Characterization of disease course and remission in early seropositive rheumatoid arthritis: results from the TACERA longitudinal cohort study

Background: To characterise disease course and remission in a longitudinal observational study of newly diagnosed, initially treatment-naïve patients with seropositive rheumatoid arthritis (RA). Methods: Patients with early untreated seropositive RA were recruited from 28 UK centres. Multiple clinical and laboratory measures were collected every 3 months for up to 18 months. Disease activity was measured using the 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI). Logistic regression models examined clinical predictors of 6-month remission and latent class mixed models characterised disease course. Results: We enrolled 275 patients of whom 267 met full eligibility and provided baseline data. According to SDAI definition, 24.3% attained 6-month remission. Lower baseline Health Assessment Questionnaire (HAQ) and SDAI predicted 6-month remission (p = 0.013 and 0.011). Alcohol intake and baseline prescribing of methotrexate with a second disease-modifying antirheumatic drug (DMARD; vs monotherapy without glucocorticoids) were also predictive. Three distinct SDAI trajectory subpopulations emerged; corresponding to an inadequate responder group (6.5%), and higher and lower baseline activity responder groups (22.4% and 71.1%). Baseline HAQ and Short Form-36 Health Survey – Mental Component Score (SF-36 MCS) distinguished these groups. In addition, a number of baseline clinical predictors correlated with disease activity severity within subpopulations. Beneficial effects of alcohol intake were found across subpopulations. Conclusion: Three distinct disease trajectory subpopulations were identified. Differential effects of functional and mental well-being, alcohol consumption, and baseline RA medication prescribing on disease activity severity were found across subpopulations. Heterogeneity across trajectories cannot be fully explained by baseline clinical predictors. We hypothesise that biological markers collected early in disease course (within 6 months) may help patient management and better targeting of existing and novel therapies

Short and long term retention in antiretroviral care in health facilities in rural Malawi and Zimbabwe.

Despite the successful scale-up of ART services over the past years, long term retention in ART care remains a major challenge, especially in high HIV prevalence and resource-limited settings. This study analysed the short (<12 months) and long (>12 months) term retention on ART in two ART programmes in Malawi (Thyolo district) and Zimbabwe (Buhera district)

Tiny cystine stones in the gallbladder of a patient with cholecystolithiasis complicating acute cholecystitis: a case report

Cystine stones, the main component of which is cystine, are very common urinary calculi, but are rare in the gall bladder. In animals, there has been only one report of cystine gallstones in tree shrews, and to our knowledge, this is the first report of cystine gallstones in humans

Oxygen for relief of dyspnoea in mildly- or non-hypoxaemic patients with cancer: a systematic review and meta-analysis

The aim of this study was to determine the efficacy of palliative oxygen for relief of dyspnoea in cancer patients. MEDLINE and EMBASE were searched for randomised controlled trials, comparing oxygen and medical air in cancer patients not qualifying for home oxygen therapy. Abstracts were reviewed and studies were selected using Cochrane methodology. The included studies provided oxygen at rest or during a 6-min walk. The primary outcome was dyspnoea. Standardised mean differences (SMDs) were used to combine scores. Five studies were identified; one was excluded from meta-analysis due to data presentation. Individual patient data were obtained from the authors of the three of the four remaining studies (one each from England, Australia, and the United States). A total of 134 patients were included in the meta-analysis. Oxygen failed to improve dyspnoea in mildly- or non-hypoxaemic cancer patients (SMD=−0.09, 95% confidence interval −0.22 to 0.04; P=0.16). Results were stable to a sensitivity analysis, excluding studies requiring the use of imputed quantities. In this small meta-analysis, oxygen did not provide symptomatic benefit for cancer patients with refractory dyspnoea, who would not normally qualify for home oxygen therapy. Further study of the use of oxygen in this population is warranted given its widespread use

Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes

Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral—but not the apical—plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion

Approaches for estimating benefits and costs of interventions in plant biosecurity across invasion phases

