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Food intake and body weight are controlled by a variety of central and peripheral factors, but the exact mechanisms behind these processes are still not fully understood. Here we show that that macrophage inhibitory cytokine-1 (MIC-1/GDF15), known to have anorexigenic effects particularly in cancer, provides protection against the development of obesity. Both under a normal chow diet and an obesogenic diet, the transgenic overexpression of MIC-1/GDF15 in mice leads to decreased body weight and fat mass. This lean phenotype was associated with decreased spontaneous but not fasting-induced food intake, on a background of unaltered energy expenditure and reduced physical activity. Importantly, the overexpression of MIC-1/GDF15 improved glucose tolerance, both under normal and high fat-fed conditions. Altogether, this work shows that the molecule MIC-1/GDF15 might be beneficial for the treatment of obesity as well as perturbations in glucose homeostasis.

We previously described a 6-item teamwork index (TEAM) with a strong relationship to provider experience, lower burnout, and intent to stay. We now sought to determine whether (1) TEAM relates to higher patient Net Promoter Score (NPS, or likelihood of patient referring to the organization) and (2) teamwork mediates a provider experience-NPS relationship. A provider wellness survey was administered in the fall of 2019 in 6 care delivery organizations (CDOs) with patient NPS data. Measures included a validated burnout item, 6-item TEAM measure, provider experience metric, standard intent-to-stay question, and NPS data from 79,254 patients matched to CDO. Regression analyses modeled relationships among TEAM, provider experience, and NPS. Open-ended comments were reviewed to confirm patient NPS findings. There were 1386 provider respondents (53% physicians, 47% advanced practice clinicians, 58% female, 62% White, 58% in primary care; response rate, 55.7%). Median NPS was 83%. TEAM was associated with patient NPS greater than the median (53% with high TEAM and high NPS vs 44% with low TEAM and high NPS; P < .001), as was provider experience (52% vs 45%; P < .05). In regression analyses, patient NPS was strongly related to TEAM (adjusted OR, 1.41; 95% CI, 1.25-1.60; P < .001). The provider experience-patient NPS relationship was partly mediated by TEAM. Open-ended comments confirmed positive or negative sentiments related to NPS. Teamwork and provider experience relate to patient NPS, and the provider experience-NPS relationship appears to be mediated by teamwork.

Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.

Active engagement in leisure activities has positive effects on individuals' health outcomes and social functioning; however, there is limited understanding of the link between participation in leisure activities, particularly non-exercise activities, and falls in older adults. This study aimed to determine the relationship between participation in leisure activities and the incidence of falls, and the variation of this relationship by dementia status in residential aged care facilities (RACFs). A retrospective longitudinal cohort study utilising routinely collected data (January 2021-August 2022) from 25 RACFs in Sydney, Australia, was conducted. The cohort included 3,024 older permanent residents (1,493 with dementia and 1,531 without) aged ≥65 and with a stay of ≥1 week. The level of participation in leisure activities was measured using the number of leisure activities per 1,000 resident days and divided into quartiles. Outcome measures were the incidence rate of all falls and injurious falls (i.e., number of falls per 1,000 resident days). We used multilevel negative binary regression to examine the relationship between leisure participation and fall incidence. For the whole sample, leisure participation was significantly inversely associated with the incidence rate of all falls and injurious falls. For example, residents in the high leisure participation group were 26% less likely to experience a fall compared to those in the low leisure participation group after controlling for confounders (incidence rate ratio = 0.74, 95% confidence interval = 0.60, 0.91). Such inverse relationship was observed in both exercise and non-exercise activities and was stronger among residents without dementia. Leisure participation is associated with a lower rate of falls, a key quality indicator by which RACFs are benchmarked and funded in Australia and many other countries. More recognition and attention are needed for the currently underfunded leisure activities in RACFs in future funding arrangement.

ObjectivesAntibiotic prescribing in primary care contributes significantly to antibiotic overuse. Nudge interventions alter the decision-making environment to achieve behaviour change without restricting options. Our objectives were to conduct a systematic review to describe the types of nudge interventions used to reduce unnecessary antibiotic prescribing in primary care, their key features, and their effects on antibiotic prescribing overall.MethodsMedline, Embase and grey literature were searched for randomised trials or regression discontinuity studies in April 2021. Risk of bias was assessed independently by two researchers using the Cochrane Effective Practice and Organisation of Care group’s tool. Results were synthesised to report the percentage of studies demonstrating a reduction in overall antibiotic prescribing for different types of nudges. Effects of social norm nudges were examined for features that may enhance effectiveness.ResultsNineteen studies were included, testing 23 nudge interventions. Four studies were rated as having a high risk of bias, nine as moderate risk of bias and six as at low risk. Overall, 78.3% (n=18, 95% CI 58.1 to 90.3) of the nudges evaluated resulted in a reduction in overall antibiotic prescribing. Social norm feedback was the most frequently applied nudge (n=17), with 76.5% (n=13; 95% CI 52.7 to 90.4) of these studies reporting a reduction. Other nudges applied were changing option consequences (n=3; with 2 reporting a reduction), providing reminders (n=2; 2 reporting a reduction) and facilitating commitment (n=1; reporting a reduction). Successful social norm nudges typically either included an injunctive norm, compared prescribing to physicians with the lowest prescribers or targeted high prescribers.ConclusionsNudge interventions are effective for improving antibiotic prescribing in primary care. Expanding the use of nudge interventions beyond social norm nudges could reap further improvements in antibiotic prescribing practices. Policy-makers and managers need to be mindful of how social norm nudges are implemented to enhance intervention effects.

To develop a brief teamwork measure and determine how teamwork relates to provider experience, burnout, and work intentions. Survey of clinicians. We analyzed data from Optum's 2019 biannual clinician survey, including a validated burnout measure and measures of provider experience and intent to stay. A 6-item measure of team effectiveness (TEAM) focused on efficiency, communication, continuous improvement, and leadership. Construct validity was assessed with content, reliability, and correlation with burnout. Generalized estimating equations with robust SEs determined relationships among TEAM score, provider experience, and intent to stay, controlling for demographics, clustering, and practice factors. Of 1500 physicians and advanced practice clinicians (1387 with complete data; response rate 56%), there were 58% in primary care; 57% were women, and 38% identified as Asian, Black/Hispanic, or another race/ethnicity other than White non-Hispanic. Burnout was present in 30%. The Cronbach α was excellent (0.86), and TEAM correlated with the validated burnout measure (adjusted odds ratio [OR] of lower burnout with high TEAM score, 0.28; 95% CI, 0.19-0.40; P < .0001). Clinicians with TEAM scores of at least 4 were more likely to have positive provider experiences (79% favorable vs 24% with low TEAM score; P < .001), had lower burnout rates (17% vs 44%%; P < .001), and more often intended to stay (93% vs 65%; P < .001). TEAM index score was strongly associated with provider experience (adjusted OR, 11.72; 95% CI, 8.11-16.95; P < .001) and intent to stay (adjusted OR, 7.24; 95% CI, 5.34-9.83; P < .001). The TEAM index is related to provider experience, burnout, and intent to stay, and it may help organizations optimize clinical work environments.

Kaposi’s sarcoma-associated herpesvirus (KSHV) establishes persistent infection in the host by encoding a vast network of proteins that aid immune evasion. One of these targeted innate immunity pathways is the cGAS-STING pathway, which inhibits the reactivation of KSHV from latency. Previously, we identified multiple cGAS/STING inhibitors encoded by KSHV, suggesting that the counteractions of this pathway by viral proteins are critical for maintaining a successful KSHV life cycle. However, the detailed mechanisms of how these viral proteins block innate immunity and facilitate KSHV lytic replication remain largely unknown. In this study, we report that ORF48, a previously identified negative regulator of the cGAS/STING pathway, is required for optimal KSHV lytic replication. We used both siRNA and deletion-based systems to evaluate the importance of intact ORF48 in the KSHV lytic cycle. In both systems, loss of ORF48 resulted in defects in lytic gene transcription, lytic protein expression, viral genome replication and infectious virion production. ORF48 genome deletion caused more robust and global repression of the KSHV transcriptome, possibly due to the disruption of RTA promoter activity. Mechanistically, overexpressed ORF48 was found to colocalize and interact with endogenous STING in HEK293 cells. Endogenous ORF48 and STING interactions were also detected in reactivated iSLK.219 cells. Compared with the control cell line, HUVEC cells stably expressing ORF48 exhibited repressed STING-dependent innate immune signaling upon ISD or diABZI treatment. However, the loss of ORF48 in our iSLK-based lytic system failed to induce IFNβ production, suggesting a redundant role of ORF48 on STING signaling during the KSHV lytic phase. Thus, ORF48 is required for optimal KSHV lytic replication through additional mechanisms that need to be further explored.

