A randomised trial of adaptive pacing therapy, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome (PACE): statistical analysis plan

BACKGROUND: The publication of protocols by medical journals is increasingly becoming an accepted means for promoting good quality research and maximising transparency. Recently, Finfer and Bellomo have suggested the publication of statistical analysis plans (SAPs).The aim of this paper is to make public and to report in detail the planned analyses that were approved by the Trial Steering Committee in May 2010 for the principal papers of the PACE (Pacing, graded Activity, and Cognitive behaviour therapy: a randomised Evaluation) trial, a treatment trial for chronic fatigue syndrome. It illustrates planned analyses of a complex intervention trial that allows for the impact of clustering by care providers, where multiple care-providers are present for each patient in some but not all arms of the trial. RESULTS: The trial design, objectives and data collection are reported. Considerations relating to blinding, samples, adherence to the protocol, stratification, centre and other clustering effects, missing data, multiplicity and compliance are described. Descriptive, interim and final analyses of the primary and secondary outcomes are then outlined. CONCLUSIONS: This SAP maximises transparency, providing a record of all planned analyses, and it may be a resource for those who are developing SAPs, acting as an illustrative example for teaching and methodological research. It is not the sum of the statistical analysis sections of the principal papers, being completed well before individual papers were drafted. TRIAL REGISTRATION: ISRCTN54285094 assigned 22 May 2003; First participant was randomised on 18 March 2005

Cheap and Commonplace: Making the Case for BCG and γδ T Cells in COVID-19.

Antigen-specific vaccines developed for the COVID-19 pandemic demonstrate a remarkable achievement and are currently being used in high income countries with much success. However, new SARS-CoV-2 variants are threatening this success via mutations that lessen the efficacy of antigen-specific antibodies. One simple approach to assisting with this issue is focusing on strategies that build on the non-specific protection afforded by the innate immune response. The BCG vaccine has been shown to provide broad protection beyond tuberculosis disease, including against respiratory viruses, and ongoing studies are investigating its efficacy as a tool against SARS-CoV-2. Gamma delta (γδ) T cells, particularly the Vδ2 subtype, undergo rapid expansion after BCG vaccination due to MHC-independent mechanisms. Consequently, γδ T cells can produce diverse defenses against virally infected cells, including direct cytotoxicity, death receptor ligands, and pro-inflammatory cytokines. They can also assist in stimulating the adaptive immune system. BCG is affordable, commonplace and non-specific, and therefore could be a useful tool to initiate innate protection against new SARS-CoV-2 variants. However, considerations must also be made to BCG vaccine supply and the prioritization of countries where it is most needed to combat tuberculosis first and foremost

Improvement of the Staggered Fermion Operators

We present a complete and detailed derivation of the finite lattice spacing corrections to staggered fermion matrix elements. Expanding upon arguments of Sharpe, we explicitly implement the Symanzik improvement program demonstrating the absence of order $a$ terms in the Symanzik improved action. We propose a general program to improve fermion operators to remove $O(a)$ corrections from their matrix elements, and demonstrate this program for the examples of matrix elements of fermion bilinears and $B_K$. We find the former does have $O(a)$ corrections while the latter does not.Comment: 16 pages, latex, 1 figur

The effect of a sertoli cell-selective knockout of the androgen receptor on testicular gene expression in prepubertal mice

To unravel the molecular mechanisms mediating the effects of androgens on spermatogenesis, testicular gene expression was compared in mice with Sertoli cell-selective androgen receptor knockout (SCARKO) and littermate controls on postnatal d 10. Microarray analysis identified 692 genes with significant differences in expression. Of these, 28 appeared to be down-regulated and 12 up-regulated at least 2-fold in SCARKOs compared with controls. For nine of the more than 2-fold down-regulated genes, androgen regulation was confirmed by treatment of wild-type mice with an antiandrogen ( flutamide). Some of them were previously described to be androgen regulated or essential for spermatogenesis. Serine-type protease inhibitors were markedly overrepresented in this down-regulated subgroup. A time study (d 8-20), followed by cluster analysis, allowed identification of distinct expression patterns of differentially expressed genes. Three genes with a pattern closely resembling that of Pem, a prototypical an-drogen-regulated gene expressed in Sertoli cells, were selected for confirmation by quantitative RTPCR and additional analysis. The data confirm that the SCARKO model allows identification of novel androgen-regulated genes in the testis. Moreover, they suggest that protease inhibitors and other proteins related to tubular restructuring and cell junction dynamics may be controlled in part by androgens

Infrared Spectroscopy on Smoke Produced by Cauterization of Animal Tissue

In view of in vivo surgical smoke studies a difference-frequency-generation (DFG) laser spectrometer (spectral range 2900–3144 cm−1) and a Fourier-transform infrared (FTIR) spectrometer were employed for infrared absorption spectroscopy. The chemical composition of smoke produced in vitro with an electroknife by cauterization of different animal tissues in different atmospheres was investigated. Average concentrations derived are: water vapor (0.87%), methane (20 ppm), ethane (4.8 ppm), ethene (17 ppm), carbon monoxide (190 ppm), nitric oxide (25 ppm), nitrous oxide (40 ppm), ethyne (50 ppm) and hydrogen cyanide (25 ppm). No correlation between smoke composition and the atmosphere or the kind of cauterized tissue was found

