Futureproofing Medical Education Through Scenario Analysis: Instrumental Case Study

Abstract Developments in technology and climate change, as well as other "megatrends" are having lasting impacts in society and healthcare. A scenario analysis was conducted to explore the impact of megatrends on medical education. Three scenarios were developed for the year 2035, showing varying levels of technological integration and environmental focus. Implications for an updated curricula focus on health inequalities, digital health, and globalization effects.Abstract Developments in technology and climate change, as well as other "megatrends" are having lasting impacts in society and healthcare. A scenario analysis was conducted to explore the impact of megatrends on medical education. Three scenarios were developed for the year 2035, showing varying levels of technological integration and environmental focus. Implications for an updated curricula focus on health inequalities, digital health, and globalization effects

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effectiveness and tolerability of adjunctive brivaracetam in patients with focal seizures: second interim analysis of 6-month data from a prospective observational study in Europe

Brivaracetam (BRV) is indicated for adjunctive treatment of focal (partial-onset) seizures with or without secondary generalisation in patients 4 years of age and older in the European Union (EU). An ongoing 12-month, prospective, non-interventional post-marketing study (EP0077; NCT02687711) is collecting real-world information on patients receiving treatment with adjunctive BRV in Europe. In this study, BRV is prescribed according to routine clinical practice and the EU Summary of Product Characteristics. This second interim analysis assessed effectiveness, tolerability and health-related quality of life outcomes for up to 6 months of treatment. At the cut-off date (13 April 2018), 266 patients from five countries had attended Visit 1, 24.1% (64/266) had completed the study, 37.6% (100/266) were ongoing, and 38.3% (102/266) had discontinued. In total, 261 patients had at least one dose of BRV and were included in the analyses. Patients had a mean time since epilepsy diagnosis of 23.2 years, a mean of eight lifetime AEDs (sum of AEDs discontinued prior to study entry and concomitant at study entry), and a median of five focal seizures per 28 days during the 3-month retrospective Baseline. 66.3% of patients initiated BRV at a dose within the recommended starting range (50–100 mg/day) and 87.1% of patients received BRV modal doses within the recommended dose range (50–200 mg/day) during the study. Retention rates were 79.1% (N = 239) at 3 months and 62.1% (N = 211) at 6 months. The 50% responder rates for focal seizures were 46.8% (N = 139) at 3 months and 53.6% (N = 97) at 6 months. The proportions of patients who were seizure-free were 10.7% (21/196) and 7.5% (15/199) at 3 and 6 months of treatment, respectively. Median percent reductions in focal seizure frequency per 28 days from Baseline to 3 and 6 months were 34.6% (N = 139) and 53.3% (N = 97), respectively. Overall, 44.2% of patients had an improvement and 15.4% had a worsening in Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 total score from Baseline to 6 months (N = 52). At least one treatment-emergent adverse event (TEAE) was reported in 51.0% (133/261) of patients, and 34.5% (90/261) of patients had drug-related TEAEs. The most common drug-related TEAEs (≥5% of patients) were drug ineffective (7.7%), seizure (6.5%), and fatigue (6.1%). In this 6-month interim analysis, BRV showed effectiveness when used in clinical practice in five European countries. BRV was well tolerated, and no new safety signals were observed

Acute symptomatic hypoglycaemia mimicking ischaemic stroke on imaging:a systemic review

<p>Abstract</p> <p>Background</p> <p>Acute symptomatic hypoglycaemia is a differential diagnosis in patients presenting with stroke-like neurological impairment, but few textbooks describe the full brain imaging appearances. We systematically reviewed the literature to identify how often hypoglycaemia may mimic ischaemic stroke on imaging, common patterns and relationships with hypoglycaemia severity, duration, clinical outcome and add two new cases.</p> <p>Methods</p> <p>We searched EMBASE and Medline databases for papers reporting imaging in adults with symptomatic hypoglycaemia. We analysed the clinical presentation, outcome, brain imaging findings, duration and severity of hypoglycaemia, time course of lesion appearance, including two new cases.</p> <p>Results</p> <p>We found 42 papers describing computed tomography or magnetic resonance imaging in 65 patients, plus our two cases with symptomatic hypoglycaemia. Imaging abnormalities on computed tomography and magnetic resonance were uni or bilateral, cortical or sub-cortical. Thirteen (20%) mimicked cortical or lacunar stroke. Acute lesions had restricted diffusion on magnetic resonance or low attenuation on computed tomography, plus swelling; older lesions showed focal atrophy or disappeared, as with ischaemic stroke. The association between the depth or duration of hypoglycaemia, the severity or extent of neurological deficit, and the imaging abnormalities, was weak.</p> <p>Conclusion</p> <p>Imaging abnormalities in patients with hypoglycaemia are uncommon but very variable, weakly associated with neurological deficit, and about a fifth mimic acute ischaemic stroke. Blood glucose testing should be routine in all patients with acute neurological impairment and hypoglycaemia should be included in the differential diagnosis of imaging appearances in patients presenting with acute stroke.</p

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studie

Intra-articular Injection Administration in UK Ex-professional Footballers During Their Playing Careers and the Association with Post-career Knee Osteoarthritis