Background Digital dashboards are widely employed across healthcare settings to present data, supporting timely risk identification and enhancing clinical decision-making. Incorporating feedback from end-users into dashboard design supports their uptake and utilisation. The current study aimed to: (a) understand how healthcare professionals working in residential aged care gather, interpret, transfer and communicate clinical information especially for falls management; and (b) utilise co-design methods to determine healthcare professionals’ preferences for presentation, content and functionality of a digital falls dashboard to support delivery of care in residential aged care. Methods Participants were recruited via aged care provider and primary health network contacts. Individual interviews with general practitioners (GPs) ( n  = 3) explored end-user needs including information needs for falls management, decision-making processes, and dashboard preferences. Dashboard prototypes were developed using the interview findings and published guidelines. Prototypes were then presented for feedback in eight workshops ( n  = 20 participants; residential aged care staff, GPs, and geriatricians) completed via videoconferencing or in-person to gain feedback. Interview and workshop transcripts were analysed using template analysis. Results During interviews, GPs discussed difficulties in accessing aged care resident information, clinical decision-making in residential aged care, and use of decision support. During workshops, healthcare professionals shared feedback on the design, content, and functionality of dashboard prototypes. Healthcare professionals also discussed themes of human-technology interaction. This included mistrust of new digital tools and barriers to their use in residential aged care. The current study found that healthcare professionals want a dashboard that displays relevant resident data, such as medications, includes features for benchmarking, and provides detailed insights to support decision making. They expressed a need for evidence-based decision support but advocated for minimal alerts. Conclusions Healthcare professionals were receptive to using a dashboard in residential aged care to minimise resident falls. They shared their design ideas in co-design interviews and workshops for a prospective dashboard. Findings informed the initial development and subsequent revisions of the dashboard to align with end-user preferences.

Background Little is known about the information needs of older people and their family caregivers, particularly around medication management. This is largely because this population are infrequently consulted in research. Health technologies such as digital dashboards can present comprehensive and timely data summaries to improve knowledge and guide decision-making. Objectives The aim of this study was to understand current information seeking-behaviours of aged care service users and their families, and their preferences for the presentation of these types of information to support the co-design of a digital aged care dashboard. Methods Aged care clients (community and residential aged care) and their family members were invited to participate in semi-structured, one-on-one interviews conducted over the telephone. The interviews explored how participants sought health information, how this information supported their clinical decision-making, and how they would want this information to be presented via a digital dashboard. Interviews were audio-recorded, transcribed verbatim and independently analysed using an inductive content approach by three reviewers to identify prominent categories. Results Aged care clients and family members sought health information from healthcare providers, aged care facilities and the Internet. Information regarding medications, medical conditions and an overview for family members were of particular importance to participants. Participants saw the usefulness of a digital dashboard displaying relevant information, and provided suggestions regarding presentation of this information. This included the use of large text, representative colours, symbols and graphs. Participants recommended being able to tailor the dashboard to individual end-users. Conclusions By engaging aged care clients and their families in research, it was found that they had positive views about a digital dashboard that presented clinical information and was readily accessible. Such a dashboard could complement their current practices of information-seeking. However, for the dashboard to be effective for this population, several suggestions for its design were raised. Understanding the information-seeking behaviours of aged care clients and their families, together with knowledge of the information that is important to them, and then subsequent incorporation of this information into a digital dashboard that reflects their design preferences, could lead to more informed decision-making in this population.

Gastrointestinal peptides are increasingly being linked to processes controlling the maintenance of bone mass. Peptide YY (PYY), a gut-derived satiety peptide of the neuropeptide Y family, is upregulated in some states that also display low bone mass. Importantly, PYY has high affinity for Y-receptors, particularly Y1R and Y2R, which are known to regulate bone mass. Anorexic conditions and bariatric surgery for obesity influence circulating levels of PYY and have a negative impact on bone mass, but the precise mechanism behind this is unclear. We thus examined whether alterations in PYY expression affect bone mass. Bone microstructure and cellular activity were analyzed in germline PYY knockout and conditional adult-onset PYY over-expressing mice at lumbar and femoral sites using histomorphometry and micro-computed tomography. PYY displayed a negative relationship with osteoblast activity. Male and female PYY knockout mice showed enhanced osteoblast activity, with greater cancellous bone mass. Conversely, PYY over-expression lowered osteoblast activity in vivo, via a direct Y1 receptor mediated mechanism involving MAPK stimulation evident in vitro. In contrast to PYY knockout mice, PYY over expression also altered bone resorption, as indicated by greater osteoclast surface, despite the lack of Y-receptor expression in osteoclastic cells. While evident in both sexes, cellular changes were generally more pronounced in females. These data demonstrate that the gut peptide PYY is critical for the control of bone remodeling. This regulatory axis from the intestine to bone has the potential to contribute to the marked bone loss observed in situations of extreme weight loss and higher circulating PYY levels, such as anorexia and bariatric obesity surgery, and may be important in the maintenance of bone mass in the general population.