Citations

Abstract Immune reactions to medical implants often lead to encapsulation by fibrotic tissue and impaired device function. This process is thought to initiate by protein adsorption, which enables immune cells to attach and mount an inflammatory response. Previously, several antifibrotic materials have been either designed to reduce protein adsorption or discovered via high‐throughput screens (HTS) to favorably regulate inflammation. The present work introduces antifouling immunomodulatory (AIM) copolymer coatings, which combine both strategies to effectively enhance implant protection. AIM copolymers synergistically integrate zwitterionic moieties to resist protein fouling, HTS‐derived antifibrotics for immunomodulation, and silane monomers for grafting to diverse substrates including elastomers, ceramics, and metals. Interestingly, simply combining these monomers into conventional random or block copolymer architectures yielded no significant advantage over homopolymers. By contrast, an unusual polymer chain architecture — a zwitterionic block flanked by a mixed zwitterionic immunomodulatory segment — showed superior fibrosis resistance in both peritoneal and subcutaneous sites over one month in immunocompetent mice. This architecture also improved the performance of two different HTS‐derived antifibrotic monomers, suggesting that tailoring AIM architectures may broadly complement immunomodulatory chemistries and provide a versatile approach to improving implant longevity.

Abstract Background The objective was to systematically evaluate the sensitivity of diffusion‐weighted magnetic resonance imaging (DW‐MRI) for transient global amnesia (TGA) across various time frames compared to the reference‐standard clinical criteria. Methods All indexed publications related to TGA and MRI through June 2020 were retrieved by a medical librarian. Two independent reviewers identified original research studies of adults with a clinical diagnosis of TGA using Caplan and Hodges and Warlow criteria (reference standard) who were evaluated with DW‐MRI. Pooled estimates and its 95% confidence intervals (CI) for the proportion of acute TGA patients with positive DW‐MRI (i.e., sensitivity) were obtained using random‐effects meta‐analysis for various time frames. Quality assessment was performed using the revised Quality of Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. Results After screening 665 reports, we identified 81 potentially relevant studies. Twenty‐three studies representing 1688 patients met eligibility criteria, but not all studies had data available for meta‐analysis. The pooled sensitivity (also described as positivity rate) of DW‐MRI was 15.6% (95% CI = 2.6%–35.0%) between 0 and 12 h from symptom onset, 23.1% (95% CI = 6.1%–45.7%) at 0–24 h, 72.8% (95% CI = 40.8%–96.3) at 12–24 h, 68.8% (95% CI = 44.8%–88.8%) at 24–36 h, 72.4% (95% CI = 59.8%–83.5%) at 36–48 h, 82.8% (95% CI = 54.7%–99.6%) at 48–60 h, 66.9% (95% CI = 47.5%–83.9%) at 60–72 h, and 72.0% (95% CI = 30.1%–100.0%) at 72–96 h. There was significant concern for risk of bias in the QUADAS‐2 domains of patient selection and index test, yielding a low level of certainty in the pooled estimates. Conclusion DW‐MRI lesions are uncommon in patients with TGA early after symptom onset, but the sensitivity (i.e., positivity rate) of DW‐MRI increases with time. Despite the limited quality of existing evidence, obtaining an early DW‐MRI in patients with clinical diagnosis of TGA in the acute setting is likely a low‐yield test.

AbstractObjectiveTo estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo‐controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox–Gastaut syndrome.MethodsPatients received plant‐derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated.ResultsOverall, 235 patients received CBD (CBD10 [GWPCARE3 only],n = 67; CBD20 [pooled GWPCARE3&4],n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6–48.0). Patients had previously discontinued a median (range) of six (0–28) antiepileptic drugs (AEDs) and were currently taking a median of three (0–5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients.SignificanceTreatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14‐week period.

AbstractNeurogenesis in the subependymal zone (SEZ) declines across the human lifespan, and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full‐length (TrkB‐TK+) and truncated TrkB receptors (TrkB‐TK‐) in the human SEZ from infancy to middle age (n = 26–35, 41 days to 43 years). We further measured TrkB‐TK+ and TrkB‐TK‐ mRNAs in the SEZ from young adulthood into ageing (n = 50, 21–103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB‐TK‐ mRNA increased in the SEZ from young adulthood into ageing, whereas TrkB‐TK+ mRNA remained stable. TrkB‐TK‐ mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete‐scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB‐TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ.