Found 18615 matches for
Ten of our researchers feature in the Highly Cited Researchers 2020 list.
Purpose: Choroideremia results from the deficiency of Rab Escort Protein 1 (REP1), encoded by CHM, involved in the prenylation of Rab GTPases. Here, we investigate whether the transcription and expression of other genes involved in the prenylation of Rab proteins correlates with disease progression in a cohort of patients with choroideremia. Methods: Rates of retinal pigment epithelial area loss in 41 patients with choroideremia were measured using fundus autofluorescence imaging for up to 4 years. From lysates of cultured skin fibroblasts donated by patients (n = 15) and controls (n = 14), CHM, CHML, RABGGTB and RAB27A mRNA expression, and REP1 and REP2 protein expression were compared. Results: The central autofluorescent island area loss in patients with choroideremia occurred with a mean half-life of 5.89 years (95% confidence interval [CI] = 5.09-6.70), with some patients demonstrating relatively fast or slow rates of progression (range = 3.3-14.1 years). Expression of CHM mRNA and REP1 protein were significantly decreased in all patients. No difference in expression of CHML, RABGGTB, RAB27A, or REP2 was seen between patients and controls. No correlation was seen between expression of the genes analyzed and rates of retinal degeneration. Non-sense induced transcriptional compensation of CHML, a CHM-like retrogene, was not observed in patients with CHM variants predicted to undergo non-sense mediated decay. Conclusions: Patients with choroideremia, who are deficient for REP1, show normal levels of expression of other genes involved in Rab prenylation, which do not appear to play any modifying role in the rate of disease progression. Translational Relevance: There remains little evidence for selection of patients for choroideremia gene therapy based on genotype.
Resting-state Amplitude of Low-frequency Fluctuation is a Potentially Useful Prognostic Functional Biomarker in Cervical Myelopathy
BackgroundCervical MRI is the standard diagnostic imaging technique for patients with cervical myelopathy. However, the utility of conventional cervical MRI as a predictive biomarker for surgical recovery remains unclear, partly because of the limited information obtained from this anatomically small area. Brain resting-state functional MRI (rs-fMRI) may help identify candidate predictive biomarkers. Two analytical methods that assess local spontaneous brain activity are widely used for rs-fMRI: functional connectivity between two brain regions and amplitude of low-frequency fluctuation (ALFF). In our previous analysis of functional connectivity, we discovered that brain functional connectivity may be a predictive biomarker for neurologic recovery in patients with cervical myelopathy; however, the functional connectivity analysis identified a correlation with only one clinical outcome (the 10-second test). To establish a comprehensive prediction measure, we need to explore other brain biomarkers that can predict recovery of other clinical outcomes in patients with cervical myelopathy.Questions/purposesWe aimed to (1) elucidate preoperative ALFF alterations in patients with cervical myelopathy and how ALFF changes after surgery, with a focus on postoperative normalization and (2) establish a predictive model using preoperative ALFF by investigating the correlation between preoperative ALFF and postoperative clinical recovery in patients with cervical myelopathy.MethodsBetween August 2015 and June 2017, we treated 40 patients with cervical myelopathy. Thirty patients met our prespecified inclusion criteria, all were invited to participate, and 28 patients opted to do so (93%; 14 men and 14 women; mean age: 67 years). The 28 patients and 28 age- and sex-matched controls underwent rs-fMRI (twice for patients with cervical myelopathy: before and 6 months after cervical decompression surgery). We analyzed the same study population that was used in our earlier study investigating functional connectivity. Controls had none of the following abnormalities: neck or arm pain, visual or auditory disorders, cognitive disorder, structural brain disorder, a history of brain surgery, mental and neurologic disorders, and medications for the central nervous system. We performed ALFF comparisons between preoperative patients with cervical myelopathy and controls, analyzed postoperative ALFF changes in patients with cervical myelopathy, and performed a correlation analysis between preoperative ALFF and clinical recovery in these patients. Clinical outcomes in the cervical myelopathy group were assessed using the 10-second test, the Japanese Orthopaedic Association upper-extremity motor (JOA-UEM) score, JOA upper-extremity sensory score (JOA-UES), and Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire for upper-extremity function (JOACMEQ-UEF) score before and 6 months after surgery, which is when we believe these scores generally reach a plateau. A total of 93% of those enrolled (26 of 28 patients) were analyzed both preoperatively and postoperatively; the other two were lost to follow-up.ResultsThe cervical myelopathy group had an increase in ALFF in the bilateral primary sensorimotor cortices (right, cluster size = 850 voxels, t-value = 6.10; left, cluster size = 370 voxels, t-value = 4.84) and left visual cortex (cluster size = 556 voxels, t-value = 4.21) compared with the control group. The cervical myelopathy group had a decrease in ALFF in the bilateral posterior supramarginal gyrus (right, cluster size = 222 voxels, t-value = 5.09; left, cluster size = 436 voxels, t-value = 5.28). After surgery, the bilateral sensorimotor cortices (right, cluster size = 468 voxels, t-value = 6.74; left, cluster size = 167 voxels, t-value = 5.40) and left visual cortex (cluster size = 3748 voxels, t-value = 6.66) showed decreased ALFF compared with preoperative