Objectives
In response to a commissioned research update on dementia during the COVID‐19 pandemic, a UK‐based working group, comprising dementia researchers from a range of fields and disciplines, ...aimed to describe the impact of the pandemic on dementia wellbeing and identify priorities for future research.
Methods
We supplemented a rapid literature search (including unpublished, non‐peer reviewed and ongoing studies/reports) on dementia wellbeing in the context of COVID‐19 with expert group members' consensus about future research needs. From this we generated potential research questions the group judged to be relevant that were not covered by the existing literature.
Results
Themes emerged from 141 studies within the six domains of the NHS England COVID‐19 Dementia Wellbeing Pathway: Preventing Well, Diagnosing Well, Treating Well, Supporting Well, Living Well and Dying Well. We describe current research findings and knowledge gaps relating to the impact on people affected by dementia (individuals with a diagnosis, their carers and social contacts, health and social care practitioners and volunteers), services, research activities and organisations. Broad themes included the potential benefits and risks of new models of working including remote healthcare, the need for population‐representative longitudinal studies to monitor longer‐term impacts, and the importance of reporting dementia‐related findings within broader health and care studies.
Conclusions
The COVID‐19 pandemic has had a disproportionately negative impact on people affected by dementia. Researchers and funding organisations have responded rapidly to try to understand the impacts. Future research should highlight and resolve outstanding questions to develop evidence‐based measures to improve the quality of life of people affected by dementia.
Key Points
The COVID‐19 pandemic has had a disproportionately negative impact on people affected by dementia, dementia services and research.
Further research on the impacts of the pandemic is needed, and directions for future work are identified in this study.
It is important to explore the potential benefits and risks of remote health and care, design inclusive and longitudinal studies to monitor longer‐term impacts, and report dementia‐specific findings within broader studies.
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of ...anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, a mutation that decreases ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.
Several enveloped viruses, including herpesviruses attach to host cells by initially interacting with cell surface heparan sulfate (HS) proteoglycans followed by specific coreceptor engagement which ...culminates in virus-host membrane fusion and virus entry. Interfering with HS-herpesvirus interactions has long been known to result in significant reduction in virus infectivity indicating that HS play important roles in initiating virus entry. In this study, we provide a series of evidence to prove that specific sulfations as well as the degree of polymerization (dp) of HS govern human cytomegalovirus (CMV) binding and infection. First, purified CMV extracellular virions preferentially bind to sulfated longer chain HS on a glycoarray compared to a variety of unsulfated glycosaminoglycans including unsulfated shorter chain HS. Second, the fraction of glycosaminoglycans (GAG) displaying higher dp and sulfation has a larger impact on CMV titers compared to other fractions. Third, cell lines deficient in specific glucosaminyl sulfotransferases produce significantly reduced CMV titers compared to wild-type cells and virus entry is compromised in these mutant cells. Finally, purified glycoprotein B shows strong binding to heparin, and desulfated heparin analogs compete poorly with heparin for gB binding. Taken together, these results highlight the significance of HS chain length and sulfation patterns in CMV attachment and infectivity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Divergent transcription: A new feature of active promoters Seila, Amy C.; Core, Leighton J.; Lis, John T. ...
Cell cycle (Georgetown, Tex.),
8/15/2009, 2009/08/15, 2009-Aug-15, 2009-08-15, 20090815, Letnik:
8, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Divergent transcription is common of many promoters in organisms as diverse as mammals and yeast. Many independent experiments indicate that RNA polymerase II is frequently initiated but paused in ...the sense direction downstream from the promoter. Similarly a second peak of transcriptionally-engaged polymerase is paused in the anti-sense direction upstream of the promoter. Chromatin modifications that are associated with active promoters reside in nucleosomes immediately flanking this pair of paused polymerases. The nucleosome-free region associated with most promoters could in part be defined by this divergent transcription. The potential implications of divergent transcription on gene regulation and possible mechanisms that give rise to this phenomenon are discussed.
Joint damage is an important outcome in trials of rheumatoid arthritis (RA), usually assessed by Total Sharp Score (TSS). It is currently unknown how it translates numerically into disability by the ...Health Assessment Questionnaire (HAQ).
To determine the units of HAQ score corresponding to one TSS unit.
A short-term observational trial of glucocorticoids in RA (the 'BEst LIfe with Rheumatoid Arthritis' (BELIRA) trial) was evaluated, using randomised controlled clinical trial (RCT) data for confirmation. For each trial arm HAQ, TSS and the Simplified Disease Activity Index (SDAI) were assessed. Based on the hypothesis that short-term HAQ changes will mostly be due to changes of disease activity, activity HAQ (ACT-HAQ) at end point (EP) was determined and remaining disability defined as damage related (DAM-HAQ). Using TSS at EP, the HAQ units corresponding to a TSS unit were estimated.
In BELIRA, one TSS unit corresponded to a mean of 0.017 HAQ units; to account for other causes of irreversible disability, the 25th percentile was used: 0.011 HAQ units/TSS unit. In RCT trial arms, the HAQ/TSS were similar (0.013 and 0.015 in established and early RA, respectively; 25th percentile: 0.010). The correlation between DAM-HAQ(EP) and TSS was r=0.829. Over 5 years, damage would amount to an increase of irreversible HAQ of 0.33 on placebo, 0.13 on disease-modifying antirheumatic drugs (DMARDs) and 0.03 on TNF inhibitors+methotrexate (MTX).
An approach to estimate the numerical relationship between HAQ and damage as 0.01 HAQ points/TSS unit is presented, although the linear relationship may not be generally valid. This allows the assessment of functional correlates of radiographic changes in trials.
The delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by brain barriers, of which the most well known are the blood-brain barrier (BBB) ...and the blood-cerebrospinal fluid (CSF) barrier. Recent studies have shown numerous additional roles of these barriers, including an involvement in neurodevelopment, in the control of cerebral blood flow, and--when barrier integrity is impaired--in the pathology of many common CNS disorders such as Alzheimer's disease, Parkinson's disease and stroke.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) ...in the PREMIER study.
Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100 at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (DeltaTSS), and percentages of progressors (DeltaTSS > 0.5).
Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally intermediate. A strong, proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy. The monotherapies approximated the radiographic efficacy of adalimumab plus MTX only among remission-like responders, although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0. Concurrent clinical (DAS28 < 2.6) and radiographic (DeltaTSS <or= 0.5) remission was significantly more frequent at Week 104 with adalimumab plus MTX (45%) than with adalimumab (25%) or MTX (18%) monotherapy.
In patients with early RA, adalimumab plus MTX resulted in less radiographic progression than MTX monotherapy across the spectrum of clinical response, including ACR20 non-responses and remission-like responses.
Clinical and radiographic responses were evaluated in patients with psoriatic arthritis (PsA) treated for up to 2 years with etanercept.
Patients were previously randomized to receive placebo or ...etanercept in a double-blind study and chose to participate in the current open-label extension phase. All patients received etanercept 25 mg twice weekly. Radiographic progression was determined at baseline, 1 year, and 2 years using the Sharp method modified to include joints frequently affected in PsA. Arthritis and psoriasis responses were determined using American College of Rheumatology 20% (ACR20) improvement criteria, PsA response criteria (PsARC), and the psoriasis area severity index (PASI).
Of 205 patients randomized, 169 entered open-label, and 141 71 randomized to receive placebo (placebo/etanercept) and 70 randomized to receive etanercept (etanercept/etanercept) had radiographic data available for analysis at 2 years. ACR20 criteria, PsARC, and PASI 50 criteria were met by 64%, 84%, and 62%, respectively, of etanercept/etanercept patients at the end of the 48-week open-label period. Placebo/etanercept patients achieved comparable results within 12 weeks that were sustained at 48 weeks (63%, 80%, and 73%). Radiographic progression was inhibited in the etanercept/ etanercept patients (mean adjusted change in total Sharp score of -0.38 from baseline to 2 yrs). In placebo/etanercept patients, disease progression was inhibited once patients began receiving etanercept (mean adjusted change of -0.22 from 1 year to 2 years). Adverse event rates were similar to those observed during randomized phase, with only one serious adverse event deemed possibly related to etanercept.
These data demonstrate a sustained benefit of etanercept treatment, including inhibition of radiographic progression, in patients with PsA.
Objective
Osteoclast‐mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an ...investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer‐based technique, digital x‐ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA.
Methods
Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer‐assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands.
Results
At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: −0.0034, denosumab 180 mg: 0.0001 gain, placebo: −0.0108; P ≤ 0.01 for both denosumab doses). Twelve‐month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio.
Conclusion
Twice‐yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.
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