Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT

Background The PACE trial was a well-powered randomised trial designed to examine the efficacy of graded exercise therapy (GET) and cognitive behavioural therapy (CBT) for chronic fatigue syndrome. Reports concluded that both treatments were moderately effective, each leading to recovery in over a fifth of patients. However, the reported analyses did not consistently follow the procedures set out in the published protocol, and it is unclear whether the conclusions are fully justified by the evidence. Methods Here, we present results based on the original protocol-specified procedures. Data from a recent Freedom of Information request enabled us to closely approximate these procedures. We also evaluate the conclusions from the trial as a whole. Results On the original protocol-specified primary outcome measure - overall improvement rates - there was a significant effect of treatment group. However, the groups receiving CBT or GET did not significantly outperform the Control group after correcting for the number of comparisons specified in the trial protocol. Also, rates of recovery were consistently low and not significantly different across treatment groups. Finally, on secondary measures, significant effects were almost entirely confined to self-report measures. These effects did not endure beyond two years. Conclusions These findings raise serious concerns about the robustness of the claims made about the efficacy of CBT and GET. The modest treatment effects obtained on self-report measures in the PACE trial do not exceed what could be reasonably accounted for by participant reporting biases

Differential regulation of GPCRs: Are GRK expression levels the key?

G protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors and their signal transduction is tightly regulated by GPCR kinases (GRKs) and β-arrestins. In this review, we discuss novel aspects of the regulatory GRK/β-arrestin system. Therefore, we briefly revise the origin of the “barcode” hypothesis for GPCR/β-arrestin interactions, which states that β-arrestins recognize different receptor phosphorylation states to induce specific functions. We emphasize two important parameters which may influence resulting GPCR phosphorylation patterns: (A) direct GPCR–GRK interactions and (B) tissue-specific expression and availability of GRKs and β-arrestins. In most studies that focus on the molecular mechanisms of GPCR regulation, these expression profiles are underappreciated. Hence we analyzed expression data for GRKs and β-arrestins in 61 tissues annotated in the Human Protein Atlas. We present our analysis in the context of pathophysiological dysregulation of the GPCR/GRK/β-arrestin system. This tissue-specific point of view might be the key to unraveling the individual impact of different GRK isoforms on GPCR regulation

Interseeded pennycress and camelina yield and influence on row crops

Field pennycress (Thlaspi arvense L.) (PC) and winter camelina [Camelina sativa (L.) Crantz] (WC) have the potential to provide ecosystem services and economic incentives when adopted as an oilseed cover crops in corn (Zea mays L.)–soybean [Glycine max (L.) Merr.] rotations. However, PC and WC establishment and yield in the northern Corn Belt and their subsequent impact on row crops are not well known. This study was conducted to determine the effects of interseeding dates (R4, R5, and R6; and R6, R7, and R8 development stages for corn and soybean, respectively) and cover crop species (PC, WC, and winter rye [Secale cereale L.]) on seed yield and oil content of interseeded oilseeds (PC and WC) and relay soybean, and 3rd‐year corn grain yield and quality. Study sites were initiated near Ames, IA; Morris and Rosemount, MN; and Prosper, ND. Late interseeding of PC and WC resulted in greater oilseed yield. Overall yields of PC (218–880 kg ha–1) and WC (15–770 kg ha–1), averaged across interseeding dates, were low when interseeded in corn and soybean. The PC and WC reduced relay‐soybean grain yield by 13–32% and 13–42%, respectively. Corn grain yield and quality following relay soybean were not affected by the residual effects of oilseed cover crops. Based on the results of our study, we do not recommend relay cropping soybean with PC and WC in the upper Midwest

Soil Nitrogen in Response to Interseeded Cover Crops in Maize–Soybean Production Systems

Improved agronomic management strategies are needed to minimize the impact that current maize (Zea mays L.) and soybean (Glycine max (L.) Merr.) production practices have on soil erosion and nutrient losses, especially nitrogen (N). Interseeded cover crops in standing maize and soybean scavenge excess soil N and thus reduce potential N leaching and runoff. The objectives were to determine the impact that pennycress (Thlaspi arvense L.) (PC), winter camelina (Camelina sativa (L.) Crantz) (WC), and winter rye (Secale cereale L.) (WR) cover crops have on soil N, and carbon (C) and N accumulation in cover-crop biomass. The cover crops were interseeded in maize at the R5 growth stage and in soybean at R7 in four replicates over two growing seasons at four locations. Soil and aboveground biomass samples were taken in autumn and spring. Data from the maize and soybean systems were analyzed separately. The results showed that cover crops had no effect on soil NH4+-N under both systems. However, winter rye decreased soil NO3−-N up to 76% compared with no-cover-crop treatment in the soybean system. Pennycress and WC scavenged less soil N than WR. Similarly, N and C accumulation in PC and WC biomass were less than in WR, in part because of their poor growth performance under the interseeding practice. Until PC and WC varieties with improved suitability for interseeding are developed, other agronomic practices may need to be explored for improving N scavenging in maize and soybean cropping systems to reduce nutrient leaching and enhance crop diversification

Establishing winter annual cover crops by interseeding into Maize and Soybean

The limited time available for cover crop establishment after maize (Zea mays L.) and soybean [Glycine max (L.) Merr.] harvest is one of the main reasons for low cover crop adoption in the upper Midwest. Therefore, a 2‐yr multilocation study was conducted to evaluate winter annual cover crops establishment, their effect on main crop grain yields, and soil water content when interseeded into standing maize and soybean. Treatments were three interseeding dates (broadcasting at R4, R5, and R6 growth stages for maize, and R6, R7, and R8 for soybean) and three cover crops (winter camelina [WC] [Camelina sativa L.], field pennycress [PC] [Thlaspi arvense L.], winter rye [Secale cereale L.] plus a no cover crop control). Cover crop establishment and growth varied with interseeding date across locations and seasons for both maize and soybean systems. Averaged over the years, rye produced more green cover and biomass than the oilseeds in spring. However, at the northern‐most site, the greatest (40%) green cover was recorded from pennycress and indicates its potential as a cover crop. Seeding date and cover crops did not negatively affect maize or soybean grain yields or soil water content. Generally, cover crop establishment and growth were better in the soybean system than maize due to better light penetration. Further research is needed to develop better suited cultivars and/or agronomic management practices for interseeding into maize. The results of this study indicate that producers could integrate these covers to diversify and add ecosystem services to soybean production practices

How Carvedilol activates β₂-adrenoceptors

Carvedilol is among the most effective β-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of β(1)-adrenoceptors, arrestin-biased signalling via β(2)-adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilol’s cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through β(2)ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the β-adrenoceptor system

Self-care and adherence to medication: a survey in the hypertension outpatient clinic

<p>Abstract</p> <p>Background</p> <p>Self-care practices for patients with hypertension include adherence to medication, use of blood pressure self-monitoring and use of complementary and alternative therapies (CAM) The prevalence of CAM use and blood pressure self-monitoring have not been described in a UK secondary care population of patients with hypertension and their impact on adherence to medication has not been described. Adherence to medication is important for blood pressure control, but poor adherence is common. The study aimed to determine the prevalence of self-care behaviours in patients attending a secondary care hypertension clinic.</p> <p>Methods</p> <p>Cross-sectional questionnaire survey. 196 patients attending a secondary care hypertension clinic in a teaching hospital serving a multiethnic population, Birmingham, UK. Main outcome measures: Prevalence of use of CAM, home monitors, adherence to anti-hypertensive medication.</p> <p>Results</p> <p>CAM use in previous 12 months was reported by 66 (43.1%) respondents. CAM users did not differ statistically from non-CAM users by age, gender, marital status or education. Vitamins, prayer a dietary supplements were the most commonly used CAM. Nine (12.7%) women reported using herbal CAM compared to one man (1.2%), (p = 0.006). Ten (6.7%) respondents reported ever being asked by a doctor about CAM use. Perfect adherence to anti-hypertensive medication was reported by 26 (44.8%) CAM-users and 46 (60.5%) non-CAM users (p = 0.07). Being female and a CAM user was significantly associated with imperfect adherence to anti-hypertensive medication. Older and white British respondents were significantly more likely to report perfect adherence. Blood pressure monitors were used by 67 (43.8%) respondents, which was not associated with gender, CAM use or adherence to medication.</p> <p>Conclusion</p> <p>Hypertensive patients use a variety of self-care methods, including CAM, home blood pressure monitors, and adherence to prescribed medication. This study found the prevalence of CAM use in hypertensive patients was higher than in the UK population. It is important to acknowledge the self-care behaviour of hypertensive patients, in order to assess potential harm, and encourage effective methods of self-care.</p