Selection on Coding and Regulatory Variation Maintains Individuality in Major Urinary Protein Scent Marks in Wild Mice

Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation) and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup) gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP) scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones

An occupational therapy intervention for residents with stroke related disabilities in UK care homes (OTCH): cluster randomised controlled trial

Objective To evaluate the clinical efficacy of an established programme of occupational therapy in maintaining functional activity and reducing further health risks from inactivity in care home residents living with stroke sequelae. Design Pragmatic, parallel group, cluster randomised controlled trial. Setting 228 care homes (>10 beds each), both with and without the provision of nursing care, local to 11 trial administrative centres across the United Kingdom. Participants 1042 care home residents with a history of stroke or transient ischaemic attack, including those with language and cognitive impairments, not receiving end of life care. 114 homes (n=568 residents, 64% from homes providing nursing care) were allocated to the intervention arm and 114 homes (n=474 residents, 65% from homes providing nursing care) to standard care (control arm). Participating care homes were randomised between May 2010 and March 2012. Intervention Targeted three month programme of occupational therapy, delivered by qualified occupational therapists and assistants, involving patient centred goal setting, education of care home staff, and adaptations to the environment. Main outcome measures Primary outcome at the participant level: scores on the Barthel index of activities of daily living at three months post-randomisation. Secondary outcome measures at the participant level: Barthel index scores at six and 12 months post-randomisation, and scores on the Rivermead mobility index, geriatric depression scale-15, and EuroQol EQ-5D-3L questionnaire, at all time points. Results 64% of the participants were women and 93% were white, with a mean age of 82.9 years. Baseline characteristics were similar between groups for all measures, personal characteristics, and diagnostic tests. Overall, 2538 occupational therapy visits were made to 498 participants in the intervention arm (mean 5.1 visits per participant). No adverse events attributable to the intervention were recorded. 162 (11%) died before the primary outcome time point, and 313 (30%) died over the 12 months of the trial. The primary outcome measure did not differ significantly between the treatment arms. The adjusted mean difference in Barthel index score at three months was 0.19 points higher in the intervention arm (95% confidence interval −0.33 to 0.70, P=0.48). Secondary outcome measures also showed no significant differences at all time points. Conclusions This large phase III study provided no evidence of benefit for the provision of a routine occupational therapy service, including staff training, for care home residents living with stroke related disabilities. The established three month individualised course of occupational therapy targeting stroke related disabilities did not have an impact on measures of functional activity, mobility, mood, or health related quality of life, at all observational time points. Providing and targeting ameliorative care in this clinically complex population requires alternative strategies

Mortality by timing of hip fracture surgery:factors and relationships at play

In hip fracture care, it is disputed whether mortality worsens when surgery is delayed. This knowledge gap matters when hospital managers seek to justify resource allocation for prioritizing access to one procedure over another. Uncertainty over the surgical timing-death association leads to either surgical prioritization without benefit or the underuse of expedited surgery when it could save lives. The discrepancy in previous findings results in part from differences between patients who happened to undergo surgery at different times. Such differences may produce the statistical association between surgical timing and death in the absence of a causal relationship. Previous observational studies attempted to adjust for structure, process, and patient factors that contribute to death, but not for relationships between structure and process factors, or between patient and process factors. In this article, we (1) summarize what is known about the factors that influence, directly or indirectly, both the timing of surgery and the occurrence of death; (2) construct a dependency graph of relationships among these factors based explicitly on the existing literature; (3) consider factors with a potential to induce covariation of time to surgery and the occurrence of death, directly or through the network of relationships, thereby explaining a putative surgical timing-death association; and (4) show how age, sex, dependent living, fracture type, hospital type, surgery type, and calendar period can influence both time to surgery and occurrence of death through chains of dependencies. We conclude by discussing how these results can inform the allocation of surgical capacity to prevent the avoidable adverse consequences of delaying hip fracture surgery

Molecular Mechanisms of Synaptic Vesicle Degradation

Neurons rely on precise spatial and temporal control of neurotransmitter release to ensure proper communication. Neurotransmission occurs when synaptic vesicles in the presynaptic compartment fuse with the plasma membrane and release their contents into the synaptic cleft, where neurotransmitters bind to receptors on the postsynaptic neuron. Synaptic vesicle pools must maintain a functional repertoire of proteins in order to efficiently release neurotransmitter. Indeed, the accumulation of old or damaged proteins on synaptic vesicle membranes is linked to synaptic dysfunction and neurodegeneration. Despite the importance of synaptic vesicle protein turnover for neuronal health, the molecular mechanisms underlying this process are unknown. In this thesis, we present work that uncovers key components that regulate synaptic vesicle degradation. Specifically, we identify a pathway that mediates the activity-dependent turnover of a subset of synaptic vesicle membrane proteins in mammalian neurons. This pathway requires the synaptic vesicle-associated GTPase Rab35, the ESCRT machinery, and synaptic vesicle protein ubiquitination. We further demonstrate that neuronal activity stimulates synaptic vesicle protein turnover by inducing Rab35 activation and binding to the ESCRT-0 component Hrs, which we have identified as a novel Rab35 effector. These actions recruit the downstream ESCRT machinery to synaptic vesicle pools, thereby initiating synaptic vesicle protein degradation via the ESCRT pathway. Interestingly, we find that not all synaptic vesicle proteins are degraded by this mechanism, suggesting that synaptic vesicles are not degraded as units, but rather that SV proteins are degraded individually or in subsets. Moreover, we find that lysine-63 ubiquitination of VAMP2 is required for its degradation, and we identify an E3 ubiquitin ligase, RNF167, that is responsible for this activity. Our findings show that RNF167 and the Rab35/ESCRT pathway facilitate the removal of specific proteins from synaptic vesicle pools, thereby maintaining presynaptic protein homeostasis. Overall, our studies provide novel mechanistic insight into the coupling of neuronal activity with synaptic vesicle protein degradation, and implicate ubiquitination as a major regulator in maintaining functional synaptic vesicle pools. These findings will facilitate future studies determining the effects of perturbations to synaptic homeostasis in neuronal dysfunction and degeneration

The uptake of the hip fracture core outcome set:analysis of 20 years of hip fracture trials

Backgroundclinical trials test the effectiveness or efficacy of treatments. It is important that researchers evaluate interventions with the most meaningful outcome measures. The 2014 hip fracture core outcome set recommended that mortality, mobility, pain, activities of daily living and health-related quality of life (HRQOL) should be assessed in all trials of patient with hip fracture. The purpose of this analysis was to determine the uptake of these recommendation.Methodsall trials registered from 1997 to 2018 recruiting participants following hip fracture were identified from the ClinicalTrials.gov trials registry. The frequency of each core domain adopted annually were assessed.Results311 trials were identified and analysed. On analysing trial registries for years which presented a minimum of 10 registrations, full core outcome set adoption ranged from 0% (2017; 2018) to 24% (2009). Mortality and mobility were the most consistently reported domains (mortality: 27% (2017) to 56% (2011); mobility: 36% (2015) to 60% (2004)). In contrast, pain and HRQOL were least reported (pain: 14% (2017) to 61% (2015); HRQOL: 10% (2010) to 11% (2008)). There was no clear change in core outcome domain set adoption following the publication of Hayward et al.’s (2014) core outcome set.Conclusionsthere has been limited adoption of the hip fracture core outcome set from its publication in 2014. Further consideration to improve implementation is required to improved uptake

A cluster randomised controlled trial of an occupational therapy intervention for residents with stroke living in UK care homes (OTCH): study protocol.

BACKGROUND: The occupational therapy (OT) in care homes study (OTCH) aims to investigate the effect of a targeted course of individual OT (with task training, provision of adaptive equipment, minor environmental adaptations and staff education) for stroke survivors living in care homes, compared to usual care. METHODS/DESIGN: A cluster randomised controlled trial of United Kingdom (UK) care homes (n = 90) with residents (n = 900) who have suffered a stroke or transient ischaemic attack (TIA), and who are not receiving end-of-life care. Homes will be stratified by centre and by type of care provided and randomised (50:50) using computer generated blocked randomisation within strata to receive either the OT intervention (3 months intervention from an occupational therapist) or control (usual care). Staff training on facilitating independence and mobility and the use of adaptive equipment, will be delivered to every home, with control homes receiving this after the 12 month follow-up.Allocation will be concealed from the independent assessors, but the treating therapists, and residents will not be masked to the intervention. Measurements are taken at baseline prior to randomisation and at 3, 6 and 12 months post randomisation. The primary outcome measure is independence in self-care activities of daily living (Barthel Activities of Daily Living Index). Secondary outcome measures are mobility (Rivermead Mobility Index), mood (Geriatric Depression Scale), preference based quality of life measured from EQ-5D and costs associated with each intervention group. Quality adjusted life years (QALYs) will be derived based on the EQ-5D scores. Cost effectiveness analysis will be estimated and measured by incremental cost effectiveness ratio. Adverse events will be recorded. DISCUSSION: This study will be the largest cluster randomised controlled trial of OT in care homes to date and will clarify the currently inconclusive literature on the efficacy of OT for stroke and TIA survivors residing in care homes. TRIAL REGISTRATION: ISRCTN00757750.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The burden of second hip fractures:provincial surgical hospitalizations over 15 years

BACKGROUND: Second hip fractures account for up to 15% of all hip fractures. We sought to determine if the proportion of hip fracture surgeries for second hip fracture changed over time in terms of patient and fracture characteristics.METHODS: We reviewed the records of patients older than 60 years hospitalized for hip fracture surgery between 1990 and 2005 in British Columbia. We studied the proportion of surgeries for second hip fracture among all hip fracture surgeries. Linear regression tested for trends across fiscal years for women and men.RESULTS: We obtained 46 341 patient records. Second hip fracture accounted for 8.3% of hip fracture surgeries. For women the proportion of second hip fracture surgeries increased linearly from 4% to 13% with each age decade (p = 0.001) and across fiscal years (p = 0.002). In men the proportion of second hip fracture surgeries was 5% for each age decade between the ages of 60 and 90 years across fiscal years, increasing to 8% for men older than 90 years across fiscal years (p = 0.20). These sex-specific trends were similar for both pertrochanteric and transcervical fracture types.CONCLUSION: Second hip fracture surgeries account for an increasing proportion of hip fracture surgeries and may require more health care resources to minimize poorer reported outcomes. Future research should determine whether more health care resources are required to manage these patients and optimize their outcomes.</p

An e-Learning Intervention for Professionals to Promote Family-Centered Cancer Care When a Significant Caregiver for Children Is at End of Life: Mixed Methods Evaluation Study

Background: Families are often unsure how best to prepare dependent children for the death of a significant caregiver with a poor cancer prognosis and seek guidance and support from health care teams. Health and social care professionals (hereafter referred to as professionals) often lack educational opportunities to gain the desired knowledge, skills, and confidence to provide family-centered supportive cancer care. e-Learning has positively impacted access and reach, improving educational opportunities in health care. Objective: We aimed to evaluate the acceptability, usability, and effectiveness of an evidence-based, theory-driven e-learning intervention to equip and promote professionals’ self-efficacy to deliver family-centered supportive cancer care when a significant caregiving member for dependent children is at the end of life. Methods: Guided by the “person-based approach,” a mixed methods outcome evaluation was used. To determine the effect on self-efficacy, participants completed a validated pre-test and post-test 12-item self-efficacy survey. The use of one-on-one, remote semistructured interviews and single-item questions determined the usability by professionals of the e-learning intervention and the acceptability of perceived learning in clinical practice. To generate enhanced insights, quantitative and qualitative data were integrated through a 4-stage, modified pillar integration process. Results: Overall, 158 participants completed the pre-test survey for the e-learning resource, with 99 (62.7%) completing the post-test survey. Semistructured interviews were conducted with 12 professionals at least 1 month after the intervention. Findings highlighted a statistically significant improvement in post-test self-efficacy (99/158, 62.7%; P&lt;.001). Usability of the e-learning intervention was positive, with participants reporting that it was clear and organized (mean 4.84, SD 0.373), the layout was appealing (mean 4.71, SD 0.539), the language was easy to understand (mean 4.71, SD 0.407), and graphics and media were purposeful (mean 4.76, SD 0.495) and engaging (mean 4.67, SD 0.703). Determining acceptability, participants considered that the intervention would positively impact practice (mean 4.60, SD 0.589) and increase knowledge (mean 4.56, SD 0.677), with appropriate practical examples to support learning (mean 4.58, SD 0.610). Following engagement with the e-learning intervention, professionals reported preparedness to deliver supportive adult-professional end-of-life cancer care, when an adult with significant caregiving responsibilities is dying. Findings demonstrated transferable learning to additional contexts, such as other close adult-child relational bonds (grandparents) and to life-limiting conditions. Conclusions: The systematic and iterative person-based approach optimized the acceptability of a novel e-learning intervention, having the potential to promote family-centered supportive end-of-life cancer care. This accessible e-learning intervention makes an important contribution to the recognized global gap of educational interventions in this field. Equipping professionals with family-centered supportive end-of-life care improves self-efficacy and preparedness to engage in challenging conversations, with the potential to promote better outcomes for affected adults and children and mediate adverse outcomes for adults and children before and after bereavement

Prescription Of analgesia in Emergency Medicine (POEM): a multicentre observational survey of pain relief in patients presenting with an isolated limb fracture and/or dislocation

Background: Acute pain is one of the most commonly cited reasons for attendance to the emergency department (ED), and the Royal College of Emergency Medicine (RCEM) Best Practice Guideline (2014) acknowledged that the current management of acute pain in UK EDs is inadequate and has a poor evidence base. Methods: The Prescription Of analgesia in Emergency Medicine (POEM) survey is a cross-sectional observational survey of consecutive patients presenting to 12 National Health Service (NHS) EDs with limb fracture and/or dislocation in England and Scotland and was carried out between 2015 and 2017. The primary outcome was to assess the adequacy of pain management in the ED against the recommendations in the RCEM Best Practice Guidelines. Results: In all, 8346 patients were identified as attending the ED with a limb fracture and/or dislocation but adherence to RCEM guidelines could only be evaluated for the 4160 (49.8%) patients with a recorded pain score. Of these, 2409/4160 (57.9%) patients received appropriate pain relief, but only 1347 patients were also assessed within 20 minutes of their arrival in the ED. Therefore, according to the RCEM guidelines, only 16.1% (1347/8346) of all patients were assessed and had satisfactory pain management in the ED. Conclusions: The POEM survey has identified that pain relief for patients with an isolated limb fracture remains inadequate when strictly compared to the RCEM Best Practice Guidelines. However, we have found that some patients receive analgesia despite having no pain score recorded, while other analgesic modalities are provided that are not currently encompassed by the Best Practice Guidelines. Future iterations of these guidelines may wish to encompass the breadth of available modalities of pain relief and the whole patient journey. In addition, more work is needed to improve timely and repeated assessment of pain and its recording, which has been better achieved in some EDs than others