A qualitative study of independent fast food vendors near secondary schools in disadvantaged Scottish neighbourhoods

Background: Preventing and reducing childhood and adolescent obesity is a growing priority in many countries. Recent UK data suggest that children in more deprived areas have higher rates of obesity and poorer diet quality than those in less deprived areas. As adolescents spend a large proportion of time in school, interventions to improve the food environment in and around schools are being considered. Nutrient standards for school meals are mandatory in the UK, but many secondary pupils purchase foods outside schools at break or lunchtime that may not meet these standards. Methods: Qualitative interviews were conducted with fast food shop managers to explore barriers to offering healthier menu options. Recruitment targeted independently-owned shops near secondary schools (pupils aged c.12-17) in low-income areas of three Scottish cities. Ten interviews were completed, recorded, and transcribed for analysis. An inductive qualitative approach was used to analyse the data in NVivo 10. Results: Five themes emerged from the data: pride in what is sold; individual autonomy and responsibility; customer demand; profit margin; and neighbourhood context. Interviewees consistently expressed pride in the foods they sold, most of which were homemade. They felt that healthy eating and general wellbeing are the responsibility of the individual and that offering what customers want to eat, not necessarily what they should eat, was the only way to stay in business. Most vendors felt they were struggling to maintain a profit, and that many aspects of the low-income neighbourhood context would make change difficult or impossible. Conclusions: Independent food shops in low-income areas face barriers to offering healthy food choices, and interventions and policies that target the food environment around schools should take the neighbourhood context into consideration

Targeted prevention of common mental health disorders in university students: randomised controlled trial of a transdiagnostic trait-focused web-based intervention

Background: A large proportion of university students show symptoms of common mental disorders, such as depression, anxiety, substance use disorders and eating disorders. Novel interventions are required that target underlying factors of multiple disorders.<p></p> Aims: To evaluate the efficacy of a transdiagnostic trait-focused web-based intervention aimed at reducing symptoms of common mental disorders in university students.<p></p> Method: Students were recruited online (n = 1047, age: M = 21.8, SD = 4.2) and categorised into being at high or low risk for mental disorders based on their personality traits. Participants were allocated to a cognitive-behavioural trait-focused (n = 519) or a control intervention (n = 528) using computerised simple randomisation. Both interventions were fully automated and delivered online (trial registration: ISRCTN14342225). Participants were blinded and outcomes were self-assessed at baseline, at 6 weeks and at 12 weeks after registration. Primary outcomes were current depression and anxiety, assessed on the Patient Health Questionnaire (PHQ9) and Generalised Anxiety Disorder Scale (GAD7). Secondary outcome measures focused on alcohol use, disordered eating, and other outcomes.<p></p> Results: Students at high risk were successfully identified using personality indicators and reported poorer mental health. A total of 520 students completed the 6-week follow-up and 401 students completed the 12-week follow-up. Attrition was high across intervention groups, but comparable to other web-based interventions. Mixed effects analyses revealed that at 12-week follow up the trait-focused intervention reduced depression scores by 3.58 (p<.001, 95%CI [5.19, 1.98]) and anxiety scores by 2.87 (p = .018, 95%CI [1.31, 4.43]) in students at high risk. In high-risk students, between group effect sizes were 0.58 (depression) and 0.42 (anxiety). In addition, self-esteem was improved. No changes were observed regarding the use of alcohol or disordered eating.<p></p> Conclusions This study suggests that a transdiagnostic web-based intervention for university students targeting underlying personality risk factors may be a promising way of preventing common mental disorders with a low-intensity intervention

Early Markers of Sickle Nephropathy in Children With Sickle Cell Anemia Are Associated With Red Cell Cation Transport Activity.

The early stages of sickle cell nephropathy (SCN) manifest in children with sickle cell anemia (SCA) as hyperfiltration and proteinuria. The physiological conditions of the renovascular system are among the most conducive to hemoglobin S polymerization in the body and will magnify small changes in red cell volume thus crucially modulating intracellular concentrations of hemoglobin S. This large cross-sectional study of children with sickle cell anemia measured glomerular filtration rates and microalbuminuria to report prevalence, clinical correlates and uniquely, association with key red cell cation transport mechanisms. One hundred and twelve patients (mean age 10.7 ± 4.1) were recruited. The prevalence of hyperfiltration and microalbuminuria was 98% and 15.1%, respectively. Glomerular filtration rates did not vary with age, but proteinuria became more prevalent with increasing age. Both features associated with markers of hemolysis, while elevated hemoglobin F was protective, but no association was seen with systolic or diastolic blood pressure. In multivariate analysis, both Gardos channel (β = 0.476, P < 0.001) and KCl co-transporter (KCC; β = -0.216, P = 0.009) activity, alongside age (β = 0.237, P = 0.004), remained independently predictive for microalbuminuria. Increased activity of Gardos channel and Psickle positively associated with microalbuminuria, while increased KCC activity associated with a reduction in microalbuminuria. This study demonstrates a direct link between the abnormally active red cell cation transport systems in sickle cell disease and sickle organopathy. Small variations in the activity of these transport mechanisms predict for SCN and measurement of them may help identify those at risk, while pharmaceutical manipulation of these excessively active systems may ameliorate their risk

EphA2 is a functional receptor for the growth factor progranulin.

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases