A novel TTC26 variant in a patient with hexadactyly, pituitary stalk interruption, hepatopathy, nephropathy, and bilateral lip-palate cleft: A case report and expansion of the phenotype.

Biallelic pathogenic variants in the TTC26 gene are known to cause BRENS (biliary, renal, neurological, skeletal) syndrome, an ultra-rare autosomal recessive condition with only few patients published to date. BRENS syndrome is characterized by hexadactyly, severe neonatal cholestasis, and involvement of the brain, heart, and kidney, however the full phenotypic and genotypic spectrum is unknown. Here, we report on a previously undescribed homozygous intronic TTC26 variant (c.1006-5 T > C) in a patient showing some of the known TTC26-associated features like hexadactyly, hypopituitarism, hepatopathy, nephropathy, and congenital heart defect. Moreover, he presented with a suspected unilateral hearing loss and bilateral cleft lip-palate. The variant is considered to affect correct splicing by the loss of the canonical acceptor splice site and activation of a cryptic acceptor splice site. Hereby, our patient represents one additional patient with BRENS syndrome carrying a previously unreported TTC26 variant. Furthermore, we confirm the involvement of the pituitary gland to be a common clinical feature of the syndrome and broaden the clinical spectrum of TTC26 ciliopathy to include facial clefts and a probable hearing involvement.

Long-Term Antibody Response to SARS-CoV-2 in Children.

Almost 2 years into the pandemic and with vaccination of children significantly lagging behind adults, long-term pediatric humoral immune responses to SARS-CoV-2 are understudied. The C19.CHILD Hamburg (COVID-19 Child Health Investigation of Latent Disease) Study is a prospective cohort study designed to identify and follow up children and their household contacts infected in the early 2020 first wave of SARS-CoV-2. We screened 6113 children < 18 years by nasopharyngeal swab-PCR in a low-incidence setting after general lockdown, from May 11 to June 30, 2020. A total of 4657 participants underwent antibody testing. Positive tests were followed up by repeated PCR and serological testing of all household contacts over 6 months. In total, the study identified 67 seropositive children (1.44%); the median time after infection at first presentation was 83 days post-symptom onset (PSO). Follow-up of household contacts showed less than 100% seroprevalence in most families, with higher seroprevalence in families with adult index cases compared to pediatric index cases (OR 1.79, P = 0.047). Most importantly, children showed sustained seroconversion up to 9 months PSO, and serum antibody concentrations persistently surpassed adult levels (ratio serum IgG spike children vs. adults 90 days PSO 1.75, P < 0.001; 180 days 1.38, P = 0.01; 270 days 1.54, P = 0.001). In a low-incidence setting, SARS-CoV-2 infection and humoral immune response present distinct patterns in children including higher antibody levels, and lower seroprevalence in families with pediatric index cases. Children show long-term SARS-CoV-2 antibody responses. These findings are relevant to novel variants with increased disease burden in children, as well as for the planning of age-appropriate vaccination strategies.

Phenotypic analysis of the pediatric immune response to SARS-CoV-2 by flow cytometry.

Pediatric SARS-CoV-2 infection is often mild or asymptomatic and the immune responses of children are understudied compared to adults. Here, we present and evaluate the performance of a two-panel (16- and 17 parameter) flow cytometry-based approach for immune phenotypic analysis of cryopreserved PBMC samples from children after SARS-CoV-2 infection. The panels were optimized based on previous SARS-CoV-2 related studies for the pediatric immune system. PBMC samples from seven SARS-CoV-2 seropositive children from early 2020 and five age-matched healthy controls were stained for analysis of T-cells (panel T), B and innate immune cells (panel B). Performance of the panels was evaluated in two parallel approaches, namely classical manual gating of known subpopulations and unbiased clustering using the R-based algorithm PhenoGraph. Using manual gating we clearly identified 14 predefined subpopulations of interest for panel T and 19 populations in panel B in low-volume pediatric samples. PhenoGraph found 18 clusters within the T-cell panel and 21 clusters within the innate and B-cell panel that could be unmistakably annotated. Combining the data of the two panels and analysis approaches, we found expected differentially abundant clusters in SARS-CoV-2 seropositive children compared to healthy controls, underscoring the value of these two panels for the analysis of immune response to SARS-CoV-2. We established a two-panel flow cytometry approach that can be used with limited amounts of cryopreserved pediatric samples. Our workflow allowed for a rapid, comprehensive, and robust pediatric immune phenotyping with comparable performance in manual gating and unbiased clustering. These panels may be adapted for large multi-center cohort studies to investigate the pediatric immune response to emerging virus variants in the ongoing and future pandemics.

How are health research partnerships assessed? A systematic review of outcomes, impacts, terminology and the use of theories, models and frameworks.

BACKGROUND: Accurate, consistent assessment of outcomes and impacts is challenging in the health research partnerships domain. Increased focus on tool quality, including conceptual, psychometric and pragmatic characteristics, could improve the quantification, measurement and reporting partnership outcomes and impacts. This cascading review was undertaken as part of a coordinated, multicentre effort to identify, synthesize and assess a vast body of health research partnership literature. OBJECTIVE: To systematically assess the outcomes and impacts of health research partnerships, relevant terminology and the type/use of theories, models and frameworks (TMF) arising from studies using partnership assessment tools with known conceptual, psychometric and pragmatic characteristics. METHODS: Four electronic databases were searched (MEDLINE, Embase, CINAHL Plus and PsycINFO) from inception to 2 June 2021. We retained studies containing partnership evaluation tools with (1) conceptual foundations (reference to TMF), (2) empirical, quantitative psychometric evidence (evidence of validity and reliability, at minimum) and (3) one or more pragmatic characteristics. Outcomes, impacts, terminology, definitions and TMF type/use were abstracted verbatim from eligible studies using a hybrid (independent abstraction-validation) approach and synthesized using summary statistics (quantitative), inductive thematic analysis and deductive categories (qualitative). Methodological quality was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). RESULTS: Application of inclusion criteria yielded 37 eligible studies. Study quality scores were high (mean 80%, standard deviation 0.11%) but revealed needed improvements (i.e. methodological, reporting, user involvement in research design). Only 14 (38%) studies reported 48 partnership outcomes and 55 impacts; most were positive effects (43, 90% and 47, 89%, respectively). Most outcomes were positive personal, functional, structural and contextual effects; most impacts were personal, functional and contextual in nature. Most terms described outcomes (39, 89%), and 30 of 44 outcomes/impacts terms were unique, but few were explicitly defined (9, 20%). Terms were complex and mixed on one or more dimensions (e.g. type, temporality, stage, perspective). Most studies made explicit use of study-related TMF (34, 92%). There were 138 unique TMF sources, and these informed tool construct type/choice and hypothesis testing in almost all cases (36, 97%). CONCLUSION: This study synthesized partnership outcomes and impacts, deconstructed term complexities and evolved our understanding of TMF use in tool development, testing and refinement studies. Renewed attention to basic concepts is necessary to advance partnership measurement and research innovation in the field. Systematic review protocol registration: PROSPERO protocol registration: CRD42021137932 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=137932 .

Ultrasound entropy may be a new non-invasive measure of pre-clinical vascular damage in young hypertensive patients.

