Evaluating the implementation of a prescription only regulatory model for nicotine vaping products: A qualitative study on the experiences and views of healthcare professionals.

BACKGROUND: Deciding how to regulate nicotine vaping products (NVPs) is a challenge for many countries. Balanced regulation should consider the potential harms to young people from uptake of NVPs alongside the possible benefits of NVPs as a smoking cessation aid. One option is to make NVPs only available via medical prescription to adults who smoke. From October 2021, Australia adopted a unique model that allows prescription access to NVPs that meet a product standard without requiring the NVPs to be approved as therapeutic goods. This research explored the impact of this regulatory model on the smoking cessation practices of health professionals, and their views on the model. METHODS: Semi-structured interviews were conducted with 39 Australian health professionals recruited from professional networks and social media. Health professionals were eligible if they provided smoking cessation advice as part of their role, and included medical practitioners (n = 9), pharmacists (n = 9), and other health professionals that provided smoking cessation counselling (n = 21). Interviews were mostly completed by phone and online teleconferencing software. Questions focused on smoking cessation practices, advice and information provided to patients about NVPs, views about the effectiveness of the model for supporting use of NVPs for smoking cessation and preventing youth uptake, and barriers and facilitators to prescribing and dispensing NVPs. Coding and analysis used a combination of inductive and deductive approaches. RESULTS: Findings indicated a lack of consensus amongst the participants about NVPs as a cessation or harm reduction tool. Participants broadly agreed that the model has not been effective in improving quality control of NVPs, or in reducing youth access. Many participants eligible to prescribe or dispense NVPs felt that the current regulatory model placed an undue time and responsibility burden on clinicians. CONCLUSION: Our research identified several limitations associated with the current Australian prescription-only regulatory model. These were perceived by healthcare professionals to limit the potential for the regulations to reduce youth use and to increase access to safer NVP products for people who smoke to use for smoking cessation.

Ubiquitin-specific protease 11 structure in complex with an engineered substrate mimetic reveals a molecular feature for deubiquitination selectivity.

Ubiquitin-specific proteases (USPs) are crucial for controlling cellular proteostasis and signaling pathways but how deubiquitination is selective remains poorly understood, in particular between paralogues. Here, we developed a fusion tag method by mining the Protein Data Bank and trapped USP11, a key regulator of DNA double-strand break repair, in complex with a novel engineered substrate mimetic. Together, this enabled structure determination of USP11 as a Michaelis-like complex that revealed key S1 and S1' binding site interactions with a substrate. Combined mutational, enzymatic, and binding experiments identified Met77 in linear diubiquitin as a significant residue that leads to substrate discrimination. We identified an aspartate "gatekeeper" residue in the S1' site of USP11 as a contributing feature for discriminating against linear diubiquitin. When mutated to a glycine, the corresponding residue in paralog USP15, USP11 acquired elevated activity toward linear diubiquitin in-gel shift assays, but not controls. The reverse mutation in USP15 confirmed that this position confers paralog-specific differences impacting diubiquitin cleavage rates. The results advance our understanding of the molecular basis for the higher selectivity of USP11 compared to USP15 and may aid targeted inhibitor development. Moreover, the reported carrier-based crystallization strategy may be applicable to other challenging targets.

Statins for extension of disability-free survival and primary prevention of cardiovascular events among older people: protocol for a randomised controlled trial in primary care (STAREE trial).

INTRODUCTION: The world is undergoing a demographic transition to an older population. Preventive healthcare has reduced the burden of chronic illness at younger ages but there is limited evidence that these advances can improve health at older ages. Statins are one class of drug with the potential to prevent or delay the onset of several causes of incapacity in older age, particularly major cardiovascular disease (CVD). This paper presents the protocol for the STAtins in Reducing Events in the Elderly (STAREE) trial, a randomised double-blind placebo-controlled trial examining the effects of statins in community dwelling older people without CVD, diabetes or dementia. METHODS AND ANALYSIS: We will conduct a double-blind, randomised placebo-controlled trial among people aged 70 years and over, recruited through Australian general practice and with no history of clinical CVD, diabetes or dementia. Participants will be randomly assigned to oral atorvastatin (40 mg daily) or matching placebo (1:1 ratio). The co-primary endpoints are disability-free survival defined as survival-free of dementia and persistent physical disability, and major cardiovascular events (cardiovascular death or non-fatal myocardial infarction or stroke). Secondary endpoints are all-cause death, dementia and other cognitive decline, persistent physical disability, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, heart failure, atrial fibrillation, fatal and non-fatal cancer, all-cause hospitalisation, need for permanent residential care and quality of life. Comparisons between assigned treatment arms will be on an intention-to-treat basis with each of the co-primary endpoints analysed separately in time-to-first-event analyses using Cox proportional hazards regression models. ETHICS AND DISSEMINATION: STAREE will address uncertainties about the preventive effects of statins on a range of clinical outcomes important to older people. Institutional ethics approval has been obtained. All research outputs will be disseminated to general practitioner co-investigators and participants, published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02099123.

Socioeconomic, Behavioural, and Social Health Correlates of Optimism and Pessimism in Older Men and Women: A Cross-Sectional Study.

BACKGROUND: Optimism is a disposition characterised by positive future expectancies, while pessimism is characterised by expecting the worst. High optimism and low pessimism promote the health of older adults and may potentiate full engagement in life. We identified socioeconomic, behavioural, and social factors associated with optimism and pessimism in older adults. METHODS: Participants included 10,146 community-dwelling, apparently healthy Australian adults aged 70 years and over from the ASPREE Longitudinal Study of Older Persons (ALSOP). Optimism and pessimism were measured using the revised Life Orientation Test. Cross-sectional ordinal logistic regression was used to determine the socioeconomic, behavioural, and social health factors associated with optimism and pessimism. RESULTS: Higher education, greater physical activity, lower loneliness, and volunteering were associated with higher optimism and lower pessimism. Low social support was associated with higher pessimism. Higher socioeconomic advantage, greater income, and living alone were associated with lower pessimism. Women were more optimistic and less pessimistic than men. The association of age, smoking status, and alcohol consumption with optimism and pessimism differed for men and women. CONCLUSIONS: Factors associated with higher optimism and lower pessimism were also those demonstrated to support healthy ageing. Health-promotion action at the individual level (e.g., smoking cessation or regular physical activity), health professional level (e.g., social prescribing or improving access and quality of care for all older adults), and community level (e.g., opportunities for volunteer work or low-cost social activities for older adults) may improve optimism and reduce pessimism, possibly also promoting healthy ageing.

The association between sex hormones and the change in brain-predicted age difference in older women.

OBJECTIVE: The role of circulating sex hormones on structural brain ageing is yet to be established. This study explored whether concentrations of circulating sex hormones in older women are associated with the baseline and longitudinal changes in structural brain ageing, defined by the brain-predicted age difference (brain-PAD). DESIGN: Prospective cohort study using data from NEURO and Sex Hormones in Older Women; substudies of the ASPirin in Reducing Events in the Elderly clinical trial. PATIENTS: Community-dwelling older women (aged 70+ years). MEASUREMENTS: Oestrone, testosterone, dehydroepiandrosterone (DHEA), and sex-hormone binding globulin (SHBG) were quantified from plasma samples collected at baseline. T1-weighted magnetic resonance imaging was performed at baseline, 1 and 3 years. Brain age was derived from whole brain volume using a validated algorithm. RESULTS: The sample comprised of 207 women not taking medications known to influence sex hormone concentrations. A statistically higher baseline brain-PAD (older brain age relative to chronological age) was seen for women in the highest DHEA tertile compared with the lowest in the unadjusted analysis (p = .04). This was not significant when adjusted for chronological age, and potential confounding health and behavioural factors. Oestrone, testosterone and SHBG were not associated with brain-PAD cross-sectionally, nor were any of the examined sex hormones or SHBG associated with brain-PAD longitudinally. CONCLUSION: No strong evidence of an association between circulating sex hormones and brain-PAD. Given there is prior evidence to suggests sex hormones may be important for brain ageing, further studies of circulating sex hormones and brain health in postmenopausal women are warranted.

PDLIM2 is highly expressed in Breast Cancer tumour-associated macrophages and is required for M2 macrophage polarization.

The PDZ-LIM domain-containing protein 2 (PDLIM2) regulates cell polarity and the protein stability of key transcription factors in epithelial and hemopoietic cells. We previously reported that PDLIM2 is more highly expressed in Triple Negative Breast Cancer (TNBC) than in other breast cancer types or normal breast tissue. In the course of the TNBC study, it was noted that PDLIM2 was highly expressed in the stroma of PDLIM2-expressing tumours. Here, we investigated the phenotype of these stromal cells and whether any infiltrating immune population was linked to PDLIM2 expression. We found that high PDLIM2 expression in breast tumours was associated with higher levels of infiltrating M2 macrophages, but was not associated with infiltrating T cell sub-populations. We then tested whether PDLIM2 contributes to macrophage differentiation or function by using cultures of bone marrow-derived macrophages from wildtype and Pdlim2 knockout mice. This demonstrated that PDLIM2 is required for naïve macrophage migration and for the full adoption of IL-4-induced M2 polarization, including expression of M2 phenotypic markers, cell adhesion and cell migration. TLR4-, TLR3- or IFNγ-induced M1 macrophage activity was less dependent on PDLIM2. Finally, analysis of publicly available breast cancer datasets showed that high PDLIM2 expression is associated with increased M2 macrophage infiltration. We conclude that PDLIM2 expression influences the tumour associated stroma and, in particular, M2 macrophage infiltration that may contribute to the progression of TNBC or other subsets of breast cancer.

The Relationship Between Paternal Preconception Obesity and Health Behaviors and Childhood Obesity: Protocol for a Systematic Review.

BACKGROUND: Childhood obesity is a global public health concern and is a priority for researchers and policy makers. To overcome the epidemic of obesity, influencing factors throughout the life span need to be addressed, including those in the preconception period. A better understanding of the association between paternal preconception factors and childhood obesity is important for public health interventions. OBJECTIVE: This systematic review will examine the relationship between paternal preconception obesity and health behaviors and their offspring's overweight or obesity. METHODS: Peer-reviewed quantitative studies and grey literature that report associations between paternal preconception obesity and health behaviors-such as smoking, exercise, and eating habits-and childhood overweight and obesity will be identified through a computerized literature search in 7 databases. The quality of each study will be assessed using the Quality Assessment Tool for Quantitative Studies. Characteristics of the included studies will be reported, and relevant findings from each paternal preconception exposure will be narratively synthesized. This review will follow the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020 guidelines. RESULTS: This systematic review is anticipated to begin in December 2021 and be completed by the end of August 2022. CONCLUSIONS: This systematic review will contribute to a better understanding of the relationship between preconception paternal exposures and their offspring's overweight or obesity. Findings will help support health professionals working with prospective parents to educate fathers on the benefits of improving their weight and health behaviors during the preconception period. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/31254.

Similar mortality risk in incident cognitive impairment and dementia: Evidence from the ASPirin in Reducing Events in the Elderly (ASPREE) trial.

BACKGROUND: This study examined the risk of mortality in older adults with newly detected cognitive impairment or dementia. METHODS: Data from the Australian cohort of the ASPirin in Reducing Events in the Elderly (ASPREE) trial were examined. The ASPREE clinical trial compared daily low-dose aspirin to a placebo and involved 16,703 individuals aged 70 years and over, who were without major cognitive impairment, physical disability, or cardiovascular disease at recruitment. During the trial, evidence of cognitive impairment, based on cognitive testing and medical record information, triggered dementia adjudication of participants using DSM-IV criteria. Cox proportional hazard models were used to compare mortality rates across the dementia, trigger-only, and no-trigger groups. RESULTS: Over a median 4.7-year follow-up period, 806 participants triggered dementia adjudication, with 485 (60.2%) judged to have dementia. Following recruitment, mortality risks were 32.9, 33.6, and 10.8 events per 1000 person-years in the dementia, trigger-no-dementia, and no-trigger groups, respectively. In the fully adjusted model, mortality risks remained higher in the dementia and trigger-no-dementia groups, with hazard ratios of 1.7 (95% CI: 1.3-2.1) and 1.9 (95% CI: 1.5-2.6), respectively. There was no discernible difference between the dementia and trigger-no-dementia groups in mortality rates following recruitment, or following a dementia trigger. These two groups were more likely to die from sepsis, respiratory disease, and dementia, but less likely to die from cancer than the no-trigger group, χ2  = 161.5, p < 0.001. CONCLUSION: ASPREE participants who triggered for a dementia evaluation experienced a substantially higher mortality rate than those who remained cognitively intact. The increase was indistinguishable among persons who met DSM-IV criteria for dementia vs. those who triggered for a dementia evaluation but failed to meet DSM-IV criteria. Future work should investigate whether earlier detection of cognitive decline can be used to identify and prevent early mortality.

