Fear-avoidant beliefs and behaviours after upper limb fracture in older people: a systematic review and meta-ethnography.

PURPOSE: This systematic review aimed to understand older people's perspectives of associated fear-avoidant beliefs following upper limb fracture. METHODS: Published and unpublished literature databases were systematically searched from inception to 1st April 2023. Qualitative studies reporting the perspectives of fear-avoidant beliefs or behaviours in people who had sustained an upper limb fracture were eligible. Data extracted included characteristics of people interviewed, experiences and perceptions of fear, fear of falling, and fear-avoidant beliefs and behaviours. Data were synthesised using a meta-ethnography approach and the GRADE-CERQUAL tool. RESULTS: Eight studies were eligible (n = 150 participants; 109 distal radial/41 humeral fracture). Three overarching themes were identified: (1) type of fear-avoidant experiences, (2) drivers of fear-avoidant beliefs and behaviours, and (3) consequences of fear-avoidant beliefs and behaviours. The themes generated were based on moderate confidence evidence. In summary, whilst some patients initially consider upper limb fractures to be relatively minor injuries, over time, the realisation occurs that they have wide-ranging consequences with longer-term perspectives on recovery. This often occurs following an initial period of reduced fear. Providing education and support immediately post-fracture to prevent or challenge initial health beliefs around fear of falls and fear of movement is imperative to recovery. CONCLUSIONS: Fear-avoidant beliefs can impact heavily on certain older people's recovery, as well as their longer-term health and wellbeing. Consideration of fear avoidance and taking steps to mitigate against this in the acute upper limb trauma setting will better serve these patients in their ongoing recovery from injury.

Diagnosis, treatment, and outcome of patients with oesophagogastric cancer during the COVID-19 pandemic: national study.

BACKGROUND: The national response to COVID-19 has had a significant impact on cancer services. This study investigated the effect of national lockdown on diagnosis, management, and outcomes of patients with oesophagogastric cancers in Scotland. METHODS: This retrospective cohort study included consecutive new patients presenting to regional oesophagogastric cancer multidisciplinary teams in National Health Service Scotland between October 2019 and September 2020. The study interval was divided into before and after lockdown, based on the first UK national lockdown. Electronic health records were reviewed and results compared. RESULTS: Some 958 patients with biopsy-proven oesophagogastric cancer in 3 cancer networks were included: 506 (52.8 per cent) before and 452 (47.2 per cent) after lockdown. Median age was 72 (range 25-95) years and 630 patients (65.7 per cent) were men. There were 693 oesophageal (72.3 per cent) and 265 gastric (27.7 per cent) cancers. Median time to gastroscopy was 15 (range 0-337) days before versus 19 (0-261) days after lockdown (P < 0.001). Patients were more likely to present as an emergency after lockdown (8.5 per cent before versus 12.4 per cent after lockdown; P = 0.005), had poorer Eastern Cooperative Oncology group performance status, were more symptomatic, and presented with a higher stage of disease (stage IV: 49.8 per cent before versus 58.8 per cent after lockdown; P = 0.04). There was a shift to treatment with non-curative intent (64.6 per cent before versus 77.4 per cent after lockdown; P < 0.001). Median overall survival was 9.9 (95 per cent c.i. 8.7 to 11.4) months before and 6.9 (5.9 to 8.3) months after lockdown (HR 1.26, 95 per cent c.i. 1.09 to 1.46; P = 0.002). CONCLUSION: This national study has highlighted the adverse impact of COVID-19 on oesophagogastric cancer outcomes in Scotland. Patients presented with more advanced disease and a shift towards treatment with non-curative intent was observed, with a subsequent negative impact on overall survival.

Eribulin Treatment for Patients with Metastatic Breast Cancer: The UK Experience - A Multicenter Retrospective Study.

