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Background Emerging reports are describing stroke in young, otherwise healthy patients with coronavirus disease 2019, consistent with the theory that some of the most serious complications of coronavirus disease 2019 are due to a systemic coagulopathy. However, the relevance of both the severity of coronavirus disease 2019 illness and established vascular risk factors in these younger patients is unknown, as reports are inconsistent. Case presentation Here we describe a 39-year-old white male, who died after presenting simultaneously with a malignant large-vessel cerebrovascular infarct and a critical coronavirus disease 2019 respiratory illness. Doppler ultrasound revealed evidence of carotid plaque thrombosis. Blood tests revealed evidence of undiagnosed diabetes mellitus; however, the patient was otherwise healthy, fit, and active. Conclusions This unique case highlights a possible interaction between established risk factors and large-vessel thrombosis in young patients with coronavirus disease 2019, and informs future research into the benefits of anticoagulation in these patients.

ObjectivePersonalised medicine (PM) allows treating patients based on their individual demographic, genomic or biological characteristics for tailoring the ‘right treatment for the right person at the right time’. Robust methodology is required for PM clinical trials, to correctly identify groups of participants and treatments. As an initial step for the development of new recommendations on trial designs for PM, we aimed to present an overview of the study designs that have been used in this field.DesignScoping review.MethodsWe searched (April 2020) PubMed, Embase and the Cochrane Library for all reports in English, French, German, Italian and Spanish, describing study designs for clinical trials applied to PM. Study selection and data extraction were performed in duplicate resolving disagreements by consensus or by involving a third expert reviewer. We extracted information on the characteristics of trial designs and examples of current applications of these approaches. The extracted information was used to generate a new classification of trial designs for PM.ResultsWe identified 21 trial designs, 10 subtypes and 30 variations of trial designs applied to PM, which we classified into four core categories (namely, Master protocol, Randomise-all, Biomarker strategy and Enrichment). We found 131 clinical trials using these designs, of which the great majority were master protocols (86/131, 65.6%). Most of the trials were phase II studies (75/131, 57.2%) in the field of oncology (113/131, 86.3%). We identified 34 main features of trial designs regarding different aspects (eg, framework, control group, randomisation). The four core categories and 34 features were merged into a double-entry table to create a new classification of trial designs for PM.ConclusionsA variety of trial designs exists and is applied to PM. A new classification of trial designs is proposed to help readers to navigate the complex field of PM clinical trials.

Geranylgeranyl diphosphate (GGPP), a prenyl diphosphate synthesized by GGPP synthase (GGPS), represents a metabolic hub for the synthesis of key isoprenoids, such as chlorophylls, tocopherols, phylloquinone, gibberellins, and carotenoids. Proteinprotein interactions and the amphipathic nature of GGPP suggest metabolite channeling and/or competition for GGPP among enzymes that function in independent branches of the isoprenoid pathway. To investigate substrate conversion efficiency between the plastid-localized GGPS isoform GGPS11 and phytoene synthase (PSY), the first enzyme of the carotenoid pathway, we used recombinant enzymes and determined their in vitro properties. Efficient phytoene biosynthesis via PSY strictly depended on simultaneous GGPP supply via GGPS11. In contrast, PSY could not access freely diffusible GGPP or time-displaced GGPP supply via GGPS11, presumably due to liposomal sequestration. To optimize phytoene biosynthesis, we applied a synthetic biology approach and constructed a chimeric GGPS11-PSY metabolon (PYGG). PYGG converted GGPP to phytoene almost quantitatively in vitro and did not show the GGPP leakage typical of the individual enzymes. PYGG expression in Arabidopsis resulted in orange-colored cotyledons, which are not observed if PSY or GGPS11 are overexpressed individually. This suggests insufficient GGPP substrate availability for chlorophyll biosynthesis achieved through GGPP flux redirection to carotenogenesis. Similarly, carotenoid levels in PYGG-expressing callus exceeded that in PSY- or GGPS11-overexpression lines. The PYGG chimeric protein may assist in provitamin A biofortification of edible plant parts. Moreover, other GGPS fusions may be used to redirect metabolic flux into the synthesis of other isoprenoids of nutritional and industrial interest.

