Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease.

BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aß) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aß IgG1 monoclonal antibody with highest affinity for aggregated Aß that has been tested for the treatment of Alzheimer's disease. METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aß42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Clinical consensus on treatments for transplant-ineligible newly diagnosed multiple myeloma: double-blinded Delphi panel.

Aim: Obtain clinical consensus on factors impacting first-line prescribing for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). Materials & methods: A double-blinded, modified Delphi panel was employed. USA-based hematologists/oncologists who treat TIE patients with NDMM were selected as expert panelists. Results: Consensus was reached that patient frailty, performance status, comorbidities, treatment efficacy, and adverse event profile affect first-line prescribing. All panelists agreed it is important to use the most efficacious treatment first; 88% of panelists considered daratumumab-containing regimens the most efficacious. Panelists agreed treatment should be continued until progression while benefits outweigh risk. Conclusion: Findings reinforce the importance of using the most efficacious regimen upfront for TIE NDMM, and nearly all panelists considered daratumumab-containing regimens the most efficacious treatment.

The purpose of this study was to determine the latest clinician preferences and opinions on factors affecting initial treatment selection for people recently diagnosed with multiple myeloma and unable to receive a bone marrow transplant, and to understand challenges with current treatments used in clinical practice. A panel of doctors with an average of two decades of experience treating blood disorders and cancers were recruited as expert panelists. Experts discussed treatment options by completing two rounds of surveys on treatment and one round of discussion. All experts agreed that the most effective treatment should be used first. Most experts considered treatment containing the drug daratumumab to be the most effective. Experts agreed that treatment should be continued until the cancer worsens if the treatment offers more benefits than side effects.

Project PRIME: road markings for motorcycle casualty reduction (an overview of findings from 2020 to 2022).

Pioneering road markings for motorcyclists, designed as Perceptual Rider Information for Maximising Expertise and Enjoyment (PRIMEs) were installed on approach to demanding bends at 22 trial sites and two comparison sites across the West Highlands of Scotland. The markings provided a series of 'gateways' to encourage safer riding. With 32,213 motorcyclists observed, the following statistically significant results were observed: speed reductions at 10 trial sites; positive changes in lateral position at the final PRIME gateway marking at 15 trial sites and positive changes in lateral position at the apex of the bend at 13 trial sites; reductions in braking at nine trial sites; increases use of PRIME road markings across 18 of the 22 trial sites. No statistically significant effects were observed at the comparison sites. These findings are discussed in relation to the 'Road Safety Framework to 2030' and the 'Safe System' approach to reducing motorcycle casualties.

This world-first research presents the largest investigation of rider behaviour involving 32,213 motorcyclists. Pioneering road markings for motorcyclists produced statistically significant positive behavioural changes in speed, lateral lane position and braking. This work identifies important behavioural factors that support the 'Safe System' approach to motorcycle casualty reduction.

Defining ruxolitinib failure and transition to next-line therapy for patients with myelofibrosis: a modified Delphi panel consensus study.

Aim: To define ruxolitinib failure and develop parameters to guide transition to next-line therapy for patients with myelofibrosis. Methods: A modified Delphi panel with 14 hematologists-oncologists. Survey concepts included defining primary refractory status, loss of response, disease progression, intolerance and transition to next-line therapy. Results: Ruxolitinib failure may be defined as no improvement in symptoms or spleen size, progressive disease or ruxolitinib intolerance, following a maximally tolerated dose for ≥3 months. Loss of spleen response 1 month after initial response may prompt discontinuation. Lack of evidence to inform transition to next-line therapy was noted; tapering ruxolitinib should be considered according to ruxolitinib dose and patient characteristics. Conclusion: Expert consensus was provided on defining ruxolitinib failure and transition to next-line therapy as summarized in this position paper, which may support considerations in the development of future clinical practice guidelines.

People with myelofibrosis who receive treatment with ruxolitinib may need to stop treatment because it is not working or they cannot tolerate the side effects. There is little good scientific information available about how and when to stop ruxolitinib treatment, and how to move to another treatment after stopping ruxolitinib. A group of clinical experts in hematology and oncology followed a scientific process, called the Delphi method, to discuss this topic and to reach agreement on the most important aspects of this challenge. The experts agreed that ruxolitinib failure may be defined as having no improvement in symptoms or spleen size, progressive disease or ruxolitinib intolerance, after the patient was receiving the highest dose they could tolerate for ≥3 months. The results of this expert discussion may support patients and their healthcare providers making decisions in real life, and development of future clinical practice guidelines.

Development of skeletal muscle fibrosis in a rodent model of cancer cachexia.

Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate-buffered saline or Lewis Lung Carcinoma (LLC) at 8-week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis-related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)-related genes beginning at 1wk post-LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM-related genes contrary to what was noted in female mice.

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

BACKGROUND: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. METHODS: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 µg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. FINDINGS: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). INTERPRETATION: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate. FUNDING: None.

Expert Consensus on the Use of Teprotumumab for the Management of Thyroid Eye Disease Using a Modified-Delphi Approach.

BACKGROUND: Teprotumumab is the first treatment for thyroid eye disease (TED), a debilitating autoinflammatory condition, approved by the Food and Drug Administration in the United States, which reduces proptosis and improves quality of life. In the absence of guidelines, clinical recommendations were developed for using teprotumumab in patients with TED in the United States. METHODS: A 3-round modified-Delphi panel was conducted between October 2020 and February 2021 with experts in the management of patients with TED. Key areas regarding the use of teprotumumab were investigated, including eligible patient populations, concomitant treatments, and assessment of response and adverse events. This used 2 survey rounds via an online questionnaire, where statements were scored using 9-point Likert scales. Statements with conflict were included in the third round, involving a consensus meeting via videoconference. RESULTS: Consensus was obtained for all statements (n = 75); of which, 56% were revised to enable agreement of the group. The consensus meeting provided agreement regarding which populations should receive teprotumumab therapy, including all adult patients with TED with a clinical activity score of ≥4. Treatment with teprotumumab can also be considered for TED patients displaying the following characteristics: a CAS of <3, lid retraction of ≥2, and mild or early optic neuropathy with close clinical observation. Further recommendations included suitability of treatment for those beyond 16 months following the initial diagnosis of TED, low CAS concomitant treatment with steroids in some cases, retreatment for those who have relapses, and finally a recommendation to continue therapy for all 8 infusions despite the lack of response by the fourth infusion. CONCLUSIONS: This work constitutes the first consensus on guidelines for the use of teprotumumab. The modified Delphi approach involved physicians with significant experience with the clinical use of teprotumumab, and recommendations were based on current evidence.

Characteristics and outcomes of COVID-19 associated stroke: a UK multicentre case-control study.

OBJECTIVE: We set out to determine which characteristics and outcomes of stroke are associated with COVID-19. METHODS: This case-control study included patients admitted with stroke to 13 hospitals in England and Scotland between 9 March and 5 July 2020. We collected data on 86 strokes (81 ischaemic strokes and 5 intracerebral haemorrhages) in patients with evidence of COVID-19 at the time of stroke onset (cases). They were compared with 1384 strokes (1193 ischaemic strokes and 191 intracerebral haemorrhages) in patients admitted during the same time period who never had evidence of COVID-19 (controls). In addition, the whole group of stroke admissions, including another 37 patients who appeared to have developed COVID-19 after their stroke, were included in two logistic regression analyses examining which features were independently associated with COVID-19 status and with inpatient mortality. RESULTS: Cases with ischaemic stroke were more likely than ischaemic controls to occur in Asians (18.8% vs 6.7%, p<0.0002), were more likely to involve multiple large vessel occlusions (17.9% vs 8.1%, p<0.03), were more severe (median National Institutes of Health Stroke Scale score 8 vs 5, p<0.002), were associated with higher D-dimer levels (p<0.01) and were associated with more severe disability on discharge (median modified Rankin Scale score 4 vs 3, p<0.0001) and inpatient death (19.8% vs 6.9%, p<0.0001). Recurrence of stroke during the patient's admission was rare in cases and controls (2.3% vs 1.0%, NS). CONCLUSIONS: Our data suggest that COVID-19 may be an important modifier of the onset, characteristics and outcome of acute ischaemic stroke.

The effect of autologous repair and voluntary wheel running on force recovery in a rat model of volumetric muscle loss.

