Methylation of elongation factor 1A by yeast Efm4 or human eEF1A-KMT2 involves a beta-hairpin recognition motif and crosstalks with phosphorylation.

Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein required for protein synthesis in eukaryotes. In both Saccharomyces cerevisiae and human, five different methyltransferases methylate specific residues on eEF1A, making eEF1A the eukaryotic protein targeted by the highest number of dedicated methyltransferases after histone H3. eEF1A methyltransferases are highly selective enzymes, only targeting eEF1A and each targeting just one or two specific residues in eEF1A. However, the mechanism of this selectivity remains poorly understood. To reveal how S. cerevisiae elongation factor methyltransferase 4 (Efm4) specifically methylates eEF1A at K316, we have used AlphaFold-Multimer modeling in combination with crosslinking mass spectrometry (XL-MS) and enzyme mutagenesis. We find that a unique beta-hairpin motif, which extends out from the core methyltransferase fold, is important for the methylation of eEF1A K316 in vitro. An alanine mutation of a single residue on this beta-hairpin, F212, significantly reduces Efm4 activity in vitro and in yeast cells. We show that the equivalent residue in human eEF1A-KMT2 (METTL10), F220, is also important for its activity towards eEF1A in vitro. We further show that the eEF1A guanine nucleotide exchange factor, eEF1Bα, inhibits Efm4 methylation of eEF1A in vitro, likely due to competitive binding. Lastly, we find that phosphorylation of eEF1A at S314 negatively crosstalks with Efm4-mediated methylation of K316. Our findings demonstrate how protein methyltransferases can be highly selective towards a single residue on a single protein in the cell.

Evolution of HIV-1 envelope towards reduced neutralization sensitivity, as demonstrated by contemporary HIV-1 subtype B from the United States.

Subtype B HIV-1 has been the primary driver of the HIV-1 epidemic in the United States (U.S.) for over forty years and is also a prominent subtype in the Americas, Europe, Australia, the Middle East and North Africa. In this study, the neutralization profiles of contemporary subtype B Envs from the U.S. were assessed to characterize changes in neutralization sensitivities over time. We generated a panel of 30 contemporary pseudoviruses (PSVs) and demonstrated continued diversification of subtype B Env from the 1980s up to 2018. Neutralization sensitivities of the contemporary subtype B PSVs were characterized using 31 neutralizing antibodies (NAbs) and were compared with strains from earlier in the HIV-1 pandemic. A significant reduction in Env neutralization sensitivity was observed for 27 out of 31 NAbs for the contemporary as compared to earlier-decade subtype B PSVs. A decline in neutralization sensitivity was observed across all Env domains; the NAbs that were most potent early in the pandemic suffered the greatest decline in potency over time. A meta-analysis demonstrated this trend across multiple subtypes. As HIV-1 Env diversification continues, changes in Env antigenicity and neutralization sensitivity should continue to be evaluated to inform the development of improved vaccine and antibody products to prevent and treat HIV-1.

Non-Interferon-Dependent Role of STING Signaling in Pulmonary Hypertension.

BACKGROUND: Patients with constitutive activation of DNA-sensing pathway through stimulator of IFN (interferon) genes (STING), such as those with STING-associated vasculopathy with onset in infancy, develop pulmonary hypertension (PH). However, the role of STING signaling in general PH patients is heretofore undescribed. Here, we seek to investigate the role of STING in PH development. METHODS: STING expression in patient lung samples was examined. PH was induced in global STING-deficient mice and global type I IFN receptor 1-deficient mice using bleomycin or chronic hypoxia exposure. PH development was evaluated by right ventricular systolic pressure and Fulton index, with additional histological and flow cytometric analysis. VEGF (vascular endothelial growth factor) expression on murine immune cells was quantified and evaluated with multiplex and flow cytometry. Human myeloid-derived cells were differentiated from peripheral blood mononuclear cells and treated with either STING agonist or STING antagonist for evaluation of VEGF secretion. RESULTS: Global STING deficiency protects mice from PH development, and STING-associated PH seems independent of type I IFN signaling. Furthermore, a role for STING-VEGF signaling pathway in PH development was demonstrated, with altered VEGF secretion in murine pulmonary infiltrated myeloid cells in a STING-dependent manner. In addition, pharmacological manipulation of STING in human myeloid-derived cells supports in vivo findings. Finally, a potential role of STING-VEGF-mediated apoptosis in disease development and progression was illustrated, providing a roadmap toward potential therapeutic applications. CONCLUSIONS: Overall, these data provide concrete evidence of STING involvement in PH, establishing biological plausibility for STING-related therapies in PH treatment.

