Advances in Drug Treatments for Companion Animal Obesity.

Companion animal obesity has emerged as a significant veterinary health concern globally, with escalating rates posing challenges for preventive and therapeutic interventions. Obesity not only leads to immediate health problems but also contributes to various comorbidities affecting animal well-being and longevity, with consequent emotional and financial burdens on owners. While past treatment strategies have shown limited success, recent breakthroughs in human medicine present new opportunities for addressing this complex issue in companion animals. Here, we discuss the potential of GLP-1 receptor agonists, specifically semaglutide and tirzepatide, already approved for human use, for addressing companion animal obesity. These drugs, originally developed to treat type 2 diabetes in humans and subsequently repurposed to treat obesity, have demonstrated remarkable weight loss effects in rodents, non-human primates and people. Additionally, newer drug combinations have shown even more promising results in clinical trials. Despite current cost and supply challenges, advancements in oral and/or extended-release formulations and increased production may make these drugs more accessible for veterinary use. Thus, these drugs may have utility in companion animal weight management, and future feasibility studies exploring their efficacy and safety in treating companion animal obesity are warranted.

Loss of Esr1 Does Not Affect Hearing and Balance.

Although estrogen affects the structure and function of the nervous system and brain and has a number of effects on cognition, its roles in the auditory and vestibular systems remain unclear. The actions of estrogen are mediated predominately through two classical nuclear estrogen receptors, estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). In the current study, we investigated the roles of ESR1 in normal auditory function and balance performance using 3-month-old wild-type (WT) and Esr1 knockout (KO) mice on a CBA/CaJ background, a normal-hearing strain. As expected, body weight of Esr1 KO females was lower than that of Esr1 KO males. Body weight of Esr1 KO females was higher than that of WT females, while there was no difference in body weight between WT and Esr1 KO males. Similarly, head diameter was higher in Esr1 KO vs. WT females. Contrary to our expectations, there were no differences in auditory brainstem response (ABR) thresholds, ABR waves I-V amplitudes and ABR waves I-V latencies at 8, 16, 32, and 48 kHz, distortion product otoacoustic emission (DPOAE) thresholds and amplitudes at 8, 16, and 32 kHz, and rotarod balance performance (latency to fall) between WT and Esr1 KO mice. Furthermore, there were no sex differences in ABRs, DPOAEs, and rotarod balance performance in Esr1 KO mice. Taken together, our findings show that Esr1 deficiency does not affect auditory function or balance performance in normal hearing mice, and suggest that loss of Esr1 is likely compensated by ESR2 or other estrogen receptors to maintain the structure and function of the auditory and vestibular systems under normal physiological conditions.

Cost-Utility Analysis of Total Ankle Replacement Compared with Ankle Arthrodesis for Patients Aged 50-85 Years with End-Stage Ankle Osteoarthritis: The TARVA Study.

BACKGROUND: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVES: Our aim was to calculate the mean incremental cost per quality-adjusted life-year (QALY) of TAR compared with AF in patients with end-stage ankle osteoarthritis, over 52 weeks and over the patients' lifetime. METHOD: We conducted a cost-utility analysis of 282 participants from 17 UK centres recruited to a randomised controlled trial (TARVA). QALYs were calculated using index values from EQ-5D-5L. Resource use information was collected from case report forms and self-completed questionnaires. Primary analysis was within-trial analysis from the National Health Service (NHS) and Personal Social Services (PSS) perspective, while secondary analyses were within-trial analysis from wider perspective and long-term economic modelling. Adjustments were made for baseline resource use and index values. RESULTS: Total cost at 52 weeks was higher in the TAR group compared with the AF group, from the NHS and PSS perspective (mean adjusted difference £2539, 95% confidence interval [CI] £1142, £3897). The difference became very small from the wider perspective (£155, 95% CI -  £1947, £2331). There was no significant difference between TAR and AF in terms of QALYs (mean adjusted difference 0.02, 95% CI -  0.015, 0.05) at 52 weeks post-operation. The incremental cost-effectiveness ratio (ICER) was £131,999 per QALY gained 52 weeks post-operation. Long-term economic modelling resulted in an ICER of £4200 per QALY gained, and there is a 69% probability of TAR being cost effective at a cost-effectiveness threshold of £20,000 per QALY gained. CONCLUSION: TAR does not appear to be cost effective over AF 52 weeks post-operation. A decision model suggests that TAR can be cost effective over the patients' lifetime but there is a need for longer-term prospectively collected data. Clinical trial registration ISRCTN60672307 and ClinicalTrials.gov NCT02128555.

