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Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.
Background
Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke.
Methods
We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602.
Findings
Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19–2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20–1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82–3·29) for intracranial haemorrhage and 1·23 (1·08–1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08–6·72] for intracranial haemorrhage vs 1·47 [1·19–1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36–9·05] vs 1·43 [1·07–1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69–15·81] vs 1·86 [1·23–2·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48–84] per 1000 patient-years vs 27 intracranial haemorrhages [17–41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46–108] per 1000 patient-years vs 39 intracranial haemorrhages [21–67] per 1000 patient-years).
Interpretation
In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden.
(1) Background: To assess orthodontic forced eruption (OFE) as a pre-restorative procedure for non-restorable permanent teeth with subgingival dental hard tissue defects after dental trauma. (2) Methods: A systematic electronic search of three databases, namely, MEDLINE, Cochrane Library, and EMBASE, revealed a total of 2757 eligible publications. Randomized controlled clinical trials (RCT), retro- and prospective clinical studies, or case series (with a minimum of three patients) were reviewed. (3) Results: Thirteen full-text papers were included: one RCT, one prospective clinical trial, two retrospective cohort studies, and nine case series. Within case series, statistical significance between age and cause of fracture (p < 0.03) was determined. The mean extrusion rate of OFE was 1.5 mm a week within a four to six weeks treatment period followed by retention. Three OFE protocols for maxillary single teeth are available: 1. OFE without migration of gingiva and alveolar bone, 2. OFE with gingival migration and slight alveolar bone migration, and 3. OFE with migration of both gingiva and alveolar bone. (4) Conclusions: The current state of the evidence suggests that OFE is a feasible pre-treatment option for non-restorable permanent teeth. OFE can promote the migration of tooth surrounding hard and soft tissues in the esthetic zone. Root resorption does not seem to be a relevant side effect of OFE.