Nonnative plant pests cause billions of dollars in damages. It is critical to prevent or reduce these losses by intervening at various stages of the invasion process, including pathway risk management (to prevent pest arrival), surveillance and eradication (to counter establishment), and management of established pests (to limit damages). Quantifying benefits and costs of these interventions is important to justify and prioritize investments and to inform biosecurity policy. However, approaches for these estimations differ in (1) the assumed relationship between supply, demand, and prices, and (2) the ability to assess different types of direct and indirect costs at invasion stages, for a given arrival or establishment probability. Here we review economic approaches available to estimate benefits and costs of biosecurity interventions to inform the appropriate selection of approaches. In doing so, we complement previous studies and reviews on estimates of damages from invasive species by considering the influence of economic and methodological assumptions. Cost accounting is suitable for rapid decisions, specific impacts, and simple methodological assumptions but fails to account for feedbacks, such as market adjustments, and may overestimate long-term economic impacts. Partial equilibrium models consider changes in consumer and producer surplus due to pest impacts or interventions and can account for feedbacks in affected sectors but require specialized economic models, comprehensive data sets, and estimates of commodity supply and demand curves. More intensive computable general equilibrium models can account for feedbacks across entire economies, including capital and labor, and linkages among these. The two major considerations in choosing an approach are (1) the goals of the analysis (e.g., consideration of a single pest or intervention with a limited range of impacts vs. multiple interventions, pests or sectors), and (2) the resources available for analysis such as knowledge, budget and time

Improving Outcomes in Infants of HIV-Infected Women in a Developing Country Setting

Since 1999 GHESKIO, a large voluntary counseling and HIV testing center in Port-au-Prince, Haiti, has had an ongoing collaboration with the Haitian Ministry of Health to reduce the rate of mother to child HIV transmission. There are limited data on the ability to administer complex regimens for reducing mother to child transmission and on risk factors for continued transmission and infant mortality within programmatic settings in developing countries.We analyzed data from 551 infants born to HIV-infected mothers seen at GHESKIO, between 1999 and 2005. HIV-infected mothers and their infants were given "short-course" monotherapy with antiretrovirals for prophylaxis; and, since 2003, highly active antiretroviral therapy (HAART) when clinical or laboratory indications were met. Infected women seen in the pre-treatment era had 27% transmission rates, falling to 10% in this cohort of 551 infants, and to only 1.9% in infants of women on HAART. Mortality rate after HAART introduction (0.12 per year of follow-up [0.08-0.16]) was significantly lower than the period before the availability of such therapy (0.23 [0.16-0.30], P<0.0001). The effects of maternal health, infant feeding, completeness of prophylaxis, and birth weight on mortality and transmission were determined using univariate and multivariate analysis. Infant HIV-1 infection and low birth weight were associated with infant mortality in less than 15 month olds in multivariate analysis.Our findings demonstrate success in prevention of mother-to-child HIV transmission and mortality in a highly resource constrained setting. Elements contributing to programmatic success include provision of HAART in the context of a comprehensive program with pre and postnatal care for both mother and infant

Open data and digital morphology

Over the past two decades, the development of methods for visualizing and analysing specimens digitally, in three and even four dimensions, has transformed the study of living and fossil organisms. However, the initial promise, that the widespread application of such methods would facilitate access to the underlying digital data, has not been fully achieved. The underlying datasets for many published studies are not readily or freely available, introducing a barrier to verification and reproducibility, and the reuse of data. There is no current agreement or policy on the amount and type of data that should be made available alongside studies that use, and in some cases are wholly reliant on, digital morphology. Here, we propose a set of recommendations for minimum standards and additional best practice for 3D digital data publication, and review the issues around data storage, management and accessibility

Mortality of Patients Lost to Follow-Up in Antiretroviral Treatment Programmes in Resource-Limited Settings: Systematic Review and Meta-Analysis

BACKGROUND: The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are in patients who are lost to programmes. METHODS AND FINDINGS: We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness. CONCLUSIONS: In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes