent on temperature in a pathophysiologically relevant range. Chimeric receptor analysis showed that the receptor's C-terminus is required for temperature-dependent modulation and experiments with the PKC inhibitor GF109203X and CaSR mutants T888A and T888M, which eliminate a key phosphorylation site, demonstrated the importance of repetitive phosphorylation and dephosphorylation. Discussion and Conclusion: CaSRs mediate temperature-sensing and the mechanism, dependent upon repetitive phosphorylation and dephosphorylation, suggests that GPCRs more generally contribute to temperature-sensing.

Exploring the relationship between breastfeeding and the incidence of infant illnesses in Ireland: evidence from a nationally representative prospective cohort study.

BACKGROUND: Ireland has one of the lowest BF rates in the world. This study investigates the association between breastfeeding and infant health in Ireland. METHODS: A cross-sectional, secondary analysis of data collected from Growing Up in Ireland (GUI): the National Longitudinal Study of Children was conducted. The average morbidity for 2212. infants exclusively breastfed for at least 90 days (EBF90days) was compared to data for 3987 infants in the non-breastfed (Non-BF) group. Data were weighted using entropy balancing to ensure the comparability of groups. Sensitivity analyses considered alternative definitions of the breastfeeding group. RESULTS: Infants who were EBF90days were significantly less likely to be admitted to hospital (CI: - 0.06 to - 0.03), spent less nights in hospital (CI: - 0.37 to - 0.11), and were less likely to develop respiratory diseases including asthma (CI: - 0.03 to - 0.01), chest infections (CI: - 0.12 to - 0.08), snuffles/common colds (CI: - 0.07 to - 0.02), ear infections (CI: - 0.08 to - 0.04), eczema (CI: - 0.08 to - 0.04), skin problems (CI: - 0.04 to - 0.00), wheezing or asthma (CI: - 0.06 to - 0.03), vomiting (CI: - 0.03 to - 0.00), and colic (CI: - 0.04 to - 0.01). Further outcomes such as current health of the infant at time of interview (CI: - 0.04 to - 0.00), feeding problems (CI: - 0.04 to - 0.02) and sleeping problems (CI: - 0.02 to - 0.00) indicated a protective effect of EBF90days versus Non-BF. However, these infants were also more likely to fail to gain weight (CI: 0.01 to 0.02) and were at a slightly higher risk of developing nappy rash (CI: 0.00 to 0.02). CONCLUSION: Exclusive breastfeeding for 90+ days is associated with protection against childhood morbidity. Given the protective effect of breastfeeding on adverse health effects in infants, policy makers should prioritise policies that support, promote and protect exclusive breastfeeding.

"There's No Heroin Around Anymore. It's All Fentanyl." Adaptation of an Opioid Overdose Prevention Counseling Approach to Address Fentanyl Overdose: Formative Study.

BACKGROUND: Drug overdose mortality continues to increase, now driven by fentanyl. Prevention tools such as naloxone and medications to treat opioid use disorder are not sufficient to control overdose rates; additional strategies are urgently needed. OBJECTIVE: We sought to adapt a behavioral intervention to prevent opioid overdose (repeated-dose behavioral intervention to reduce opioid overdose [REBOOT]) that had been successfully piloted in San Francisco, California, United States, to the setting of Boston, Massachusetts, United States, and the era of fentanyl for a full efficacy trial. METHODS: We used the assessment, decision, adaptation, production, topical experts, integration, training, and testing (ADAPT-ITT) framework for intervention adaptation. We first identified opioid overdose survivors who were actively using opioids as the population of interest and REBOOT as the intervention to be adapted. We then performed theater testing and elicited feedback with 2 focus groups (n=10) in Boston in 2018. All participants had used opioids that were not prescribed to them in the past year and experienced an opioid overdose during their lifetime. We incorporated focus group findings into our initial draft of the adapted REBOOT intervention. The adapted intervention was reviewed by 3 topical experts, and their feedback was integrated into a subsequent draft. We trained study staff on the intervention and made final refinements based on internal piloting. This paper describes the overall ADAPT-ITT process for intervention adaptation, as well as a qualitative analysis of the focus groups. Working independently, 2 authors (VMM and JA) reviewed the focus group transcripts and coded them for salient and common themes using the constant comparison method, meeting to discuss any discrepancies until consensus was reached. Codes and themes were then mapped onto the REBOOT counseling steps. RESULTS: Focus group findings contributed to substantial changes in the counseling intervention to better address fentanyl overdose risk. Participants described the widespread prevalence of fentanyl and said that, although they tried to avoid it, avoidance was becoming impossible. Using alone and lower opioid tolerance were identified as contributors to overdose risk. Slow shots or tester shots were acceptable and considered effective to reduce risk. Naloxone was considered an effective reversal strategy. Although calling emergency services was not ruled out, participants described techniques to prevent the arrival of police on the scene. Expert review and internal piloting improved the intervention manual through increased participant centeredness, clarity, and usability. CONCLUSIONS: We successfully completed the ADAPT-ITT approach for an overdose prevention intervention, using theater testing with people who use opioids to incorporate the perspectives of people who use drugs into a substance use intervention. In the current crisis, overdose prevention strategies must be adapted to the context of fentanyl, and innovative strategies must be deployed, including behavioral interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03838510; https://clinicaltrials.gov/ct2/show/NCT03838510.