INTRODUCTION: This study examined real-world data from patients who received eribulin for metastatic breast cancer (MBC) collected from 14 hospitals across the UK. METHODS: Anonymized data were collected retrospectively from patients with MBC who had received eribulin. The data included the hormone-receptor status, histological diagnosis, age, prior chemotherapy, response to eribulin, progression-free survival (PFS), and overall survival (OS). RESULTS: Among 577 patients analyzed, the median age was 56 years, and most patients (73%) were estrogen-receptor positive. The median OS was 288 days (95% confidence interval [CI]: 261-315), and the PFS was 117 days (95% CI: 105-129). The median OS was higher among older patients (≥65 vs. <65 years: 325 days [95% CI: 264-385] vs. 285 days [95% CI: 252-317]; p = 0.028). The median OS was also higher in patients who received eribulin after fewer prior lines of chemotherapy (≤2 vs. >2 prior: 328 days [95% CI: 264-385] vs. 264 days [95% CI: 229-298]; p = 0.042). DISCUSSION/CONCLUSION: These retrospective data suggest that eribulin can be successfully used in older patients with MBC. Eribulin treatment was more effective in earlier-line settings, which, while predictable, supports consideration of eribulin as a second-line treatment option.

Lateralisation of subcortical functional connectivity during and after general anaesthesia.

BACKGROUND: Arousal and awareness are two important components of consciousness states. Functional neuroimaging has furthered our understanding of cortical and thalamocortical mechanisms of awareness. Investigating the relationship between subcortical functional connectivity and arousal has been challenging owing to the relatively small size of brainstem structures and thalamic nuclei, and their depth in the brain. METHODS: Resting state functional MRI scans of 72 healthy volunteers were acquired before, during, 1 h after, and 1 day after sevoflurane general anaesthesia. Functional connectivity of subcortical regions of interest vs whole brain and homotopic functional connectivity for assessment of left-right symmetry analyses of both cortical and subcortical regions of interest were performed. Both analyses used high resolution atlases generated from deep brain stimulation applications. RESULTS: Functional connectivity in subcortical loci within the thalamus and of the ascending reticular activating system was sharply restricted under anaesthesia, featuring a general lateralisation of connectivity. Similarly, left-right homology was sharply reduced under anaesthesia. Subcortical bilateral functional connectivity was not fully restored after emergence from anaesthesia, although greater restoration was seen between ascending reticular activating system loci and specific thalamic nuclei thought to be involved in promoting and maintaining arousal. Functional connectivity was fully restored to baseline by the following day. CONCLUSIONS: Functional connectivity in the subcortex is sharply restricted and lateralised under general anaesthesia. This restriction may play a part in loss and return of consciousness. CLINICAL TRIAL REGISTRATION: NCT02275026.

The feasibility and acceptability of assessing and managing sarcopenia and frailty among older people with upper limb fracture.

BACKGROUND: sarcopenia and frailty are associated with increased risk of falls and fractures. This study evaluated the feasibility of assessing sarcopenia and frailty among older people attending fracture clinics. METHODS: patients aged 65+ years with an arm fracture attending fracture clinics in one UK city were recruited. Sarcopenia was assessed using gait speed, grip strength, skeletal muscle mass index SMI, SARC-F questionnaire and the European Working Group on Sarcopenia in Older People (EWGSOP) I and II criteria. Frailty was assessed using Fried Frailty Phenotype (FFP), FRAIL scale, PRISMA-7, electronic Frailty Index (e-FI), Clinical Frailty Score (CFS) and Study of Osteoporotic Fracture. The sensitivity and specificity of each tool was calculated against the EWGSOP II criteria (sarcopenia) and FFP (frailty). Patients identified to have either condition were referred for Comprehensive Geriatric Assessment (CGA). Interviews with 13 patients and nine staff explored the acceptability of this process. RESULTS: hundred patients (Mean age 75 years) were recruited. Most sarcopenia and frailty assessments were quick with complete data collection and were acceptable to patients and staff. Sarcopenia was identified among 4-39% participants depending on the tool and frailty among 9-25%. Both conditions were more common among men than women with all tools. The SARC-F and PRISMA-7 had the best sensitivity (100 and 93%, respectively) and specificity (96 and 87%). CGA among 80% of referred participants led to three interventions per participant (e.g. medication changes and investigations). CONCLUSION: SARC-F and PRISMA-7 are recommended for use in fracture clinics to screen for sarcopenia and frailty.

Cognitive Recovery by Decade in Healthy 40- to 80-Year-Old Volunteers After Anesthesia Without Surgery.