© 2020, The Author(s). Background: The long-term risk from knee intra-articular (KIA) injections in professional athletes such as ex-footballers remains unknown. The use of KIA injections is controversial and remains anecdotally prolific as it is perceived as being safe/beneficial. The aim of this study was to determine the number, type and frequency KIA injections administered to retired professional footballers during their playing careers and the associations with post-career knee osteoarthritis (KOA). Methods: This is a cross-sectional study involving a postal questionnaire (n = 1207) and subsequent knee radiographs in a random sample of questionnaire responders (n = 470). Footballers self-reported in the questionnaire whether they had received KIA injections and the estimated total number over the course of their playing career. Participant characteristics and football career-related details were also recorded. KOA was measured as self-reported knee pain (KP), total knee replacement (TKR) and radiographic KOA (RKOA). Results: 44.5% of footballers had received at least one KIA injection (mean: 7.5; SD ± 11.2) during their professional career. 71% of knee injections were cortisone/corticosteroid based. Multivariate logistic regression, adjusting for age, body mass index (BMI) and significant knee injury identified that footballers with injections weretwo times more likely to have KP (OR 1.81, 95% CI 1.40–2.34) and TKR (OR 2.21, 95% CI 1.43–3.42) than those without injections. However, there was no association with RKOA (OR 1.30, 95% CI 0.85–2.01). Given, the association with KP and TKR, we found a significant dose–response relationship as the more injections a player received (by dose–response groups), the greater the risk of KP and TKR outcomes after adjustment for knee injury and other confounders (p for trend < 0.01). Conclusion: On average, 8 KIA injections were given to the ex-footballers during their professional career. The most commonly administered injections were cortisone based. These injections associated with KP and TKR after they retired. The associations are independent of knee injuries and are dose dependent. The study suggests that there may have been excessive use of KIA injections to expedite return to play and this contributed to detrimental long-term outcomes such as KP and TKR post-retirement from professional football

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizure

Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing

Persistent latent reservoir of replication-competent proviruses in memory CD4 T cells is a major obstacle to curing HIV infection. Pharmacological activation of HIV expression in latently infected cells is being explored as one of the strategies to deplete the latent HIV reservoir. In this study, we characterized the ability of romidepsin (RMD), a histone deacetylase inhibitor approved for the treatment of T-cell lymphomas, to activate the expression of latent HIV. In an in vitro T-cell model of HIV latency, RMD was the most potent inducer of HIV (EC50 = 4.5 nM) compared with vorinostat (VOR; EC50 = 3,950 nM) and other histone deacetylase (HDAC) inhibitors in clinical development including panobinostat (PNB; EC50 = 10 nM). The HIV induction potencies of RMD, VOR, and PNB paralleled their inhibitory activities against multiple human HDAC isoenzymes. In both resting and memory CD4 T cells isolated from HIV-infected patients on suppressive combination antiretroviral therapy (cART), a 4-hour exposure to 40 nM RMD induced a mean 6-fold increase in intracellular HIV RNA levels, whereas a 24-hour treatment with 1 μM VOR resulted in 2- to 3-fold increases. RMD-induced intracellular HIV RNA expression persisted for 48 hours and correlated with sustained inhibition of cell-associated HDAC activity. By comparison, the induction of HIV RNA by VOR and PNB was transient and diminished after 24 hours. RMD also increased levels of extracellular HIV RNA and virions from both memory and resting CD4 T-cell cultures. The activation of HIV expression was observed at RMD concentrations below the drug plasma levels achieved by doses used in patients treated for T-cell lymphomas. In conclusion, RMD induces HIV expression ex vivo at concentrations that can be achieved clinically, indicating that the drug may reactivate latent HIV in patients on suppressive cART

Attenuated CSF-1R signalling drives cerebrovascular pathology

Cerebrovascular pathologies occur in up to 80% of cases of Alzheimer's disease; however, the underlying mechanisms that lead to perivascular pathology and accompanying blood-brain barrier (BBB) disruption are still not fully understood. We have identified previously unreported mutations in colony stimulating factor-1 receptor (CSF-1R) in an ultra-rare autosomal dominant condition termed adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP). Cerebrovascular pathologies such as cerebral amyloid angiopathy (CAA) and perivascular p-Tau were some of the primary neuropathological features of this condition. We have identified two families with different dominant acting alleles with variants located in the kinase region of the CSF-1R gene, which confer a lack of kinase activity and signalling. The protein product of this gene acts as the receptor for 2 cognate ligands, namely colony stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). Here, we show that depletion in CSF-1R signalling induces BBB disruption and decreases the phagocytic capacity of peripheral macrophages but not microglia. CSF-1R signalling appears to be critical for macrophage and microglial activation, and macrophage localisation to amyloid appears reduced following the induction of Csf-1r heterozygosity in macrophages. Finally, we show that endothelial/microglial crosstalk and concomitant attenuation of CSF-1R signalling causes re-modelling of BBB-associated tight junctions and suggest that regulating BBB integrity and systemic macrophage recruitment to the brain may be therapeutically relevant in ALSP and other Alzheimer's-like dementias