Meeting report: plant-rich dietary patterns and health.

Dietary patterns (DP) rich in plant foods are associated with improved health and reduced non-communicable disease risk. In October 2021, the Nutrition Society hosted a member-led conference, held online over 2 half days, exploring the latest research findings examining plant-rich DP and health. The aim of the present paper is to summarise the content of the conference and synopses of the individual speaker presentations are included. Topics included epidemiological analysis of plant-rich DP and health outcomes, the effects of dietary interventions which have increased fruit and vegetable (FV) intake on a range of health outcomes, how adherence to plant-rich DP is assessed, the use of biomarkers to assess FV intake and a consideration of how modifying behaviour towards increased FV intake could impact environmental outcomes, planetary health and food systems. In conclusion, although there are still considerable uncertainties which require further research, which were considered as part of the conference and are summarised in this review, adopting a plant-rich DP at a population level could have a considerable impact on diet and health outcomes, as well as planetary health.

Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells.

BACKGROUND: Impaired mineral ion metabolism is a hallmark of CKD-metabolic bone disorder. It can lead to pathologic vascular calcification and is associated with an increased risk of cardiovascular mortality. Loss of calcium-sensing receptor (CaSR) expression in vascular smooth muscle cells exacerbates vascular calcification in vitro. Conversely, vascular calcification can be reduced by calcimimetics, which function as allosteric activators of CaSR. METHODS: To determine the role of the CaSR in vascular calcification, we characterized mice with targeted Casr gene knockout in vascular smooth muscle cells ( SM22α CaSR Δflox/Δflox ). RESULTS: Vascular smooth muscle cells cultured from the knockout (KO) mice calcified more readily than those from control (wild-type) mice in vitro. However, mice did not show ectopic calcifications in vivo but they did display a profound mineral ion imbalance. Specifically, KO mice exhibited hypercalcemia, hypercalciuria, hyperphosphaturia, and osteopenia, with elevated circulating fibroblast growth factor 23 (FGF23), calcitriol (1,25-D3), and parathyroid hormone levels. Renal tubular α-Klotho protein expression was increased in KO mice but vascular α-Klotho protein expression was not. Altered CaSR expression in the kidney or the parathyroid glands could not account for the observed phenotype of the KO mice. CONCLUSIONS: These results suggest that, in addition to CaSR's established role in the parathyroid-kidney-bone axis, expression of CaSR in vascular smooth muscle cells directly contributes to total body mineral ion homeostasis.

The effect of animal versus plant protein on muscle mass, muscle strength, physical performance and sarcopenia in adults: protocol for a systematic review.

