The electronic frailty index as an indicator of community healthcare service utilisation in the older population

Background: older people with frailty are particularly high users of healthcare services, however a lack of standardised recording of frailty in different healthcare electronic datasets has limited investigations into healthcare service usage and demand of the older frail population. Objectives: to investigate the community service demand of frail patients using the electronic frailty index (eFI) as a measure of frailty. Study design and setting a retrospective cohort study using anonymised linked healthcare patient data from primary care, community services and acute hospitals in Norfolk. Participants: patients aged 65 and over who had an eFI assessment score established in their primary care electronic patient record in Norwich based General Practices. Results: we include data from 22,859 patients with an eFI score. Frailty severity increased with age and was associated with increased acute hospital admission within a 6-month window. Patients with a frail eFI score were also more likely to have a community service referral within a 6-month window of frailty assessment, with a RR of 1.84 (1.76–1.93) for mild frailty, 1.96 (1.83–2.09) for moderate frailty and 2.95 (2.76–3.14) for severe frailty scores. We also found that frail patients had more community referrals per patient then those classified as fit and required more care plans per community referral. Conclusions: eFI score was an indicator of community service use, with increasing severity of frailty being associated with higher community healthcare requirements. The eFI may help planning of community services for the frail population

UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in spinal muscular atrophy

Deafferentation of motor neurons as a result of defective sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted sensory neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates sensory neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.</p

Adverse effects of Z-drugs for sleep disturbance in people living with dementia:a population-based cohort study

Background: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia. Methods: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates. Results: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13–2.46), 1.96 (1.16–3.31), 1.33 (1.06–1.66), and 1.88 (1.14–3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64–0.83]). Conclusions: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed. Trial registration: ENCePP e-register of studies, EUPAS18006

Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia:a series of cohort studies

BACKGROUND: Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia. OBJECTIVES: To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance. DESIGN: A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia. DATA SOURCES: Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial. SETTING: Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England. PARTICIPANTS: Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively. INTERVENTIONS: The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics. MAIN OUTCOME MEASURES: Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance. RESULTS: The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life. LIMITATIONS: Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses. CONCLUSIONS: We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed. FUTURE WORK: More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia. STUDY REGISTRATION: This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information

Elemental Composition and Chemical Evolution of Geologic Materials in Gale Crater, Mars: APXS Results From Bradbury Landing to the Vera Rubin Ridge

The Alpha Particle X-ray Spectrometer (APXS) on the rover Curiosity has analyzed the composition of geologic materials along a >20-km traverse in Gale crater on Mars. The APXS dataset after 6.5 Earth years (2,301 sols) includes 712 analyses of soil, sand, float, bedrock, and drilled/scooped fines. We present the APXS results over this duration and provide stratigraphic context for each target. We identify the best APXS measurement of each of the 22 drilled and scooped samples that were delivered to the instruments Chemistry and Mineralogy (CheMin; X-ray diffractometer) and Sample Analysis at Mars (SAM; mass spectrometer and gas chromatograph) during this period. The APXS results demonstrate that the basaltic and alkali-rich units in the Bradbury group (sols 0-750) show minimal alteration indicating an arid climate. In contrast, the Murray formation of the Mount Sharp group (sols ∼750-2,301) has compositions indicating pervasive alteration. Diagenetic features are common and show fluid interaction with the sediment after (and possibly during) lithification. A sandstone unit, the Stimson formation, overlies part of the Murray formation. This has a composition similar to the basaltic sand and soil, suggesting a shared source. Cross-cutting, fracture-associated haloes are evidence of late-stage fluid alteration after lithification of the sediment. The APXS dataset, evaluated in concert with the full science payload of Curiosity, indicates that Gale crater was habitable, and that liquid water was stable for extended periods.We are indebted to NASA-JPL, the Canadian Space Agency, and Australian Research Council (DP150104604) for supporting our work and the MSL mission. A portion of this study was conducted at the Jet Propulsion Laboratory, California Institute of Technology under a contract with the National Aeronautics and Space Administration

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Evaluation of Candidate Stromal Epithelial Cross-Talk Genes Identifies Association between Risk of Serous Ovarian Cancer and TERT, a Cancer Susceptibility “Hot-Spot”

We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes involved in stromal epithelial interactions in the Ovarian Cancer Association Consortium (OCAC). In the discovery stage, cases with epithelial ovarian cancer (n = 675) and controls (n = 1,162) were genotyped at 1,536 SNPs using an Illumina GoldenGate assay. Based on Positive Predictive Value estimates, three SNPs—PODXL rs1013368, ITGA6 rs13027811, and MMP3 rs522616—were selected for replication using TaqMan genotyping in up to 3,059 serous invasive cases and 8,905 controls from 16 OCAC case-control studies. An additional 18 SNPs with Pper-allele<0.05 in the discovery stage were selected for replication in a subset of five OCAC studies (n = 1,233 serous invasive cases; n = 3,364 controls). The discovery stage associations in PODXL, ITGA6, and MMP3 were attenuated in the larger replication set (adj. Pper-allele≥0.5). However genotypes at TERT rs7726159 were associated with ovarian cancer risk in the smaller, five-study replication study (Pper-allele = 0.03). Combined analysis of the discovery and replication sets for this TERT SNP showed an increased risk of serous ovarian cancer among non-Hispanic whites [adj. ORper-allele 1.14 (1.04–1.24) p = 0.003]. Our study adds to the growing evidence that, like the 8q24 locus, the telomerase reverse transcriptase locus at 5p15.33, is a general cancer susceptibility locus

The fusion crust of the Winchcombe meteorite: a preserved record of atmospheric entry processes

Fusion crusts form during the atmospheric entry heating of meteorites and preserve a record of the conditions that occurred during deceleration in the atmosphere. The fusion crust of the Winchcombe meteorite closely resembles that of other stony meteorites, and in particular CM2 chondrites, since it is dominated by olivine phenocrysts set in a glassy mesostasis with magnetite, and is highly vesicular. Dehydration cracks are unusually abundant in Winchcombe. Failure of this weak layer is an additional ablation mechanism to produce large numbers of particles during deceleration, consistent with the observation of pulses of plasma in videos of the Winchcombe fireball. Calving events might provide an observable phenomenon related to meteorites that are particularly susceptible to dehydration. Oscillatory zoning is observed within olivine phenocrysts in the fusion crust, in contrast to other meteorites, perhaps owing to temperature fluctuations resulting from calving events. Magnetite monolayers are found in the crust, and have also not been previously reported, and form discontinuous strata. These features grade into magnetite rims formed on the external surface of the crust and suggest the trapping of surface magnetite by collapse of melt. Magnetite monolayers may be a feature of meteorites that undergo significant degassing. Silicate warts with dendritic textures were observed and are suggested to be droplets ablated from another stone in the shower. They, therefore, represent the first evidence for intershower transfer of ablation materials and are consistent with the other evidence in the Winchcombe meteorite for unusually intense gas loss and ablation, despite its low entry velocity.Science and Technology Facilities Council (STFC): ST/V000799/

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Author Correction: Drivers of seedling establishment success in dryland restoration efforts

1 Pág. Correción errata.In the version of this Article originally published, the surname of author Tina Parkhurst was incorrectly written as Schroeder. This has now been corrected.Peer reviewe