ALFF, indicating postoperative normalization of spontaneous brain activities in these regions. However, the bilateral posterior supramarginal gyrus did not show an increase in ALFF postoperatively, although ALFF in this region decreased preoperatively. Greater levels of ALFF at the left and right frontal pole and left pars opercularis of the inferior frontal gyrus before surgery in the cervical myelopathy group were correlated with larger improvements in the JOACMEQ-UEF score 6 months after surgery (r = 0.784; p < 0.001, r = 0.734; p < 0.001 and r = 0.770, respectively; p < 0.001). The prediction formula, based on preoperative ALFF values in the left frontal pole, was as follows: the predicted postoperative improvement in the JOACMEQ-UEF score = 34.6 × preoperative ALFF value - 7.0 (r2= 0.614; p < 0.001).ConclusionsOur findings suggest that preoperative ALFF may be a biomarker for postoperative recovery in that it predicted postoperative JOACMEQ-UEF scores. To establish a comprehensive prediction measure for neurologic recovery in patients with cervical myelopathy, a multicenter study is underway.Level of EvidenceLevel II, diagnostic study.
Ageing is associated with disrupted reinforcement learning whilst learning to help others is preserved
AbstractReinforcement learning is a fundamental mechanism displayed by many species. However, adaptive behaviour depends not only on learning about actions and outcomes that affect ourselves, but also those that affect others. Using computational reinforcement learning models, we tested whether young (age 18–36) and older (age 60–80, total n = 152) adults learn to gain rewards for themselves, another person (prosocial), or neither individual (control). Detailed model comparison showed that a model with separate learning rates for each recipient best explained behaviour. Young adults learned faster when their actions benefitted themselves, compared to others. Compared to young adults, older adults showed reduced self-relevant learning rates but preserved prosocial learning. Moreover, levels of subclinical self-reported psychopathic traits (including lack of concern for others) were lower in older adults and the core affective-interpersonal component of this measure negatively correlated with prosocial learning. These findings suggest learning to benefit others is preserved across the lifespan with implications for reinforcement learning and theories of healthy ageing.
AbstractRecent studies indicate that COVID-19 infection can lead to serious neurological consequences in a small percentage of individuals. However, in the months following acute illness, many more suffer from fatigue, low motivation, disturbed mood, poor sleep and cognitive symptoms, colloquially referred to as ‘brain fog’. But what about individuals who do not report any ongoing symptoms after recovering from COVID-19? Here we examined a wide range of cognitive functions critical for daily life (including sustained attention, memory, motor control, planning, semantic reasoning, mental rotation and spatial-visual attention) in people who had previously suffered from COVID-19 but were not significantly different from a control group on self-reported fatigue, forgetfulness, sleep abnormality, motivation, depression, anxiety and personality profile. COVID-19 survivors displayed significantly worse episodic memory (up to 6 months post infection) and greater decline in vigilance and motivation with time on task (for up to 9 months). Overall, the results show that chronic cognitive impairments following COVID-19 are evident on objective testing even amongst those who do not report a greater symptom burden. Importantly, in the sample tested here, these were not significantly different from normal after six-nine months, demonstrating evidence of recovery over time.
Background Insomnia is a prevalent and debilitating disorder commonly managed by family physicians. Insomnia guidelines recommend cognitive behavioral therapy for insomnia (CBTi) as the 'first-line' treatment. However, family physicians report limited time, knowledge, access, support, and referral options to manage patients with CBTi. Consequently, many patients with insomnia are prescribed potentially harmful and addictive sedative-hypnotic medicines (e.g. benzodiazepines). Family physicians require an insomnia management pathway that is specifically tailored to the guideline-recommendations, time demands, and capacity of family practice. Methods This mixed-methods implementation trial will test the feasibility, acceptability and effectiveness of a comprehensive digital insomnia management pathway in family practice. This novel pathway includes digital recruitment of family physicians, automatic identification of patients whose electronic medical records contain recent sedative-hypnotic prescriptions using a software management pathway and real-time notifications prompting physicians to refer patients to a well-established digital CBTi program. At least 10 family physicians and 375 patients with insomnia will be recruited. Physicians will be provided with an eBook to guide gradual sedative-hypnotic withdrawal. Feasibility and acceptability will be assessed from the perspective of patients and physicians. Effectiveness will be determined by co-primary outcomes: cessation of sedative-hypnotic use, and improvement in self-reported insomnia symptoms from baseline to 12-month follow-up. Analysis of trends in costs, cost-effectiveness and cost-utility analyses will be conducted from a societal perspective. Results and discussion This implementation trial will pave the way for future scaling-up of this insomnia management pathway to improve access to CBTi and reduce reliance on sedative-hypnotic medicines in family practice. Trial Registration: This trial was prospectively registered on the Australian and New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001539123).