BACKGROUND: The evidence base for the role of dietary protein in maintaining good muscle health in older age is strong; however, the importance of protein source remains unclear. Plant proteins are generally of lower quality, with a less favourable amino acid profile and reduced bioavailability; therefore, it is possible that their therapeutic effects may be less than that of higher quality animal proteins. This review aims to evaluate the effectiveness of plant and animal protein interventions on muscle health outcomes. METHODS: A robust search strategy was developed to include terms relating to dietary protein with a focus on protein source, for example dairy, meat and soy. These were linked to terms related to muscle health outcomes, for example mass, strength, performance and sarcopenia. Five databases will be searched: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Embase and Web of Science. Studies included will be randomised controlled trials with an adult population (≥ 18) living in the community or residential homes for older adults, and only English language articles will be included. Two independent reviewers will assess eligibility of individual studies. The internal validity of included studies will be assessed using Cochrane Risk of Bias 2.0 tool. Results will be synthesised in narrative format. Where applicable, standardised mean differences (SMD) (95% confidence interval [CI]) will be combined using a random-effects meta-analysis, and tests of homogeneity of variance will be calculated. DISCUSSION: Dietary guidelines recommend a change towards a plant-based diet that is more sustainable for health and for the environment; however, reduction of animal-based foods may impact protein quality in the diet. High-quality protein is important for maintenance of muscle health in older age; therefore, there is a need to understand whether replacement of animal protein with plant protein will make a significant difference in terms of muscle health outcomes. Findings from this review will be informative for sustainable nutritional guidelines, particularly for older adults and for those following vegan or vegetarian diets. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420201886582.

Food environment intervention improves food knowledge, wellbeing and dietary habits in primary school children: Project Daire, a randomised-controlled, factorial design cluster trial.

BACKGROUND: Evidence suggests that dietary intake of UK children is suboptimal. As schools provide an ideal natural environment for public health interventions, effective and sustainable methods of improving food knowledge and dietary habits in this population must be identified. Project Daire aimed to improve children's health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions. METHODS: Daire was a randomised-controlled, factorial design trial evaluating two interventions across four arms. Primary schools in Northern Ireland were randomised to one of four 6-month intervention arms: i) 'Nourish', ii) 'Engage', iii) 'Nourish' and 'Engage' and iv) Control (Delayed). 'Nourish' was an intervention aiming to alter the whole-school food environment, provide food-related experiences and exposure to locally produced foods. 'Engage' was an age-appropriate, cross-curricular educational intervention on food, agriculture, nutrition science and related careers. Primary outcomes were emotional and behavioural wellbeing and health-related quality of life. A number of secondary outcomes, including dietary intake, cooking competence and food-related knowledge, were also measured. RESULTS: Fifteen schools from areas of varying socio-economic status participated in the randomised trial. A total of 903 (n = 445 aged 6-7 years and n = 458 aged 10-11 years) primary school pupils took part. Total Difficulties Score improved in all pupils (6-7 and 10-11 year old pupils) who received the 'Nourish' intervention compared with those that did not (adjusted difference in mean = - 0.82; 95% CI -1.46, - 0.17; P < 0.02). No statistically significant difference in Health-Related Quality of Life was observed. The 'Nourish' intervention also produced some changes in school-based dietary behaviour, which were most apparent in the 10-11 year old pupils. The 'Nourish' intervention also produced improvements in understanding of food labels (adjusted difference in mean = 0.15; 95% CI 0.05, 0.25; P < 0.01) and knowledge of vegetables in season (adjusted difference in mean = 0.29; 95% CI 0.01,0.56; P = 0.04) whilst an increased willingness to try new foods and improved perceived cooking competence was also observed. CONCLUSIONS: Improvements in childhood emotional and behavioural wellbeing, dietary intake, knowledge about food, cooking skills and willingness to try new foods were associated with the 'Nourish' whole-school food environment intervention. Exploration of the sustainability and long-term effectiveness of such whole-school food interventions should be conducted. TRIAL REGISTRATION: National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312 ).

Empirical evidence for cognitive subgroups in body dysmorphic disorder.

OBJECTIVE: Current understanding of cognitive functioning in body dysmorphic disorder is limited, owing to few studies, small sample sizes and assessment across only limited cognitive domains. Existing research has also shown inconsistent findings, with both intact and impaired cognition reported in body dysmorphic disorder, which might point towards cognitive heterogeneity in the disorder. This study aimed to examine the cognitive profile of body dysmorphic disorder in a large sample across eight cognitive domains, and to explore whether cognitive subgroups might be identified within body dysmorphic disorder. METHOD: Cognitive domains of inhibition/flexibility, working memory, speed of processing, reasoning and problem-solving, visual and verbal learning, attention/vigilance and social cognition were assessed and compared between 65 body dysmorphic disorder patients and 70 healthy controls. Then, hierarchical clustering analysis was conducted on the body dysmorphic disorder group's cognitive data. RESULTS: Group-average comparisons demonstrated significantly poorer cognitive functioning in body dysmorphic disorder than healthy controls in all domains except for attention/vigilance and social cognition. Cluster analysis identified two divergent cognitive subgroups within our body dysmorphic disorder cohort characterised by (1) broadly intact cognitive function with mild selective impairments (72.3%), and (2) broadly impaired cognitive function (27.7%). However, the clusters did not significantly differ on clinical parameters or most sociodemographic characteristics. CONCLUSION: Our findings demonstrate considerable cognitive heterogeneity among persons with body dysmorphic disorder, rather than uniform deficits. Poor performances in the broadly impaired subgroup may have driven group-level differences. However, our findings also suggest a dissociation between cognitive functioning and clinical characteristics in body dysmorphic disorder that has implications for current aetiological models. Additional research is needed to clarify why some people with body dysmorphic disorder demonstrate cognitive deficits while others do not.