Real-world utilization, patient characteristics, and treatment patterns among men with localized prostate cancer tested with the 17-gene genomic prostate score® (GPSTM) assay.

OBJECTIVES: Descriptive study focusing on real-world utilization and characteristics of men with prostate cancer tested with the 17-gene Genomic Prostate Score® (GPS™) assay by linking administrative claims and electronic health record (EHR) data with GPS results. METHODS: This retrospective, observational cohort study (January 1, 2013 to December 31, 2020) included men aged 40-80 years with localized prostate cancer claims, continuous enrollment in Optum's Integrated Claims data set, ≥1 day of EHR clinical activity, and a GPS result. Men were classified as undergoing definitive therapy (DT) (prostatectomy, radiation, or focal therapy) or active surveillance (AS). AS and DT distribution were analyzed across GPS results, National Comprehensive Cancer Network® (NCCN®) risk, and race. Costs were assessed 6 months after the first GPS result (index); clinical outcomes and AS persistence were assessed during the variable follow-up. All variables were analyzed descriptively. RESULTS: Of 834 men, 650 (77.9%) underwent AS and 184 (22.1%) DT. Most men had Quan-Charlson comorbidity scores of 1-2 and a tumor stage of T1c (index). The most common Gleason patterns were 3 + 3 (79.6%) (AS cohort) and 3 + 4 (55.9%) (DT cohort). The mean (standard deviation) GPS results at index were 23.2 (11.3) (AS) and 30.9 (12.9) (DT). AS decreased with increasing GPS result and NCCN risk. Differences between races were minimal. Total costs were substantially higher in the DT cohort. CONCLUSIONS: Most men with GPS-tested localized prostate cancer underwent AS, indicating the GPS result can inform clinical management. Decreasing AS with increasing GPS result and NCCN risk suggests the GPS complements NCCN risk stratification.

Effectiveness of fall prevention interventions in residential aged care and community settings: an umbrella review.

INTRODUCTION: Preventing falls is a priority for aged care providers. Research to date has focused on fall prevention strategies in single settings (e.g., residential aged care (RAC) or community settings). However, some aged care providers deliver care, including fall prevention interventions, across RAC and community settings. We conducted an umbrella review to identify what type of fall prevention interventions had the greatest impact on falls outcomes in RAC and community settings. METHODS: Five databases were searched for systematic reviews of falls prevention randomised control trials in older adults living in the community or RAC. Data extracted included systematic review methods, population characteristics, intervention characteristics, setting details (RAC or community), and fall-related outcomes (falls, people who have had a fall, fall-related hospitalisations, and fall-related fractures). Review quality was appraised using the Assessment of Multiple Systematic Reviews-2 tool. RESULTS: One-hundred and six systematic reviews were included; 63 and 19 of these stratified results by community and RAC settings respectively, the remainder looked at both settings. The most common intervention types discussed in reviews included 'exercise' (61%, n = 65), 'multifactorial' (two or more intervention types delivered together) (26%, n = 28), and 'vitamin D' (18%, n = 19). In RAC and community settings, 'exercise' interventions demonstrated the most consistent reduction in falls and people who have had a fall compared to other intervention types. 'Multifactorial' interventions were also beneficial in both settings however demonstrated more consistent reduction in falls and people who fall in RAC settings compared to community settings. 'Vitamin D' interventions may be beneficial in community-dwelling populations but not in RAC settings. It was not possible to stratify fall-related hospitalisation and fall-related fracture outcomes by setting due to limited number of RAC-specific reviews (n = 3 and 0 respectively). CONCLUSION: 'Exercise' interventions may be the most appropriate falls prevention intervention for older adults in RAC and community settings as it is beneficial for multiple fall-related outcomes (falls, fall-related fractures, and people who have had a fall). Augmenting 'exercise' interventions to become 'multifactorial' interventions may also improve the incidence of falls in both settings.

Mobile phone-based interventions for improving contraception use.

BACKGROUND: Contraception provides significant benefits for women's and children's health, yet many women have an unmet need for contraception. Rapid expansion in the use of mobile phones in recent years has had a dramatic impact on interpersonal communication. Within the health domain text messages and smartphone applications offer means of communication between clients and healthcare providers. This review focuses on interventions delivered by mobile phone and their effect on use of contraception. OBJECTIVES: To evaluate the benefits and harms of mobile phone-based interventions for improving contraception use. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was August 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of mobile phone-based interventions to improve forms of contraception use amongst users or potential users of contraception. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. uptake of contraception, 2. uptake of a specific method of contraception, 3. adherence to contraception method, 4. safe method switching, 5. discontinuation of contraception and 6. pregnancy or abortion. Our secondary outcomes were 7. road traffic accidents, 8. any physical or psychological effect reported and 9. violence or domestic abuse. MAIN RESULTS: Twenty-three RCTs (12,793 participants) from 11 countries met our inclusion criteria. Eleven studies were conducted in high-income resource settings and 12 were in low-income settings. Thirteen studies used unidirectional text messaging-based interventions, six studies used interactive text messaging, four used voice message-based interventions and two used mobile-phone apps to improve contraception use. All studies received funding from non-commercial bodies. Mobile phone-based interventions probably increase contraception use compared to the control (odds ratio (OR) 1.30, 95% confidence interval (CI) 1.06 to 1.60; 16 studies, 8972 participants; moderate-certainty evidence). There may be little or no difference in rates of unintended pregnancy with the use of mobile phone-based interventions compared to control (OR 0.82, 95% CI 0.48 to 1.38; 8 trials, 2947 participants; moderate-certainty evidence). Subgroup analysis assessing unidirectional mobile phone interventions versus interactive mobile phone interventions found evidence of a difference between the subgroups favouring interactive interventions (P = 0.003, I2 = 88.5%). Interactive interventions had an OR of 1.71 (95% CI 1.28 to 2.29; P = 0.0003, I2 = 63%; 8 trials, 3089 participants) whilst unidirectional interventions had an OR of 1.03 (95% CI 0.87 to 1.22; P = 0.72, I2 = 17%; 9 trials, 5883 participants). Subgroup analysis assessing high-income versus low-income trial settings found no difference between groups (subgroup difference test: P = 0.70, I2 = 0%). Only six trials reported on safety and unintended outcomes; one trial reported increased partner violence whilst another four trials reported no difference in physical violence rates between control and intervention groups. One trial reported no road traffic accidents with mobile phone intervention use. AUTHORS' CONCLUSIONS: This review demonstrates there is evidence to support the use of mobile phone-based interventions in improving the use of contraception, with moderate-certainty evidence. Interactive mobile phone interventions appear more effective than unidirectional methods. The cost-effectiveness, cost benefits, safety and long-term effects of these interventions remain unknown, as does the evidence of this approach to support contraception use among specific populations. Future research should investigate the effectiveness and safety of mobile phone-based interventions with better quality trials to help establish the effects of interventions delivered by mobile phone on contraception use. This review is limited by the quality of the studies due to flaws in methodology, bias or imprecision of results.

Innovative approaches to analysing aged care falls incident data: international classification for patient safety and correspondence analysis.

Falls in residential aged care facilities (RACFs) are common and can have significant health consequences. Understanding how and why falls occur in RACFs is an essential step to design targeted fall prevention and intervention programmes; however, little is known about falls' mechanisms in RACFs. This study aims to use international incident classification systems and novel analysis techniques to describe factors that contribute to falls requiring hospitalization in RACFs. Retrospective data of falls assessed by nurses as requiring hospitalization from 429 residents in 22 Australian RACFs in 2019 were used. Data were reviewed using a modified version of the International Classification for Patient Safety (ICPS), which categorizes patient safety into incident types and contributing factors using a three-tiered structure. The ICPS codes were summarized using the descriptive statistics. The association between assigned ICPS codes were analysed using correspondence analysis. Six hundred and three falls assessed as requiring hospitalization were classified into 659 incident types, with the most common incident type being 'patient incidents' (injury sustained/adverse effect in the health care system) (603, 91.5%) at Level 1, 'falls' (601, 91.2%) at Level 2, and 'falls involving bedrooms' (214, 32.5%) at Level 3. The 603 falls had 1082 contributing factors, with the most common contributing factor being 'patient factors' (events affected by factors associated with the patient) (982, 90.8%) at Level 1, 'patient not elsewhere classified' (characteristics of the patient contributed to the incident not classified elsewhere) (571, 52.8%) at Level 2, and 'loss of balance' (361, 33.4%) at Level 3. In a correspondence analysis, three dimensions were responsible for 81.2% of the variation in falls incidents and environmental and organizational factors were important factors contributing to falls. The application of the ICPS demonstrated that personal factors (e.g. pre-existing physical and psychological health or impairment) were the most common contributing factors to falls assessed as requiring hospitalization, while the correspondence analysis highlighted the role of environmental and organizational factors. The results signal the need for more research into multifactorial falls prevention interventions in RACFs.

A wrinkle in time: circadian biology in pulmonary vascular health and disease.

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently use the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

The use and predictive performance of the Peninsula Health Falls Risk Assessment Tool (PH-FRAT) in 25 residential aged care facilities: a retrospective cohort study using routinely collected data.

BACKGROUND: The Peninsula Health Falls Risk Assessment Tool (PH-FRAT) is a validated and widely applied tool in residential aged care facilities (RACFs) in Australia. However, research regarding its use and predictive performance is limited. This study aimed to determine the use and performance of PH-FRAT in predicting falls in RACF residents. METHODS: A retrospective cohort study using routinely-collected data from 25 RACFs in metropolitan Sydney, Australia from Jul 2014-Dec 2019. A total of 5888 residents aged ≥65 years who were assessed at least once using the PH-FRAT were included in the study. The PH-FRAT risk score ranges from 5 to 20 with a score > 14 indicating fallers and ≤ 14 non-fallers. The predictive performance of PH-FRAT was determined using metrics including area under receiver operating characteristics curve (AUROC), sensitivity, specificity, sensitivityEvent Rate(ER) and specificityER. RESULTS: A total of 27,696 falls were reported over 3,689,561 resident days (a crude incident rate of 7.5 falls /1000 resident days). A total of 38,931 PH-FRAT assessments were conducted with a median of 4 assessments per resident, a median of 43.8 days between assessments, and an overall median fall risk score of 14. Residents with multiple assessments had increased risk scores over time. The baseline PH-FRAT demonstrated a low AUROC of 0.57, sensitivity of 26.0% (sensitivityER 33.6%) and specificity of 88.8% (specificityER 82.0%). The follow-up PH-FRAT assessments increased sensitivityER values although the specificityER decreased. The performance of PH-FRAT improved using a lower risk score cut-off of 10 with AUROC of 0.61, sensitivity of 67.5% (sensitivityER 74.4%) and specificity of 55.2% (specificityER 45.6%). CONCLUSIONS: Although PH-FRAT is frequently used in RACFs, it demonstrated poor predictive performance raising concerns about its value. Introducing a lower PH-FRAT cut-off score of 10 marginally enhanced its predictive performance. Future research should focus on understanding the feasibility and accuracy of dynamic fall risk predictive tools, which may serve to better identify residents at risk of falls.

The use of predictive fall models for older adults receiving aged care, using routinely collected electronic health record data: a systematic review.

BACKGROUND: Falls in older adults remain a pressing health concern. With advancements in data analytics and increasing uptake of electronic health records, developing comprehensive predictive models for fall risk is now possible. We aimed to systematically identify studies involving the development and implementation of predictive falls models which used routinely collected electronic health record data in home-based, community and residential aged care settings. METHODS: A systematic search of entries in Cochrane Library, CINAHL, MEDLINE, Scopus, and Web of Science was conducted in July 2020 using search terms relevant to aged care, prediction, and falls. Selection criteria included English-language studies, published in peer-reviewed journals, had an outcome of falls, and involved fall risk modelling using routinely collected electronic health record data. Screening, data extraction and quality appraisal using the Critical Appraisal Skills Program for Clinical Prediction Rule Studies were conducted. Study content was synthesised and reported narratively. RESULTS: From 7,329 unique entries, four relevant studies were identified. All predictive models were built using different statistical techniques. Predictors across seven categories were used: demographics, assessments of care, fall history, medication use, health conditions, physical abilities, and environmental factors. Only one of the four studies had been validated externally. Three studies reported on the performance of the models. CONCLUSIONS: Adopting predictive modelling in aged care services for adverse events, such as falls, is in its infancy. The increased availability of electronic health record data and the potential of predictive modelling to document fall risk and inform appropriate interventions is making use of such models achievable. Having a dynamic prediction model that reflects the changing status of an aged care client is key to this moving forward for fall prevention interventions.

Epidemiology of falls in 25 Australian residential aged care facilities: a retrospective longitudinal cohort study using routinely collected data.

BACKGROUND: Falls are frequent among older adults and have significant health and economic consequences. There have been few studies on the epidemiology of falls in residential aged care facilities (RACFs). OBJECTIVE: To determine the incidence of falls in RACFs using longitudinal routinely collected incident data over 5 years (July 2014-December 2019). METHODS: A retrospective cohort study is conducted using fall incident data from 25 RACFs in Sydney, NSW, Australia. Incidents relating to a population of 6163 aged care residents aged ≥65 years were included. Outcome measures were incidents of all falls, injurious falls and falls requiring hospitalization. The risk-adjusted incidence rate (IR) for each outcome indicator for each of the 25 facilities was calculated. RESULTS: A total of 27 878 falls were reported over 3 906 772 resident days (a crude rate of 7.14 incidents per 1000 resident days; 95% confidence interval (CI) 6.81-7.48). Of these, 10 365 (37.2%) were injurious and 2733 (9.8%) required hospitalization. The crude IRs were 2.65 incidents per 1000 resident days (95% CI 2.53-2.78) for injurious falls and 0.70 incidents per 1000 resident days (95% CI 0.66-0.74) for falls requiring hospitalization. The incidence of falls was significantly higher in respite compared to permanent residents for all falls (adjusted IR ratio (aIRR) 1.33; 95% CI 1.18-1.51) and injurious falls (aIRR 1.30; 95% CI 1.14-1.48) and for men compared to women for all outcomes (all falls aIRR 1.69; 95% CI 1.54-1.86; injurious falls aIRR 1.87; 95% CI 1.71-2.04 and falls requiring hospitalization aIRR 1.29; 95% CI 1.12-1.48). The risk-adjusted IRs per 1000 resident days between facilities varied substantially (all falls 0.57-12.93 falls; injurious falls 0.25-4.47 and falls requiring hospitalization 0.10-1.70). CONCLUSION: Falls are frequent in RACFs, often resulting in injury and hospitalization. The study provides robust and comprehensive information that may help inform future initiatives to minimize the incidence of falls in RACFs.

Discovery of Arginine Methylation, Phosphorylation, and Their Co-occurrence in Condensate-Associated Proteins in Saccharomyces cerevisiae.

The formation of condensates in membraneless organelles is thought to be driven by protein phase separation. Arginine methylation and serine/threonine phosphorylation are important in the phase separation process; however, these post-translational modifications are often present in intrinsically disordered regions that are difficult to analyze with standard proteomic techniques. To understand their presence and co-occurrence in condensate-associated proteins, here, we use a multiprotease and multi-tandem mass spectrometry (MS/MS) fragmentation approach, coupled with heavy methyl stable isotope labeling of amino acids in cell culture (SILAC) and phospho- or methyl-peptide enrichment. For Saccharomyces cerevisiae, we report a 50% increase in the known arginine methylproteome, involving 15 proteins that are all condensate-associated. Importantly, some of these proteins have arginine methylation on all predicted sites-providing evidence that this modification can be pervasive. We explored whether arginine-methylated, condensate-associated proteins are also phosphorylated and found 12 such proteins to carry phosphorylated serine or threonine. In Npl3, Ded1, and Sbp1, single peptides were found to carry both modifications, indicating a co-occurrence in close proximity and on the same protein molecule. These co-modifications occur in regions of disorder, whereas arginine methylation is typically on regions of disorder that are also basic. For phosphorylation, its association with charged regions of condensate-associated proteins was less consistent, although some regions with multisite phosphorylation sites were strongly acidic. We conclude that arginine-methylated proteins associated with condensates are typically also modified with protein phosphorylation.

Communicating deprescribing decisions made in hospital with general practitioners in the community.

BACKGROUND: Deprescribing, the supervised withdrawal of inappropriate medications, intends to manage polypharmacy, which is prevalent in older patients. AIMS: To examine general practitioner (GP) perceptions of communication processes between clinicians in hospital and GP in the community about deprescribing decisions made in hospital. METHODS: Focus groups and interviews were held with 15 GP, exploring deprescribing in hospitals, communication of deprescribing information and the format of communications. Sessions were audiotaped, transcribed and analysed using an inductive approach. RESULTS: GP stated that they should be involved in deprescribing decisions, especially for older complex patients, because of their good knowledge of their patients. Barriers to effective communication included the acute nature of hospital stays and lack of time. Facilitators included long-term relationships of GP with their patients and engaged patients. GP preferred communication of deprescribing decisions to be over the telephone while the patient was still in hospital, and with a concise, electronic discharge summary at the time of discharge. GP indicated that rationale for medication changes and recommended follow-up actions were crucial in a discharge summary to enable care post-discharge. CONCLUSIONS: GP welcome increased communication with hospital clinicians regarding deprescribing decisions made while patients are in hospital. Communication needs to be timely, transparent, succinct and accessible. Lack of time and difficulties contacting hospital clinicians challenge this process.

A mixed-methods study evaluating the impact of an excursion-based social group on quality of life of older adults.

BACKGROUND: Social isolation is an increasing concern for older adults who live in the community. Despite some availability of social support programs to address social isolation, their effectiveness is not routinely measured. This study aimed to evaluate an innovative excursion-based program offering unique social experiences to older adults receiving aged care services. METHODS: This six-month before and after mixed-methods study evaluated the outcomes of an Australian excursion-based program which offered social and physical outings to bring older adults receiving aged care services into the wider community. The study combined two parts: Part 1 was a pre-post survey assessing the quality of life of older adults who received the excursion-based program for 6 months (n = 56; two time-points, analysed using signed rank test) and Part 2 involved qualitative in-depth, semi-structured interviews (n = 24 aged care staff, older adults and carers; analysed using thematic analysis). RESULTS: Older adults experienced a significant increase in quality of life scores (p < 0.001) between baseline and 6 months. Interviews confirmed these observations and suggested that benefits of participation included increased opportunities for social participation, psychological wellbeing, physical function, and carer respite. Interviews also revealed being in a group setting, having tailored, convenient and accessible activities, alongside supportive staff were key drivers in improving the wellbeing of participants. CONCLUSIONS: Participating in an excursion-based community program may improve wellbeing in older adults. Aging policy should focus on prioritizing initiatives that promote social connectivity with the wider community and assist in improving outcomes for older adults.

Neuropeptide Y Regulation of Energy Partitioning and Bone Mass During Cold Exposure.

The maintenance of whole body energy homeostasis is critical to survival and mechanisms exist whereby an organism can adapt to its environment and the stresses placed upon it. Environmental temperature and thermogenesis are key components known to affect energy balance. However, little is known about how these processes are balanced against the overall energy balance. We show that even mild cold exposure has a significant effect on energy expenditure and UCP-1 levels which increase by 43% and 400%, respectively, when wild-type (WT) mice at thermoneutral (29 °C) were compared to mice at room temperature (22 °C) conditions. Interestingly, bone mass was lower in cold-stressed WT mice with significant reductions in femoral bone mineral content (- 19%) and bone volume (- 13%). Importantly, these cold-induced skeletal changes were absent in mice lacking NPY, one of the main controllers of energy homeostasis, highlighting the critical role of NPY in this process. However, energy expenditure was significantly greater in cold-exposed NPY null mice, indicating that suppression of non-thermogenic tissues, like bone, contributes to the adaptive responses to cold exposure. Altogether, this work identifies NPY as being crucial in coordinating energy and bone homeostasis where it suppresses energy expenditure, UCP-1 levels and lowers bone mass under conditions of cold exposure.