BACKGROUND: The identification of pre-clinical microvascular damage in hypertension by non-invasive techniques has proved frustrating for clinicians. This proof of concept study investigated whether entropy, a novel summary measure for characterizing blood velocity waveforms, is altered in participants with hypertension and may therefore be useful in risk stratification. METHODS: Doppler ultrasound waveforms were obtained from the carotid and retrobulbar circulation in 42 participants with uncomplicated grade 1 hypertension (mean systolic/diastolic blood pressure (BP) 142/92 mmHg), and 26 healthy controls (mean systolic/diastolic BP 116/69 mmHg). Mean wavelet entropy was derived from flow-velocity data and compared with traditional haemodynamic measures of microvascular function, namely the resistive and pulsatility indices. RESULTS: Entropy, was significantly higher in control participants in the central retinal artery (CRA) (differential mean 0.11 (standard error 0.05 cms(-1)), CI 0.009 to 0.219, p 0.017) and ophthalmic artery (0.12 (0.05), CI 0.004 to 0.215, p 0.04). In comparison, the resistive index (0.12 (0.05), CI 0.005 to 0.226, p 0.029) and pulsatility index (0.96 (0.38), CI 0.19 to 1.72, p 0.015) showed significant differences between groups in the CRA alone. Regression analysis indicated that entropy was significantly influenced by age and systolic blood pressure (r values 0.4-0.6). None of the measures were significantly altered in the larger conduit vessel. CONCLUSION: This is the first application of entropy to human blood velocity waveform analysis and shows that this new technique has the ability to discriminate health from early hypertensive disease, thereby promoting the early identification of cardiovascular disease in a young hypertensive population. CLINICAL TRIAL REGISTRATION: Clinical Trials.gov, NCT01047423.

Reduced Humoral and Cellular Immune Response to Primary COVID-19 mRNA Vaccination in Kidney Transplanted Children Aged 5-11 Years.

The situation of limited data concerning the response to COVID-19 mRNA vaccinations in immunocom-promised children hinders evidence-based recommendations. This prospective observational study investigated humoral and T cell responses after primary BNT162b2 vaccination in secondary immunocompromised and healthy children aged 5-11 years. Participants were categorized as: children after kidney transplantation (KTx, n = 9), proteinuric glomerulonephritis (GN, n = 4) and healthy children (controls, n = 8). Expression of activation-induced markers and cytokine secretion were determined to quantify the T cell response from PBMCs stimulated with peptide pools covering the spike glycoprotein of SARS-CoV-2 Wuhan Hu-1 and Omicron BA.5. Antibodies against SARS-CoV-2 spike receptor-binding domain were quantified in serum. Seroconversion was detected in 56% of KTx patients and in 100% of the GN patients and controls. Titer levels were significantly higher in GN patients and controls than in KTx patients. In Ktx patients, the humoral response increased after a third immunization. No differences in the frequency of antigen-specific CD4+ and CD8+ T cells between all groups were observed. T cells showed a predominant anti-viral capacity in their secreted cytokines; however, this capacity was reduced in KTx patients. This study provides missing evidence concerning the humoral and T cell response in immunocompromised children after COVID-19 vaccination.

Specific CD4+ T Cell Responses to Ancestral SARS-CoV-2 in Children Increase With Age and Show Cross-Reactivity to Beta Variant.

SARS-CoV-2 is still a major burden for global health despite effective vaccines. With the reduction of social distancing measures, infection rates are increasing in children, while data on the pediatric immune response to SARS-CoV-2 infection is still lacking. Although the typical disease course in children has been mild, emerging variants may present new challenges in this age group. Peripheral blood mononuclear cells (PBMC) from 51 convalescent children, 24 seronegative siblings from early 2020, and 51 unexposed controls were stimulated with SARS-CoV-2-derived peptide MegaPools from the ancestral and beta variants. Flow cytometric determination of activation-induced markers and secreted cytokines were used to quantify the CD4+ T cell response. The average time after infection was over 80 days. CD4+ T cell responses were detected in 61% of convalescent children and were markedly reduced in preschool children. Cross-reactive T cells for the SARS-CoV-2 beta variant were identified in 45% of cases after infection with an ancestral SARS-CoV-2 variant. The CD4+ T cell response was accompanied most predominantly by IFN-γ and Granzyme B secretion. An antiviral CD4+ T cell response was present in children after ancestral SARS-CoV-2 infection, which was reduced in the youngest age group. We detected significant cross-reactivity of CD4+ T cell responses to the more recently evolved immune-escaping beta variant. Our findings have epidemiologic relevance for children regarding novel viral variants of concern and vaccination efforts.

