Does genetic anticipation occur in familial Alexander disease?

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent–offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon

Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition that primarily affects the motor system and shares many features with frontotemporal dementia (FTD). Evidence suggests that ALS is a ‘dying-back’ disease, with peripheral denervation and axonal degeneration occurring before loss of motor neuron cell bodies. Distal to a nerve injury, a similar pattern of axonal degeneration can be seen, which is mediated by an active axon destruction mechanism called Wallerian degeneration. Sterile alpha and TIR motif-containing 1 (Sarm1) is a key gene in the Wallerian pathway and its deletion provides long-term protection against both Wallerian degeneration and Wallerian-like, non-injury induced axonopathy, a retrograde degenerative process that occurs in many neurodegenerative diseases where axonal transport is impaired. Here, we explored whether Sarm1 signalling could be a therapeutic target for ALS by deleting Sarm1 from a mouse model of ALS-FTD, a TDP-43Q331K, YFP-H double transgenic mouse. Sarm1 deletion attenuated motor axon degeneration and neuromuscular junction denervation. Motor neuron cell bodies were also significantly protected. Deletion of Sarm1 also attenuated loss of layer V pyramidal neuronal dendritic spines in the primary motor cortex. Structural MRI identified the entorhinal cortex as the most significantly atrophic region, and histological studies confirmed a greater loss of neurons in the entorhinal cortex than in the motor cortex, suggesting a prominent FTD-like pattern of neurodegeneration in this transgenic mouse model. Despite the reduction in neuronal degeneration, Sarm1 deletion did not attenuate age-related behavioural deficits caused by TDP-43Q331K. However, Sarm1 deletion was associated with a significant increase in the viability of male TDP-43Q331K mice, suggesting a detrimental role of Wallerian-like pathways in the earliest stages of TDP-43Q331K-mediated neurodegeneration. Collectively, these results indicate that anti-SARM1 strategies have therapeutic potential in ALS-FTD

Persistent neuropsychiatric symptoms after COVID-19: a systematic review and meta-analysis.

The nature and extent of persistent neuropsychiatric symptoms after COVID-19 are not established. To help inform mental health service planning in the pandemic recovery phase, we systematically determined the prevalence of neuropsychiatric symptoms in survivors of COVID-19. For this pre-registered systematic review and meta-analysis (PROSPERO ID CRD42021239750), we searched MEDLINE, EMBASE, CINAHL and PsycINFO to 20 February 2021, plus our own curated database. We included peer-reviewed studies reporting neuropsychiatric symptoms at post-acute or later time-points after COVID-19 infection and in control groups where available. For each study, a minimum of two authors extracted summary data. For each symptom, we calculated a pooled prevalence using generalized linear mixed models. Heterogeneity was measured with I 2. Subgroup analyses were conducted for COVID-19 hospitalization, severity and duration of follow-up. From 2844 unique titles, we included 51 studies (n = 18 917 patients). The mean duration of follow-up after COVID-19 was 77 days (range 14-182 days). Study quality was most commonly moderate. The most prevalent neuropsychiatric symptom was sleep disturbance [pooled prevalence = 27.4% (95% confidence interval 21.4-34.4%)], followed by fatigue [24.4% (17.5-32.9%)], objective cognitive impairment [20.2% (10.3-35.7%)], anxiety [19.1% (13.3-26.8%)] and post-traumatic stress [15.7% (9.9-24.1%)]. Only two studies reported symptoms in control groups, both reporting higher frequencies in COVID-19 survivors versus controls. Between-study heterogeneity was high (I 2 = 79.6-98.6%). There was little or no evidence of differential symptom prevalence based on hospitalization status, severity or follow-up duration. Neuropsychiatric symptoms are common and persistent after recovery from COVID-19. The literature on longer-term consequences is still maturing but indicates a particularly high prevalence of insomnia, fatigue, cognitive impairment and anxiety disorders in the first 6 months after infection

Young hands, old books: : Drawings by children in a fourteenth-century manuscript, LJS MS. 361

This article scrutinises three marginal drawings in LJS 361, Kislak Center for Special Collections, Rare Books and Manuscripts, University of Pennsylvania Libraries. It first considers the provenance of the manuscript, questioning how it got into the hands of children. Then, it combines developmental psychology with close examination of the material evidence to develop a list of criteria to attribute the drawings to children. There is consideration of the features that help us estimate the age of the artists, and which indicate that one drawing was a collaborative effort between two children. A potential relationship is identified between the doodles and the subject matter of the text, prompting questions about pre-modern child education and literacy. Finally, the article considers the implications of this finding in both codicology and social history since these marginal illustrations demonstrate that children were active in the material life of medieval books

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Navigation of vertebro-pelvic fixations based on CT-fluoro matching

Different navigation procedures (based on 2D-, 3D-fluoroscopy or CT modalities) with their respective limitations are established in orthopedic surgery. The hypothesis is that intraoperative matching of different modalities (fluoro and CT) increases the precision of navigated screw placement and reduces the fluoroscopy time. Vertical unstable pelvic ring fractures of 12 patients were treated with vertebro-pelvic fixations (6 in the standard technique and 6 using the fluoro-CT navigation). An optimal osseous corridor could be determined by the navigation procedure increasing the overall precision of screw placement (no misplacement in the second group as compared to one malplaced pedicle screw in the standard group). The achieved screw lengths were [(mean ± SE) 78 ± 5 vs. 53 ± 4 mm, p < 0.001). Less invasive open approaches and a reduction of fluoroscopy time (time per screw in seconds: 121 vs. 62 s) were observed. CT-fluoro-matched navigation improves the intraoperative visualization of osseous structures and increases the precision of screw placement with less radiation exposure