Successful Rapid Desensitization to Micafungin in a Pediatric Patient.

Introduction: Echinocandin antifungal medications including micafungin are being used more commonly in the treatment of invasive fungal infections in both pediatric and adult patients. Micafungin is also a first-line therapeutic option for candidemia and antifungal prophylaxis in a variety of clinical settings. Hypersensitivity reactions have not been well described; however, isolated cases have been reported. No cases of desensitization to echinocandins have been previously described. Case Presentation: In this report, we described a 14-year-old female with high-risk pre-B cell acute lymphoblastic leukemia diagnosed with pulmonary aspergillosis. She developed a hypersensitivity reaction to micafungin, which was deemed first-line therapy for the infection. A rapid intravenous desensitization protocol was successfully completed without reactions. The patient completed the remaining 2 months of therapy without reactions. Conclusion: This report outlines the first report of a successful desensitization to micafungin or any echinocandin. This is a safe method of completing antifungal therapy in a patient with echinocandin hypersensitivity and may be considered for other patients with micafungin hypersensitivities.

Effect of Aspirin on Activities of Daily Living Disability in Community-Dwelling Older Adults.

BACKGROUND: Cerebrovascular events, dementia, and cancer can contribute to physical disability with activities of daily living (ADL). It is unclear whether low-dose aspirin reduces this burden in aging populations. In a secondary analysis, we now examine aspirin's effects on incident and persistent ADL disability within a primary prevention aspirin trial in community-dwelling older adults. METHODS: The ASPREE (ASPirin in Reducing Events in the Elderly) trial of daily 100 mg aspirin versus placebo recruited 19 114 healthy adults aged 70+ years (65+ years if U.S. minority) in Australia and the United States. Six basic ADLs were assessed every 6 months. Incident ADL disability was defined as inability or severe difficulty with ≥1 ADL; persistence was confirmed if the same ADL disability remained after 6 months. Proportional hazards modeling compared time to incident or persistent ADL disability for aspirin versus placebo; death without prior disability was a competing risk. RESULTS: Over a median of 4.7 years, incident ADL disability was similar in those receiving aspirin (776/9525) and placebo (787/9589) with walking, bathing, dressing, and transferring the most commonly reported. Only 24% of incident ADL disability progressed to persistent. Persistent ADL disability was lower in the aspirin group (4.3 vs 5.3 events/1000 py; hazard ratio [HR] = 0.81, 95% confidence interval [CI]: 0.66-1.00), with bathing and dressing the most common ADL disabilities in both groups. Following persistent ADL disability, there were more deaths in the aspirin group (24 vs 12). DISCUSSION: Low-dose aspirin in initially healthy older people did not reduce the risk of incident ADL disability, although there was evidence of reduced persistent ADL disability.

Comparison between the Healthy Start-Départ Santé online and in-person training of childcare educators to improve healthy eating and physical activity practices and knowledge of physical activity and fundamental movement skills: A controlled trial.

Online training may be a more effective and sustainable way to reach educators in early childcare centres (ECCs). This study compared the effectiveness of an online version of the Healthy Start-Départ Santé (HSDS) training to the traditional in-person version of the training as well as to the usual practice condition on ECC educators' healthy eating (HE) and physical activity (PA) practices and knowledge of PA and fundamental movement skills (FMS). Seventy-eight ECCs were randomly chosen across the provinces of New Brunswick and Saskatchewan, Canada and were allocated to either the online training, the in-person training or the usual practice groups between 2013 and 2018. Educators in each group completed a self-administered questionnaire before and nine months after the intervention, which included questions regarding their HE and PA practices in the ECC, as well as their knowledge of children's FMS and PA. Group differences were assessed with mixed-effect models. Compared to educators in the usual practice group, educators in the online training group reported a greater improvement in scores for HE and PA practices (p = 0.03 and 0.03, respectively), but change for educators in the in-person training group were not different (p = 0.8 and 0.56, respectively). The rate of improvement in FMS and PA knowledge did not differ across all three groups (p = 0.9). The HSDS online training is an effective method of improving educators' HE and PA practices in ECCs. Trial registration: ClinicalTrials.gov (NCT02375490).

Baseline characteristics and age-related macular degeneration in participants of the "ASPirin in Reducing Events in the Elderly" (ASPREE)-AMD trial.

PURPOSE: To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression. METHODS: Australian participants from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants. RESULTS: ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early [OR = 1.37 (1.16, 1.62)], and intermediate [OR = 1.35 (1.12, 1.63)] AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors. CONCLUSIONS: Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.

Effectiveness of the Healthy Start-Départ Santé approach on physical activity, healthy eating and fundamental movement skills of preschoolers attending childcare centres: a randomized controlled trial.

BACKGROUND: Since young children spend approximately 30 h per week in early childcare centres (ECC), this setting is ideal to foster healthy behaviours. This study aimed to assess the effectiveness of the Healthy Start-Départ Santé (HSDS) randomized controlled trial in increasing physical activity (PA) levels and improving healthy eating and fundamental movement skills in preschoolers attending ECC. METHODS: Sixty-one ECC were randomly selected and allocated to either the usual practice (n = 30; n = 433 children) or intervention group (n = 31; n = 464 children). The HSDS intervention group was provided a 3-h on-site training for childcare educators which aimed to increase their knowledge and self-efficacy in promoting healthy eating, PA and development of fundamental movement skills in preschoolers. PA was measured during childcare hours for five consecutive days using the Actical accelerometer. Preschoolers' fundamental movement skills were assessed using the standard TGMD-II protocol and POMP scores. Food intake was evaluated using digital photography-assisted weighted plate waste at lunch, over two consecutive days. All data were collected prior to the HSDS intervention and again 9 months later. Mixed-effect models were used to analyse the effectiveness of the HSDS intervention on all outcome measures. RESULTS: Total number of children who provided valid data at baseline and endpoint for PA, food intake and fundamental movement skills were 259, 670 and 492, respectively. Children in the HSDS intervention group had, on average, a 3.33 greater point increase in their locomotor motor skills scores than children in the control group (ß = 3.33, p = 0.009). No significant differences in effects were observed for object control, PA and food intake. However, results demonstrated a marginal increase in portions of fruits and vegetables served in the intervention group compared to control group (ß = 0.06, p = 0.05). CONCLUSION: Of the 12 outcome variables investigated in this study, 10 were not different between the study groups and two of them (locomotor skills and vegetables and fruits servings) showed a significant improvement. This suggests that HSDS is an effective intervention for the promotion of some healthy behaviours among preschoolers attending ECC. TRIAL REGISTRATION: Clinical Trials NCT02375490. Registered on February 24, 2015; 77 retrospectively registered.

Implementing and Evaluating a Multihospital Standardized Opioid Curriculum for Surgical Providers.

OBJECTIVE: (1) To identify gaps in providers knowledge on opioid medication and dosing, patient-specific characteristics that require alterations in dosing, and patient monitoring and treatment adjustments. (2) To evaluate an educational intervention aimed at minimizing these deficits. DESIGN: Observational prospective study. Providers took an anonymous paired pre-and posteducation knowledge assessment before and after participating in a 75-minute educational session. Results before and after the educational session were compared. SETTING: Surgical providers included nurse practitioners, physician assistants, preinterns, and general surgery residents across 4 quaternary care hospitals in Boston. Participants There were 194 participants and 174 completed both pre- and posteducation knowledge assessments. RESULTS: Average scores on the educational assessment increased from 59% before the course to 68% after the session. Posteducation, providers reported increased comfort in prescribing and 95% stated that the curriculum would impact their practice. CONCLUSIONS: Surgical providers at multiple hospitals have significant gaps in knowledge for optimal prescribing and management of opioid prescriptions. A 75-minute opioid education session increased prescriber knowledge as well as comfort in prescribing. This multicenter study demonstrates how an educational initiative can be implemented broadly and result in decreased knowledge gaps.

Frailty, oral health and nutrition in geriatrics inpatients: A cross-sectional study.

BACKGROUND: Poor nutritional status is a risk factor for the development of frailty. Likewise, oral health is independently associated with nutrition. The potential association between oral health and frailty in hospitalised elderly adults has, however, not previously been investigated. OBJECTIVE: To investigate the relationship between oral health and frailty in hospitalised elderly adults and to identify the predictors of frailty. METHOD: A cross-sectional study of 168 geriatric inpatients >65 years old was performed from August to December 2016. Patients of non-English speaking background, with impaired cognition (MMSE <24), severe hearing or visual impairment or active delirium were excluded. Oral health, nutrition and frailty were assessed using previously validated tools, namely the Geriatric Oral Health Assessment Index (GOHAI), Mini Nutrition Assessment (MNA) and Reported Edmonton Frailty Scale (REFS). Other data collected included demographics, co-morbidities, level of education and smoking/alcohol history. RESULTS: On univariate analysis, the REFS score decreased with better nutritional status/higher MNA (P < 0.001) and better self-reported oral health/higher GOHAI (P = 0.023). Nutritional status accounted for 17% of variability in frailty assessment. On multivariate analysis, co-morbidities (P < 0.001), MNA (P < 0.001) and living in residential care (P < 0.001) were independent predictors of frailty. After adjusting for nutrition and co-morbidities, self-reported oral health was found to have an independent negative association with frailty (P = 0.019). CONCLUSION: Poor self-reported oral health was found to be independently associated with frailty. Further research should be directed at whether interventions to maintain good oral health can prevent or slow the progression of frailty.

The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel.

Ubiquitin-specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor ß (TGF-ß) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on USP15's catalytic domain is currently unavailable. Here, we determined crystal structures of the USP15 catalytic core domain, revealing a canonical USP fold, including a finger, palm, and thumb region. Unlike for the structure of paralog USP4, the catalytic triad is in an inactive configuration with the catalytic cysteine ∼10 Å apart from the catalytic histidine. This conformation is atypical, and a similar misaligned catalytic triad has so far been observed only for USP7, although USP15 and USP7 are differently regulated. Moreover, we found that the active-site loops are flexible, resulting in a largely open ubiquitin tail-binding channel. Comparison of the USP15 and USP4 structures points to a possible activation mechanism. Sequence differences between these two USPs mainly map to the S1' region likely to confer specificity, whereas the S1 ubiquitin-binding pocket is highly conserved. Isothermal titration calorimetry monoubiquitin- and linear diubiquitin-binding experiments showed significant differences in their thermodynamic profiles, with USP15 displaying a lower affinity for monoubiquitin than USP4. Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone in vitro A USP15-mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1' binding site. Our results reveal first insights into USP15's catalytic domain structure, conformational changes, differences between paralogs, and small-molecule interactions and establish a framework for cellular probe and inhibitor development.

The safety and sensitivity of a telemetric capsule to monitor gastrointestinal hydrogen production in vivo in healthy subjects: a pilot trial comparison to concurrent breath analysis.

BACKGROUND: Intestinal gases are currently used for the diagnosis of disorders including small intestinal bacterial overgrowth and carbohydrate malabsorption. AIM: To compare the performance of measuring hydrogen production within the gut directly with the telemetric gas-sensing capsule with that of indirect measurement through breath testing. METHODS: Using standard breath testing protocols, the capsules and breath tests were simultaneously evaluated in a single-blinded trial in 12 healthy subjects. Eight received a single dose of 1.25-40 g inulin and four 20 or 40 g glucose. Safety and reliability of the capsules were also assessed. RESULTS: There were no reported adverse events. All capsules were retrieved and operated without failure. Capsule measurements were in agreement with breath test measurements in magnitude but not in timing; minimal hydrogen production was observed after glucose ingestion and capsule measurements correlated with breath hydrogen after ingestion of 40 g inulin. A dose-dependent increase in concentration of hydrogen was observed from the capsule following ingestion of inulin as low as 1.25 g compared with >10 g for breath measurements. Specifically, the capsule measured >3000 times higher concentrations of hydrogen compared to breath tests, resulting in a signal-to-noise ratio of 23.4 for the capsule compared to 4.2 for the breath test. CONCLUSIONS: The capsule showed high sensitivity and signal-to-noise ratio in measuring luminal hydrogen concentrations, provided information on the site of intestinal gas production, and demonstrated safety and reliability. The capsule has potential for improving diagnostic precision for disorders such as small intestinal bacterial overgrowth.

Promoting physical activity, healthy eating and gross motor skills development among preschoolers attending childcare centers: Process evaluation of the Healthy Start-Départ Santé intervention using the RE-AIM framework.

BACKGROUND: The Healthy Start-Départ Santé intervention was developed to promote physical activity, gross motor skills and healthy eating among preschoolers attending childcare centers. This process evaluation aimed to report the reach, effectiveness, adoption, implementation and maintenance of the Healthy Start-Départ Santé intervention. METHODS: The RE-AIM framework was used to guide this process evaluation. Data were collected across 140 childcare centers who received the Healthy Start-Départ Santé intervention in the provinces of Saskatchewan and New Brunswick, Canada. Quantitative data were collected through director questionnaires at 10 months and 2 years after the initial training and analyzed using descriptive statistics. Qualitative data were collected throughout the intervention. RESULTS: The intervention was successful in reaching a large number of childcare centres and engaging both rural and urban communities across Saskatchewan and New Brunswick. Centres reported increasing opportunities for physical activity and healthy eating, which were generally low-cost, easy and quick to implement. However, these changes were rarely transformed into formal written policies. A total of 87% of centers reported using the physical activity resource and 68% using the nutrition resource on a weekly basis. Implementation fidelity of the initial training was high. Of those centers who received the initial training, 75% participated in the mid-point booster session training. Two year post-implementation questionnaires indicated that 47% of centers were still using the Active Play Equipment kit, while 42% were still using the physical activity resource and 37% were still using the nutrition resource. Key challenges to implementation and sustainability identified during the evaluation were consistent among all of the REAIM elements. These challenges included lack of time, lack of support from childcare staff and low parental engagement. CONCLUSIONS: Findings from this study suggest the implementation of Healthy Start-Départ Santé may be improved further by addressing resistance to change and varied levels of engagement among childcare staff. In addition, further work is needed to provide parents with opportunities to engage in HSDS with their children.

Association between childcare educators' practices and preschoolers' physical activity and dietary intake: a cross-sectional analysis.

INTRODUCTION: Childcare educators may be role models for healthy eating and physical activity (PA) behaviours among young children. This study aimed to identify which childcare educators' practices are associated with preschoolers' dietary intake and PA levels. METHODS: This cross-sectional analysis included 723 preschoolers from 50 randomly selected childcare centres in two Canadian provinces. All data were collected in the fall of 2013 and 2014 and analysed in the fall of 2015. PA was assessed using Actical accelerometers during childcare hours for 5 consecutive days. Children's dietary intake was measured at lunch on 2 consecutive days using weighed plate waste and digital photography. Childcare educators' nutrition practices (modelling, nutrition education, satiety recognition, verbal encouragement and not using food as rewards) and PA practices (informal and formal PA promotion) were assessed by direct observation over the course of 2 days, using the Nutrition and Physical Activity Self-Assessment for Child Care tool. Associations between educators' practices and preschoolers' PA and dietary intake were examined using multilevel linear regressions. RESULTS: Overall, modelling of healthy eating was positively associated with children's intake of sugar (ß=0.141, 95% CI 0.03 to 0.27), while calorie (ß=-0.456, 95% CI -1.46 to -0.02) and fibre intake (ß=-0.066, 95% CI -0.12 to -0.01) were negatively associated with providing nutrition education. Not using food as rewards was also negatively associated with fat intake (ß=-0.144, 95% CI -0.52 to -0.002). None of the educators' PA practices were associated with children's participation in PA. CONCLUSIONS: Modelling healthy eating, providing nutrition education and not using food as rewards are associated with children's dietary intake at lunch in childcare centres, highlighting the role that educators play in shaping preschoolers' eating behaviours. Although PA practices were not associated with children's PA levels, there is a need to reduce sedentary time in childcare centres.