Process evaluation of a randomised pilot trial of home-based rehabilitation compared to usual care in patients with heart failure with preserved ejection fraction and their caregiver's.

BACKGROUND: Whilst almost 50% of heart failure (HF) patients have preserved ejection fraction (HFpEF), evidence-based treatment options for this patient group remain limited. However, there is growing evidence of the potential value of exercise-based cardiac rehabilitation. This study reports the process evaluation of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention for HFpEF patients and their caregivers conducted as part of the REACH-HFpEF pilot trial. METHODS: Process evaluation sub-study parallels to a single-centre (Tayside, Scotland) randomised controlled pilot trial with qualitative assessment of both intervention fidelity delivery and HFpEF patients' and caregivers' experiences. The REACH-HF intervention consisted of self-help manual for patients and caregivers, facilitated over 12 weeks by trained healthcare professionals. Interviews were conducted following completion of intervention in a purposeful sample of 15 HFpEF patients and seven caregivers. RESULTS: Qualitative information from the facilitator interactions and interviews identified three key themes for patients and caregivers: (1) understanding their condition, (2) emotional consequences of HF, and (3) responses to the REACH-HF intervention. Fidelity analysis found the interventions to be delivered adequately with scope for improvement in caregiver engagement. The differing professional backgrounds of REACH-HF facilitators in this study demonstrate the possibility of delivery of the intervention by healthcare staff with expertise in HF, cardiac rehabilitation, or both. CONCLUSIONS: The REACH-HF home-based facilitated intervention for HFpEF appears to be a feasible and a well-accepted model for the delivery of rehabilitation, with the potential to address key unmet needs of patients and their caregivers who are often excluded from HF and current cardiac rehabilitation programmes. Results of this study will inform a recently funded full multicentre randomised clinical trial. TRIAL REGISTRATION: ISRCTN78539530 (date of registration 7 July 2015).

Bacteriophage Rescue Therapy of a Vancomycin-Resistant Enterococcus faecium Infection in a One-Year-Old Child following a Third Liver Transplantation.

Phage therapy is an experimental therapeutic approach used to target multidrug-resistant bacterial infections. A lack of reliable data with regard to its efficacy and regulatory hurdles hinders a broad application. Here we report, for the first time, a case of vancomycin-resistant Enterococcus faecium abdominal infection in a one-year-old, critically ill, and three times liver transplanted girl, which was successfully treated with intravenous injections (twice per day for 20 days) of a magistral preparation containing two Enterococcus phages. This correlated with a reduction in baseline C-reactive protein (CRP), successful weaning from mechanical ventilation and without associated clinical adverse events. Prior to clinical use, phage genome was sequenced to confirm the absence of genetic determinants conferring lysogeny, virulence or antibiotic resistance, and thus their safety. Using a phage neutralization assay, no neutralizing anti-phage antibodies in the patient's serum could be detected. Vancomycin-susceptible E. faecium isolates were identified in close relation to phage therapy and, by using whole-genome sequencing, it was demonstrated that vancomycin-susceptible E. faecium emerged from vancomycin-resistant progenitors. Covering a one year follow up, we provide further evidence for the feasibility of bacteriophage therapy that can serve as a basis for urgently needed controlled clinical trials.

Presence of positive skin prick tests to inhalant allergens and markers of T2 inflammation in subjects with chronic spontaneous urticaria (CSU): a systematic literature review.