CooC11 and CooC7: the development and validation of age appropriate children's perceived cooking competence measures.

BACKGROUND: Learning cooking skills during childhood and adolescence is associated with positive dietary outcomes in adulthood as well as being tracked from adolescence to adulthood. In addition studies have found that perceived competence to be a greater motivator to perform a behaviour than actual competence. However, a lack of validated tools that effectively measure behavioural and dietary changes including cooking confidence in children is a limitation. Therefore, this research aimed to develop and validate age-appropriate perceived cooking competence measures for younger and older primary school aged children. METHODS: Two measures of perceived Cooking Competence (CooC11 and CooC7) for older (8-12 years) and younger (6-7 years) children were developed from a critical evaluation of publically available recommendations and expert consultation. The cooking skills within the measures were illustrated by a graphic designer in consultation with a chef and reviewed in an iterative manner by the research team. The measures were piloted for clarity, ease of use and initial face validity. Multiple studies were used for both CooC11 and CooC7 to establish psychometric properties of the measures, temporal stability, internal consistency reliability, construct validity, as well as responsiveness to change for CooC11. Analysis included Exploratory Factor Analysis, Confirmatory Factor Analysis, Intraclass Correlation Coefficients, Pearson's Correlations, ANOVAs and Cronbach's Alphas. RESULTS: Both measures had high levels of face validity and received positive user feedback. Two factors were shown in both measures with the measures showing excellent temporal stability (ICC > 0.9) and good internal consistency (Cronbach's Alphas > 0.7). Both measures showed initial discriminant validity, with significant differences (P< 0.001) between those who reported assisting their parents with dinner preparation and those who did not. Additionally, CooC11 was significantly correlated with an adult cooking measure and had a significant responsiveness to change (P< 0.01). CONCLUSIONS: The CooC11 and CooC7 are the first validated age-appropriate measures for assessing children's perceived Cooking Competence for ages 8-12 and 6-7 years respectively. They can be used to evaluate the efficacy of children's cooking intervention studies or school nutrition education programmes.

Caenorhabditis elegans processes sensory information to choose between freeloading and self-defense strategies.

Hydrogen peroxide is the preeminent chemical weapon that organisms use for combat. Individual cells rely on conserved defenses to prevent and repair peroxide-induced damage, but whether similar defenses might be coordinated across cells in animals remains poorly understood. Here, we identify a neuronal circuit in the nematode Caenorhabditis elegans that processes information perceived by two sensory neurons to control the induction of hydrogen peroxide defenses in the organism. We found that catalases produced by Escherichia coli, the nematode's food source, can deplete hydrogen peroxide from the local environment and thereby protect the nematodes. In the presence of E. coli, the nematode's neurons signal via TGFß-insulin/IGF1 relay to target tissues to repress expression of catalases and other hydrogen peroxide defenses. This adaptive strategy is the first example of a multicellular organism modulating its defenses when it expects to freeload from the protection provided by molecularly orthologous defenses from another species.

Cells of all kinds often wage chemical warfare against each other. Hydrogen peroxide is often the weapon of choice on the microscopic battlefield, where it is used to incapacitate opponents or to defend against attackers. For example, some plants produce hydrogen peroxide in response to infection to fight off disease-causing microbes. Individual cells have also evolved defenses to prevent or repair 'injuries' caused by hydrogen peroxide. These are similar across many different species. They include enzymes called catalases, which break down hydrogen peroxide, and others to repair damage. However, scientists still do not fully understand how animals and other multicellular organisms might coordinate these defenses across their cells. Caenorhabditis elegans is a microscopic species of worm that lives in rotting fruits. It often encounters the threat of cellular warfare: many types of bacteria in its environment generate hydrogen peroxide, and some can make enough to kill the worms outright. Like other organisms, C. elegans also produces catalases to defend itself against hydrogen peroxide attacks. However, it must activate its defenses at the right time; if it did so when they were not needed, this would result in a detrimental energy 'cost' to the worm. Although C. elegans is a small organism containing only a defined number of cells, exactly why and how it switches its chemical defenses on or off remains unknown. Schiffer et al. therefore set out to determine how C. elegans controls these defenses, focusing on the role of the brain in detecting and processing information from its environment. Experiments looking at the brains of genetically manipulated worms revealed a circuit of sensory nerve cells whose job is to tell the rest of the worm's tissues that they no longer need to produce defense enzymes. Crucially, the circuit became active when the worms sensed E. coli bacteria nearby. Bacteria in the same family as E. coli are normally found in in the same habitat as C. elegans and these bacteria are also known to make enzymes of their own to eliminate hydrogen peroxide around them. These results indicate that C. elegans can effectively decide, based on the activity of its circuit, when to use its own defenses and when to 'freeload' off those of neighboring bacteria. This work is an important step towards understanding how sensory circuits in the brain can control hydrogen peroxide defenses in multicellular organisms. In the future, it could help researchers work out how more complex animals, like humans, coordinate their cellular defenses, and therefore potentially yield new strategies for improving health and longevity.

Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent ß-catenin stabilization in osteoblasts.

The calcium-sensing receptor (CaSR) is critical for skeletal development, but its mechanism of action in osteoblasts is not well-characterized. In the central nervous system (CNS), Homer scaffolding proteins form signaling complexes with two CaSR-related members of the G protein-coupled receptor (GPCR) family C, metabotropic glutamate receptor 1 (mGluR1) and mGluR5. Here, we show that CaSR and Homer1 are co-expressed in mineralized mouse bone and also co-localize in primary human osteoblasts. Co-immunoprecipitation experiments confirmed that Homer1 associates with CaSR in primary human osteoblasts. The CaSR-Homer1 protein complex, whose formation was increased in response to extracellular Ca2+, was bound to mechanistic target of rapamycin (mTOR) complex 2 (mTORC2), a protein kinase that phosphorylates and activates AKT Ser/Thr kinase (AKT) at Ser473 siRNA-based gene-silencing assays with primary osteoblasts revealed that both CaSR and Homer1 are required for extracellular Ca2+-stimulated AKT phosphorylation and thereby inhibit apoptosis and promote AKT-dependent ß-catenin stabilization and cellular differentiation. To confirm the role of the CaSR-Homer1 complex in AKT initiation, we show that in HEK-293 cells, co-transfection with both Homer1c and CaSR, but neither with Homer1c nor CaSR alone, establishes sensitivity of AKT-Ser473 phosphorylation to increases in extracellular Ca2+ concentrations. These findings indicate that Homer1 mediates CaSR-dependent AKT activation via mTORC2 and thereby stabilizes ß-catenin in osteoblasts.

Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by heterozygous, gain-of-function mutations of the calcium-sensing receptor gene (CAR). Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria. Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635) on 3 consecutive days. Pharmacokinetics, pharmacodynamics, efficacy, and safety were assessed. Parallel in vitro testing with subject CaR mutations assessed the effects of NPSP795 on cytoplasmic calcium concentrations (Ca2+i ), and ERK and p38MAPK phosphorylation. These effects were correlated with clinical responses to administration of NPSP795. NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels. Fractional excretion of calcium (FECa) trended down but not significantly so. Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation. NPSP795 was generally safe and well-tolerated. There was significant variability in response clinically across genotypes. In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any clinical parameters. NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1. Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug. © 2019 American Society for Bone and Mineral Research.

Postnatal Lifestyle Intervention for Overweight Women With Previous Gestational Diabetes: A Randomized Controlled Trial.

Background: Gestational diabetes mellitus (GDM) is associated with a sevenfold increased lifetime risk of type 2 diabetes. Excessive gestational weight gain and postpartum weight retention are established predictors of long-term obesity. Objective: To determine the impact of a postnatal lifestyle intervention program for overweight women with previous gestational diabetes mellitus (PAIGE). Design: Postnatal overweight women with previous GDM participated in a multicenter randomized controlled trial between June 2013 and December 2014. The intervention comprised a 1-hour educational program, a free 3-month referral to a commercial weight management organization (Slimming World), a pedometer, and structured telephone and text support, in addition to usual care. The control group received usual care only. The primary outcome was weight loss at 6 months. Results: Sixty women were randomized (29 intervention; 31 control) in two centers based on their week of attendance. The intervention group demonstrated significant weight loss at 6 months after randomization compared with the control group: mean ±SD, 3.9 ± 7.0 kg vs 0.7 ±3.8 kg (P = 0.02). Blood glucose levels did not significantly differ. With respect to well-being measures, a bodily pain was significantly reduced in the intervention group (P = 0.007). Conclusions: PAIGE resulted in significantly greater weight loss at 6 months compared with usual care. Such weight loss could prove beneficial in terms of better long-term health and subsequent prevention of type 2 diabetes in overweight women with previous GDM. Future interventions must consider recruitment strategies, timing of the intervention, and inclusion of partners and/or other family members.

Mediators of Behavior Change Maintenance in Physical Activity Interventions for Young and Middle-Aged Adults: A Systematic Review.

Background: Regular physical activity is important for maintaining physical and mental health. Benefits are optimized when physical activity is maintained. Understanding causal mechanisms is important to inform future interventions. Purpose: To investigate mediators of physical activity maintenance. Methods: Six databases were searched (Medline, EMBASE, PsycINFO, CINAHL, Cochrane Database of Systematic Reviews, and Web of Science). Eligibility criteria included adult nonclinical populations, validated measure of physical activity behavior at baseline and at least 6 months postbaseline, control/comparison group(s), and reported mediators of physical activity behavior change. Mediators were examined according to (i) formal mediation tests, (ii) mediator association with physical activity outcome, and (iii) intervention effects on mediators. Results: There were few formal mediation tests conducted (n = 12/39 included studies), and various other methodological limitations were identified. There was some evidence that effective mediators in formal mediation tests at 6 months and later included the "behavioral processes of change" (n = 5/6). Many of the included interventions were not effective for changing targeted mediators (only 34% of 413 tests of mediator changes were significant). Conclusions: There were a number of methodological and statistical limitations in the evidence base. In future, prespecified formal mediation tests should be carried out and could be aided by a formal framework. Social and environmental variables should be considered in addition to intrapersonal variables. Improving knowledge of how to change hypothesized mediators, based on theory and evidence, will reveal how physical activity behavior change maintenance can be achieved. Maintenance research would be enhanced by establishing a formal definition of behavior change "maintenance." PROSPERO registration: PROSPERO 2015:CRD- 42015025462.

Emergency airway and ventilator procedures for community based home care staff validation of an educational program.

BACKGROUND: Children discharged home with tracheostomy and chronic mechanical ventilator support are at high risk for complications and adverse events. Private duty nursing and home respiratory care services are a critical support necessary for successful discharge. The literature suggests that there are opportunities for home care staff (HCS) to improve upon the skills necessary to assess and intervene in an emergency thereby increasing the likelihood of improving long-term outcomes. METHODS: HCS (RN, LPN, RRT) participated in a 4-h session comprised of lecture and simulation. Lecture content focused on tracheostomy safety, operation of the Trilogy and LTV home ventilators, and review of their common alarms. Simulation included two scenarios simulating tracheostomy decannulation and mucous plugging events. Participant comfort with tracheostomy and ventilator management skills were measured on a five item self-assessment tool and clinical knowledge was measured using an 11 item multiple choice skills test, both of which were completed before and after the session. We tested to see if there was a change in test scores from pre- to post-intervention. RESULTS: Fifty-four HCS participated in the program and provided complete data sets. The vast majority (68%) were registered nurses, followed by licensed practical nurses (19%) and respiratory therapists (12%). Participant self-reported comfort with emergency skills prior to intervention was 3.2/5 which increased to 4.1/5 after intervention (P > 0.0001). Average test score prior to intervention was 62%, post intervention score increased to 82% which represented significant improvement (P > 0.0001). DISCUSSION: HCS are generally unprepared to intervene in an acute airway or ventilator emergency. This short, manageable program provided education that resulted in a significant improvement in both skill level and confidence.