Abstract only Introduction: Diffusion-weighted imaging (DWI) lesions in intracerebral hemorrhage (ICH) have been associated with vasculopathy, blood pressure (BP) lowering, and poor functional ...outcomes. We sought to identify predictors of DWI lesion formation and one-year case-fatality in ICH. Methods: In this retrospective study of primary ICH at our institution from 2009-2011, cases were identified by ICD-9 code and verified by physician review. Only subjects undergoing brain MRI within 72 hours of presentation were included. In addition to standard chart review, we abstracted all BPs available prior to MRI. Vasculopathy severity was assessed by white matter disease score and microbleed burden. Univariate analysis was stratified by DWI lesion presence; logistic regression analyses assessed predictors of DWI lesions and all-cause one-year case-fatality. Results: Of 500 subjects in the overall ICH cohort 98 met inclusion criteria for this analysis, of which 20 (20.4%) had DWI lesions. Selected univariate analysis is shown in the Table. In the best clinical model fit, intraventricular extension (OR 5.63 (1.60, 19.85), p=0.007), microbleeds (OR 3.43 (0.95, 12.34), p=0.06), and delta systolic BP lowering (((max systolic BP-min systolic BP)/max systolic BP)*100) (OR 0.97 (0.95, 0.99), p=0.0005) were associated with DWI lesion presence. Overall one-year case-fatality was 16.3%; age (OR 1.04 (1.00, 1.07), p=0.05), GCS (OR 1.30 (1.09, 1.56), p=0.004), and DWI lesions (OR 3.80 (1.14, 12.61), p=0.03) were independently associated. Conclusions: Predictors of DWI lesions in ICH include underlying vasculopathy but the impact of BP lowering on DWI lesion formation remains unclear. Further investigation of BP effects on DWI lesion formation is warranted with larger cohorts given the association with DWI lesions and one-year case-fatality. Future trials of BP control in ICH should consider stratifying by imaging biomarkers for underlying vasculopathy.
Abstract only Introduction: Intracerebral hemorrhage (ICH) patients often require percutaneous endoscopic gastrostomy (PEG) placement. Previous studies identifying predictors of PEG placement in ICH ...have been small and have not accounted for specific clinical findings on validated stroke severity scores. We sought to determine early predictors of PEG placement in a large cohort of ICH patients. Methods: We retrospectively identified all primary ICH cases by ICD-9 code at our two academic centers from 2009-2011. All cases were physician-reviewed. Patients who were made comfort care only, transferred to hospice, or died within 72 hours of presentation were excluded. Demographic data, stroke characteristics including clinical severity scores, processes of care, and outcomes were ascertained. We also constructed an abbreviated four-item NIHSS composite score, which included level of consciousness (item 1a), facial palsy (4), best language (9), and dysarthria (10). Variables with p-values <0.25 in the univariate were considered for regression analysis. Linearity of the logit was assessed for continuous variables. Results: Of the 610 subjects with primary ICH, 519 met inclusion criteria and 89 (17.1%) underwent PEG placement. Median time from presentation to PEG placement was 11.8 days. Univariate predictors of PEG placement are shown in the Table. In the best multivariate logistic regression model we found younger age (OR 0.99 (0.97, 1.00), p=0.04), higher four-item NIHSS composite score (OR 1.15 (1.05, 1.26), p=0.003), lower initial GCS (OR 0.91 (0.85, 0.97), p=0.003), and greater ICH volume (OR 2.97 (1.11, 7.97) for highest quintile vs. lowest, p=0.02) were independently associated with PEG placement. This model achieved an area under the curve of 0.78 with a good fit. Conclusions: We identified several independent early predictors of PEG placement in ICH. Early identification of ICH patients who will require PEG placement could result in reduced resource utilization, quicker initiation of rehabilitation, shorter hospital length of stay, and reduction of preventable complications. Prospective studies are required to determine optimal patient selection and timing for PEG placement.
Venous thromboembolism (VTE) causes significant morbidity and mortality in hospitalized medical populations; however, medical patients do not currently receive thromboprophylaxis beyond their ...hospital stay. We reviewed the real-life occurrence of VTE-related care for 100 days post-hospitalization in Calgary, Canada. Using medical visit records with a unique patient identifier number applied throughout the city’s hospitals, 989 high-risk patients were selected for review. Almost three-quarters of the elderly patients received appropriate prophylaxis while in hospital, and only 2% received prophylaxis on discharge. Over the 100-day follow-up, 21% of the patients presented with clinically suspected VTE, of which 3.8% had confirmed VTE. Patients with multiple risk factors (≥3) had the highest frequency of confirmed VTE (≥6.1%). This study suggests that the actual rate of VTE-related follow-up care in patients post-hospitalization is high in the first 100 days, particularly among those who have multiple risk factors, warranting consideration of extended thromboprophylaxis in this population.
A key knowledge gap blocking development of effective therapeutics for Alzheimer’s disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein ...cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD.
