Effect of plasma-to-RBC ratios in trauma patients: a cohort study with time-dependent data*.

BACKGROUND: A widespread approach today is to transfuse bleeding trauma patients with RBC concentrates and plasma at a 1:1 ratio. This regime is supported by a range of observational studies showing lower mortality in bleeding patients receiving equal volumes of plasma and RBCs. The rationale for this practice is still unclear with several studies failing to show any survival benefits of increased plasma use, perhaps due to a failure to account for the timing of transfused units. OBJECTIVE: To study the association between plasma-to-RBC ratios and risk of death in trauma patients, using appropriate methods. DESIGN, SETTINGS, AND PARTICIPANTS: In a retrospective cohort study, we assembled data on 741 transfused trauma patients at a large trauma center. Measures of transfusion therapy were assessed entirely time dependently, and relative risk of death was compared between patients receiving low to high plasma-to-RBC ratio (< 0.85 vs > 0.85). MEASUREMENTS AND RESULTS: In the time-dependent analyses, we saw no significant association between a low plasma ratio and the risk of death. However, age more than 75 years, injury severity score greater than 33, Glasgow Coma Scale less than 8, and systolic blood pressure lower than 90 mm Hg were all significantly associated with increased risk of death. Conversely, when the analyses were conducted with conventional methods, a strong protective effect of high plasma ratios was seen. CONCLUSIONS: The key finding in our study is the strikingly different results produced by time-dependent analyses and the conventional analyses when studying survival and plasma-to-RBC ratio, supporting recent claims that prior studies showing benefit of high plasma ratios might have suffered from survival bias. There is a great need for further studies on the subject to enable improvements in treatment of massively bleeding trauma patients.

A flow cytometry-based proliferation assay for clinical evaluation of T-cell memory against SARS-CoV-2.

In general, the method of choice for evaluating immunity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is detection of antibodies against the virus in patient sera. However, this is not feasible in patients who do not produce antibodies, either due to a primary immunodeficiency or secondary to treatment with immunosuppressive drugs. Assessment of the antiviral T cell response is an alternative to serological tests, but most T cell assays are labor-intensive and unsuitable for a clinical routine laboratory. We developed a flow cytometry-based assay for T cell proliferative responses against SARS-CoV-2, based on the detection of blast transformation of activated cells. The assay was validated on previously SARS-CoV-2 infected individuals and healthy seronegative blood donors, displaying 74% sensitivity and 96% specificity for previous infection with SARS-CoV-2. The usefulness of the assay was demonstrated in a patient with common variable immunodeficiency with a history of COVID-19. The described T-cell assay is a clinically relevant complement to serology in the evaluation of cellular immunity against SARS-CoV-2, which can be emulated by any routine lab with flow cytometric competence.

Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. METHODS: We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005-08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. FINDINGS: 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0.7, 95% CI 0.04-1.39; p=0.03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition [AQT] form: difference 12.4, 95% CI 6.0-30.9; p=0.004), there were no significant differences between the groups in secondary outcome measures. INTERPRETATION: Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. FUNDING: The Western Norway Regional Health Authority; H Lundbeck A/S.

Cerebrospinal fluid total tau is associated with shorter survival in dementia with Lewy bodies.

A pathology typical of dementia with Lewy bodies (DLB) has been demonstrated to increase mortality to a greater extent than the pathology of Alzheimer's disease (AD). However, mortality in DLB has also been shown to increase with concomitant AD pathology. Furthermore, in a recent publication, we showed that there is a robust and specific increase in CSF calcium and magnesium in DLB patients compared to both AD patients and controls. Thus, in order to explore the influence of CSF AD markers and trace element concentrations on mortality in DLB, we undertook a longitudinal prospective study of 47 clinically diagnosed DLB patients and 157 AD patients as well as 49 healthy volunteers. Both AD and DLB patients showed an increased mortality compared to the healthy controls (relative risk: 10 and 8, respectively; p < 0.001). Increased levels of CSF total tau were associated with increased mortality among the DLB patients (p < 0.05), but not among the AD patients or controls. Gender, age, MMSE score, Abeta42 concentration and phosphorylated tau, and CSF trace element concentrations did not influence survival in the obtained models.

Low CSF levels of both α-synuclein and the α-synuclein cleaving enzyme neurosin in patients with synucleinopathy.

Neurosin is a protease that in vitro degrades α-synuclein, the main constituent of Lewy bodies found in brains of patients with synucleinopathy including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several studies have reported reduced cerebrospinal fluid (CSF) levels of α-synuclein in synucleinopathy patients and recent data also proposes a significant role of α-synuclein in the pathophysiology of Alzheimer's disease (AD). To investigate potential links between neurosin and its substrate α-synuclein in vivo we used a commercially available sandwich ELISA and an in-house developed direct ELISA to quantify CSF levels of α-synuclein and neurosin in patients diagnosed with DLB, PD and PD dementia (PDD) versus AD patients and non-demented controls. We found that patients with synucleinopathy displayed lower CSF levels of neurosin and α-synuclein compared to controls and AD patients. In contrast, AD patients demonstrated significantly increased CSF α-synuclein but similar neurosin levels compared to non-demented controls. Further, CSF neurosin and α-synuclein concentrations were positively associated in controls, PD and PDD patients and both proteins were highly correlated to CSF levels of phosphorylated tau in all investigated groups. We observed no effect of gender or presence of the apolipoprotein Eε4 allele on neither neurosin or α-synuclein CSF levels. In concordance with the current literature our study demonstrates decreased CSF levels of α-synuclein in synucleinopathy patients versus AD patients and controls. Importantly, decreased α-synuclein levels in patients with synucleinopathy appear linked to low levels of the α-synuclein cleaving enzyme neurosin. In contrast, elevated levels of α-synuclein in AD patients were not related to any altered CSF neurosin levels. Thus, altered CSF levels of α-synuclein and neurosin in patients with synucleinopathy versus AD may not only mirror disease-specific neuropathological mechanisms but may also serve as fit candidates for future biomarker studies aiming at identifying specific markers of synucleinopathy.

CSF Mg and Ca as diagnostic markers for dementia with Lewy bodies.

Accumulating evidence implicates a role for altered metal homeostasis in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD). However, few investigations have addressed this issue in dementia with Lewy bodies (DLB). The aim of the present study was to investigate metal concentrations in cerebrospinal fluid (CSF) and plasma from patients with DLB and other neurodegenerative disorders. To that end, CSF and plasma samples were collected from 29 patients with DLB, 174 patients with AD, 90 patients with AD with minor vascular components, and 51 healthy volunteers. Total concentrations of Mg, Ca, Mn, Fe, Cu, Zn, Rb, Sr, and Cs were determined using mass spectrometry. Patients with DLB had elevated Ca and Mg levels in CSF and Mg levels in plasma as compared to all other groups (p<0.001). Furthermore, a combination of CSF-Mg and CSF-Ca could distinguish DLB from AD with a sensitivity of 93% and a specificity of 85%. Cu levels in both CSF and plasma tended to be higher in DLB compared to the other groups, but these trends failed to reach significance after correction for multiple comparisons. Mn, Fe, Zn, Rb, and Sr concentration in CSF or plasma were similar in all groups. The observed elevations of CSF-Mg, CSF-Ca and CSF-Cu may contribute to or be associated with the neurodegenerative process in DLB. Furthermore, determination of CSF-Mg and CSF-Ca concentration may be a valuable tool in distinguishing DLB from AD.

Patients with dementia with lewy bodies have more impaired quality of life than patients with Alzheimer disease.

The primary aim of this study was to compare quality of life (QoL) in patients with Dementia with Lewy Bodies (DLB) and patients with Alzheimer disease (AD). The secondary aim of this study was to investigate determinants of QoL in DLB. Thirty-four patients with DLB at the Neuropsychiatry clinic, University Hospital MAS, Malmö, Sweden, were included in a cross-sectional study. These patients were matched to 34 patients with AD. Two QoL instruments, the EQ-5D instrument and the Quality of Life-Alzheimer disease (QoL-AD) instrument, were applied in this study. Both instruments were administered to both patients and caregivers. Patients with DLB in this study have significantly lower QoL than patients with AD regardless of instrument or whether patient or caregiver-reported QoL was used. Furthermore, this study shows that important determinants of QoL in DLB include Neuropsychiatric Inventory score, independency in instrumental activities of daily living, whether the patient is living with the caregiver and the presence of apathy and delusions.

Patients with Lewy body dementia use more resources than those with Alzheimer's disease.

OBJECTIVES: The purpose of this study was to compare resource use and costs in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) and to assess determinants of costs of care in DLB. METHOD: Thirty-four patients with DLB were included in a cross-sectional study. The patients were matched with respect to age, gender and Mini Mental State Examination (MMSE) score to 34 patients with AD. Both groups were examined using Resource Utilisation in Dementia (RUD Lite), MMSE and the Neuropsychiatric inventory (NPI). The DLB patients were additionally examined using the Disability Assessment for Dementia Scale (DAD). RESULTS: Costs of care in patients suffering from DLB was on average 348,000 SEK (37,500 euro) per year compared to 169,000 SEK (18,200 euro) in the AD group (p < 0.001). Within the DLB group, care costs correlated significantly (r(c) = 2.77, p < 0.001) with dependency in instrumental activities of daily living measured with DAD, whereas MMSE and NPI were not significantly correlated to resource use in the DLB group. CONCLUSIONS: DLB patients use more resources, and are more costly than AD patients. Dependency in instrumental activities of daily living is strongly correlated to resource use in DLB patients.