Engagement With Stop Smoking Services After Referral or Signposting: A Mixed Methods Study.

INTRODUCTION: Screening for smoking when people interact with healthcare services and referral of those who smoke to stop smoking services (SSSs) is a key component of efforts to tackle tobacco use. However, little is known about what happens after someone is referred or signposted to SSSs. METHODS: As part of the Cessation of Smoking Trial in the Emergency Department (NCT04854616), those randomised to intervention (n= 505) were referred to local SSSs (along with receiving brief advice and an e-cigarette starter kit) and those randomised to control (n= 502) were given contact details for the same services (signposted). SSS engagement data was collected: 1) directly from participants and 2) from SSS, additional qualitative data came from 33 participant interviews. RESULTS: Engagement with SSSs was very low. 3.2% (n=16) of those in the intervention group and 2.4% (n=12) in the control group reported attending a one-to-one support session. From SSS data, engagement was also low with 8.9% (n=43) of those referred engaging and 3.1% (n=15) going on to quit with SSS support. The majority of the 24 intervention participants interviewed did not recall being contacted by an SSS. CONCLUSION: Referral or signposting to stop smoking services within an Emergency Department based trial resulted in very low levels of engagement. Barriers to engagement identified included participants not being contacted by SSSs and the support offered not meeting their needs. IMPLICATIONS: Referral or signposting of those who smoke to Stop smoking services from the Emergency Department resulted in low rates of engagement in this large multi-centre randomised controlled trial. In order to better support those who smoke it may be more effective for smoking cessation advice to be offered 'in the moment' within clinical settings, and follow-up to be proactively offered rather than relying on people being motivated to contact the services themselves or engaging when contacted.

Cessation of Smoking Trial in the Emergency Department (COSTED): a multicentre randomised controlled trial.

BACKGROUND: Supporting people to quit smoking is one of the most powerful interventions to improve health. The Emergency Department (ED) represents a potentially valuable opportunity to deliver a smoking cessation intervention if it is sufficiently resourced. The objective of this trial was to determine whether an opportunistic ED-based smoking cessation intervention can help people to quit smoking. METHODS: In this multicentre, parallel-group, randomised controlled superiority trial conducted between January and August 2022, adults who smoked daily and attended one of six UK EDs were randomised to intervention (brief advice, e-cigarette starter kit and referral to stop smoking services) or control (written information on stop smoking services). The primary outcome was biochemically validated abstinence at 6 months. RESULTS: An intention-to-treat analysis included 972 of 1443 people screened for inclusion (484 in the intervention group, 488 in the control group). Of 975 participants randomised, 3 were subsequently excluded, 17 withdrew and 287 were lost to follow-up. The 6-month biochemically-verified abstinence rate was 7.2% in the intervention group and 4.1% in the control group (relative risk 1.76; 95% CI 1.03 to 3.01; p=0.038). Self-reported 7-day abstinence at 6 months was 23.3% in the intervention group and 12.9% in the control group (relative risk 1.80; 95% CI 1.36 to 2.38; p<0.001). No serious adverse events related to taking part in the trial were reported. CONCLUSIONS: An opportunistic smoking cessation intervention comprising brief advice, an e-cigarette starter kit and referral to stop smoking services is effective for sustained smoking abstinence with few reported adverse events. TRIAL REGISTRATION NUMBER: NCT04854616.

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to ß cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on ß-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of ß-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Do attachment-related differences in reflective functioning explain associations between expressed emotion and youth self-harm?

Youth self-harm is associated with poor health outcomes and attempted and completed suicide. Associations exist between self-harm and expressed emotion (EE), attachment insecurity, and reflective functioning (RF), but these associations are poorly understood. This study evaluates a mediation model in which perceived caregiver EE (pEE) exerts an indirect effect on youth self-harm through attachment insecurity and RF uncertainty. 461 participants aged 16-24 years completed an online survey. Statistical analyses revealed significant direct effects of pEE on attachment insecurity, and of RF uncertainty on self-harm; however, some direct effects were specific to pEE from female caregivers, and attachment insecurity in youth relationships with female caregivers. A significant direct effect of pEE on self-harm was found for pEE from male caregivers only. Significant indirect effects of pEE on self-harm through attachment anxiety and RF uncertainty were found only in relation to female caregivers. The findings encourage family-, attachment-, and mentalization-based approaches to preventing and treating youth self-harm, with a recommendation that caregivers are given adequate support, education, and skills-based training following youth disclosures of self-harm. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03614-w.

Sick of the Sick Role: Narratives of What "Recovery" Means to People With CFS/ME.

Little is known about what recovery means to those with chronic fatigue syndrome/myalgic encephalomyelitis, a poorly understood, disabling chronic health condition. To explore this issue, semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10) after a guided self-help intervention, and analyzed via "constant comparison." The meaning of recovery differed between participants-expectations for improvement and deployment of the sick role (and associated stigma) were key influences. While some saw recovery as complete freedom from symptoms, many defined it as freedom from the "sick role," with functionality prioritized. Others redefined recovery, reluctant to return to the lifestyle that may have contributed to their illness, or rejected the concept as unhelpful. Recovery is not always about eliminating all symptoms. Rather, it is a nexus between the reality of limited opportunities for full recovery, yet a strong desire to leave the illness behind and regain a sense of "normality."

Materialization of a Geometrically Frustrated Magnet in a Hybrid Coordination Framework: A Study of the Iron(II) Oxalate Fluoride Framework, KFe(C2O4)F.

Here we discuss magnetic hybrid coordination frameworks in relation to the realization of new geometrically frustrated magnets. In particular, we present the nuclear and magnetic structures of one such system-the Fe2+-based oxalate fluoride framework KFe(C2O4)F-through analysis of the powder neutron diffraction and muon spectroscopy data. KFe(C2O4)F retains an orthorhombic Cmc21 structure upon cooling to 2 K composed of quasi-one-dimensional iron fluoride chains connected to a distorted triangular network via oxalate anions. Previous magnetometry measurements of KFe(C2O4)F indicate that it is a strongly interacting system with a Weiss constant θ ≈ -300 K that undergoes a magnetic ordering transition at TN ≈ 20 K, yielding a frustration index, f = |θ|/TN ≈ 15, reflective of high-spin frustration. We determine the nature of this frustrated antiferromagnetic ordering below TN and show that the resulting magnetic structure is best described by a model in the Cmc'21' magnetic space group.

Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial.

BACKGROUND: Graded exercise therapy is an effective and safe treatment for chronic fatigue syndrome, but it is therapist intensive and availability is limited. We aimed to test the efficacy and safety of graded exercise delivered as guided self-help. METHODS: In this pragmatic randomised controlled trial, we recruited adult patients (18 years and older) who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome from two secondary-care clinics in the UK. Patients were randomly assigned to receive specialist medical care (SMC) alone (control group) or SMC with additional guided graded exercise self-help (GES). Block randomisation (randomly varying block sizes) was done at the level of the individual with a computer-generated sequence and was stratified by centre, depression score, and severity of physical disability. Patients and physiotherapists were necessarily unmasked from intervention assignment; the statistician was masked from intervention assignment. SMC was delivered by specialist doctors but was not standardised; GES consisted of a self-help booklet describing a six-step graded exercise programme that would take roughly 12 weeks to complete, and up to four guidance sessions with a physiotherapist over 8 weeks (maximum 90 min in total). Primary outcomes were fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale); both were self-rated by patients at 12 weeks after randomisation and analysed in all randomised patients with outcome data at follow-up (ie, by modified intention to treat). We recorded adverse events, including serious adverse reactions to trial interventions. We used multiple linear regression analysis to compare SMC with GES, adjusting for baseline and stratification factors. This trial is registered at ISRCTN, number ISRCTN22975026. FINDINGS: Between May 15, 2012, and Dec 24, 2014, we recruited 211 eligible patients, of whom 107 were assigned to the GES group and 104 to the control group. At 12 weeks, compared with the control group, mean fatigue score was 19·1 (SD 7·6) in the GES group and 22·9 (6·9) in the control group (adjusted difference -4·2 points, 95% CI -6·1 to -2·3, p<0·0001; effect size 0·53) and mean physical function score was 55·7 (23·3) in the GES group and 50·8 (25·3) in the control group (adjusted difference 6·3 points, 1·8 to 10·8, p=0·006; 0·20). No serious adverse reactions were recorded and other safety measures did not differ between the groups, after allowing for missing data. INTERPRETATION: GES is a safe intervention that might reduce fatigue and, to a lesser extent, physical disability for patients with chronic fatigue syndrome. These findings need confirmation and extension to other health-care settings. FUNDING: UK National Institute for Health Research Research for Patient Benefit Programme and the Sue Estermann Fund.

Extending the Family of V(4+) S=(1/2) Kagome Antiferromagnets.

The ionothermal synthesis, structure, and magnetic susceptibility of a novel inorganic-organic hybrid material, imidazolium vanadium(III,IV) oxyfluoride [C3 H5 N2 ][V9 O6 F24 (H2 O)2 ] (ImVOF) are presented. The structure consists of inorganic vanadium oxyfluoride slabs with kagome layers of V(4+) S=${{ 1/2 }}$ ions separated by a mixed valence layer. These inorganic slabs are intercalated with imidazolium cations. Quinuclidinium (Q) and pyrazinium (Pyz) cations can also be incorporated into the hybrid structure type to give QVOF and PyzVOF analogues, respectively. The highly frustrated topology of the inorganic slabs, along with the quantum nature of the magnetism associated with V(4+) , means that these materials are excellent candidates to host exotic magnetic ground states, such as the highly sought quantum spin liquid. Magnetic susceptibility measurements of all samples suggest an absence of conventional long-range magnetic order down to 2 K despite considerable antiferromagnetic exchange.

Cessation of smoking trial in the emergency department (CoSTED): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Attendees of emergency departments (EDs) have a higher than expected prevalence of smoking. ED attendance may be a good opportunity to prompt positive behaviour change, even for smokers not currently motivated to quit. This study aims to determine whether an opportunist smoking cessation intervention delivered in the ED can help daily smokers attending the ED quit smoking and is cost-effective. METHODS AND ANALYSIS: A two-arm pragmatic, multicentred, parallel-group, individually randomised, controlled superiority trial with an internal pilot, economic evaluation and mixed methods process evaluation. The trial will compare ED-based brief smoking cessation advice, including provision of an e-cigarette and referral to local stop smoking services (intervention) with the provision of contact details for local stop smoking services (control). Target sample size is 972, recruiting across 6 National Health Service EDs in England and Scotland. Outcomes will be collected at 1, 3 and 6 months. The primary outcome at 6 months is carbon monoxide verified continuous smoking abstinence. ETHICS AND DISSEMINATION: The trial was approved by the South Central-Oxford B Research Committee (21/SC/0288). Dissemination will include the publication of outcomes, and the process and economic evaluations in peer-reviewed journals. The findings will also be appropriately disseminated to relevant practice, policy and patient representative groups. TRIAL REGISTRATION NUMBER: NCT04854616; protocol V.4.2.

Uncovering the Kagome Ferromagnet within a Family of Metal-Organic Frameworks.

Kagome networks of ferromagnetically or antiferromagnetically coupled magnetic moments represent important models in the pursuit of a diverse array of novel quantum and topological states of matter. Here, we explore a family of Cu2+-containing metal-organic frameworks (MOFs) bearing kagome layers pillared by ditopic organic linkers with the general formula Cu3(CO3)2(x)3·2ClO4 (MOF-x), where x is 1,2-bis(4-pyridyl)ethane (bpe), 1,2-bis(4-pyridyl)ethylene (bpy), or 4,4'-azopyridine (azpy). Despite more than a decade of investigation, the nature of the magnetic exchange interactions in these materials remained unclear, meaning that whether the underlying magnetic model is that of an kagome ferromagnet or antiferromagnet is unknown. Using single-crystal X-ray diffraction, we have developed a chemically intuitive crystal structure for this family of materials. Then, through a combination of magnetic susceptibility, powder neutron diffraction, and muon-spin spectroscopy measurements, we show that the magnetic ground state of this family consists of ferromagnetic kagome layers that are coupled antiferromagnetically via their extended organic pillaring linkers.

Long-term outcomes after autograft versus homograft aortic root replacement in adults with aortic valve disease: a randomised controlled trial.

BACKGROUND: The ideal substitute for aortic valve replacement in patients with aortic valve disease is not known. Our hypothesis was that the regulatory and adaptive properties of a living valve substitute could improve the long-term outcomes in patients. We therefore compared these outcomes after autograft aortic root replacement (Ross procedure) versus homograft aortic root replacement in adults. METHODS: Male and female patients (<69 years) requiring aortic valve surgery were randomly assigned in a one-to-one ratio to receive an autograft or a homograft aortic root replacement in one centre in the UK. The random allocation sequence was computer generated. Treatment was not masked. The primary endpoint was survival of patients at 10 years after surgery. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN03530985. FINDINGS: 228 patients were randomly assigned to receive an autograft or a homograft aortic root replacement. 12 patients were excluded because they were younger than 18 years; 108 in each group received the surgery they were assigned to and were analysed. There was one (<1%) perioperative death in the autograft group versus three (3%) in the homograft group (p=0.621). At 10 years, four patients died in the autograft group versus 15 in the homograft group. Actuarial survival at 10 years was 97% (SD 2) in the autograft group versus 83% (4) in the homograft group. Hazard ratio for death in the homograft group was 4.61 (95% CI 1.71-16.03; p=0.0060). Survival of patients in the autograft group was similar to that in an age-matched and sex-matched British population (96%). INTERPRETATION: Our findings support the hypothesis that a living valve implanted in the aortic position can significantly improve the long-term outcomes in patients. FUNDING: Funding Magdi Yacoub Institute.

Service use and costs for people with headache: a UK primary care study.

This paper aims to estimate the service and social costs of headache presenting in primary care and to identify predictors of headache costs. Patients were recruited from GP practices in England and service use and lost employment recorded. Predictors of cost were identified using regression models. Service and social costs were available on 288 and 282 patients, respectively. Average service costs over 3 months were £117 whilst total costs (including lost production) were £582. Patients referred to neurologists had service costs that were £82 higher than those not referred (90% CI £36-£128). Costs including lost employment were higher by £150, but this was not significant (90% CI -£139-£439). The annual mean service and social costs, weighted to represent population rates of referral, were £468 and £2328, respectively. Higher costs were significantly related to pain. Age was linked to higher service costs and lower social costs. The figures extrapolated to the whole of the UK suggest £956 million due to service use and £4.8 billion including lost employment. These are likely to be underestimates because many people experiencing headaches do not consult their GP.

Guided graded exercise self-help for chronic fatigue syndrome: Long term follow up and cost-effectiveness following the GETSET trial.