BackgroundNeurological disorders account for 20% of acute medical admissions and 7% of GP consulta- tions. We evaluated our acute neurology service with the catchment area of 3 million people. Moreover, we investigated the impact on the service during the COVID19 pandemic.MethodsWe identified 6618 urgent phone calls logged between March 2017 and June 2020. We performed a detailed analysis of 800 referrals: 400 in 10 weeks before and 400 in 11 weeks during the first national lockdown.ResultsReferrals were made by teaching hospitals (43%), district general hospitals (35%) and GPs (22%). The reasons for referrals were similar between hospitals and GPs: epilepsy (33% vs 30%), headache (15% vs 20%), sensory symptoms (10% vs 7%) and weakness (10% vs 8%). The outcomes of these referrals were telephone advice only (64%), neurology ward admission (9%), rapid assessment and other outpatient clinics (8% and 25% respectively). There was a threefold decrease in the number of phone calls during the initial four weeks of national lockdown. However, the patient demographics and the range of diagnoses remained overall unchanged.ConclusionsThis provides important descriptive data on demographics and outcomes for acute neurology referrals, which can be used to guide service provision and training.alexandergrundmann@nhs.net45

Table 1 provides the background history.Table 1 Patient’s clinical and social background Medical history Steroid responsive pulmonary fibrosis (usual interstitial pneumonia pattern)—June 2019 left cerebellar infarct 4 months before, confirmed on MRI: presented with dysarthria and vertigo from which he fully recovered. The presence of complex ophthalmoplegia and other cranial nerve involvement further narrows the differential diagnosis.Table 2 Differential diagnosis Pathophysiology Differential diagnosis Inflammatory Miller Fisher syndrome pharyngo-cervical-brachial variant of Guillain-Barré syndrome Sjögren’s syndrome systemic lupus erythematosus sarcoidosis inflammatory neuropathy associated with antidisialosyl antibodies: CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, monoclonal protein, cold agglutinins and disialosyl antibodies) Paraneoplastic Anti-Hu syndrome anti-CV2, anti-PNMA2, anti-MA1, anti-amphiphysin and anti-CRMP-5 syndromes Toxic Cisplatin and other chemotherapeutics pyridoxine toxicity Inherited or degenerative Friedreich’s ataxia CANVAS (cerebellar ataxia, neuropathy and vestibular areflexia syndrome) Infective HIV syphilis Lyme disease Idiopathic Several immune-mediated neuropathies are compatible with this cluster of symptoms and subacute presentation. Table 3 outlines the results.Table 3 Clinical and laboratory investigations and results Investigation Result MR scan of brain on admission Deep left frontal and left cerebellar white matter T2 lesions consistent with previous infarcts no other findings to account for presentation CSF analysis Opening pressure not elevated protein 0.78 g, white cell count 2, glucose 4.4 IgG band detected that was matched in the serum Nerve conduction studies Upper limb: markedly reduced or absent sensory responses with motor responses within the normal range lower limb: acceptable responses, no reason identified for lower limb ataxia needle EMG: chronic neurogenic changes in right upper limb, lower limbs and thoracic paraspinal muscles Blood results at presentation Routine bloods were unremarkable normal serum B12 and folate infective screen normal including: HIV, Hep B and C, syphilis, Lyme serology negative antinuclear antibody, ANCA, serum ACE. Serum kappa/lambda ratio normal cold agglutinins negative CT scan of chest, abdomen and pelvis no evidence of malignancy bilateral lower lobe predominant fibrotic changes associated prominent mediastinal and hilar lymphadenopathy thought likely to be reactive. no pelvic or axillary lymphadenopathy Clinical course continued gradual progression 9 weeks from symptom onset Schirmer’s test negative Blood results 9 weeks into presentation Antineuronal antibody panel (including Hu, amphiphysin and CRMP5): negative anti-ganglioside antibody panel: positive GD1b IgM, GD1a IgG and IgM, GM1 IgM and GQ1b IgM ACE, Angiotensin-converting enzyme; ANCA, Anti-neutrophil cytoplasm antibodies; CSF, Cerebrospinal fluid; EMG, Electromyography.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies. A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Neurological complications occur in 4% of patients following acute COVID-19 infection, causing significant morbidity with lasting health economic consequences. However treatment studies to date in COVID-19 have not addressed neurological complications as outcome measures.We therefore performed a retrospective, non-interventional cohort study using the ISARIC-4C platform, assessing 62,729 hospital inpatients with severe COVID-19 between 31 Jan 2020 and 29 Jun 2021. Treatment with dexamethasone, remdesivir or both was compared to standard of care. The primary outcome was a neurological complication, namely stroke, seizure, meningitis/encephalitis or any other neurological complication, occurring at the point of death, discharge, or resolution of the COVID-19 clinical episode. A propensity scoring methodology was used to balance confounding between treatment groups and between patients with and without neurological complications.Treatment with dexamethasone, remdesivir or both reduced the incidence of neurological complications from severe COVID-19, with odds ratios of 0.76 (0.69-0.83), 0.68 (0.51-0.90) and 0.64 (0.56 -0.72) respec- tively. Neurological complications were associated with increased length of hospital stay, worse ability to self-care on discharge and increased mortality.This study is the first to focus on the prevention of neurological complications and strongly supports the continued use of both dexamethasone and remdesivir in severe COVID-19. Our results suggest that the established benefit of dexamethasone on mortality in COVID-19 is not associated with an increased burden of long-term neurological disability.

Abstract To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely.