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Background: Frailty is characterised by a decline in physical, cognitive, energy, and health reserves and is linked to greater functional dependency and higher social care utilisation. However, the relationship between receiving care, or receiving insufficient care among older people with different frailty status and the risk of unplanned admission to hospital for any cause, or the risk of falls and fractures remains unclear. Methods and findings: This study used information from 7,656 adults aged 60 and older participating in the English Longitudinal Study of Ageing (ELSA) waves 6–8. Care status was assessed through received care and self-reported unmet care needs, while frailty was measured using a frailty index. Competing-risk regression analysis was used (with death as a potential competing risk), adjusted for demographic and socioeconomic confounders. Around a quarter of the participants received care, of which approximately 60% received low levels of care, while the rest had high levels of care. Older people who received low and high levels of care had a higher risk of unplanned admission independent of frailty status. Unmet need for care was not significantly associated with an increased risk of unplanned admission compared to those receiving no care. Older people in receipt of care had an increased risk of hospitalisation due to falls but not fractures, compared to those who received no care after adjustment for covariates, including frailty status. Conclusions: Care receipt increases the risk of hospitalisation substantially, suggesting this is a group worthy of prevention intervention focus. [ABSTRACT FROM AUTHOR]

The article focuses on food deserts are created in part by unintended consequences of urban planning. It explore causes of hunger in communities and argue that the only solution to solving hunger is by state intervention and coupled with unregulated market forces of food retailers who profit from a boom-bust cycle of business. It also mentions legislative effort attempted to address the crisis by offering loans to the same retailers.

Care home residents comprise a significant minority of ambulance patients, but little is known about how care homes impact ambulance service workload. This study aims to quantify differences in the workload of ambulance paramedics associated with patient residence (care home vs private). This was an observational study using routine ambulance service data and Clinical Frailty Scale scores from patients attended by 112 study paramedics between January 1, 2021, and June 30, 2021. 3056 patients (459 in care homes) aged ≥50 attended by the North East Ambulance Service NHS Foundation Trust, England. This study used 2 outcome measures of treatment: time spent at scene and conveyance to hospital. Anonymized patient data and incident time logs were collected from ambulance electronic patient care records. The relationships between care home residency, conveyance to hospital, and time spent at scene were investigated using ordinal logistic regression and quantile regression. Models were weighted to address potential sampling imbalance using anonymised call logs containing all eligible ambulance callouts. Care home residents were less likely to be conveyed to hospital [odds ratio: 0.75 (0.59-0.96)] and received shorter treatment time than community residents [median −7.0 (−12.0, −1.9) minutes for patients conveyed to hospital, −2.8 (−5.4, −0.3) minutes for patients discharged at scene]. Our results suggest that care homes provide support that reduces demand on the ambulance service and other "downstream" services in secondary care. This study also points to a need to enhance care for older people in private households to contain the demands on ambulance services. These findings have implications for countries like England, where ambulance services struggle to meet target response times, which may affect patient outcomes. [ABSTRACT FROM AUTHOR]

Background frailty is a condition of reduced function and health due to ageing processes and is associated with a higher risk of falls, hospitalisation, disability and mortality. Objective to determine the relationship between household wealth and neighbourhood deprivation with frailty status, independently of demographic factors, educational attainment and health behaviours. Design population-based cohort study. Setting communities in England. Subjects in total 17,438 adults aged 50+ from the English Longitudinal Study of Ageing. Methods multilevel mixed-effects ordered logistic regression was used in this study. Frailty was measured using a frailty index. We defined small geographic areas (neighbourhoods) using English Lower layer Super Output Areas. Neighbourhood deprivation was measured by the English Index of Multiple Deprivation, grouped into quintiles. Health behaviours included in this study are smoking and frequency of alcohol consumption. Results the proportion of respondents who were prefrail and frail were 33.8% [95% confidence interval (CI) 33.0–34.6%] and 11.7 (11.1–12.2)%, respectively. Participants in the lowest wealth quintile and living in the most deprived neighbourhood quintile had 1.3 (95% CI = 1.2–1.3) and 2.2 (95% CI = 2.1–2.4) times higher odds of being prefrail and frail, respectively, than the wealthiest participants living in the least deprived neighbourhoods Living in more deprived neighbourhood and poorer wealth was associated with an increased risk of becoming frail. Those inequalities did not change over time. Conclusions in this population-based sample, living in a deprived area or having low wealth was associated with frailty in middle-aged and older adults. This relationship was independent of the effects of individual demographic characteristics and health behaviours. [ABSTRACT FROM AUTHOR]