OBJECTIVE: The GETSET trial found that guided graded exercise self-help (GES) improved fatigue and physical functioning more than specialist medical care (SMC) alone in adults with chronic fatigue syndrome (CFS) 12 weeks after randomisation. In this paper, we assess the longer-term clinical and health economic outcomes. METHODS: GETSET was a randomised controlled trial of 211 UK secondary care patients with CFS. Primary outcomes were the Chalder fatigue questionnaire and the physical functioning subscale of the short-form-36 survey. Postal questionnaires assessed the primary outcomes and cost-effectiveness of the intervention 12 months after randomisation. Service costs and quality-adjusted life years (QALYs) were combined in a cost-effectiveness analysis. RESULTS: Between January 2014 and March 2016, 164 (78%) participants returned questionnaires 15 months after randomisation. Results showed no main effect of intervention arm on fatigue (chi2(1) = 4.8, p = 0.03) or physical functioning (chi2(1) = 1.3, p = 0.25), adjusting for multiplicity. No other intervention arm or time*arm effect was significant. The short-term fatigue reduction was maintained at long-term follow-up for participants assigned to GES, with improved fatigue from short- to long-term follow up after SMC, such that the groups no longer differed. Healthcare costs were £85 higher for GES and produced more QALYs. The incremental cost-effectiveness ratio was £4802 per QALY. CONCLUSIONS: The short-term improvements after GES were maintained at long-term follow-up, with further improvement in the SMC group such that the groups no longer differed at long-term follow-up. The cost per QALY for GES compared to SMC alone was below the usual threshold indicating cost-effectiveness, but with uncertainty around the result.

Mental health, well-being and support interventions for UK ambulance services staff: an evidence map, 2000 to 2020.

BACKGROUND: Prior to COVID-19 there had been a renewed policy focus in the National Health Service on the health and well-being of the healthcare workforce, with the ambulance sector identified as a priority area. This focus is more important than ever as the sector deals with the acute and longer-term consequences of a pandemic. AIM: To systematically identify, summarise and map the evidence regarding mental health, well-being and support interventions for United Kingdom ambulance services staff and to identify evidence gaps. METHOD: Evidence mapping methodology of published and grey original research published in English from 1 January 2000 to 23 May 2020 describing the health risk, mental health and/or well-being of UK ambulance services staff including retired staff, volunteers and students. MEDLINE, EMBASE, PsychINFO, CINAHL and AMED databases, plus EThOS, Zetoc, OpenGrey and Google, were searched, alongside hand-searching of grey literature and bibliographies. Information was extracted on study aims, sample, design and methodology, funding source, country and key findings. Included studies were categorised into seven a priori theme areas. RESULTS: Of 1862 identified articles, 45 peer-reviewed studies are included as well as 24 grey literature documents. Peer-reviewed research was largely observational and focused on prevalence studies, post-traumatic stress disorder or organisational and individual social factors related to health and well-being. Most grey literature reported the development and testing of interventions. Across all study types, underpinning theory was often not cited. CONCLUSION: To date, intervention research has largely been funded by charities and published in the grey literature. Few studies were identified on self-harm, bullying, sleep and fatigue or alcohol and substance use. Theoretically informed intervention development and testing, including adaptation of innovations from other countries and 24-hour workforces, is needed. This evidence map provides important context for planning of staff well-being provision and research as the sector responds to and recovers from the pandemic. PROSPERO REGISTRATION NUMBER: CRD42018104659.

Central sensitisation in chronic fatigue syndrome and fibromyalgia; a case control study.

INTRODUCTION: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are both complex conditions that are challenging to treat. This may be related to an incomplete understanding of their pathophysiology, itself obfuscated by their heterogeneity. The symptomatic overlap between them and their common comorbidity suggests a shared vulnerability, which might be explained by central sensitisation. METHODS: 19 CFS cases, 19 FM cases and 20 age and sex matched healthy controls (HC) were recruited primarily from secondary care clinics in London. Those with other pain disorders, psychiatric diagnoses and those taking centrally acting or opiate medications were excluded. Participants were asked to abstain from alcohol and over the counter analgaesia 48 h prior to assessment by static and dynamic quantitative sensory tests, including measures of temporal summation (TS) and conditioned pain modulation (CPM). RESULTS: CS, as defined by the presence of both enhanced TS and inefficient CPM, was present in 16 (84%) CFS cases, 18 (95%) FM cases, and none of the HC (p < 0.001). Pressure pain thresholds were lower in CFS (Median222kPaIQR 146-311; p = 0.04) and FM cases (Median 189 kPa; IQR 129-272; p = 0.003) compared to HC (Median 311 kPa; IQR 245-377). FM cases differed from HC in cold-induced (FM = 22.6 °C (15.3-27.7) vs HC = 14.2 °C (9.0-20.5); p = 0.01) and heat-induced (FM = 38.0 °C (35.2-44.0) vs HC = 45.3 °C (40.1-46.8); p = 0.03) pain thresholds, where CFS cases did not. CONCLUSION: Central sensitisation may be a common endophenotype in chronic fatigue syndrome and fibromyalgia. Further research should address whether central sensitisation is a cause or effect of these disorders.