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•Aβ and tau work together to cause behavioral and transcriptional deficits in mice•In mice with Aβ and tau, glial gene expression increases and synaptic genes decrease•Tau is present in synaptic terminals in APP/PS1+Tau mice and human Alzheimer brain•In mice, lowering tau levels improves cognition and restores gene expression
One of the mysteries of Alzheimer’s disease is how the two key pathological proteins, amyloid beta and tau, interact. Pickett et al. use a mouse model to show that these proteins cooperate to change behavior and gene expression and that these phenotypes recover when tau levels are lowered.
DNA ligases are widely used in molecular biology to generate recombinant DNA. However, having evolved for nick-sealing, they are inefficient at catalysing the blunt-ended ligations that are critical ...to many biotechnological applications, including next-generation sequencing. To facilitate engineering of superior blunt-ended DNA ligases, we have developed and validated a compartmentalised self-replication protocol that can select for the most effective ligases from a library of variants. Parallel cultures of Escherichia coli cells expressing different plasmid-encoded variants act as both a source of template DNA for discrete whole-plasmid PCR reactions, and a source of expressed ligase to circularise the corresponding PCR amplicons. The most efficient ligases generate the greatest number of self-encoding plasmids, and are thereby selected over successive rounds of transformation, amplification and ligation. By individually optimising critical steps, we arrived at a coherent protocol that, over five rounds of selection, consistently enriched for cells expressing the more efficient of two recombinant DNA ligases.
•Plasmids bearing DNA ligase genes are PCR amplified from cultured cells.•Amplicons are then circularised using ligase in the corresponding culture lysate.•The most effective blunt-end DNA ligases thereby generate more transformed cells.•Successive selection rounds enrich for superior DNA ligases from the starting pool.
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results ...in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts, whereas monounsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated toward monounsaturated VLCFA and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to monounsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
To evaluate Medicare reimbursement and clinical activity between male and female dermatologic surgeons.
A retrospective review of the Medicare Provider Utilization and Payment data from 2018 was ...performed for all dermatologists performing MMS. Provider gender, place of service, number of services, and average payment per service was recorded for all relevant procedure codes.
Women represented 31.5% of the 2,581 surgeons who performed MMS in 2018. Women were paid significantly less than men (mean difference, -$73,033). On average, women performed 123 fewer cases than their male counterparts. When surgeons were stratified by productivity, remuneration was the same.
Remuneration from CMS was disparate between male and female dermatologic surgeons, which may be attributed to submission of fewer charges by women. Further efforts are necessary to better evaluate and address causes for this discrepancy, because greater parity of opportunity and pay would greatly benefit this subspecialty of dermatology.
One of the key knowledge gaps in the field of Alzheimer's disease research is the lack of understanding of how amyloid beta and tau cooperate to cause neurodegeneration. We recently generated a mouse ...model (APP/PS1 + Tau) that develops amyloid plaque pathology and expresses human tau in the absence of endogenous murine tau. These mice exhibit an age‐related behavioural hyperactivity phenotype and transcriptional deficits which are ameliorated by tau transgene suppression. We hypothesized that these mice would also display memory and hippocampal synaptic plasticity deficits as has been reported for many plaque bearing mouse models which express endogenous mouse tau. We observed that our APP/PS1 + Tau model does not exhibit novel object memory or robust long‐term potentiation deficits with age, whereas the parent APP/PS1 line with mouse tau did develop the expected deficits. These data are important as they highlight potential functional differences between mouse and human tau and the need to use multiple models to fully understand Alzheimer's disease pathogenesis and develop effective therapeutic strategies.
Tulloch et al. observe memory and long‐term potentiation deficits in the APP/PS1 mouse model of familial Alzheimer's disease, which are prevented by genetic removal of endogenous mouse tau. Expression of human tau in APP/PS1 mice with endogenous tau knockout does not reinstate the memory and plasticity deficits. These results highlight the importance of understanding differences between mouse and human tau in modelling Alzheimer's disease.
A scalable approach for synthesis of ultra-thin (<10 nm) transition metal dichalcogenides (TMD) films on stretchable polymeric materials is presented. Specifically, magnetron sputtering from pure TMD ...targets, such as MoS2 and WS2, was used for growth of amorphous precursor films at room temperature on polydimethylsiloxane substrates. Stacks of different TMD films were grown upon each other and integrated with optically transparent insulating layers such as boron nitride. These precursor films were subsequently laser annealed to form high quality, few-layer crystalline TMDs. This combination of sputtering and laser annealing is commercially scalable and lends itself well to patterning. Analysis by Raman spectroscopy, scanning probe, optical, and transmission electron microscopy, and x-ray photoelectron spectroscopy confirm our assertions and illustrate annealing mechanisms. Electrical properties of simple devices built on flexible substrates are correlated to annealing processes. This new approach is a significant step toward commercial-scale stretchable 2D heterostructured nanoelectronic devices.
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