We propose the misclassified Ising Model: a framework for analyzing dependent binary data where the binary state is susceptible to error. We extend previous theoretical results of a model selection method based on applying the LASSO to logistic regression at each node and show that the method will still correctly identify edges in the underlying graphical model under suitable misclassification settings. With knowledge of the misclassification process, an expectation maximization algorithm is developed that accounts for misclassification during model selection. We illustrate the increase of performance of the proposed expectation maximization algorithm with simulated data, and using data from a functional magnetic resonance imaging analysis. [ABSTRACT FROM AUTHOR]

This article problematises protection for lesbian, gay, bisexual, transgender, and intersex (LGBTI) refugees in contexts of state-condoned persecution against this group. Based on ethnographic evidence from Kampala, Uganda, we draw attention to the homogenising tendencies of centralised protection systems in cities in the global south, which are primarily centred on nationality-based communities. We examine the processes of social exclusion that limit the involvement of LGBTI refugees from the Great Lakes Region in such communities, de facto placing them outside the parameters of institutional refugee protection. We then focus on their relational experiences of protection and safety within the office of an LGBTI support group in Kampala and argue for a micro-level approach that considers how LGBTI refugee protection is grounded in the geopolitics of the everyday. Our findings underscore the limitations of institutional policy and practice, which continues to overlook the protection gap that exists for LGBTI persons within the refugee population in Uganda. In order to remedy this protection gap, we suggest that a critical reconsideration is needed of the participatory spaces and cooperation between LGBTI refugee-led advocates and refugee serving institutions and decision-makers. [ABSTRACT FROM AUTHOR]

Background: COVID-19 vaccination in many countries, including England, has been prioritised primarily by age. However, people of the same age can have very different health statuses. Frailty is a commonly used metric of health and has been found to be more strongly associated with mortality than age among COVID-19 inpatients. Methods: We compared the number of first vaccine doses administered across the 135 NHS Clinical Commissioning Groups (CCGs) of England to both the over 50 population and the estimated frail population in each area. Area-based frailty estimates were generated using the English Longitudinal Survey of Ageing (ELSA), a national survey of older people. We also compared the number of doses to the number of people with other risk factors associated with COVID-19: atrial fibrillation, chronic kidney disease, diabetes, learning disabilities, obesity and smoking status. Results: We estimate that after 79 days of the vaccine program, across all Clinical Commissioning Group areas, the number of people who received a first vaccine per frail person ranged from 4.4 (95% CI 4.0-4.8) and 20.1 (95% CI 18.3-21.9). The prevalences of other risk factors were also poorly associated with the prevalence of vaccination across England. Conclusions: Vaccination with age-based priority created area-based inequities in the number of doses administered relative to the number of people who are frail or have other risk factors associated with COVID-19. As frailty has previously been found to be more strongly associated with mortality than age for COVID-19 inpatients, an age-based priority system may increase the risk of mortality in some areas during the vaccine roll-out period. Authorities planning COVID-19 vaccination programmes should consider the disadvantages of an age-based priority system. [ABSTRACT FROM AUTHOR]

The hippocampus encodes distinct contexts with unique patterns of activity. Representational shifts with changes in context, referred to as remapping, have been extensively studied. However, less is known about transitions between representations. In this study, we leverage a large dataset of neuronal recordings taken while rats performed an olfactory memory task with a predictable temporal structure involving trials and intertrial intervals (ITIs), separated by salient boundaries at the trial start and trial end. We found that trial epochs were associated with stable hippocampal representations despite moment‐to‐moment variability in stimuli and behavior. Representations of trial and ITI epochs were far more distinct than spatial factors would predict and the transitions between the two were abrupt. The boundary was associated with a large spike in multiunit activity, with many individual cells specifically active at the start or end of each trial. Both epochs and boundaries were encoded by hippocampal populations, and these representations carried information on orthogonal axes readily identified using principal component analysis. We suggest that the hippocampus orthogonalizes representations of the trial and ITI epochs and the activity spike at trial boundaries might serve to drive hippocampal activity from one stable state to the other. [ABSTRACT FROM AUTHOR]

We introduce a one-step EM algorithm to estimate the graphical structure in a Poisson-Log-Normal graphical model. This procedure is equivalent to a normality transformation that makes the problem of identifying relationships in high-throughput microRNA (miRNA) sequence data feasible. The Poisson-log-normal model moreover allows us to directly account for known overdispersion relationships present in this data set. We show that our EM algorithm provides a provable increase in performance in determining the network structure. The model is shown to provide an increase in performance in simulation settings over a range of network structures. The model is applied to high-throughput miRNA sequencing data from patients with breast cancer from The Cancer Genome Atlas (TCGA). By selecting the most highly connected miRNA molecules in the fitted network we find that nearly all of them are known to be involved in the regulation of breast cancer. [ABSTRACT FROM AUTHOR]