BACKGROUND: Postoperative delirium and postoperative cognitive dysfunction are the most common complications for older surgical patients. General anesthesia may contribute to the development of these conditions, but there are little data on the association of age with cognitive recovery from anesthesia in the absence of surgery or underlying medical condition. METHODS: We performed a single-center cohort study of healthy adult volunteers 40 to 80 years old (N = 71, mean age 58.5 years, and 44% women) with no underlying cognitive dysfunction. Volunteers underwent cognitive testing before and at multiple time points after 2 hours of general anesthesia consisting of propofol induction and sevoflurane maintenance, akin to a general anesthetic for a surgical procedure, although no procedure was performed. The primary outcome was time to recovery to cognitive baseline on the Postoperative Quality of Recovery Scale (PQRS) within 30 days of anesthesia. Secondary cognitive outcomes were time to recovery on in-depth neuropsychological batteries, including the National Institutes of Health Toolbox and well-validated paper-and-pencil tests. The primary hypothesis is that time to recovery of cognitive function after general anesthesia increases across decades from 40 to 80 years of age. We examined this with discrete-time logit regression (for the primary outcome) and linear mixed models for interactions of age decade with time postanesthesia (for secondary outcomes). RESULTS: There was no association between age group and recovery to baseline on the PQRS; 36 of 69 (52%) recovered within 60-minute postanesthesia and 63 of 69 (91%) by day 1. Hazard ratios (95% confidence interval) for each decade compared to 40- to 49-year olds were: 50 to 59 years, 1.41 (0.50-4.03); 60 to 69 years, 1.03 (0.35-3.00); and 70 to 80 years, 0.69 (0.25-1.88). There were no significant differences between older decades relative to the 40- to 49-year reference decade in recovery to baseline on secondary cognitive measures. CONCLUSIONS: Recovery of cognitive function to baseline was rapid and did not differ between age decades of participants, although the number in each decade was small. These results suggest that anesthesia alone may not be associated with cognitive recovery in healthy adults of any age decade.

Oligomeric Aß in the monkey brain impacts synaptic integrity and induces accelerated cortical aging.

As the average age of the population continues to rise, the number of individuals affected with age-related cognitive decline and Alzheimer's disease (AD) has increased and is projected to cost more than $290 billion in the United States in 2019. Despite significant investment in research over the last decades, there is no effective treatment to prevent or delay AD progression. There is a translational gap in AD research, with promising drugs based on work in rodent models failing in clinical trials. Aging is the leading risk factor for developing AD and understanding neurobiological changes that affect synaptic integrity with aging will help clarify why the aged brain is vulnerable to AD. We describe here the development of a rhesus monkey model of AD using soluble oligomers of the amyloid beta (Aß) peptide (AßOs). AßOs infused into the monkey brain target a specific population of spines in the prefrontal cortex, induce neuroinflammation, and increase AD biomarkers in the cerebrospinal fluid to similar levels observed in patients with AD. Importantly, AßOs lead to similar dendritic spine loss to that observed in normal aging in monkeys, but so far without detection of amyloid plaques or tau pathology. Understanding the basis of synaptic impairment is the most effective route to early intervention and prevention or postponement of age-related cognitive decline and transition to AD. These initial findings support the use of monkeys as a platform to understand age-related vulnerabilities of the primate brain and may help develop effective disease-modifying therapies for treatment of AD and related dementias.

Processed intraoperative burst suppression and postoperative cognitive dysfunction in a cohort of older noncardiac surgery patients.

Postoperative cognitive dysfunction (POCD) is a decline in cognitive test performance which persists months after surgery. There has been great interest in the anesthesia community regarding whether variables generated by commercially available processed EEG monitors originally marketed to prevent awareness under anesthesia can be used to guide intraoperative anesthetic management to prevent POCD. Processed EEG monitors represent an opportunity for anesthesiologists to directly monitor the brain even if they have not been trained to interpret EEG waveforms. There is continued equipoise regarding whether any of the variables generated by the machines' interpretation of raw data are associated with POCD. Most literature has focused on the depth of anesthesia number, however recent studies have shown that processed depth may not be accurate in older age groups due to reduced alpha band power. Burst suppression is an encephalographic pattern of high voltage activity alternating with periods of electrical silence and is another marker of depth which can be obtained from commercial processed EEG monitors. We performed a prospective cohort study to determine whether burst suppression and burst suppression ratio as measured by the BIS Monitor (Bispectral Index, BIS Medtronic, Boulder CO), is associated with cognitive dysfunction 3 months after surgery. We recruited 167 elective surgery patients, 65 years of age and older, anticipated to require at least 2 day inpatient admission. Our main outcome measure was cognitive decline in composite z-score on the Alzheimer's Disease Research Center UDS Battery of at least 1 standard deviation 3 months after surgery relative to preoperative baseline. 14% experienced POCD, this group was older (72 [70, 74] versus 70 [67, 75] years), and had frailty scores as measured by the FRAIL Scale (2 [0, 3] versus 1 [0, 2]) and lower baseline z-scores (- 0.2 [- 0.6, 0.5] versus 0.1 [- 0.3, 0.5]). There was a univariable association between suppression ratio > 10 (SR > 10) and POCD (4.8 [0, 37.3] versus 15.4 [4.0-142.4] min), p = .038. However, after adjustment this relationship did not persist, only anesthetic technique, age, and pain remained in the model. In our cohort of older elective noncardiac surgery patients we found a marginal association between processed burst suppression (total burst suppression p = .067, SR > 5 p = .052, SR > 10.038) which did not persist in a multivariable model. Patients with POCD had almost twice the number of minutes of burst suppression, and three times the amount of time for SR > 5 and > 10. Our finding may be a limitation of the monitor's ability to detect burst suppression. The consistent trend towards more intraoperative burst suppression in patients who developed POCD suggests that future studies are needed to investigate the relationship of raw intraoperative burst suppression and POCD.Trial registry Clinical trial number and registry URL: Optimizing Postoperative Cognitive Dysfunction in the Elderly-PRESERVE, Clinical Trials Gov# NCT02650687; https://clinicaltrials.gov/ct2/show/NCT02650687 .

Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers.

Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.

The impact of COVID-19 on systemic anticancer treatment delivery in Scotland.

Understanding the impact of the COVID-19 pandemic on systemic anticancer therapy delivery (SACT) is crucial to appreciate the short- and long-term consequences for cancer patients and plan future care. Here, we report real-time national SACT delivery data from NHS Scotland. We demonstrate an initial rapid reduction in patient attendance of 28.7% with subsequent rapid recovery following service redesign. The smallest decrease was seen in breast cancer (19.7%), which also had the most rapid recovery and the largest decrease seen in colorectal cancer (43.4%). Regional variation in the magnitude of impact on SACT delivery was observed, but nadirs occurred at the same time and the rate of recovery was similar across all regions. This recovery reflected a coordinated national approach and associated patient and clinician support structures, which facilitated the creation of COVID-19-protected areas for SACT delivery in Scottish cancer centres enabling rapid sharing of successful and innovative strategies. The data show that these actions have limited the disadvantage to cancer patients.

Does Postoperative Cognitive Decline Result in New Disability After Surgery?

OBJECTIVE: Establish whether POCD is associated with new disability after surgery, which would inform whether POCD impacts patient-centered outcomes. BACKGROUND: POCD is a decline in neuropsychiatric tests scores from presurgical baseline which occurs in approximately 15% of older patients 3 months after surgery. POCD is a research construct meant to investigate patient and family reports of older adults who were "never the same after surgery." However, many patients with POCD do not perceive difficulty with thinking and memory, and the question remains whether POCD impacts patient function. METHODS: We performed a prospective cohort study of 167 older adults undergoing major noncardiac surgery (requiring at least a 2-day hospital stay). Exclusion criteria were: history of dementia, cardiac or intracranial procedure, inability to consent for themselves, or emergency surgery. We administered formal neuropsychiatric testing (Alzheimer Disease Research Center UDS battery), basic and instrumental activities of daily living (Alzheimer Disease Research Center IADLs), pain (geriatric pain measure), and depression screening (hospital depression and anxiety scale) before and 3 months after surgery. We recorded all patient refined diagnostic related groups codes, blood pressure, anesthetics and narcotics administered, surgical and anesthesia duration, and measured complications and severity, length of stay, and readmissions. RESULTS: Patients with POCD (21/167, 14.1%) had twice the proportion of new impairment in IADL as compared to those without POCD (57% vs 27%, P = .01). The most common areas of decline were social activities, ability to find items around the house, remember appointments, shop and pay for items, do laundry, drive a car/use public transport, and do housework. Predictors of IADL change after surgery included POCD, presurgical cognition, presurgical function, postoperative depression, and the development of postoperative complications. CONCLUSIONS: Patients with POCD experience a much higher incidence of new disability after surgery. Baseline cognitive or functional limitations are also risk factors for new disability. Many patients are not aware of their limitations before surgery. Future study is needed to identify practical ways to routinely screen patients and reduce risk. Patients need to be informed of their risk for new disability after surgery to inform their medical decision making.

2019 EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older.

OBJECTIVE: To establish European League Against Rheumatism (EULAR) points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older. METHODS: Points to consider were developed in accordance with EULAR standard operating procedures for EULAR-endorsed recommendations, led by an international multidisciplinary task force, including patient research partners and different health professionals from 10 European countries. Level of evidence and strength of recommendation were determined for each point to consider, and the mean level of agreement among the task force members was calculated. RESULTS: Two overarching principles and seven points to consider were formulated based on scientific evidence and the expert opinion of the task force. The two overarching principles focus on shared decisions between patients and non-physician health professionals and involvement of different non-physician health professionals in prevention and management of fragility fractures. Four points to consider relate to prevention: identification of patients at risk of fracture, fall risk evaluation, multicomponent interventions to prevent primary fracture and discouragement of smoking and overuse of alcohol. The remaining three focus on management of fragility fractures: exercise and nutritional interventions, the organisation and coordination of multidisciplinary services for post-fracture models of care and adherence to anti-osteoporosis medicines. The mean level of agreement among the task force for the overarching principles and the points to consider ranged between 8.4 and 9.6. CONCLUSION: These first EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older serve to guide healthcare practice and education.

Effects of nicotinic antagonists on working memory performance in young rhesus monkeys.

Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4ß2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-ß-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.

Prefrontal cortex and cognitive aging in macaque monkeys.

Cognitive impairments that accompany aging, even in the absence of neurodegenerative diseases, include deficits in executive function and memory mediated by the prefrontal cortex. Because of the unique differentiation and expansion of the prefrontal cortex in primates, investigations of the neurobiological basis of cognitive aging in nonhuman primates have been particularly informative about the potential basis for age-related cognitive decline in humans. We review the cognitive functions mediated by specific subregions of prefrontal cortex, and their corresponding connections, as well as the evidence for age-related alterations in specific regions of prefrontal cortex. We also discuss evidence for similarities and differences in the effects of aging on prefrontal cortex across species.

Combining precision medicine and prophylaxis in oesophageal squamous cell carcinoma.

A trial update confirms improved survival for prophylactic elective nodal irradiation and addition of erlotinib to definitive chemoradiotherapy in oesophageal squamous cell carcinoma (ESCC). High tumour EGFR protein expression shows promise to identify those who will benefit from erlotinib. This represents therapeutic progress, and has wider relevance for precision medicine strategies in ESCC.

Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons.

Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation that are disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence, a period when cannabis use in humans has been linked to subsequent vulnerability to psychiatric disorders such as addiction and schizophrenia. Here, we investigated in a rat model the effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), a psychoactive component of cannabis, on the morphological architecture and transcriptional profile of layer III pyramidal neurons-using cell type- and layer-specific high-resolution microscopy, laser capture microdissection and next-generation RNA-sequencing. The results confirmed known normal expansions in basal dendritic arborization and dendritic spine pruning during the transition from late adolescence to early adulthood that were accompanied by differential expression of gene networks associated with neurodevelopment in control animals. In contrast, THC exposure disrupted the normal developmental process by inducing premature pruning of dendritic spines and allostatic atrophy of dendritic arborization in early adulthood. Surprisingly, there was minimal overlap of the developmental transcriptomes between THC- and vehicle-exposed rats. THC altered functional gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization. Marked developmental network disturbances were evident for epigenetic regulators with enhanced co-expression of chromatin- and dendrite-related genes in THC-treated animals. Dysregulated PFC co-expression networks common to both the THC-treated animals and patients with schizophrenia were enriched for cytoskeletal and neurite development. Overall, adolescent THC exposure altered the morphological and transcriptional trajectory of PFC pyramidal neurons, which could enhance vulnerability to psychiatric disorders.

Human plasma biomarker responses to inhalational general anaesthesia without surgery.

BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses. METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]). RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged. CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure. CLINICAL TRIAL REGISTRATION: NCT02275026.

