Rituximab and intravenous immunoglobulin treatment in PM/Scl antibody-associated disease: case-based review.

Autoantibodies to the 75-kDa and 100-kDa subunits of the PM/Scl nucleolar protein complex are associated with an overlap syndrome, manifesting with clinical features of systemic sclerosis and idiopathic inflammatory myopathy. We describe the diverse clinical features in a series of 4 cases with anti-PM/Scl-75 and/or anti-PM/Scl-100 antibodies, including severe proximal muscle weakness, oesophageal dysfunction, respiratory weakness requiring mechanical ventilation, Raynaud's, calcinosis cutis, sclerodactyly and critical digital ischaemia. Despite the severity of striated and oesophageal muscle weakness, all patients responded very well to immune suppression, and calcinosis cutis in one case regressed substantially. We highlight the efficacy of Rituximab and intravenous immunoglobulin therapy (IVIg) in these cases, enabling return to normal muscle function within six months. Rituximab was preferentially chosen for cases with hyper-gammaglobulinemia and multiple autoantibodies in addition to anti-PM/Scl, and IVIg was utilised for cases where a rapid onset of effect was required, such as severe ventilator-dependent respiratory muscle weakness and oesophageal dysfunction

meCLICK-Seq, a Substrate-Hijacking and RNA Degradation Strategy for the Study of RNA Methylation.

The fates of RNA species in a cell are controlled by ribonucleases, which degrade them by exploiting the universal structural 2'-OH group. This phenomenon plays a key role in numerous transformative technologies, for example, RNA interference and CRISPR/Cas13-based RNA editing systems. These approaches, however, are genetic or oligomer-based and so have inherent limitations. This has led to interest in the development of small molecules capable of degrading nucleic acids in a targeted manner. Here we describe click-degraders, small molecules that can be covalently attached to RNA species through click-chemistry and can degrade them, that are akin to ribonucleases. By using these molecules, we have developed the meCLICK-Seq (methylation CLICK-degradation Sequencing) a method to identify RNA modification substrates with high resolution at intronic and intergenic regions. The method hijacks RNA methyltransferase activity to introduce an alkyne, instead of a methyl, moiety on RNA. Subsequent copper(I)-catalyzed azide-alkyne cycloaddition reaction with the click-degrader leads to RNA cleavage and degradation exploiting a mechanism used by endogenous ribonucleases. Focusing on N6-methyladenosine (m6A), meCLICK-Seq identifies methylated transcripts, determines RNA methylase specificity, and reliably maps modification sites in intronic and intergenic regions. Importantly, we show that METTL16 deposits m6A to intronic polyadenylation (IPA) sites, which suggests a potential role for METTL16 in IPA and, in turn, splicing. Unlike other methods, the readout of meCLICK-Seq is depletion, not enrichment, of modified RNA species, which allows a comprehensive and dynamic study of RNA modifications throughout the transcriptome, including regions of low abundance. The click-degraders are highly modular and so may be exploited to study any RNA modification and design new technologies that rely on RNA degradation.UKRI (BBSRC DTP scholarships to S.M. and H.K.C) and the Jardine Foundation and Cambridge Trust (PhD scholarship to M.E.H.)

Reduced level of arousal and increased mortality in adult acute medical admissions: a systematic review and meta-analysis

Abstract Background Reduced level of arousal is commonly observed in medical admissions and may predict in-hospital mortality. Delirium and reduced level of arousal are closely related. We systematically reviewed and conducted a meta-analysis of studies in adult acute medical patients of the relationship between reduced level of arousal on admission and in-hospital mortality. Methods We conducted a systematic review (PROSPERO: CRD42016022048), searching MEDLINE and EMBASE. We included studies of adult patients admitted with acute medical illness with level of arousal assessed on admission and mortality rates reported. We performed meta-analysis using a random effects model. Results From 23,941 studies we included 21 with 14 included in the meta-analysis. Mean age range was 33.4 - 83.8 years. Studies considered unselected general medical admissions (8 studies, n=13,039) or specific medical conditions (13 studies, n=38,882). Methods of evaluating level of arousal varied. The prevalence of reduced level of arousal was 3.1%-76.9% (median 13.5%). Mortality rates were 1.7%-58% (median 15.9%). Reduced level of arousal was associated with higher in-hospital mortality (pooled OR 5.71; 95% CI 4.21-7.74; low quality evidence: high risk of bias, clinical heterogeneity and possible publication bias). Conclusions Reduced level of arousal on hospital admission may be a strong predictor of in-hospital mortality. Most evidence was of low quality. Reduced level of arousal is highly specific to delirium, better formal detection of hypoactive delirium and implementation of care pathways may improve outcomes. Future studies to assess the impact of interventions on in-hospital mortality should use validated assessments of both level of arousal and delirium

Trajectory of vitamin D status during pregnancy in relation to neonatal birth size and fetal survival: a prospective cohort study

Background: We investigated the associations between vitamin D status in early and late pregnancy with neonatal small for gestational age (SGA), low birth weight (LBW) and preterm delivery. Furthermore, associations between vitamin D status and pregnancy loss were studied. Methods: Serum 25-hydroxyvitamin D (25OHD) was sampled in gestational week ≤ 16 (trimester 1 (T1), N = 2046) and > 31 (trimester 3 (T3), N = 1816) and analysed using liquid chromatography tandem mass spectrometry. Pregnant women were recruited at antenatal clinics in south-west Sweden at latitude 57–58°N. Gestational and neonatal data were retrieved from medical records. Multiple gestations and terminated pregnancies were excluded from the analyses. SGA was defined as weight and/or length at birth < 2 SD of the population mean and LBW as < 2500 g. Preterm delivery was defined as delivery < 37 + 0 gestational weeks and pregnancy loss as spontaneous abortion or intrauterine fetal death. Associations between neonatal outcomes and 25OHD at T1, T3 and change in 25OHD (T3-T1) were studied using logistic regression. Results: T1 25OHD was negatively associated with pregnancy loss and 1 nmol/L increase in 25OHD was associated with 1% lower odds of pregnancy loss (OR 0.99, p = 0.046). T3 25OHD ≥ 100 nmol/L (equal to 40 ng/ml) was associated with lower odds of SGA (OR 0.3, p = 0.031) and LBW (OR 0.2, p = 0.046), compared to vitamin D deficiency (25OHD < 30 nmol/L, or 12 ng/ml). Women with a ≥ 30 nmol/L increment in 25OHD from T1 to T3 had the lowest odds of SGA, LBW and preterm delivery. Conclusions: Vitamin D deficiency in late pregnancy was associated with higher odds of SGA and LBW. Lower 25OHD in early pregnancy was only associated with pregnancy loss. Vitamin D status trajectory from early to late pregnancy was inversely associated with SGA, LBW and preterm delivery with the lowest odds among women with the highest increment in 25OHD. Thus, both higher vitamin D status in late pregnancy and gestational vitamin D status trajectory can be suspected to play a role in healthy pregnancy

The development of a multidisciplinary fall risk evaluation tool for demented nursing home patients in the Netherlands

BACKGROUND: Demented nursing home patients are at high risk for falls. Falls and associated injuries can have a considerable influence on the autonomy and quality of life of patients. The prevention of falls among demented patients is therefore an important issue. In order to intervene in an efficient way in this group of patients, it is important to systematically evaluate the fall risk profile of each individual patient so that for each patient tailor-made preventive measures can be taken. Therefore, the objective of the present study is to develop a feasible and evidence based multidisciplinary fall risk evaluation tool to be used for tailoring preventive interventions to the needs of individual demented patients. METHODS: To develop this multidisciplinary fall risk evaluation tool we have chosen to combine scientific evidence on the one hand and experts' opinions on the other hand. Firstly, relevant risk factors for falling in elderly persons were gathered from the literature. Secondly, a group of Dutch experts in the field of falls and fall prevention in the elderly were consulted to judge the suitability of these risk factors for use in a multidisciplinary fall risk evaluation tool for demented nursing home patients. Thirdly, in order to generate a compact list of the most relevant risk factors for falling in demented elderly, all risk factors had to fulfill a set of criteria indicating their relevance for this specific target population. Lastly the final list of risk factors resulting from the above mentioned procedure was presented to the expert group. The members were also asked to give their opinion about the practical use of the tool. RESULTS: The multidisciplinary fall risk evaluation tool we developed includes the following items: previous falls, use of medication, locomotor functions, and (correct) choice and use of assistive and protective devices. The tool is developed for the multidisciplinary teams of the nursing homes. CONCLUSION: This evidence and practice based multidisciplinary fall risk evaluation tool targets the preventive interventions aimed to prevent falls and their negative consequences in demented nursing home patients

Structural diversity in binary nanoparticle superlattices

Assembly of small building blocks such as atoms, molecules and nanoparticles into macroscopic structures - that is, 'bottom up' assembly - is a theme that runs through chemistry, biology and material science. Bacteria(1), macromolecules(2) and nanoparticles(3) can self-assemble, generating ordered structures with a precision that challenges current lithographic techniques. The assembly of nanoparticles of two different materials into a binary nanoparticle superlattice (BNSL)(3-7) can provide a general and inexpensive path to a large variety of materials (metamaterials) with precisely controlled chemical composition and tight placement of the components. Maximization of the nanoparticle packing density has been proposed as the driving force for BNSL formation(3,8,9), and only a few BNSL structures have been predicted to be thermodynamically stable. Recently, colloidal crystals with micrometre-scale lattice spacings have been grown from oppositely charged polymethyl methacrylate spheres(10,11). Here we demonstrate formation of more than 15 different BNSL structures, using combinations of semiconducting, metallic and magnetic nanoparticle building blocks. At least ten of these colloidal crystalline structures have not been reported previously. We demonstrate that electrical charges on sterically stabilized nanoparticles determine BNSL stoichiometry; additional contributions from entropic, van der Waals, steric and dipolar forces stabilize the variety of BNSL structures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62551/1/nature04414.pd

Relationship between subjective fall risk assessment and falls and fall-related fractures in frail elderly people

<p>Abstract</p> <p>Background</p> <p>Objective measurements can be used to identify people with risks of falls, but many frail elderly adults cannot complete physical performance tests. The study examined the relationship between a subjective risk rating of specific tasks (SRRST) to screen for fall risks and falls and fall-related fractures in frail elderly people.</p> <p>Methods</p> <p>The SRRST was investigated in 5,062 individuals aged 65 years or older who were utilized day-care services. The SRRST comprised 7 dichotomous questions to screen for fall risks during movements and behaviours such as walking, transferring, and wandering. The history of falls and fall-related fractures during the previous year was reported by participants or determined from an interview with the participant's family and care staff.</p> <p>Results</p> <p>All SRRST items showed significant differences between the participants with and without falls and fall-related fractures. In multiple logistic regression analysis adjusted for age, sex, diseases, and behavioural variables, the SRRST score was independently associated with history of falls and fractures. Odds ratios for those in the high-risk SRRST group (≥ 5 points) compared with the no risk SRRST group (0 point) were 6.15 (p < 0.01) for a single fall, 15.04 (p < 0.01) for recurrent falls, and 5.05 (p < 0.01) for fall-related fractures. The results remained essentially unchanged in subgroup analysis accounting for locomotion status.</p> <p>Conclusion</p> <p>These results suggest that subjective ratings by care staff can be utilized to determine the risks of falls and fall-related fractures in the frail elderly, however, these preliminary results require confirmation in further prospective research.</p

A systematic review of studies measuring health-related quality of life of general injury populations

Background. It is important to obtain greater insight into health-related quality of life (HRQL) of injury patients in order to document people's pathways to recovery and to quantify the impact of injury on population health over time. We performed a systematic review of studies measuring HRQL in general injury populations with a generic health state measure to summarize existing knowledge. Methods. Injury studies (1995-2009) were identified with main inclusion criteri

Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis

The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2–5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs

Discomfort and agitation in older adults with dementia

<p>Abstract</p> <p>Background</p> <p>A majority of patients with dementia present behavioral and psychological symptoms, such as agitation, which may increase their suffering, be difficult to manage by caregivers, and precipitate institutionalization. Although internal factors, such as discomfort, may be associated with agitation in patients with dementia, little research has examined this question. The goal of this study is to document the relationship between discomfort and agitation (including agitation subtypes) in older adults suffering from dementia.</p> <p>Methods</p> <p>This correlational study used a cross-sectional design. Registered nurses (RNs) provided data on forty-nine residents from three long-term facilities. Discomfort, agitation, level of disability in performing activities of daily living (ADL), and severity of dementia were measured by RNs who were well acquainted with the residents, using the Discomfort Scale for patients with Dementia of the Alzheimer Type, the Cohen-Mansfield Agitation Inventory, the ADL subscale of the Functional Autonomy Measurement System, and the Functional Assessment Staging, respectively. RNs were given two weeks to complete and return all scales (i.e., the Cohen-Mansfield Agitation Inventory was completed at the end of the two weeks and all other scales were answered during this period). Other descriptive variables were obtained from the residents' medical file or care plan.</p> <p>Results</p> <p>Hierarchical multiple regression analyses controlling for residents' characteristics (sex, severity of dementia, and disability) show that discomfort explains a significant share of the variance in overall agitation (28%, <it>p </it>< 0.001), non aggressive physical behavior (18%, <it>p </it>< 0.01) and verbally agitated behavior (30%, <it>p </it>< 0.001). No significant relationship is observed between discomfort and aggressive behavior but the power to detect this specific relationship was low.</p> <p>Conclusion</p> <p>Our findings provide further evidence of the association between discomfort and agitation in persons with dementia and reveal that this association is particularly strong for verbally agitated behavior and non aggressive physical behavior.</p