What matters to children with CFS/ME?:A conceptual model as the first stage in developing a PROM

Background: Paediatric chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) is relatively common and disabling. Research is hampered because current patient-reported outcome measures (PROMs) do not capture outcomes that are important to children with CFS/ME. Aim: The aim of this study was to explore the aspects of life and health outcomes that matter to children with CFS/ME. Methods: Twenty-five children with CFS/ME were interviewed (11 males, 14 females; mean age 12.9 years (SD 2.2), range 8–17). Twelve were trial participants interviewed during the trial and 13 were recruited as part of a follow-up qualitative study. Parents were present in 19 interviews with their children. Three mothers participated in a focus group. All the interviews and the focus group were audio-recorded and transcribed. Data were analysed thematically using techniques of constant comparison. NVivo was used to structure and categorise data in a systematic way. Results: Children identified four key themes (health outcome domains): ‘symptoms’ that fluctuated, which caused an unpredictable reduction in both ‘physical activity’ and ‘social participation’ all of which impacted on ‘emotional well-being’. These domains were influenced by both ‘management’ and ‘contextual factors’, which could be positive and negative. The relationship between healthcare and school was considered pivotal. Conclusions: Children's descriptions helped to inform a conceptual model that is necessary to develop a new paediatric CFS/ME PROM. Doctors need to be aware of how children conceptualise CFS/ME; the relationship between healthcare and school is fundamental to ameliorate the impact of CFS/ME. Trial registration number: ISRCTN81456207

‘Asking for help’:a qualitative interview study exploring the experiences of interpersonal counselling (IPC) compared to low-intensity cognitive behavioural therapy (CBT) for women with depression during pregnancy.

Abstract Background Treating depression early in pregnancy can improve health outcomes for women and their children. Current low-intensity psychological therapy for perinatal depression is a supported self-help approach informed by cognitive behavioural therapy (CBT) principles. Interpersonal counselling (IPC) may be a more appropriate low-intensity talking therapy for addressing the problems experienced by pregnant women with depression. A randomised feasibility trial (ADAGIO) has compared the acceptability of offering IPC for mild-moderate antenatal depression in routine NHS services compared to low-intensity CBT. This paper reports on a nested qualitative study which explored women’s views and expectations of therapy, experiences of receiving IPC, and Psychological Wellbeing Practitioners (PWPs - junior mental health workers) views of delivering the low-intensity therapy. Methods A qualitative study design using in-depth semi-structured interviews and focus groups. Thirty-two pregnant women received talking therapy within the ADAGIO trial; 19 contributed to the interview study from July 2019 to January 2020; 12 who had IPC and seven who had CBT. All six PWPs trained in IPC took part in a focus group or interview. Interviews and focus groups were recorded, transcribed, anonymised, and analysed using thematic methods. Results Pregnant women welcomed being asked about their mental health in pregnancy and having the chance to have support in accessing therapy. The IPC approach helped women to identify triggers for depression and explored relationships using strategies such as ‘promoting self-awareness through mood timelines’, ‘identifying their circles of support’, ‘developing communication skills and reciprocity in relationships’, and ‘asking for help’. PWPs compared how IPC differed from their prior experiences of delivering low-intensity CBT. They reported that IPC included a useful additional emotional component which was relevant to the perinatal period. Conclusions Identifying and treating depression in pregnancy is important for the future health of both mother and child. Low-intensity perinatal-specific talking therapies delivered by psychological wellbeing practitioners in routine NHS primary care services in England are acceptable to pregnant women with mild-moderate depression. The strategies used in IPC to manage depression, including identifying triggers for low mood, and communicating the need for help, may be particularly appropriate for the perinatal period. Trial registration ISRCTN 11513120. 02/05/2019

Randomised controlled trial of early frenotomy in breastfed infants with mild-moderate tongue-tie

TRIAL DESIGN: A randomised, parallel group, pragmatic trial. SETTING: A large UK maternity hospital. PARTICIPANTS: Term infants <2 weeks old with a mild or moderate degree of tongue-tie, and their mothers who were having difficulties breastfeeding. OBJECTIVES: To determine if immediate frenotomy was better than standard breastfeeding support. INTERVENTIONS: Participants were randomised to an early frenotomy intervention group or a ‘standard care’ comparison group. OUTCOMES: Primary outcome was breastfeeding at 5 days, with secondary outcomes of breastfeeding self-efficacy and pain on feeding. Final assessment was at 8 weeks; 20 also had qualitative interviews. Researchers assessing outcomes, but not participants, were blinded to group assignment. RESULTS: 107 infants were randomised, 55 to the intervention group and 52 to the comparison group. Five-day outcome measures were available for 53 (96%) of the intervention group and 52 (100%) of the comparison group, and intention-to-treat analysis showed no difference in the primary outcome—Latch, Audible swallowing, nipple Type, Comfort, Hold score. Frenotomy did improve the tongue-tie and increased maternal breastfeeding self-efficacy. At 5 days, there was a 15.5% increase in bottle feeding in the comparison group compared with a 7.5% increase in the intervention group. After the 5-day clinic, 44 of the comparison group had requested a frenotomy; by 8 weeks only 6 (12%) were breastfeeding without a frenotomy. At 8 weeks, there were no differences between groups in the breastfeeding measures or in the infant weight. No adverse events were observed. CONCLUSIONS: Early frenotomy did not result in an objective improvement in breastfeeding but was associated with improved self-efficacy. The majority in the comparison arm opted for the intervention after 5 days

Stepwise Optimization of the Procedure for Assessment of Circulating Progenitor Cells in Patients with Myocardial Infarction

The number and functional activity of circulating progenitor cells (CPCs) is altered in diabetic patients. Furthermore, reduced CPC count has been shown to independently predict cardiovascular events. Validation of CPCs as a biomarker for cardiovascular risk stratification requires rigorous methodology. Before a standard operation protocol (SOP) can be designed for such a trial, a variety of technical issues have to be addressed fundamentally, which include the appropriate type of red blood cell lysis buffer, FMO or isotype controls to identify rare cell populations from background noise, optimal antibody dilutions and conditions of sample storage. We herein propose improvements in critical steps of CPC isolation, antigenic characterization and determination of functional competence for final application in a prospective investigation of CPCs as a biomarker of outcome following acute myocardial infarction.In this validation study, we refined the standard operating procedure (SOP) for flow cytometry characterisation and functional analysis of CPCs from the first 18 patients of the Progenitor Cell Response after Myocardial Infarction Study (ProMIS). ProMIS aims to verify the prognostic value of CPCs in patients with either ST elevation or non-ST elevation myocardial infarction with or without diabetes mellitus, using cardiac magnetic resonance imaging (MRI) for assessment of ventricular function as a primary endpoint. Results indicate crucial steps for SOP implementation, namely timely cell isolation after sampling, use of appropriate lysis buffer to separate blood cell types and minimize the acquisition events during flow cytometry, adoption of proper fluorophore combination and antibody titration for multiple antigenic detection and introduction of counting beads for precise quantification of functional CPC activity in migration assay.With systematic specification of factors influencing the enumeration of CPC by flow cytometry, the abundance and migration capacity of CPCs can be correctly assessed. Adoption of validated SOP is essential for refined comparison of patients with different comorbidities in the analysis of risk stratification

Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2

Notch receptors are normally cleaved during maturation by a furin-like protease at an extracellular site termed S1, creating a heterodimer of non-covalently associated subunits. The S1 site lies within a key negative regulatory region (NRR) of the receptor, which contains three highly conserved Lin12/Notch repeats and a heterodimerization domain (HD) that interact to prevent premature signaling in the absence of ligands. Because the role of S1 cleavage in Notch signaling remains unresolved, we investigated the effect of S1 cleavage on the structure, surface trafficking and ligand-mediated activation of human Notch1 and Notch2, as well as on ligand-independent activation of Notch1 by mutations found in human leukemia.The X-ray structure of the Notch1 NRR after furin cleavage shows little change when compared with that of an engineered Notch1 NRR lacking the S1-cleavage loop. Likewise, NMR studies of the Notch2 HD domain show that the loop containing the S1 site can be removed or cleaved without causing a substantial change in its structure. However, Notch1 and Notch2 receptors engineered to resist S1 cleavage exhibit unexpected differences in surface delivery and signaling competence: S1-resistant Notch1 receptors exhibit decreased, but detectable, surface expression and ligand-mediated receptor activation, whereas S1-resistant Notch2 receptors are fully competent for cell surface delivery and for activation by ligands. Variable dependence on S1 cleavage also extends to T-ALL-associated NRR mutations, as common class 1 mutations display variable decrements in ligand-independent activation when introduced into furin-resistant receptors, whereas a class 2 mutation exhibits increased signaling activity.S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or T-ALL-associated mutations lead to conformational changes of the NRR that permit metalloprotease cleavage

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Surface processes recorded by rocks and soils on Meridiani Planum, Mars: Microscopic Imager observations during Opportunity's first three extended missions

The Microscopic Imager (MI) on the Mars Exploration Rover Opportunity has returned images of Mars with higher resolution than any previous camera system, allowing detailed petrographic and sedimentological studies of the rocks and soils at the Meridiani Planum landing site. Designed to simulate a geologist's hand lens, the MI is mounted on Opportunity's instrument arm and can resolve objects 0.1 mm across or larger. This paper provides an overview of MI operations, data calibration, and analysis of MI data returned during the first 900 sols (Mars days) of the Opportunity landed mission. Analyses of Opportunity MI data have helped to resolve major questions about the origin of observed textures and features. These studies support eolian sediment transport, rather than impact surge processes, as the dominant depositional mechanism for Burns formation strata. MI stereo observations of a rock outcrop near the rim of Erebus Crater support the previous interpretation of similar sedimentary structures in Eagle Crater as being formed by surficial flow of liquid water. Well-sorted spherules dominate ripple surfaces on the Meridiani plains, and the size of spherules between ripples decreases by about 1 mm from north to south along Opportunity's traverse between Endurance and Erebus craters

Ice structures, patterns, and processes: A view across the ice-fields

We look ahead from the frontiers of research on ice dynamics in its broadest sense; on the structures of ice, the patterns or morphologies it may assume, and the physical and chemical processes in which it is involved. We highlight open questions in the various fields of ice research in nature; ranging from terrestrial and oceanic ice on Earth, to ice in the atmosphere, to ice on other solar system bodies and in interstellar space