The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes. [ABSTRACT FROM AUTHOR]

Background A growing number of older people provide unpaid care, but contemporary research evidence on this group is limited. Aim This study aims to describe the characteristics of older people who provide unpaid care and how these vary by socioeconomic position. Methods Using recent information from the English Longitudinal Study of Ageing (ELSA wave 9, 2019), we analysed cross-sectional data on 1,282 unpaid carers aged ≥50. Data on sociodemographics, health, social wellbeing, care intensity and caregiver–recipient relationships were extracted. Total net non-pension wealth quintiles were used as a relative measure of socioeconomic position. Differences between the poorest and richest wealth quintiles were examined through logistic regression. Findings Most older carers in ELSA were female and looking after another older person. Poor mental and physical health and social isolation were common, and socially patterned. Compared with carers in the middle wealth group, the poorest group were more likely to be living with the person they cared for (odds ratio (OR) 1.56 [95% confidence interval (CI) 1.03–2.36]) and more likely to experience loneliness (OR 2.29 [95% CI 1.42–3.69]), dependency (i.e. the need for help with activities of daily living) (OR 1.62 [95% CI 1.05–2.51]), chronic pain (OR 1.81 [95% CI 1.23–2.67]), a higher number of diseases (OR 1.75 [95% CI 1.15–2.65]) and fair/poor self-rated health (OR 2.59 [95% CI 1.79–3.76]). The poorest carers were also less likely to have a high quality of life (OR 0.51 [95% CI 0.33–0.80]) or be in work (OR 0.33 [95% CI 0.19–0.59]). Conclusion Our findings suggest that financially disadvantaged unpaid carers (and their households) may have the greatest needs for intervention and support. Focussing resources on this group has potential to address social inequalities. [ABSTRACT FROM AUTHOR]

The NAD + -dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1–7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development. [ABSTRACT FROM AUTHOR]

Background: Documents from advocacy and fund-raising organizations for child mass deworming programmes in low- and middle-income countries cite unpublished economic studies claiming long-term effects on health, schooling and economic development.Methods: To summarize and appraise these studies, we searched for and included all long-term follow-up studies based on cluster-randomized trials included in a 2015 Cochrane review on deworming. We used Cochrane methods to assess risk of bias, and appraised the credibility of the main findings. Where necessary we contacted study authors for clarifications.Results: We identified three studies (Baird 2016, Ozier 2016 and Croke 2014) evaluating effects more than 9 years after cluster-randomized trials in Kenya and Uganda. Baird and Croke evaluate short additional exposures to deworming programmes in settings where all children were dewormed multiple times. Ozier evaluates potential spin-off effects to infants living in areas with school-based deworming. None of the studies used pre-planned protocols nor blinded the analysis to treatment allocation.Conclusions: In the context of reliable epidemiological methods, all three studies are at risk of substantial methodological bias. They therefore help in generating hypotheses, but should not be considered to provide reliable evidence of effects. [ABSTRACT FROM AUTHOR]

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stemcells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan. [ABSTRACT FROM AUTHOR]

It is unclear whether polypharmacy is associated with difficulty taking medications amongst people aged ≥85 living at home. This is despite the projected decline in availability of family carers, who may support independent living. Using Newcastle 85+ Study data and mixed‐effects modelling, we investigated the association between polypharmacy and difficulty taking medications amongst 85‐year‐olds living at home, over a 10‐year time period. Polypharmacy was not associated with difficulty taking medications as either a continuous (OR = 0.99 [0.91–1.08]) or categorical variable (5–9 medications, OR = 0.69 [0.34–1.41]; ≥10 medications, OR = 0.85 [0.34–2.07]). The significant predictors included disability, visual impairment and cognitive impairment. Our results suggest that people aged ≥85 living at home with disability, visual impairment and/or cognitive impairment will have difficulty taking their medications, regardless of how many they are prescribed. Therefore, healthcare professionals should routinely ask about, assess and address problems that these patient groups may have with taking their medicines, independent of the number of drugs taken. [ABSTRACT FROM AUTHOR]

Fertility is the first biological process to break down during aging, thereby making it a useful tool to understand fundamental processes of aging. Reproductive aging in females is associated with a loss of ovarian function characterised by a reduction in the number and quality of oocytes. The central dogma, namely that females are born with a fixed pool of oocytes that progressively decline with increasing maternal age, has been challenged by evidence supporting postnatal oogenesis in mammals. Reports demonstrating formation of new oocytes from newly discovered germline stem cells, referred to as oogonial stem cells (OSCs), has opened new avenues for treatment of female infertility. In this review we discuss why the OSCs possibly lose their regenerative potential over time, and focus specifically on the aging process in germline stem cells as a possible mechanism for understanding female age-related infertility and how we can slow or delay ovarian aging. This review discusses the link between stem cells, fertility and aging. The work listed provides insight into an emerging field in female fertility, namely, germline stem cells or OSCs and postnatal oogenesis. Given that oocyte numbers decline with age, it is possible that menopause is not a result of exhaustion of the ovarian reserve, rather a result of aging of OSCs. [ABSTRACT FROM AUTHOR]

Highlights: [•] Sirtuins (SIRT1–7) are NAD+-dependent deacylases that promote homeostasis. [•] SIRT1 activation shows promise for the treatment of aging and age-related diseases. [•] Natural and synthetic SIRT1 activators (STACs) have been discovered. [•] There is a common SIRT1 activation mechanism mediated by an N-terminal domain. [•] Clinical trials indicate that STACs are efficacious but questions remain. [ABSTRACT FROM AUTHOR]

The mammalian sirtuins (SIRT1-7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans. [ABSTRACT FROM AUTHOR]

The mammalian sirtuins (SIRT1-7) are NAD+-dependent lysine deacylases that play central roles in cell survival, inflammation, energy metabolism, and aging. Members of this family of enzymes are considered promising pharmaceutical targets for the treatment of age-related diseases including cancer, type 2 diabetes, inflammatory disorders, and Alzheimer's disease. SIRT1-activating compounds (STACs), which have been identified from a variety of chemical classes, provide health benefits in animal disease models. Recent data point to a common mechanism of allosteric activation by natural and synthetic STACs that involves the binding of STACs to a conserved N-terminal domain in SIRT1. Compared with polyphenols such as resveratrol, the synthetic STACs show greater potency, solubility, and target selectivity. Although considerable progress has been made regarding SIRT1 allosteric activation, key questions remain, including how the molecular contacts facilitate SIRT1 activation, whether other sirtuin family members will be amenable to activation, and whether STACs will ultimately prove safe and efficacious in humans. [ABSTRACT FROM AUTHOR]

David Sinclair and colleagues discuss their experience at the Ghana National Drugs Programme reviewing the international evidence base for five priority pediatric medicines and report that applying the global recommendations to Ghana was not straightforward for any of the five medicines. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

Background: Research in 2007 showed that World Health Organization (WHO) recommendations were largely based on expert opinion, rarely used systematic evidence-based methods, and did not follow the organization's own “Guidelines for Guidelines”. In response, the WHO established a “Guidelines Review Committee” (GRC) to implement and oversee internationally recognized standards. We examined the impact of these changes on WHO guideline documents and explored senior staff's perceptions of the new procedures. Methods and Findings: We used the AGREE II guideline appraisal tool to appraise ten GRC-approved guidelines from nine WHO departments, and ten pre-GRC guidelines matched by department and topic. We interviewed 20 senior staff across 16 departments and analyzed the transcripts using the framework approach. Average AGREE II scores for GRC-approved guidelines were higher across all six AGREE domains compared with pre-GRC guidelines. The biggest changes were noted for “Rigour of Development” (up 37.6%, from 30.7% to 68.3%) and “Editorial Independence” (up 52.7%, from 20.9% to 73.6%). Four main themes emerged from the interviews: (1) high standards were widely recognized as essential for WHO credibility, particularly with regard to conflicts of interest; (2) views were mixed on whether WHO needed a single quality assurance mechanism, with some departments purposefully bypassing the procedures; (3) staff expressed some uncertainties in applying the GRADE approach, with departmental staff concentrating on technicalities while the GRC remained concerned the underlying principles were not fully institutionalized; (4) the capacity to implement the new standards varied widely, with many departments looking to an overstretched GRC for technical support. Conclusions: Since 2007, WHO guideline development methods have become more systematic and transparent. However, some departments are bypassing the procedures, and as yet neither the GRC, nor the quality assurance standards they have set, are fully embedded within the organization. [ABSTRACT FROM AUTHOR]

The EXO collaboration has built and operated a 200 kg liquid xenon detector for studies of double beta decay. This paper summarizes the results obtained so far and their significance. The excellent performance of the detector encourages the concept of a much larger detector to obtain improved sensitivity to the possible detection of the neutrinoless decay mode of xenon. [ABSTRACT FROM AUTHOR]

To undertake a review of the literature on the epidemiology of meningococcal disease in India, with a view to informing future control policies. We searched the PUBMED, EMBASE, Global Health, IMSEAR and MedIND databases for observational studies relating to the burden of endemic meningococcal disease in India, the occurrence and epidemiological characteristics of epidemics, and the prevalence of individual meningococcal serogroups. The relatively few reports identified suggest that the incidence of endemic meningococcal disease in India is low, but that occasional epidemics of meningococcal disease have been recorded for at least 100 years. The larger epidemics have affected mainly the cities of northern India and have almost universally been caused by meningococci belonging to serogroup A. These epidemics have showed a few characteristics, including a marked seasonality, which are similar to those of epidemic meningococcal A disease in Africa. New serogroup A-containing meningococcal conjugate vaccines are now being developed and reaching the market, including an affordable monovalent serogroup A vaccine manufactured in India, but intended primarily for use in Africa. These new tools may have a role in containing future Indian epidemics, but their usefulness is dependent on early identification of epidemics. This will require a functional disease surveillance system with adequate laboratory support throughout India. [ABSTRACT FROM AUTHOR]

Abstract: Of all the proposed causes of ageing, DNA damage remains a leading, though still debated theory. Unlike most other types of age-related cellular damage, which can hypothetically be reversed, mutations in DNA are permanent. Such errors result in the accumulation of changes to RNA and protein sequences with age, and are tightly linked to cellular senescence and overall organ dysfunction. Over the past few years, an additional, more global role has emerged for the contribution of DNA damage and genomic instability to the ageing process. We, and others have found that DNA damage and the concomitant repair process can induce genome-wide epigenetic changes, which may promote a variety of age-related transcriptional and functional changes. Here, we discuss the link between DNA damage, chromatin alterations and ageing, an interplay that explains how seemingly random DNA damage could manifest in predictable phenotypic changes that define ageing, changes that may ultimately be reversible. [Copyright &y& Elsevier]

Many plant molecules interact with and modulate key regulators of mammalian physiology in ways that are beneficial to health, but why? We propose that heterotrophs (animals and fungi) are able to sense chemical cues synthesized by plants and other autotrophs in response to stress. These cues provide advance warning about deteriorating environmental conditions, allowing the heterotrophs to prepare for adversity while conditions are still favorable. [Copyright &y& Elsevier]

The search for antibodies that will reliably diagnose, predict and monitor the autoimmune thyroid diseases is a quest that is beset with difficulties. This review will describe the various antigens involved in autoimmune thyroid disease, the development of a humoral response to these antigens and some of the technical difficulties involved in trying to detect and then measure their concentrations. Multiple antigen configurations of thyroglobulin (TG) are produced when it is iodinated resulting in functionally active but immunologically distinct molecules. Thyroid peroxidase (TPO), originally described as thyroid microsomal antigen, is present on the apical surface of thyroid follicular cells and is the antigen most closely involved in cell-mediated cytotoxicity. Multiple B cell reactive epitopes exist each giving rise to different antibodies. The third antigen is the TSH receptor (TSHR) which is a two subunit glycoprotein. The extracellular A subunit is recognised by thyroid stimulating antibodies whilst those antibodies recognising the B subunit, located much nearer the cell surface, appear to function as blocking antibodies. The aetiology and mechanics of the autoimmune cellular and antibody responses involves a combination of HLA linkage, genetics and environmental factors to determine the initial and subsequent stages of the development of autoimmune thyroid disease. Starting off with immunofluorescence or passive tanned red cell agglutination assays, we now favour more sensitive TPO antibody quantitative immunoassays which are standardised using MRC 66/387. The apparent incidence of these antibodies is influenced by the techniques used to detect them and the significance of those positive antibody concentrations detected using assays that report very high incidence rates in the "normal" population remains to be proven using longitudinal studies. Older immunofluorescence and passive tanned red cell agglutination methods have been improved upon to give the current, competitive and non-competitive immunoassays that are much more sensitive and specific for anti-TG antibodies. However, because a wide-range of methods are still being used in clinical laboratories, the sensitivity and specificity of available methods will vary depending on the method used. There are still assays that are calibrated with purified or crude preparations of TG antibody by pooling patient sera or blood donor material. These various secondary standards are often, but not always, calibrated against the primary standard (MRC 65/93). All requests for TG estimation in thyroid carcinoma patients should have TG antibody estimated at the same time because of the possibility of interference in the tumour marker assay by the antibody. Two methods are widely used for the estimation of TSHR antibodies. The first involves bioassays based on cultured cells to measure the stimulating class of antibodies and the second involves receptor assays based on 125I-labeled TSH. The most widely used assay uses detergent-solubilized porcine TSHR with TSHR antibodies to inhibit the TSHR-125I-TSH interaction, and polyethylene glycol to separate receptor-bound and free labelled-TSH by precipitation. TSHR antibody heterogeneity can coexist within an individual patient and change over time is one reason why it has been difficult to develop diagnostically accurate TSHR antibody tests. [ABSTRACT FROM AUTHOR]

Systemic vasculitis, although rare, is often diagnosed late and long after the onset of symptoms. The small vessel vasculitides are recognized clinically by their multisystem presentation, markers of inflammation and evidence for an acute glomerulonephritis (GN), with the most apparent organ involved directing referral to secondary care. Routine laboratory tests are usually non-specific in systemic vasculitis but the use of anti-neutrophil cytoplasmic antibodies (ANCAs) and glomerular basement membrane (GBM) antibodies can aid diagnosis, treatment and monitoring decisions. These antibodies are detected and quantified by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA), usually in combination for ANCA, and ELISA systems (or direct IIF on kidney biopsy) for GBM antibodies. The presence or absence of ANCA does not confirm or exclude the diagnosis of systemic vasculitis but negative and positive predictive values will be strongly influenced by clinical presentation. Various large studies have been unable to conclude that following serial ANCA titres has great clinical utility in each case but each patient must be considered on its own merits; for example the reappearance of ANCA in a patient who was rendered ANCA negative following treatment is more likely to indicate relapse. The adoption of consensus guidelines that direct testing towards patients with rapidly progressive GN, pulmonary haemorrhage, persistent and destructive ear, nose and upper airways problems, such as subglottic tracheal stenosis, a retro-orbital mass and cutaneous vasculitis with systemic features or peripheral neuropathy, will greatly increase the clinical utility and positive predictive value of these tests. [ABSTRACT FROM AUTHOR]

Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time — a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA–protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms. [ABSTRACT FROM AUTHOR]

Abstract: Buprenorphine (Subutex®) is widely abused in Finland. A combination of buprenorphine plus naloxone (Suboxone®) has been available since late 2004, permitting a comparison of the abuse of the two products among untreated intravenous (IV) users. A survey was distributed to attendees at a Helsinki needle exchange program over 2-weeks in April, 2005, At least 30% were returned anonymously. Survey variables included: years of prior IV opioid abuse, years of buprenorphine abuse, frequency, dosage, route of administration and reasons for use, concomitant IV abuse of other substances and amount paid on the street for both buprenorphine and buprenorphine+naloxone. Buprenorphine was the most frequently used IV drug for 73% of the respondents. More than 75% said they used IV buprenorphine to self-treat addiction or withdrawal. Most (68%) had tried the buprenorphine+naloxone combination IV, but 80% said they had a “bad” experience. Its street price was less than half that of buprenorphine alone. The buprenorphine+naloxone combination appears to be a feasible tool, along with easier access to addiction treatment, for decreasing IV abuse of buprenorphine. [Copyright &y& Elsevier]

Bacterial acetyl-coenzyme A (acetyl-CoA) synthetase (AceCS), an evolutionarily conserved enzyme that converts acetate to acetyl-CoA, is activated by sirtuin-mediated deacetylation. Two recent studies show that this mechanism of regulation is also crucial for mammalian AceCS activity, indicating that control of metabolism at the step of converting acetate to acetyl-CoA is conserved. These findings highlight a metabolic regulatory network controlled by sirtuins that has implications for the mechanisms of calorie restriction and modulation of mammalian lifespan. [Copyright &y& Elsevier]

The article presents an excerpt from the book "Lifespan: Why We Age and Why We Don't Have To" by David A. Sinclair which focuses on plant-based diet and longevity.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans. [ABSTRACT FROM AUTHOR]

The design and self-assembly of six new supramolecular complexes (four triangles and two 2+2 assemblies) are described. These assemblies incorporate two new bispyridyl cavitand building blocks and were prepared in excellent yields (85–95%). The assemblies and building blocks were characterized with multinuclear NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis. Isotopically resolved mass spectrometry along with NMR data confirms the existence of the six assemblies. [ABSTRACT FROM AUTHOR]

This review describes the aetiology of the major thyroid antigens. Iodination of thyroglobulin produces multiple antigen configurations which are functionally active but immunologically distinct. The thyroid stimulating hormone (TSH) receptor is a two-subunit glycoprotein; the extracellular A subunit is recognized by thyroid stimulating antibodies, while those antibodies recognizing the B subunit, located much nearer the cell surface, appear to function as blocking antibodies. Thyroid peroxidase (TPO), originally described as thyroid microsomal antigen, is present on the apical surface of thyroid follicular cells and is the antigen involved in cell-mediated cytotoxicity. Multiple B-cell-reactive epitopes exist, each giving rise to different antibodies. The aetiology and mechanics of the autoimmune cellular and antibody responses involves a combination of human leucocyte antigen (HLA) linkage, genetics and environmental factors to determine the initial and subsequent stages of the development of autoimmune thyroid disease. Depending on the antibody, a combination of enzyme-linked immunosorbent assay for TPO and thyroglobulin and bioassays and/or radioimmunoassay for TSH receptor antibodies are used to estimate their concentrations. The other conditions with which autoimmune thyroid diseases are associated include, for example, pernicious anaemia, connective tissue disorders, diabetes, coeliac disease, mood disorders like depression and fertility-related problems such as miscarriage, infertility, in vitro fertilization failure, pre-term delivery and postpartum thyroiditis. Often, there is no cause-and-effect relationship between them and it is debatable in some cases whether it is worthwhile monitoring patients with autoimmune thyroid disease for other conditions or vice versa. The review also itemizes the circumstances in which it might be useful to measure each antibody (i.e. the use of TPO antibodies in investigation of goitre, diagnosis of Graves' and Hashimoto's disease and the prediction of risk of developing hypothyroidism during subclinical thyroid disease; TSH receptor antibodies in maternal and neonatal hyperthyroidism and thyroglobulin antibodies in the monitoring and treatment of thyroid carcinoma). Finally, taking the current literature into account, an algorithm is recommended for the most effective use of these antibodies in the investigation of autoimmune thyroid disease. [ABSTRACT FROM AUTHOR]

m- or p-diiodobenzene undergoes selective double coupling reactions with arylboronic acids and esters. Selectivity for double coupling over single coupling is remarkably strong: even with a diiodobenzene:monoboronic acid ratio of 10:1, the products of double coupling are formed in good yields. Steric hindrance and electronic influences of the boronic acid or ester, and reaction conditions do not appear to impact significantly upon the outcome of the reaction. In contrast, m- and p-dibromobenzenes undergo single couplings with aryl boronic acids with high selectivity. [ABSTRACT FROM AUTHOR]

Background: There are reports in the literature describing artefactually raised phosphate concentrations in serum samples of patients with myeloma. However, IgA paraproteins have been reported only rarely as a potential cause. Methods: Following the detection of a grossly elevated phosphate concentration in a patient with an IgA paraprotein and another with an IgG paraprotein, we estimated phosphate concentrations in a further 73 patients with paraproteins using the Bayer ADVIA 1650 and Ortho Vitros 950 analysers. The latter method has been reported to be unaffected by pseudohyperphosphataemia. Results: Deproteinization of the serum samples containing the IgA and IgG paraproteins showed that they were responsible for the interference. No significant difference in serum phosphate concentrations measured by the two analysers was noted for the larger study of serum IgG or IgM paraproteins. However, a statistically significant but clinically trivial difference in phosphate concentration was noted for serum IgA paraproteins, with the Ortho Vitros 950 giving slightly higher phosphate concentrations. Deproteinization of these samples yielded similar phosphate concentrations. Phosphate estimation in serum samples without paraproteins using both analysers yielded results that were not statistically different. Conclusion: On occasion, serum samples containing IgA paraproteins may give rise to erroneous phosphate concentrations when the Bayer ADVIA is used [ABSTRACT FROM AUTHOR]

The design of a specialised query language for content based image retrieval provides a means of addressing many of the problems associated with commonly used query paradigms such as query-by-example and query-by-sketch. By basing such a language on an extensible ontology, which encompasses both high-level and low-level image properties and relations, one can go a long way towards bridging the semantic gap between user models of saliency and relevance and those employed by a retrieval system.This paper discusses these issues and illustrates the design and use of an ontological retrieval language through the example of the OQUEL query language. The retrieval process takes place entirely within the ontological domain defined by the syntax and semantics of the user query. Since the system does not rely on the pre-annotation of images with sentences in the language, the format of text queries is highly flexible. The language is also extensible to allow for the definition of higher-level terms such as ‘cars’, ‘people’, etc. on the basis of existing language constructs through the use of Bayesian inference networks. The matching process utilises automatically extracted image segmentation and classification information and can incorporate any other feature extraction mechanisms or contextual knowledge available at processing time to satisfy a given user request. [Copyright &y& Elsevier]

Background: The demand for screening for coeliac disease has grown rapidly over the last few years. Laboratories depending on immunofluorescence assays are faced with an increasing workload using a labour-intensive test, and an alternative to this test has been sought. This study compares tissue transglutaminase (TTG) and endomysium antibodies (EMA) in a routine clinical laboratory situation. Methods: An immunofluorescence IgA EMA test was compared with a guinea pig TTG antibody ELISA for 816 unselected requests for gut antibody screening. Discrepant results were investigated more fully using a variety of human source TTG antigen kits. Results: Guinea pig TTG ELISA and EMA assays showed agreement for 93·6% of samples. Four samples were misclassified and 48 samples gave false positive TTG results. Study of 46 EMA samples (this group included 39 of the 'discrepant' negative EMA/positive guinea pig TTG group) using three different human purified and/or recombinant TTG sources showed that 42 patients had no TTG antibodies using human sources, three were misclassified and one patient had negative EMA and positive TTG results that could not be readily explained. Further study of 32 EMA positive samples showed almost complete agreement between the human source TTG kits. Conclusions: We can recommend the replacement of EMA with ELISA for TTG antibodies for the routine screening for coeliac disease, but all positive TTG antibodies should still be followed up with IgA EMA and samples should be screened for IgA deficiency. [ABSTRACT FROM AUTHOR]

A chronological summary of the contributions made by researchers in Nottingham, UK, to developing the scope for the intramolecular Stille reaction in target natural product syntheses, e.g. leinamycin, the virginiamycins, macrolactin A, rhizoxin, the amphidinolides, lophotoxin, and pateamine, is described. [Copyright &y& Elsevier]

Focuses on a study which examined the telomere position effect (TPE) in human cells. Factors that might mediate human TPE; Effect of TPE on replicative aging in vitro; Influence of TPE on human aging.

This paper discusses the implementation of total quality (TQ)-based performance measurement in the context of service-based organizations. TQ-based performance measurement with all of its intricacies and the issues surrounding its application are examined through examples involving the following service-oriented organizations: Mercury Communication Ltd; National Westminster Life Assurance; American Express Travel Related Services; Barclays Card Related Services Division; Girobank plc; and National and Provincial Building Society. The paper concludes by highlighting some factors that affect the implementation of the total quality management-based measurement. [ABSTRACT FROM AUTHOR]

Investigates the role of Sgs1 gene in recombination-mediated lengthening of terminal telomeric repeats in Bloom syndrome, Rothmund-Thomson and Werner syndromes cells. Examination of whether Sgs1 has a telomeric function in the absence of a telomerase, before and after senescence and during recovery; Cre-lox system for deleting telomerase gene.

Focuses on the constitutional measures adopted by the labor government elected in Great Britain in May 1997 and identifies further changes that will need to follow in order to accommodate the early changes. Results of the first elections for the Scottish Parliament held on May 6, 1999; Creation of the Welsh Assembly; Number of members of the Northern Ireland Assembly.

Changes in phenology are a common response to climate change, but their impact on population dynamics is often ambiguous and at‐risk species are omitted from most analyses. We assessed the relationship between change in abundance and change in phenology for 114 butterfly populations of 31 at‐risk species from five families in 10 US states. We used data from Pollard‐walk and similar monitoring programmes for which count data were collected on multiple occasions per year. We also collected information from managers on site‐level management interventions. To estimate abundance, we first fit separate smoothing splines for each species at each site. Yearly abundance was estimated as the area under the activity curve for that year, and from this, we estimated abundance trends over the period for which we had population data. Phenological shifts were measured as the changes in median activity date, beginning of flight season, duration of flight season and phenological constancy (negative of the magnitude of trends in median activity date). We also evaluated the association of ecological traits (voltinism, diet breadth, position within geographic range, ecoregion, overwintering stage and seasonality) and management (proportion of years with interventions) with trends in abundance and in phenology. Across all populations, the estimated trend in abundance was −0.085, equivalent to an 8.1% decline/year. Positive trends in abundance were associated with smaller shifts in the median flight date (higher constancy). We also found strong associations between trends in abundance and management interventions, with increased management associated with increasing abundance trends. In general, ecological traits were not strongly associated with trends in phenology or trends in abundance. Synthesis and applications: Populations with less phenological constancy are more likely to be rapidly declining and populations with more frequent management interventions are increasing. These results suggest that one key outcome of management interventions may be to mitigate some of the impacts of climate change, which in turn may contribute to higher population growth. These results also imply that managers may need to alter the timing of appropriate management to synchronize with activities of at‐risk species as species shift their phenology. [ABSTRACT FROM AUTHOR]

Focuses on a study which examined whether yeast cells held in a stationary phase exhibit any of the phenotypes found in replicatively aging Saccharomyces cerevisiae mother cells. Methodology of the study; Results and discussion; Conclusion.

Focuses on the Labour Party's constitutional revolution in Great Britain in 1997-1998. Devolution and decentralization of the British constitution; British government's pledge to incorporate European Convention on Human Rights into the country's law; Electoral reform.