NEW FINDINGS: What is the central question of this study? Following large traumatic loss of muscle tissue (volumetric muscle loss; VML), permanent functional and cosmetic deficits present themselves and regenerative therapies alone have not been able to generate a robust regenerative response: how does the addition of rehabilitative therapies affects the regenerative response? What is the main finding and its importance? Using exercise along with autologous muscle repair, we demonstrated accelerated muscle force recovery response post-VML. The accentuated force recovery 2 weeks post-VML would allow patients to return home sooner than allowed with current therapies. ABSTRACT: Skeletal muscle can regenerate from damage but is overwhelmed with extreme tissue loss, known as volumetric muscle loss (VML). Patients suffering from VML do not fully recover force output in the affected limb. Recent studies show that replacement tissue (i.e., autograph) into the VML defect site plus physical activity show promise for optimizing force recovery post-VML. The purpose of this study was to measure the effects of autologous repair and voluntary wheel running on force recovery post-VML. Thirty-two male Sprague-Dawley rats had 20% of their left tibialis anterior (LTA) excised then replaced and sutured into the intact muscle (autologous repair). The right tibialis anterior (RTA) acted as the contralateral control. Sixteen rats were given free access to a running wheel (Wheel) whereas the other 16 remained in a cage with the running wheel locked (Sed). At 2 and 8 weeks post-VML, the LTA underwent force testing; then the muscle was removed and morphological and gene expression analysis was conducted. At 2 weeks post-injury, normalized LTA force was 58% greater in the Wheel group compared to the Sed group. At 8 weeks post-VML, LTA force was similar between the Wheel and Sed groups but was still lower than the uninjured RTA. Gene expression analysis at 2 weeks post-VML showed the wheel groups had lower mRNA content of interleukin (IL)-1ß, IL-6 and tumour necrosis factor α compared to the Sed group. Overall, voluntary wheel running promoted early force recovery, but was not sufficient to fully restore force. The accentuated early force recovery is possibly due to a more pro-regenerative microenvironment.

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Theoretical study of the adsorption of analgesic environmental pollutants on pristine and nitrogen-doped graphene nanosheets.

Interactions of the analgesic medications dextropropoxyphene (DPP, opioid), paracetamol (PCL, nonnarcotic), tramadol (TDL, nonnarcotic), ibuprofen (IBN, nonsteroidal anti-inflammatory drug (NSAID)), and naproxen (NPX, NSAID) with pristine graphene (GN) and nitrogen-doped GN (NGN; containing only graphitic N atoms) nanosheets were explored using density functional theory (DFT) in the gas and aqueous phases. Calculations in the aqueous phase were performed using the integral equation formalism polarized continuum model (IEFPCM). Calculated geometry-optimized structures, partial atomic charges (determined using Natural Bond Orbital analysis), highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps, work functions (determined using time-dependent DFT), and molecular electrostatic potential plots showed that the adsorption process is physical in nature (viz. physisorption), primarily due to noncovalent π-π and van der Waals interactions. In addition, calculated adsorption energies (ΔEad) were exergonic, indicating that formation of the analgesic/GN and analgesic/NGN complexes is thermodynamically favorable in the gas (ΔEad values for analgesic/GN and analgesic/NGN were in the range of -66.56 kJ mol-1 to -106.78 kJ mol-1) and aqueous phases (ΔEad values for analgesic/GN and analgesic/NGN complexes were in the range of -58.75 kJ mol-1 to -100.46 kJ mol-1). Generally, for GN and NGN, adsorption was more endergonic in the aqueous phase by as much as +10.41 kJ mol-1. Calculated solvation energies (ΔEsolvation) were exergonic for all analgesic/GN complexes (ΔEsolvation values were in the range of -56.50 kJ mol-1 to -66.17 kJ mol-1) and analgesic/NGN complexes (ΔEsolvation values were in the range of -77.26 kJ mol-1 to -87.96 kJ mol-1), with analgesic/NGN complexes exhibiting greater stability in aqueous solutions (∼20 kJ mol-1 more stable). In summary, the results of this theoretical study demonstrate that the adsorption and solvation of analgesics on GN and NGN nanosheets is thermodynamically favorable. In addition, generally, analgesic/NGN complexes exhibit higher adsorption affinities and solvation energies in the gas and aqueous phases. Therefore, GN and NGN nanosheets are potential adsorbents for extracting analgesic contaminants from aqueous environments such as aquatic ecosystems.

Mild cognitive impairment: the Manchester consensus.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI.

Characteristics and Outcomes in Patients With COVID-19 and Acute Ischemic Stroke: The Global COVID-19 Stroke Registry.

Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institutes of Health Stroke Scale was 10 (interquartile range [IQR], 4-18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institutes of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4-18] versus 6 [IQR, 3-14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08-2.65] for higher National Institutes of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2-6] versus 2 [IQR, 1-4], P<0.001) and death (odds ratio, 4.3 [95% CI, 2.22-8.30]) compared with patients without COVID-19. Our findings suggest that COVID-19 associated ischemic strokes are more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes.

Identification of lipid biomarkers of metastatic potential and gene expression (HER2/p53) in human breast cancer cell cultures using ambient mass spectrometry.

In breast cancer, overexpression of human epidermal growth factor receptor 2 (HER2) correlates with overactivation of lipogenesis, mutation of tumor suppressor p53, and increased metastatic potential. The mechanisms through which lipids mediate p53, HER2, and metastatic potential are largely unknown. We have developed a desorption electrospray ionization mass spectrometry (DESI-MS) method to identify lipid biomarkers of HER2/p53 expression, metastatic potential, and disease state (viz. cancer vs. non-cancerous) in monolayer and suspension breast cancer cell cultures (metastatic potential: MCF-7, T-47D, MDA-MB-231; HER2/p53: HCC2218 (HER2+++/p53+), HCC1599 (HER2-/p53-), HCC202 (HER2++/p53-), HCC1419 (HER2+++/p53-) HCC70 (HER2-/p53+++); non-cancerous: MCF-10A). Unsupervised principal component analysis (PCA) of DESI-MS spectra enabled identification of twelve lipid biomarkers of metastatic potential and disease state, as well as ten lipids that distinguish cell lines based on HER2/p53 expression levels (> 200 lipids were identified per cell line). In addition, we developed a DESI-MS imaging (DESI-MSI) method for mapping the spatial distribution of lipids in metastatic spheroids (MDA-MB-231). Of the twelve lipids that correlate with changes in the metastatic potential of monolayer cell cultures, three were localized to the necrotic core of spheroids, indicating a potential role in promoting cancer cell survival in nutrient-deficient environments. One lipid species, which was not detected in monolayer MDA-MB-231 cultures, was spatially localized to the periphery of the spheroid, suggesting a potential role in invasion and/or proliferation. These results demonstrate that combining DESI-MS/PCA of monolayer and suspension cell cultures with DESI-MSI of spheroids is a promising approach for identifying lipid biomarkers of specific genotypes and phenotypes, as well as elucidating the potential function of these biomarkers in breast cancer. Graphical Absract.

Amyloid PET imaging in clinical practice.

Amyloid positron emission tomography (PET) imaging enables in vivo detection of brain Aß deposition, one of the neuropathological hallmarks of Alzheimer's disease. There is increasing evidence to support its clinical utility, with major studies showing that amyloid PET imaging improves diagnostic accuracy, increases diagnostic certainty and results in therapeutic changes. The Amyloid Imaging Taskforce has developed appropriate use criteria to guide clinicians by predefining certain scenarios where amyloid PET would be justified. This review provides a practical guide on how and when to use amyloid PET, based on the available research and our own experience. We discuss its three main appropriate indications and illustrate these with clinical cases. We stress the importance of a multidisciplinary approach when deciding who might benefit from amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in its interpretation.

Subarachnoid haemorrhage due to intracranial vertebral artery dissection presenting with atypical cauda equina syndrome features: case report.

BACKGROUND: Failing to recognise the signs and symptoms of subarachnoid haemorrhage (SAH) causes diagnostic delay and may result in poorer outcomes. We report a rare case of SAH secondary to a vertebral artery dissection (VAD) that initially presented with cauda equina-like features, followed by symptoms more typical of SAH. CASE PRESENTATION: A 55-year-old man developed severe lower back pain after sudden movement. Over the next 5 days he developed paraesthesiaes in the feet, progressing to the torso gradually, and reported constipation and reduced sensation when passing urine. On day six he developed left facial palsy, and later gradual-onset headache and intermittent confusion. Magnetic resonance imaging of the brain showed diffuse subarachnoid FLAIR hyperintensity, concerning for blood, including a focus of cortical/subcortical high signal in the left superior parietal lobule, which was confirmed by computed tomography. Digital subtraction angiography demonstrated a left VAD with a fusiform aneurysm. CONCLUSION: We present a very rare case of intracranial VAD with SAH initially presenting with spinal symptoms. The majority of subsequent clinical features were consistent with a parietal focus of cortical subarachnoid blood, as observed on neuroimaging.

Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice.

Cancer-cachexia (CC) is a wasting condition directly responsible for 20-40% of cancer-related deaths. The mechanisms controlling development of CC-induced muscle wasting are not fully elucidated. Most investigations focus on the postcachectic state and do not examine progression of the condition. We recently demonstrated mitochondrial degenerations precede muscle wasting in time course progression of CC. However, the extent of muscle perturbations before wasting in CC is unknown. Therefore, we performed global gene expression analysis in CC-induced muscle wasting to enhance understanding of intramuscular perturbations across the development of CC. Lewis lung carcinoma (LLC) was injected into the hind-flank of C57BL6/J mice at 8 wk of age with tumor allowed to develop for 1, 2, 3, or 4 wk and compared with PBS-injected control. Muscle wasting was evident at 4 wk LLC. RNA sequencing of gastrocnemius muscle samples showed widespread alterations in LLC compared with PBS animals with largest differences seen in 4 wk LLC, suggesting extensive transcriptomic alterations concurrent to muscle wasting. Commonly altered pathways included: mitochondrial dysfunction and protein ubiquitination, along with other less studied processes in this condition regulating transcription/translation and cytoskeletal structure. Current findings present novel evidence of transcriptomic shifts and altered cellular pathways in CC-induced muscle wasting.

Clinical utility of amyloid PET imaging with (18)F-florbetapir: a retrospective study of 100 patients.

BACKGROUND AND OBJECTIVE: Amyloid-positron emission tomography (PET) imaging (API) detects amyloid-beta pathology early in the course of Alzheimer's disease (AD) with high sensitivity and specificity. (18)F-florbetapir (Amyvid) is an amyloid-binding PET ligand with a half-life suitable for clinical use outside of the research setting. How API affects patient investigation and management in the 'real-world' arena is unknown. To address this, we retrospectively documented the effect of API in patients in the memory clinic. METHODS: We reviewed the presenting clinical features, the pre-API and post-API investigations, diagnosis and outcomes for the first 100 patients who had API as part of their routine work-up at the Imperial Memory Centre, a tertiary referral clinic in the UK National Health Service. RESULTS: API was primarily used to investigate patients with atypical clinical features (56 cases) or those that were young at onset (42 cases). MRI features of AD did not always predict positive API (67%), and 6 of 23 patients with MRIs reported as normal were amyloid-PET positive. There were significantly more cases categorised as non-AD dementia post-API (from 11 to 23). Patients investigated when API was initially available had fewer overall investigations and all patients had significantly fewer investigations in total post-API. CONCLUSIONS: API has a clear impact on the investigation of young-onset or complex dementia while reducing the overall burden of investigations. It was most useful in younger patients, atypical presentations or individuals with multiple possible causes of cognitive impairment.

Patterns of solid particle embolization during transcatheter aortic valve implantation and correlation with aortic valve calcification.

OBJECTIVES: To evaluate solid embolization during transcatheter aortic valve implantation (TAVI) and correlate this with aortic valve calcification. BACKGROUND: There is a known stroke risk with TAVI, thought partly to be due to dislodgement of native aortic valve particles during implantation. However, to date there is little evidence that aortic valve calcification actually impacts embolic risk. METHODS: Transcranial Doppler (TCD) was performed on consecutive suitable patients undergoing TAVI, using hardware and software enabling differentiation between solid and gaseous emboli. Data was analyzed by time points during the TAVI procedure. These results were correlated with aortic valve calcification. RESULTS: TCD was successfully performed on 63 patients. The median number of solid emboli was 76.0. The most common time point for solid embolization was during valve positioning. Forty-five of these patients had an appropriate CT scan which could be analyzed for an Agatston calcium score. The mean scores in the aortic valve and aortic root were 3382.4 and 754.9. There were significant correlations between the total number of solid emboli and valve calcium score (P = 0.033) and solid emboli during valve positioning and valve calcium score (P = 0.035). There was no relationship between gaseous emboli and valve calcium score. CONCLUSIONS: TAVI is associated with significant solid particle embolization, with the most common time point being during valve positioning. Solid embolization correlates with aortic valve calcium score, suggesting that valve calcification is a factor in embolic risk. This should be taken into consideration along with other clinical factors when assessing embolic risk.

A Protocol-Driven Assessment Promotes a More Accurate Diagnosis of Irritable Bowel Syndrome.

A diverse range of conditions share symptoms commonly identified with irritable bowel syndrome. The objective of this study was to examine the diagnostic process in identifying additional diagnoses in women who are attending a clinic for evaluation of symptoms suggestive of irritable bowel syndrome. A retrospective audit was conducted of anonymous data gathered on consecutive female patients presenting to a specialist nurse-led service in Christchurch, New Zealand, with a provisional diagnosis of irritable bowel syndrome. A protocol containing routine pathology investigations and physical examination was used. Alarm features were identified and pertinent investigations were implemented. Rectocele was detected on rectal examination. Final diagnosis was noted and compared with baseline symptom data. Of 231 patients, 187 initially met Rome III criteria for irritable bowel syndrome. Red flags and abnormal investigations led to an alternate diagnosis in a further 27 patients. Of the 160 patients with irritable bowel syndrome, 31% were found to have a rectocele. They were seven times more likely to report a symptom associated with pelvic floor dysfunction (p < .0001) and four times more likely to report constipation (p = .0003). The use of a protocol including routine investigations and physical examination improves diagnostic yield. Pelvic floor dysfunction should be considered in those with unique symptom patterns and rectocele in the setting of irritable bowel syndrome.