Resting-state functional connectivity in early postanaesthesia recovery is characterised by globally reduced anticorrelations.

BACKGROUND: A growing body of literature addresses the possible long-term cognitive effects of anaesthetics, but no study has delineated the normal trajectory of neural recovery attributable to anaesthesia alone in adults. We obtained resting-state functional MRI scans on 72 healthy human volunteers between ages 40 and 80 (median: 59) yr before, during, and after general anaesthesia with sevoflurane, in the absence of surgery, as part of a larger study on cognitive function postanaesthesia. METHODS: Region-of-interest analysis, independent component analysis, and seed-to-voxel analysis were used to characterise resting-state functional connectivity and to differentiate between correlated and anticorrelated connectivity before, during, and after general anaesthesia. RESULTS: Whilst positively correlated functional connectivity remained essentially unchanged across these perianaesthetic states, anticorrelated functional connectivity decreased globally by 35% 1 h after emergence from general anaesthesia compared with baseline, as seen by the region-of-interest analysis. This decrease corresponded to a consistent reduction in expression of canonical resting-state networks, as seen by independent component analysis. All measures returned to baseline 1 day later. CONCLUSIONS: The normal perianaesthesia trajectory of resting-state connectivity in healthy adults is characterised by a transient global reduction in anticorrelated activity shortly after emergence from anaesthesia that returns to baseline by the following day. CLINICAL TRIAL REGISTRATION: NCT02275026.

Deletion of the KH1 Domain of Fmr1 Leads to Transcriptional Alterations and Attentional Deficits in Rats.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. It is a leading monogenic cause of autism spectrum disorder and inherited intellectual disability and is often comorbid with attention deficits. Most FXS cases are due to an expansion of CGG repeats leading to suppressed expression of fragile X mental retardation protein (FMRP), an RNA-binding protein involved in mRNA metabolism. We found that the previously published Fmr1 knockout rat model of FXS expresses an Fmr1 transcript with an in-frame deletion of exon 8, which encodes for the K-homology (KH) RNA-binding domain, KH1. Notably, 3 pathogenic missense mutations associated with FXS lie in the KH domains. We observed that the deletion of exon 8 in rats leads to attention deficits and to alterations in transcriptional profiles within the medial prefrontal cortex (mPFC), which map to 2 weighted gene coexpression network modules. These modules are conserved in human frontal cortex and enriched for known FMRP targets. Hub genes in these modules represent potential therapeutic targets for FXS. Taken together, these findings indicate that attentional testing might be a reliable cross-species tool for investigating FXS and identify dysregulated conserved gene networks in a relevant brain region.

Physical activity in hospitalised older people: the feasibility and acceptability of a volunteer-led mobility intervention in the SoMoVe™ study.

OBJECTIVES: to determine the feasibility and acceptability of a volunteer-led mobility intervention to improve activity levels of older inpatients. DESIGN: pre-post mixed methods study. SETTING: acute medical wards for older people. PARTICIPANTS: one hundred inpatients aged ≥70 years who were mobile prior to hospitalisation: 50 participants were recruited before and 50 after the intervention was established. Twenty-five participants (patients, nurses, therapists and volunteers) were interviewed to determine the acceptability of the intervention. INTERVENTIONS: twice daily volunteer-led mobility and bedside exercises. MAIN OUTCOME MEASURES: the feasibility of delivering a volunteer-led mobility intervention, including the recruitment, training and retention of volunteers and the acceptability of the intervention to patients and healthcare professionals. Secondary outcome measures included objectively measured daily step count, length of stay, 30-day readmission and any adverse events. RESULTS: seventeen volunteers were recruited, 16 completed training and 12 were retained. Fifty participants (mean age 86 years) received the intervention, with a median daily step count of 912 steps (interquartile range [IQR] 295-1824) compared to the baseline group (n = 50, mean age 87 years) of 636 steps (IQR 298-1468). No adverse events were reported. The intervention was acceptable to patients and staff. Facilitating factors of the intervention included the social aspect of the intervention and perceived benefits by stakeholders. Barriers identified included the busy clinical environment and lack of awareness of the intervention among staff. CONCLUSIONS: it was feasible to deliver a volunteer-led mobility intervention including the recruitment, training and retention of volunteers. The intervention was safe and acceptable to healthcare professionals and patients.