Exploring community insights on antimicrobial resistance in Nepal: a formative qualitative study.

BACKGROUND: Antimicrobial resistance (AMR) is the process by which microbes evolve mechanisms to survive the medicines designed to destroy them i.e. antimicrobials (AMs). Despite being a natural process, AMR is being hastened by the abuse of AMs. In context of Nepal, there is limited information on drivers of AMR and barriers in addressing it from a community perspective. This study explores the local language and terminology used around AMs in the community, commonly used AMs and reasons for their usage, how these AMs are sourced, and the perceived barriers to addressing AMR via One Health approach. METHODS: A phenomenological study design was utilized with applied qualitative research theoretically framed as pragmatism. Twelve in-depth interviews and informal discussions with a One Health focus, were purposively conducted with wide range of stakeholders and community resident of Kapilvastu municipality of Nepal during April 2022. The acquired data was analyzed manually via a thematic framework approach. The study obtained ethical approval from ethical review board of Nepal Health Research Council and University of Leeds. RESULTS: Nepali and Awadhi languages does not have specific words for AMs or AMR, which is understandable by the community people. Rather, community use full explanatory sentences. People use AMs but have incomplete knowledge about them and they have their own local words for these medicines. The knowledge and usage of AMs across human and animal health is impacted by socio-structural factors, limited Government regulation, inadequate supply of AMs in local government health facilities and the presence of various unregulated health providers that co-exist within the health system. Novel ideas such as the use of visual and smart technology, for instance mobile phones and social media exposure, can enable access to information about AMs and AMR. CONCLUSION: This study shows that terminology that is understandable by the community referring to AMs and AMR in Nepali and Awadhi languages does not exist, but full explanatory sentences and colloquial names are used. Despite regular utilisation, communities have incomplete knowledge regarding AMs. Since, knowledge alone cannot improve behaviour, behavioural interventions are required to address AMR via community engagement to co-produce their own solutions. TRIAL REGISTRATION: Not applicable.

Role for Nongenomic Estrogen Signaling in Male Fertility.

Estrogen actions are mediated by both nuclear (n) and membrane (m) localized estrogen receptor 1 (ESR1). Male Esr1 knockout (Esr1KO) mice lacking functional Esr1 are infertile, with reproductive tract abnormalities. Male mice expressing nESR1 but lacking mESR1 (nuclear-only estrogen receptor 1 mice) are progressively infertile due to testicular, rete testis, and efferent ductule abnormalities similar to Esr1KO males, indicating a role for mESR1 in male reproduction. The H2NES mouse expresses only mESR1 but lacks nESR1. The goal of this study was to identify the functions of mESR1 alone in mice where nESR1 was absent. Breeding trials showed that H2NES males are fertile, with decreased litter numbers but normal pup numbers/litter. In contrast to Esr1KO mice, H2NES testicular, and epididymal weights were not reduced, and seminiferous tubule abnormalities were less pronounced. However, Esr1KO and H2NES males both had decreased sperm motility and a high incidence of abnormal sperm morphology. Seminiferous tubule and rete testis dilation and decreased efferent ductule epithelial height characteristic of Esr1KO males were reduced in H2NES. Consistent with this, expression of genes involved in fluid transport and ion movement that were reduced in Esr1KO (Aqp1, Car2, Car14, Cftr) were partially or fully restored to wild-type levels in H2NES. In summary, in contrast to Esr1KO males, H2NES males are fertile and have reduced phenotypic and functional abnormalities in the testis and efferent ductules. Thus, mESR1 alone, in the absence of nESR1, can partially regulate male reproductive tract structure and function, emphasizing its importance for overall estrogen action.

Targeting estrogen signaling and biosynthesis for aged skin repair.

Non-healing skin wounds are disproportionally prevalent in older adults. Current treatments do not account for the particularities of aged skin and result in inadequate outcomes. Overall, healing chronic wounds in the elderly remains a major unmet clinical need. Estrogens play a critical role in reproduction but also have important actions in non-reproductive organs. Estrogen biosynthesis and signaling pathways are locally activated during physiological wound healing, processes that are inhibited in elderly estrogen-deprived skin. Estrogen deprivation has been shown to be a critical mediator of impaired wound healing in both postmenopausal women and aged men, and topical estrogen application reverses age-associated delayed wound healing in both elderly men and women. These data indicate that adequate estrogen biosynthesis and properly regulated estrogen signaling pathways are essential for normal wound healing and can be targeted to optimize tissue repair in the elderly. However, due to fundamental questions regarding how to safely restore estrogen signaling locally in skin wounds, there are currently no therapeutic strategies addressing estrogen deficiency in elderly chronic wounds. This review discusses established and recent literature in this area and proposes the hypothesis that estrogen plays a pleiotropic role in skin aging and that targeting estrogen signaling and biosynthesis could promote skin repair in older adults.

Addressing antimicrobial resistance through community engagement: a framework for developing contextually relevant and impactful behaviour change interventions.

Background: Community engagement (CE) interventions often explore and promote behaviour change around a specific challenge. Suggestions for behaviour change should be co-produced in partnership with the community. To facilitate this, it is essential that the intervention includes key content that unpacks the challenge of interest via multiple sources of knowledge. However, where community lived experience and academic evidence appear misaligned, tensions can appear within the co-production dynamic of CE. This is specifically so within the context of antimicrobial resistance (AMR) where ideal behaviours are often superseded by what is practical or possible in a particular community context. Methods: Here we describe a framework for the equitable development of contextually appropriate, clearly evidenced behavioural objectives for CE interventions. This framework explores different sources of knowledge on AMR, including the potentially competing views of different stakeholders. Findings: The framework allows key content on AMR to be selected based upon academic evidence, contextual appropriateness and fit to the chosen CE approach. A case study of the framework in action exemplifies how the framework is applicable to a range of contexts, CE approaches and One Health topics beyond just AMR. Conclusions: Within CE interventions, academic evidence is crucial to develop well-informed key content. However, this formative work should also involve community members, ensuring that their contextual knowledge is valued. The type of CE approach also needs careful consideration because methodological constraints may limit the breadth and depth of information that can be delivered within an intervention, and thus the scope of key content.

Practitioner Review: Effectiveness and mechanisms of change in participatory arts-based programmes for promoting youth mental health and well-being - a systematic review.

BACKGROUND: Participatory arts-based (PAB) programmes refer to a diverse range of community programmes involving active engagement in the creation process that appear helpful to several aspects of children's and young people's (CYP) mental health and well-being. This mixed-methods systematic review synthesises evidence relating to the effectiveness and mechanisms of change in PAB programmes for youth. METHOD: Studies were identified following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach. Eleven electronic databases were searched for studies of PAB programmes conducted with CYP (aged 4-25 years), which reported mental health and well-being effectiveness outcomes and/or mechanisms of change. A mixed-methods appraisal tool assessed study quality. A narrative synthesis was conducted of effectiveness and challenges in capturing this. Findings relating to reported mechanisms of change were integrated via a metasummary. RESULTS: Twenty-two studies were included. Evidence of effectiveness from quantitative studies was limited by methodological issues. The metasummary identified mechanisms of change resonant with those proposed in talking therapies. Additionally, PAB programmes appear beneficial to CYP by fostering a therapeutic space characterised by subverting restrictive social rules, communitas that is not perceived as coercive, and inviting play and embodied understanding. CONCLUSIONS: There is good evidence that there are therapeutic processes in PAB programmes. There is a need for more transdisciplinary work to increase understanding of context-mechanism-outcome pathways, including the role played by different art stimuli and practices. Going forward, transdisciplinary teams are needed to quantify short- and long-term mental health and well-being outcomes and to investigate optimal programme durations in relation to population and need. Such teams would also be best placed to work on resolving inter-disciplinary methodological tensions.

Co-designing community-based interventions to tackle antimicrobial resistance (AMR): what to include and why.

Antimicrobial resistance (AMR) is a social and biological problem. Although resistance to antimicrobials is a natural phenomenon, many human behaviors are increasing the pressure on microbes to develop resistance which is resulting in many commonly used treatments becoming ineffective. These behaviors include unregulated use of antimicrobial medicines, pesticides and agricultural chemicals, the disposal of heavy metals and other pollutants into the environment, and human-induced climatic change. Addressing AMR thus calls for changes in the behaviors which drive resistance. Community engagement for antimicrobial resistance (CE4AMR) is an international and interdisciplinary network focused on tackling behavioural drivers of AMR at community level. Since 2019 this network has worked within Low-Middle Income Countries (LMICs), predominantly within Southeast Asia, to tackle behavioral drivers of AMR can be mitigated through bottom-up solutions championed by local people. This commentary presents seven Key Concepts identified from across the CE4AMR portfolio as integral to tackling AMR. We suggest it be used to guide future interventions aimed at addressing AMR via social, participatory, and behavior-change approaches.

Uterine-specific Ezh2 deletion enhances stromal cell senescence and impairs placentation, resulting in pregnancy loss.

Maternal uterine remodeling facilitates embryo implantation, stromal cell decidualization and placentation, and perturbation of these processes may cause pregnancy loss. Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that epigenetically represses gene transcription; loss of uterine EZH2 affects endometrial physiology and induces infertility. We utilized a uterine Ezh2 conditional knockout (cKO) mouse to determine EZH2's role in pregnancy progression. Despite normal fertilization and implantation, embryo resorption occurred mid-gestation in Ezh2cKO mice, accompanied by compromised decidualization and placentation. Western blot analysis revealed Ezh2-deficient stromal cells have reduced amounts of the histone methylation mark H3K27me3, causing upregulation of senescence markers p21 and p16 and indicating that enhanced stromal cell senescence likely impairs decidualization. Placentas from Ezh2cKO dams on gestation day (GD) 12 show architectural defects, including mislocalization of spongiotrophoblasts and reduced vascularization. In summary, uterine Ezh2 loss impairs decidualization, increases decidual senescence, and alters trophoblast differentiation, leading to pregnancy loss.

Exploring the potential for children to act on antimicrobial resistance in Nepal: Valuable insights from secondary analysis of qualitative data.

This study explores the perceived roles of children in antimicrobial resistance (AMR) in two sites across Nepal. AMR is a global challenge and underpinned by many complex behavioural drivers including how antimicrobial medicines are sourced and used. Because of this social dynamic, several research groups are using community engagement (CE) approaches to understand AMR at community level. However, most data negate the importance of children in behaviours linked to, and potentially driving AMR. In this study, authors apply secondary analysis methods to 10 transcripts representing the views of 23 adults engaged in an AMR-focused film-making project. By focusing on participants' reference to children, we reveal that antimicrobial usage and adherence to health providers' messages can be influenced by the age of the patient. Secondly that children are involved in some of the behaviours which are known to drive antimicrobial resistance such as purchasing over-the-counter antibiotic drugs. Finally, community members discuss that, with careful creation of resources, AMR could be meaningfully presented in educational settings with a view to children acting as agents of change around AMR-driving behaviours. Findings suggest that age-inclusive community engagement projects could be effective in tackling AMR at community level in Nepal and other low resource settings.

Total ankle replacement versus ankle arthrodesis for patients aged 50-85 years with end-stage ankle osteoarthritis: the TARVA RCT.

Background: We aimed to compare the clinical effectiveness, cost-effectiveness and complication rates of total ankle replacement with those of arthrodesis (i.e. ankle fusion) in the treatment of end-stage ankle osteoarthritis. Methods: This was a pragmatic, multicentre, parallel-group, non-blinded randomised controlled trial. Patients with end-stage ankle osteoarthritis who were aged 50-85 years and were suitable for both procedures were recruited from 17 UK hospitals and randomised using minimisation. The primary outcome was the change in the Manchester-Oxford Foot Questionnaire walking/standing domain scores between the preoperative baseline and 52 weeks post surgery. Results: Between March 2015 and January 2019, 303 participants were randomised using a minimisation algorithm: 152 to total ankle replacement and 151 to ankle fusion. At 52 weeks, the mean (standard deviation) Manchester-Oxford Foot Questionnaire walking/standing domain score was 31.4 (30.4) in the total ankle replacement arm (n = 136) and 36.8 (30.6) in the ankle fusion arm (n = 140); the adjusted difference in the change was -5.6 (95% confidence interval -12.5 to 1.4; p = 0.12) in the intention-to-treat analysis. By week 52, one patient in the total ankle replacement arm required revision. Rates of wound-healing issues (13.4% vs. 5.7%) and nerve injuries (4.2% vs. < 1%) were higher and the rate of thromboembolic events was lower (2.9% vs. 4.9%) in the total ankle replacement arm than in the ankle fusion arm. The bone non-union rate (based on plain radiographs) in the ankle fusion arm was 12.1%, but only 7.1% of patients had symptoms. A post hoc analysis of fixed-bearing total ankle replacement showed a statistically significant improvement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score (-11.1, 95% confidence interval -19.3 to -2.9; p = 0.008). We estimate a 69% likelihood that total ankle replacement is cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over the patient's lifetime. Limitations: This initial report contains only 52-week data, which must therefore be interpreted with caution. In addition, the pragmatic nature of the study means that there was heterogeneity between surgical implants and techniques. The trial was run across 17 NHS centres to ensure that decision-making streams reflected the standard of care in the NHS as closely as possible. Conclusions: Both total ankle replacement and ankle fusion improved patients' quality of life at 1 year, and both appear to be safe. When total ankle replacement was compared with ankle fusion overall, we were unable to show a statistically significant difference between the two arms in terms of our primary outcome measure. The total ankle replacement versus ankle arthrodesis (TARVA) trial is inconclusive in terms of superiority of total ankle replacement, as the 95% confidence interval for the adjusted treatment effect includes both a difference of zero and the minimal important difference of 12, but it can rule out the superiority of ankle fusion. A post hoc analysis comparing fixed-bearing total ankle replacement with ankle fusion showed a statistically significant improvement of total ankle replacement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score. Total ankle replacement appears to be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime based on long-term economic modelling. Future work: We recommend long-term follow-up of this important cohort, in particular radiological and clinical progress. We also recommend studies to explore the sensitivity of clinical scores to detect clinically important differences between arms when both have already achieved a significant improvement from baseline. Trial registration: This trial is registered as ISRCTN60672307 and ClinicalTrials.gov NCT02128555. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 5. See the NIHR Journals Library website for further project information.

Each year, over 29,000 patients with ankle osteoarthritis seek a specialist opinion, of whom 4000 undergo NHS surgical treatment. The main surgical treatments for severe ankle osteoarthritis are total ankle replacement or arthrodesis (i.e. ankle fusion). Both are known to be good treatments to relieve pain, and each has its advantages. Total ankle replacement is a more popular patient choice than ankle fusion. When deciding whether to undergo ankle replacement or fusion, patients consult various sources, but the majority of them rely on the advice of their surgeon to make a final decision. To the best of our knowledge, there has never been a high-quality randomised clinical trial comparing these two treatments and there are no published guidelines on the most suitable management. In this study, 303 patients were randomised to a type of ankle surgery: 138 in the total ankle replacement arm and 144 in the ankle fusion arm received surgery. We found that both total ankle replacement and ankle fusion improved patients' walking ability, but we did not find a statistically significant difference between the treatment arms based on our primary outcome measure at 1 year. When we considered the type of total ankle replacement implant, we found that the implant most commonly used in the NHS (a fixed-bearing two-component implant) had better outcomes at 1 year than ankle fusion. Both total ankle replacement and ankle fusion appear to be safe. However, there were more wound-healing issues and nerve injuries in the total ankle replacement arm than in the ankle fusion arm. Twelve per cent of patients experienced bone non-union in the ankle fusion arm, but only 7.1% experienced symptoms. We estimate that there is a 69% chance that total ankle replacement would be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime. This study provides the NHS with important information that could help to obtain the best possible outcome for patients with severe ankle arthritis.

Functions of Steroid Hormones in the Male Reproductive Tract as Revealed by Mouse Models.

Steroid hormones are capable of diffusing through cell membranes to bind with intracellular receptors to regulate numerous physiological processes. Three classes of steroid hormones, namely androgens, estrogens and glucocorticoids, contribute to the development of the reproductive system and the maintenance of fertility. During the past 30 years, mouse models have been produced in which the expression of genes encoding steroid hormone receptors has been enhanced, partially compromised or eliminated. These mouse models have revealed many of the physiological processes regulated by androgens, estrogens and to a more limited extent glucocorticoids in the testis and male accessory organs. In this review, advances provided by mouse models that have facilitated a better understanding of the molecular regulation of testis and reproductive tract processes by steroid hormones are discussed.

Total Ankle Replacement Versus Arthrodesis for End-Stage Ankle Osteoarthritis: A Randomized Controlled Trial.

BACKGROUND: End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVE: To determine which treatment is superior in terms of clinical scores and adverse events. DESIGN: A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307). SETTING: 17 National Health Service trusts across the United Kingdom. PATIENTS: Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure. INTERVENTION: Patients were randomly assigned to TAR or AF surgical treatment. MEASUREMENTS: The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible. RESULTS: Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]). LIMITATION: Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques. CONCLUSION: Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Heath Technology Assessment Programme.

Identification and characterization of novel abdominal and pelvic brown adipose depots in mice.

Brown adipose tissue (BAT) generates heat through non-shivering thermogenesis, and increasing BAT amounts or activity could facilitate obesity treatment and provide metabolic benefits. In mice, BAT has been reported in perirenal, thoracic and cranial sites. Here, we describe new pelvic and lower abdominal BAT depots located around the urethra, internal reproductive and urinary tract organs and major lower pelvic blood vessels, as well as between adjacent muscles where the upper hind leg meets the abdominal cavity. Immunohistochemical, western blot and PCR analyses revealed that these tissues expressed BAT markers such as uncoupling protein 1 (UCP1) and CIDEA, but not white adipose markers, and ß3-adrenergic stimulation increased UCP1 amounts, a classic characteristic of BAT tissue. The newly identified BAT stores contained extensive sympathetic innervation with high mitochondrial density and multilocular lipid droplets similar to interscapular BAT. BAT repositories were present and functional neonatally, and showed developmental changes between the neonatal and adult periods. In summary, several new depots showing classical BAT characteristics are reported and characterized in the lower abdominal/pelvic region of mice. These BAT stores are likely significant metabolic regulators in the mouse and some data suggests that similar BAT depots may also exist in humans.

Pharmacological Inhibition of Inositol Hexakisphosphate Kinase 1 Protects Mice against Obesity-Induced Bone Loss.

Obesity and type II diabetes mellitus (T2DM) are prominent risk factors for secondary osteoporosis due to the negative impacts of hyperglycemia and excessive body fat on bone metabolism. While the armamentarium of anti-diabetic drugs is expanding, their negative or unknown impacts on bone metabolism limits effectiveness. The inactivation of inositol hexakisphosphate kinase 1 (IP6K1) protects mice from high-fat-diet (HFD)-induced obesity (DIO) and insulin resistance by enhancing thermogenic energy expenditure, but the role of this kinase and the consequences of its inhibition on bone metabolism are unknown. To determine if IP6K1 inhibition in obese mice affords protection against obesity-induced metabolic derangements and bone loss, we maintained 2-month-old mice on a normal chow control diet or HFD under thermal neutral conditions for 100 d. Beginning on day 40, HFD-fed mice were divided into two groups and administered daily injections of vehicle or the pan-IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purine]. HFD-fed mice developed obesity, hyperglycemia, hyperlipidemia, and secondary osteoporosis, while TNP administration protected mice against HFD-induced metabolic and lipid derangements and preserved bone mass, mineral density, and trabecular microarchitecture, which correlated with reduced serum leptin levels, reduced marrow adiposity, and preservation of marrow resident skeletal stem/progenitor cells (SSPCs). TNP also exhibited hypotensive activity, an unrealized benefit of the drug, and its prolonged administration had no adverse impacts on spermatogenesis. Together, these data indicate that the inhibition of IP6K1 using selective inhibitors, such as TNP, may provide an effective strategy to manage obesity and T2DM due to its bone sparing effects.

Gender and Antimicrobial Resistance: What Can We Learn From Applying a Gendered Lens to Data Analysis Using a Participatory Arts Case Study?

Antimicrobial resistance (AMR), the natural process by which bacteria become resistant to the medicines used to kill them, is becoming one of the greatest threats to health globally. AMR is accelerating at alarming rates due to behaviors across human, animal, and environmental health sectors as well as governance and policy shortfalls across each sector. Antimicrobial resistant infections occur through the same channels as other infectious diseases and are most common in countries/areas where there is limited access to improved sanitation facilities, reliable healthcare and health education. At the community level, much remains to be understood about the drivers of antimicrobial resistance and how to generate community-led, acceptable solutions. Gender can influence every part of an individual's health experiences; access to knowledge, healthcare facilities, financial resources and paid employment are all heavily gendered and influence behaviors relating to the procurement of antimicrobial and antibiotic agents. This analysis uses data gathered during a participatory video study designed to work with two communities in Nepal to understand drivers of antibiotic mis and over use from the perspective of the communities themselves. Findings reveal that gender impacts upon many aspects of AMR-driving behaviors within this community and stimulate essential discussion as to the importance of gender in future AMR research. This paper places a spotlight on gender in the wider AMR conversation, an area that is currently neglected, and improve our collective knowledge on the drivers of AMR from a gendered perspective.

Epidural Steroid Injections Acutely Suppress Bone Formation Markers in Postmenopausal Women.

CONTEXT: Over 9 million epidural steroid injections (ESIs) are performed annually in the United States. Although these injections effectively treat lumbar radicular pain, they may have adverse consequences, including bone loss. OBJECTIVE: To investigate acute changes in bone turnover following ESI. We focused on postmenopausal women, who may be at greatest risk for adverse skeletal consequences due to the combined effects of ESIs with aging and estrogen deficiency. METHODS: Single-center prospective observational study. Postmenopausal women undergoing lumbar ESIs and controls with no steroid exposure were included. Outcomes were serum cortisol, markers of bone formation, osteocalcin, and procollagen type-1 N-terminal propeptide (P1NP), and bone resorption by C-telopeptide (CTX) measured at baseline, 1, 4, 12, 26, and 52 weeks after ESIs. RESULTS: Among ESI-treated women, serum cortisol declined by ~50% 1 week after injection. Bone formation markers significantly decreased 1 week following ESIs: osteocalcin by 21% and P1NP by 22%. Both markers remained suppressed at 4 and 12 weeks, but returned to baseline levels by 26 weeks. There was no significant change in bone resorption measured by CTX. Among controls, there were no significant changes in cortisol or bone turnover markers. CONCLUSION: These results provide evidence of an early and substantial reduction in bone formation markers following ESIs. This effect persisted for over 12 weeks, suggesting that ESIs may have lasting skeletal consequences. Given the large population of older adults who receive ESIs, further investigation into the long-term skeletal sequelae of these injections is warranted.

Safeguarding adolescent mental health in India (SAMA): study protocol for codesign and feasibility study of a school systems intervention targeting adolescent anxiety and depression in India.

INTRODUCTION: Symptoms of anxiety and depression in Indian adolescents are common. Schools can be opportune sites for delivery of mental health interventions. India, however, is without a evidence-based and integrated whole-school mental health approach. This article describes the study design for the safeguarding adolescent mental health in India (SAMA) project. The aim of SAMA is to codesign and feasibility test a suite of multicomponent interventions for mental health across the intersecting systems of adolescents, schools, families and their local communities in India. METHODS AND ANALYSIS: Our project will codesign and feasibility test four interventions to run in parallel in eight schools (three assigned to waitlist) in Bengaluru and Kolar in Karnataka, India. The primary aim is to reduce the prevalence of adolescent anxiety and depression. Codesign of interventions will build on existing evidence and resources. Interventions for adolescents at school will be universal, incorporating curriculum and social components. Interventions for parents and teachers will target mental health literacy, and also for teachers, training in positive behaviour practices. Intervention in the school community will target school climate to improve student mental health literacy and care. Intervention for the wider community will be via adolescent-led films and social media. We will generate intervention cost estimates, test outcome measures and identify pathways to increase policy action on the evidence. ETHICS AND DISSEMINATION: Ethical approval has been granted by the National Institute of Mental Health Neurosciences Research Ethics Committee (NIMHANS/26th IEC (Behv Sc Div/2020/2021)) and the University of Leeds School of Psychology Research Ethics Committee (PSYC-221). Certain data will be available on a data sharing site. Findings will be disseminated via peer-reviewed journals and conferences.

Nonclassical androgen and estrogen signaling is essential for normal spermatogenesis.

Signaling by androgens through androgen receptor (AR) is essential to complete spermatogenesis in the testis. Similarly, loss of the main estrogen receptor, estrogen receptor 1 (ESR1; also known as ERα), results in male infertility, due in part to indirect deleterious effects on the seminiferous epithelium and spermatogenesis. Effects of steroid hormones are induced primarily through genomic changes induced by hormone-mediated activation of their intracellular receptors and subsequent effects on nuclear gene transcription. However, androgens and estrogens also signal through rapid nonclassical pathways involving actions initiated at the cell membrane. Here we review the data that nonclassical androgen and estrogen signaling pathways support processes essential for male fertility in the testis and reproductive tract. The recent development of transgenic mice lacking nonclassical AR or ESR1 signaling but retaining genomic nuclear signaling has provided a powerful tool to elucidate the function of nonclassical signaling in the overall response to androgens and estrogens. Results from these mice have emphasized that nonclassical signaling is essential for full responses to these hormones, and absence of either nonclassical or classical AR or ESR1 pathways produces abnormalities in spermatogenesis and the male reproductive tract. Although additional work is required to fully understand how classical and nonclassical receptor signaling synergize to produce full steroid hormone responses, here we summarize the known physiological functions of the classical and nonclassical androgen and estrogen signaling pathways in the testis and reproductive tract.