A feasibility study to assess the design of a multicentre randomized controlled trial of the clinical and cost-effectiveness of a caregiving intervention for people following hip fracture surgery.

AIMS: This study aims to assess the feasibility of conducting a pragmatic, multicentre randomized controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery. METHODS: This will be a mixed-methods feasibility RCT, recruiting 60 patients following hip fracture surgery and their informal caregivers. Patients will be randomized to usual NHS care, versus usual NHS care plus a caregiver-patient dyad training programme (HIP HELPER). This programme will comprise of three, one-hour, one-to-one training sessions for the patient and caregiver, delivered by a nurse, physiotherapist, or occupational therapist. Training will be delivered in the hospital setting pre-patient discharge. It will include practical skills for rehabilitation such as: transfers and walking; recovery goal setting and expectations; pacing and stress management techniques; and introduction to the HIP HELPER Caregiver Workbook, which provides information on recovery, exercises, worksheets, and goal-setting plans to facilitate a 'good' recovery. After discharge, patients and caregivers will be supported in delivering rehabilitation through three telephone coaching sessions. Data, collected at baseline and four months post-randomization, will include: screening logs, intervention logs, fidelity checklists, quality assurance monitoring visit data, and clinical outcomes assessing quality of life, physical, emotional, adverse events, and resource use outcomes. The acceptability of the study intervention and RCT design will be explored through qualitative methods with 20 participants (patients and informal caregivers) and 12 health professionals. DISCUSSION: A multicentre recruitment approach will provide greater external validity across population characteristics in England. The mixed-methods approach will permit in-depth examination of the intervention and trial design parameters. The findings will inform whether and how a definitive trial may be undertaken to test the effectiveness of this caregiver intervention for patients after hip fracture surgery. Cite this article: Bone Jt Open 2021;2(11):909-920.

Rate of progression and functional significance of aortic root calcification after homograft versus freestyle aortic root replacement.

BACKGROUND: Calcification is an important limitation after aortic root replacement. The aims were to compare the long-term degree and rate of calcification of homografts versus Medtronic freestyle aortic roots to determine the functional consequences and predictive factors. METHODS AND RESULTS: One hundred sixty-six patients were prospectively randomized to undergo homograft versus freestyle total aortic root replacement. Of those, 98 patients underwent a total of 248 electron beam computed tomography studies at 0.5, 1, 1.5, 2, 3, and 8 years. All patients underwent yearly clinical and echocardiographic follow-up. Calcium scores were measured using Agatston scoring. Mixed effects models demonstrate significantly higher calcium scores in homograft roots than freestyle at 1.5 years (P=0.02), 2 years (P=0.02), and 3 years (P=0.01), with a trend at 1 year (P=0.06) and 8 years (P=0.1). Homograft calcification occurs significantly faster than in freestyle prostheses between 6 months and 3 years after surgery (P=0.02). Calcification occurs at a similar rate thereafter up to 8 years (P=0.3). At 8 years, freedom from aortic valve dysfunction was lower in homografts than freestyle roots (P=0.06). Freedom from reoperation was 93+/-4% in the homograft group versus 100+/-0% in the freestyle group at 8 years (P=0.01). On multivariate analysis, redo surgery (P<0.001), smoking (P<0.01), atrial fibrillation (P=0.001), family history of coronary artery disease (P<0.01), and a degenerative etiology (P=0.02) were predictive of higher calcium scores. CONCLUSIONS: Homograft roots exhibit significantly higher calcium scores than freestyle roots because of faster early calcification.

Guided graded Exercise Self-help for chronic fatigue syndrome: patient experiences and perceptions.

Purpose: This study explored patient experiences of Guided graded Exercise Self-help (GES) delivered as part of a randomised controlled trial for people with chronic fatigue syndrome/myalgic encephalomyelitis. The trial found that GES was better than specialist medical care at reducing fatigue and improving physical functioning.Methods: Semi-structured interviews were conducted with patients reporting improvement (n = 9) and deterioration (n = 10), and analysis involved thematic "constant comparison."Results: The improved group described more facilitators to doing GES, and were more likely to describe high levels of self-motivation, whereas the deteriorated group described more barriers to GES (including worse exacerbation of symptoms after GES, greater interference from comorbid conditions, and obstacles to GES in their lives), and had been ill for longer. Having the capacity to do GES was important; of note, those with relatively lower levels of functioning sometimes had more time and space in their lives to support their GES engagement. We identified an important "indeterminate phase" early on, in which participants did not initially improve.Conclusions: GES may be improved by targeting those most likely to improve, and teaching about the indeterminate phase.Implications for rehabilitationUsing the Guided Exercise Self-help booklet alone is unlikely to be sufficient to support patients through Guided Exercise Self-help successfully.Additional guidance from skilled physiotherapists/health professionals who demonstrate an understanding of what it is like to cope with chronic fatigue syndrome/myalgic encephalomyelitis is also important.Those using Guided Exercise Self-help may need additional support through a commonly experienced "indeterminate phase" - an initial phase in the programme where few benefits, along with various challenges associated with increasing activity, are experienced.Individuals who have been ill with chronic fatigue syndrome/myalgic encephalomyelitis for a relatively longer period of time and/or have additional comorbid conditions may benefit from more bespoke therapies with greater health professionals input, delivered by appropriate therapists.

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex-miRNAs) are putative, minimally invasive biomarkers of DMD. Specific ex-miRNAs (e.g. miR-1, miR-133a, miR-206, and miR-483) are highly up-regulated in the serum of DMD patients and dystrophic animal models and are restored to wild-type levels following exon skipping-mediated dystrophin rescue in mdx mice. As such, ex-miRNAs are promising pharmacodynamic biomarkers of exon skipping efficacy. Here, we aimed to determine the degree to which ex-miRNA levels reflect the underlying level of dystrophin protein expression in dystrophic muscle. METHODS: Candidate ex-miRNA biomarker levels were investigated in mdx mice in which dystrophin was restored with peptide-PMO (PPMO) exon skipping conjugates and in mdx-XistΔhs mice that express variable amounts of dystrophin from birth as a consequence of skewed X-chromosome inactivation. miRNA profiling was performed in mdx-XistΔhs mice using the FirePlex methodology and key results validated by small RNA TaqMan RT-qPCR. The muscles from each animal model were further characterized by dystrophin western blot and immunofluorescence staining. RESULTS: The restoration of ex-myomiR abundance observed following PPMO treatment was not recapitulated in the high dystrophin-expressing mdx-XistΔhs group, despite these animals expressing similar amounts of total dystrophin protein (~37% of wild-type levels). Instead, ex-miRNAs were present at high levels in mdx-XistΔhs mice regardless of dystrophin expression. PPMO-treated muscles exhibited a uniform pattern of dystrophin localization and were devoid of regenerating fibres, whereas mdx-XistΔhs muscles showed non-homogeneous dystrophin staining and sporadic regenerating foci. CONCLUSIONS: Uniform dystrophin expression is required to prevent ex-miRNA release, stabilize myofiber turnover, and attenuate pathology in dystrophic muscle.