Better outcomes for patients with gout.

Gout is increasing in prevalence despite effective pharmacotherapies. Barriers to effective management are largely educational deficiencies. Sufferers, usually men, need to understand more about gout, especially that maintaining serum urate below 0.36 mmol/L will eliminate recurrent attacks. Also, of great importance is appreciating that sub-optimal adherence to urate-lowering therapy (ULT) will result in a return of attacks. Prescribers also need to understand that acute attacks are likely to occur in the first few months of urate-lowering therapy (ULT), but these can be mitigated by commencing with a dose of ULT reflective of renal function and escalating the dose slowly, every 2-5 weeks until target serum urate is achieved. Prophylaxis against acute attacks over the initial 6 months period of ULT can be enhanced further with concomitant colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs).Gout is largely managed in primary care. Rates of adherence to ULT are 50% or less, worse than most other chronic illnesses. Efforts at educating primary care physicians to, firstly, manage gout effectively and, secondly, to educate their gout patients sufficiently have not been successful. Allied health practitioners, such as nurses, working with prescribers in primary care settings and given the mandate to educate and manage patients with gout, have been spectacularly effective. However, this approach is resource intensive. 'Personalised' eHealth interventions show promise as an alternative strategy, notably in improving adherence to ULT.Numerous applications for smart phones (apps) are now available to assist people with chronic health conditions. Their design needs to accommodate the barriers and enablers perceived by patients to maintaining adherence to prescribed therapies. Personalised feedback of serum urate may represent an important enabler of adherence to ULT in the case of gout.Harnessing mobile apps to support patients managing their chronic illnesses represents an important opportunity to enhance health outcomes. Rigorous, patient-centred and driven development is critical. These tools also require careful evaluation for effectiveness.

Patients' use of mobile health applications: what general practitioners think.

BACKGROUND: Chronic disease patients are adopting self-management techniques, such as using mobile health applications (apps). As GPs are the main caregivers of chronic disease patients, obtaining GP perspectives regarding patient use of mobile health apps is vital in understanding longer term value and feasibility of these apps. OBJECTIVE: The aim was to determine GP perceptions of their current and potential roles in the use of health apps by their patients and how patient-focused apps affect patient management. METHODS: Ten GPs participated in semi-structured, face-to-face interviews, which focused on their perceptions of, and involvement in, the use of patient-focused health apps. Interviews were transcribed verbatim and thematically analysed by two independent reviewers. RESULTS: GPs found that apps complemented their role in patient management as additional sources of medical information of their patients. They perceived that patient-focused apps would be part of their future practices; however they noted that further work was required to incorporate them into their current practices. Currently, the main role of GPs was in promoting apps to patients. Suggestions for further engagement in mobile health included regularly reviewing patient data entered into health apps during consultations. CONCLUSION: GPs view patient-focused health apps positively, particularly to support them in providing patient care. Discussing information recorded in apps during consultations and frequent promotion of apps are feasible ways to integrate apps into their current work practices. Further studies involving evaluations of apps in improving health care delivery and patient communication in general practice are required.

Diet-induced obesity suppresses cortical bone accrual by a neuropeptide Y-dependent mechanism.

OBJECTIVE: To determine whether age and neuropeptide Y (NPY) were involved in the skeletal response to extended periods of diet-induced obesity. METHODS: Male wild-type (WT) and NPY null (NPYKO) mice were fed a mild (23% fat) high-fat diet for 10 weeks from 6 or 16 weeks of age. Metabolism and bone density were assessed during feeding. Skeletal changes were assessed by microCT and histomorphometry. RESULTS: High-fat feeding in 6-week-old WT mice led to significantly increased body weight, adiposity and serum leptin levels, accompanied with markedly suppressed cortical bone accrual. NPYKO mice were less susceptible to fat accrual but, importantly, displayed a complete lack of suppression of bone accrual or cortical bone loss. In contrast, when skeletally mature (16 week old) mice underwent 10 weeks of fat feeding, the metabolic response to HFD was similar to younger mice, however bone mass was not affected in either WT or NPYKO. Thus, growing mice are particularly susceptible to the detrimental effects of HFD on bone mass, through suppression of bone accrual involving NPY signalling. CONCLUSION: This study provides new insights into the relationship between the opposing processes of a positive weight/bone relationship and the negative 'metabolic' effect of obesity on bone mass. This negative effect is particularly active in growing skeletons, which have heightened sensitivity to changes in obesity. In addition, NPY is identified as a fundamental driver of this negative 'metabolic' pathway to bone.

Maintenance of the HIV Reservoir Is Antagonized by Selective BCL2 Inhibition.

Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV-infected cells. This expansion reflects homeostatic proliferation of infected cells by interleukin-7 (IL-7) or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate Bak to induce apoptosis of infected cells. In circumstances where expression of the anti-apoptotic protein BCL2 is high, Casp8p41 instead binds BCL2, and cell death does not occur. This effect can be overcome by treating cells with the clinically approved BCL2 antagonist venetoclax, which prevents Casp8p41 from binding BCL2, thereby allowing Casp8p41 to bind Bak and kill the infected cell. Here we assess whether the events that maintain the HIV reservoir are also antagonized by venetoclax. Using the J-Lat 10.6 model of persistent infection, we demonstrate that proliferation and HIV expression are countered by the use of venetoclax, which causes preferential killing of the HIV-expressing cells. Similarly, during new rounds of infection of primary CD4 T cells, venetoclax causes selective killing of HIV-infected cells, resulting in decreased numbers of HIV DNA-containing cells.IMPORTANCE Cure of HIV infection requires an intervention that reduces the HIV reservoir size. A variety of approaches are being tested for their ability to impact HIV reservoir size. Even if successful, however, these approaches will need to be combined with additional complementary approaches that prevent replenishment or repopulation of the HIV reservoir. Our previous studies have shown that the FDA-approved BCL2 antagonist venetoclax has a beneficial effect on the HIV reservoir size following HIV reactivation. Here we demonstrate that venetoclax also has a beneficial effect on HIV reservoir size in a model of homeostatic proliferation of HIV as well as in acute spreading infection of HIV in primary CD4 T cells. These results suggest that venetoclax, either alone or in combination with other approaches to reducing HIV reservoir size, is a compound worthy of further study for its effects on HIV reservoir size.

Prevalence of Persistent Median Arteries in the Pediatric Population on Ultrasonography.

OBJECTIVES: To use real-time ultrasonography to estimate the prevalence of persistent median arteries in a cohort of pediatric orthopedic patients. METHODS: With Institutional Review Board approval, patients between the ages of 3 months and 19 years were recruited for this cross-sectional study. Variables of interest included demographics, underlying diagnoses, and the presence of a Doppler-confirmed median artery. Ultrasonographic examinations were performed on both upper extremities by a single investigator. Patient- and limb-level analyses were performed. A multivariable generalized logistic regression analysis was used to test the association between the prevalence of limb-specific persistent median arteries and age. A generalized estimating equation was used to adjust for the inclusion of multiple limbs from the same patient. RESULTS: A total of 135 patients (270 limbs) were evaluated. The patient-specific prevalence rate (persistent median arteries present in 1 or both limbs) was 26.7%. Among these patients (n = 36), a persistent median artery was present bilaterally in 55.6% (n = 20). The limb-specific prevalence rate (proportion of limbs with a persistent median artery) was 20.7%. After adjusting for race, for every 1-year increase in age, the odds of a persistent median artery decreased by 4.4%. After adjusting for age, African Americans were significantly more likely to present with a persistent median artery (odds ratio, 3.78; 95% confidence interval, 1.25-11.48). CONCLUSIONS: Ultrasonography can effectively visualize anatomic variants, such as persistent median arteries, in the pediatric population. The prevalence of persistent median arteries was higher than anticipated, especially among African American patients.