Does adjunctive digital CBT for insomnia improve clinical outcomes in an improving access to psychological therapies service?
BACKGROUND: Insomnia has a bidirectional relationship with broader mental health functioning, including anxiety and depression. Yet, poor sleep has historically been neglected as a specific treatment target in mental health programmes (Freeman, Sheaves, Waite, Harvey, & Harrison, 2020). METHOD: All patients over a 12-month period entering the Improving Access to Psychological Therapies (IAPT) service endorsing a 'poor sleep' questionnaire item at assessment, were offered a self-guided digital sleep intervention, Sleepio, in addition to routine care. Sleepio is based on the principles of Cognitive Behavioural Therapy for Insomnia (CBT-I). Propensity score matching established a non-Sleepio control group matched on demographic and baseline clinical measures. RESULTS: Patients who signed up to Sleepio (n = 510) achieved significantly better outcomes on core clinical metrics (PHQ-9, GAD-7, WSAS) than controls. IAPT recovery rates1 (on PHQ-9 and GAD-7) were 64.7%, versus 58% in the control group. Duration of clinical contact time was marginally elevated overall in the Sleepio group but by less than 1 h CONCLUSIONS: Significant clinical benefit was associated with the introduction of an evidence-based digital sleep intervention alongside other mental health interventions for depression and anxiety. Widespread deployment was achieved with immediate availability, minimal additional clinical time or staff training. This approach provides a feasible and highly scalable model for improving mental health outcomes in clinical services.
“SAH-RISK”: Risk factors for subarachnoid haemorrhage (SAH) - a descriptive and comparative study using electronic health records.
The incidence of SAH is 7.9/100 000 person-years, with average age of onset of 62 (1). Non-traumatic subarachnoid haemorrhage (SAH) is most commonly caused by rupture of a weakness of an intra-cranial blood vessel (aneurysm). Although it represents only 5% of all strokes, SAH accounts for a similar number of years of life lost as the more common types of stroke (2-4). Despite improvements in clinical management of patients, outcomes after SAH remain poor, with an estimated 26% mortality rate and only 55% of patients regaining independent function (4). Knowledge of modifiable risk factors for SAH is important in terms of prevention. Prospective population-based studies suggest that women have a 1.24 times greater risk of SAH than men. This becomes apparent after 50 years of age, and increases with each decade (5). An explanation for this observation is lacking, however. Loss of the protective effects of oestrogen in the post-menopausal state has been proposed, but studies comparing hormone replacement therapy (HRT) exposure vs. no HRT exposure on SAH incidence draw conflicting conclusions (6, 7). Hypertension is an established modifiable risk factor for SAH, approximately doubling the risk of SAH (8, 9). A rise of 10mmHg in systolic blood pressure increases risk of SAH by 21% (10). A recent meta-analysis demonstrates a global decline in blood pressure which parallels a decrease in the global incidence of SAH (1) - highlighting the importance of primary prevention. Whilst calcium channel blockers are routinely used to prevent secondary ischaemia following SAH, there is no evidence to support the preferential use of specific anti-hypertensives in patients at risk. There is some evidence that certain classes of antihypertensive may offer greater protection against stroke compared to other antihypertensives. One meta-analysis found that calcium channel blockers (CCBs) were associated with a reduced risk ratio (RR) of stroke incidence, compared to other antihypertensive classes (RR 0.83, 95% confidence interval 0.79-0.89)(11). In addition, angiotensin 2 inhibitors (ARBs) may reduce stroke risk compared to angiotensin-converting enzyme inhibitors (ACEis)(12), but the literature is inconsistent (11, 13). These findings are often based on meta-analyses of randomised controlled trials that recorded stroke as a secondary outcome – often not specifying if the stroke was haemorrhagic or ischaemic. This protocol describes: 1) a descriptive study of the antecedent demographics and characteristics of SAH patients; 2) a comparative study investigating sex-differences and antihypertensive use on the risk of SAH.
Differential psychological response to the COVID-19 pandemic in psychiatric inpatients compared to a non-clinical population from Germany.
The COVID-19 pandemic is an inherently stressful situation, which may lead to adverse psychosocial outcomes in various populations. Yet, individuals may not be affected equally by stressors posed by the pandemic and those with pre-existing mental disorders could be particularly vulnerable. To test this hypothesis, we assessed the psychological response to the pandemic in a case-control design. We used an age-, sex- and employment status-matched case-control sample (n = 216) of psychiatric inpatients, recruited from the LMU Psychiatry Biobank Munich study and non-clinical individuals from the general population. Participants completed validated self-report measures on stress, anxiety, depression, paranoia, rumination, loneliness, well-being, resilience, and a newly developed index of stressors associated with the COVID-19 pandemic. Multiple linear regression analyses were conducted to assess the effects of group, COVID-19-specific stressors, and their interaction on the different psychosocial outcomes. While psychiatric inpatients reported larger mental health difficulties overall, the impact of COVID-19-specific stressors was lower in patients and not associated with worse psychological functioning compared to non-clinical individuals. In contrast, depressive symptoms, rumination, loneliness, and well-being were more strongly associated with COVID-19-specific stressors in non-clinical individuals and similar to the severity of inpatients for those who experienced the greatest COVID-19-specific stressor impact Contrary to expectations, the psychological response to the pandemic may not be worse in psychiatric inpatients compared to non-clinical individuals. Yet, individuals from the general population, who were hit hardest by the pandemic, should be monitored and may be in need of mental health prevention and treatment efforts.
RNA Binding Proteins As Regulators of Oxidative Stress Identified by a Targeted CRISPR-Cas9 Single Guide RNA Library.
The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome editing system has been broadly adopted for high-throughput genetic screens. However, the application of genome-wide single guide RNA (sgRNA) libraries can be challenging. We generated a custom sgRNA library, an order of magnitude smaller than genome-wide alternatives, to facilitate the genetic screening of RNA binding proteins (RBPs). We demonstrated the utility of our reagent in a genetic screen for RBPs that conveyed cellular resistance or sensitivity to oxidative stress induced by paraquat. This identified that CSDE1 and STRAP, proteins that interact with each other, convey sensitivity to oxidative stress and that Pumilio homologues (PUM1 and PUM2) convey resistance. Targeting eIF4-E1 and -A1 protected cells from high-dose paraquat, whereas eIF4E2 targeted cells did less well. We also found that G3BP1 promoted sensitivity to a low dose of paraquat but protected cells at a higher dose. Our study highlights the use of genetic screens to identify roles of RBPs and identifies novel genes regulating sensitivity to oxidative stress.
Interactions between Apolipoprotein E Metabolism and Retinal Inflammation in Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a multifactorial retinal disorder that is a major global cause of severe visual impairment. The development of an effective therapy to treat geographic atrophy, the predominant form of AMD, remains elusive due to the incomplete understanding of its pathogenesis. Central to AMD diagnosis and pathology are the hallmark lipid and proteinaceous deposits, drusen and reticular pseudodrusen, that accumulate in the subretinal pigment epithelium and subretinal spaces, respectively. Age-related changes and environmental stressors, such as smoking and a high-fat diet, are believed to interact with the many genetic risk variants that have been identified in several major biochemical pathways, including lipoprotein metabolism and the complement system. The APOE gene, encoding apolipoprotein E (APOE), is a major genetic risk factor for AMD, with the APOE2 allele conferring increased risk and APOE4 conferring reduced risk, in comparison to the wildtype APOE3. Paradoxically, APOE4 is the main genetic risk factor in Alzheimer’s disease, a disease with features of neuroinflammation and amyloid-beta deposition in common with AMD. The potential interactions of APOE with the complement system and amyloid-beta are discussed here to shed light on their roles in AMD pathogenesis, including in drusen biogenesis, immune cell activation and recruitment, and retinal inflammation.
Does raising heart rate prior to a behavioural test enhance learning in cognitive therapy for anxiety? An experimental test for the treatment of fear of heights using virtual reality.
BACKGROUND: A key clinical issue is how to maximise the belief change central to cognitive therapy. Physiological arousal is a key internal cue confirming threat beliefs in anxiety disorders. Deeper extinction of anxiety may occur if catastrophizing responses to physiological arousal are inhibited prior to joint exposure with external phobic stimuli. The aim of the study was to test whether increasing physiological arousal using exercise increases the benefits of behavioural tests. METHODS: Sixty individuals with a fear of heights had one session of VR cognitive treatment. They were randomised to have the treatment either with periods of intense physical exercise (cycling at 80% of maximum heart rate) prior to exposures or without. Linear mixed effects models were used to check the manipulation and test the primary hypothesis of a group difference in degree of conviction in the phobic threat belief. RESULTS: Heart rate was significantly higher in the exercise group throughout compared with the control group. Both groups showed significant reductions in threat beliefs after the VR treatment (d = 1.0, p