BACKGROUND: Current guidelines do not recommend performing aeroallergen skin prick testing (SPT) in chronic spontaneous urticaria (CSU). OBJECTIVE: The objective of this review was to investigate the presence of aeroallergen sensitization and markers of T2 inflammation in subjects with CSU. METHODS: Systematic literature reviews to identify all studies that evaluated the presence of T2 markers of allergic inflammation in CSU subjects were performed. RESULTS: In 16 studies that assessed the prevalence of positive SPT to multiple aeroallergens in CSU, 38.5% of CSU subjects had positive SPT. In three controlled studies, 34.2% of CSU subjects had positive SPT to multiple aeroallergens, compared to 13.6% of controls (p = 0.047). In 18 studies that assessed the prevalence of house dust mite (HDM) positive SPT in CSU, 27.5% of CSU subjects had positive SPT. In three controlled studies, 27.5% of CSU subjects had positive SPT to HDM, compared to 2.1% of controls (p = 0.047). Overall, CSU subjects were 3.1 times more likely to be aeroallergen-sensitized (95% CI 1.7-5.8, p = 0.0002) and 6.1 times more likely to be HDM-sensitized (95% CI 3.7-9.9, p < 0.00001) than controls. Mean total serum IgE (tIgE) levels were 238 kU/L and median tIgE levels were 164 kU/L, which was greater than the upper 90th percentile of normal (< 137 kU/L). Compared to healthy controls, CSU subjects were 6.5 times more likely to have IgG autoantibody against FcεR1α (p = 0.001), 2.4 times more likely to have IgG anti-IgE antibody (p = 0.03) and 5 times more likely to have anti-thyroid peroxidase (anti-TPO) antibody (p = 0.02). When corticosteroids were withheld for ≥ 28 days, mean blood eosinophil percentage was elevated at 5.9% (normal < 4%), but other studies reporting absolute count found the mean was in the normal range, 239 × 10 6 / L (normal < 400 × 10 6 / L). CONCLUSION: Increased aeroallergen sensitization, tIgE, autoantibodies and blood eosinophil percentage in the CSU subjects indicates the possible importance of T2 inflammation in the pathogenesis of CSU. Further studies may be warranted to determine if specific allergen avoidance, desensitization or improvement in the mucosal allergic inflammation present in asthma and/or rhinitis has any benefit in the management of CSU.

Home-based rehabilitation for heart failure with reduced ejection fraction: mixed methods process evaluation of the REACH-HF multicentre randomised controlled trial.

OBJECTIVE: To identify and explore change processes explaining the effects of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention taking account of reach, amount of intervention received, delivery fidelity and patient and caregiver perspectives. DESIGN: Mixed methods process evaluation parallel to a randomised controlled trial using data from the intervention group (REACH-HF plus usual care). SETTING: Four centres in the UK (Birmingham, Cornwall, Gwent and York). PARTICIPANTS: People with heart failure with reduced ejection fraction (HFrEF) and their caregivers. METHODS: The REACH-HF intervention consisted of a self-help manual for patients with HFrEF and caregivers facilitated over 12 weeks by trained healthcare professionals. The process evaluation used multimodal mixed methods analysis. Data consisted of audio recorded intervention sessions; demographic data; intervention fidelity scores for intervention group participants (107 patients and 53 caregivers); qualitative interviews at 4 and 12 months with a sample of 19 patients and 17 caregivers. OUTCOME MEASURES: Quantitative data: intervention fidelity and number, frequency and duration of intervention sessions received. Qualitative data: experiences and perspectives of intervention participants and caregivers. RESULTS: Intervention session attendance with facilitators was high. Fidelity scores were indicative of adequate quality of REACH-HF intervention delivery, although indicating scope for improvement in several areas. Intervention effectiveness was contingent on matching the intervention implementation to the concerns, beliefs and goals of participants. Behaviour change was sustained when shared meaning was established. Respondents' comorbidities, socio-economic circumstances and existing networks of support also affected changes in health-related quality of life. CONCLUSIONS: By combining longitudinal mixed methods data, the essential ingredients of complex interventions can be better identified, interrogated and tested. This can maximise the clinical application of research findings and enhance the capacity of multidisciplinary and multisite teams to implement the intervention. TRIAL REGISTRATION NUMBER: ISRCTN25032672; Pre-results.

Caregiver outcomes of the REACH-HF multicentre randomized controlled trial of home-based rehabilitation for heart failure with reduced ejection fraction.

BACKGROUND: Caregivers frequently provide support to people living with long-term conditions. However, there is paucity of evidence of interventions that support caregivers in their role. Rehabilitation EnAblement in Chronic Heart Failure (REACH-HF) is a novel home-based, health-professional-facilitated, self-management programme for patients with heart failure (HF) and their caregivers. METHODS: Based on the random allocation of individual adult patients with reduced ejection fraction (HFrEF) and left ventricular ejection fraction <45% within the past five years, the caregiver of patients was allocated to receive the REACH-HF intervention over 12 weeks (REACH-HF group) or not (control group). Caregiver outcomes were generic health-related quality of life (EQ-5D-5L), Family Caregiver Quality of Life Scale questionnaire (FamQol), Caregiver Burden Questionnaire HF (CBQ-HF), Caregiver Contribution to Self-care of HF Index questionnaire (CC-SCHFI) and Hospital Anxiety and Depression Scale (HADS). Outcomes were compared between groups at 4, 6 and 12 months follow-up. Twenty caregivers receiving REACH-HF were purposively selected for qualitative interviews at 4 and 12 months. RESULTS: Compared with controls (44 caregivers), the REACH-HF group (53 caregivers) had a higher mean CC-SCHFI confidence score at 12 months (57.5 vs 62.8, adjusted mean difference: 9.3, 95% confidence interval: 1.8-16.8, p = 0.016). No significant between group differences were seen in other caregiver outcomes. Qualitative interviews showed that most caregivers who received the REACH-HF intervention made positive changes to how they supported the HF patient they were caring for, and perceived that they had increased their confidence in the caregiver role over time. CONCLUSION: Provision of the REACH-HF intervention for caregivers of HF patients improved their confidence of self-management and was perceived for some to be helpful in supporting their caregiver role.

The effects and costs of home-based rehabilitation for heart failure with reduced ejection fraction: The REACH-HF multicentre randomized controlled trial.

BACKGROUND: Cardiac rehabilitation improves health-related quality of life (HRQoL) and reduces hospitalizations in patients with heart failure, but international uptake of cardiac rehabilitation for heart failure remains low. DESIGN AND METHODS: The aim of this multicentre randomized trial was to compare the REACH-HF (Rehabilitation EnAblement in CHronicHeart Failure) intervention, a facilitated self-care and home-based cardiac rehabilitation programme to usual care for adults with heart failure with reduced ejection fraction (HFrEF). The study primary hypothesis was that the addition of the REACH-HF intervention to usual care would improve disease-specific HRQoL (Minnesota Living with Heart Failure questionnaire (MLHFQ)) at 12 months compared with usual care alone. RESULTS: The study recruited 216 participants, predominantly men (78%), with an average age of 70 years and mean left ventricular ejection fraction of 34%. Overall, 185 (86%) participants provided data for the primary outcome. At 12 months, there was a significant and clinically meaningful between-group difference in the MLHFQ score of -5.7 points (95% confidence interval -10.6 to -0.7) in favour of the REACH-HF intervention group ( p = 0.025). With the exception of patient self-care ( p < 0.001) there was no significant difference in other secondary outcomes, including clinical events ( p > 0.05) at follow-up compared with usual care. The mean cost of the REACH-HF intervention was £418 per participant. CONCLUSIONS: The novel REACH-HF home-based facilitated intervention for HFrEF was clinically superior in disease-specific HRQoL at 12 months and offers an affordable alternative to traditional centre-based programmes to address current low cardiac rehabilitation uptake rates for heart failure.

The cost effectiveness of REACH-HF and home-based cardiac rehabilitation compared with the usual medical care for heart failure with reduced ejection fraction: A decision model-based analysis.

BACKGROUND: The REACH-HF (Rehabilitation EnAblement in CHronic Heart Failure) trial found that the REACH-HF home-based cardiac rehabilitation intervention resulted in a clinically meaningful improvement in disease-specific health-related quality of life in patients with reduced ejection fraction heart failure (HFrEF). The aims of this study were to assess the long-term cost-effectiveness of the addition of REACH-HF intervention or home-based cardiac rehabilitation to usual care compared with usual care alone in patients with HFrEF. DESIGN AND METHODS: A Markov model was developed using a patient lifetime horizon and integrating evidence from the REACH-HF trial, a systematic review/meta-analysis of randomised trials, estimates of mortality and hospital admission and UK costs at 2015/2016 prices. Taking a UK National Health and Personal Social Services perspective we report the incremental cost per quality-adjusted life-year (QALY) gained, assessing uncertainty using probabilistic and deterministic sensitivity analyses. RESULTS: In base case analysis, the REACH-HF intervention was associated with per patient mean QALY gain of 0.23 and an increased mean cost of £400 compared with usual care, resulting in a cost per QALY gained of £1720. Probabilistic sensitivity analysis indicated a 78% probability that REACH-HF is cost effective versus usual care at a threshold of £20,000 per QALY gained. Results were similar for home-based cardiac rehabilitation versus usual care. Sensitivity analyses indicate the findings to be robust to changes in model assumptions and parameters. CONCLUSIONS: Our cost-utility analyses indicate that the addition of the REACH-HF intervention and home-based cardiac rehabilitation programmes are likely to be cost-effective treatment options versus usual care alone in patients with HFrEF.

A randomised controlled trial of a facilitated home-based rehabilitation intervention in patients with heart failure with preserved ejection fraction and their caregivers: the REACH-HFpEF Pilot Study.

INTRODUCTION: Home-based cardiac rehabilitation may overcome suboptimal rates of participation. The overarching aim of this study was to assess the feasibility and acceptability of the novel Rehabilitation EnAblement in CHronic Hear Failure (REACH-HF) rehabilitation intervention for patients with heart failure with preserved ejection fraction (HFpEF) and their caregivers. METHODS AND RESULTS: Patients were randomised 1:1 to REACH-HF intervention plus usual care (intervention group) or usual care alone (control group). REACH-HF is a home-based comprehensive self-management rehabilitation programme that comprises patient and carer manuals with supplementary tools, delivered by trained healthcare facilitators over a 12 week period. Patient outcomes were collected by blinded assessors at baseline, 3 months and 6 months postrandomisation and included health-related quality of life (primary) and psychological well-being, exercise capacity, physical activity and HF-related hospitalisation (secondary). Outcomes were also collected in caregivers.We enrolled 50 symptomatic patients with HF from Tayside, Scotland with a left ventricular ejection fraction ≥45% (mean age 73.9 years, 54% female, 100% white British) and 21 caregivers. Study retention (90%) and intervention uptake (92%) were excellent. At 6 months, data from 45 patients showed a potential direction of effect in favour of the intervention group, including the primary outcome of Minnesota Living with Heart Failure Questionnaire total score (between-group mean difference -11.5, 95% CI -22.8 to 0.3). A total of 11 (4 intervention, 7 control) patients experienced a hospital admission over the 6 months of follow-up with 4 (control patients) of these admissions being HF-related. Improvements were seen in a number intervention caregivers' mental health and burden compared with control. CONCLUSIONS: Our findings support the feasibility and rationale for delivering the REACH-HF facilitated home-based rehabilitation intervention for patients with HFpEF and their caregivers and progression to a full multicentre randomised clinical trial to test its clinical effectiveness and cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN78539530.

Optimising self-care support for people with heart failure and their caregivers: development of the Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention using intervention mapping.

BACKGROUND: We aimed to establish the support needs of people with heart failure and their caregivers and develop an intervention to improve their health-related quality of life. METHODS: We used intervention mapping to guide the development of our intervention. We identified "targets for change" by synthesising research evidence and international guidelines and consulting with patients, caregivers and health service providers. We then used behaviour change theory, expert opinion and a taxonomy of behaviour change techniques, to identify barriers to and facilitators of change and to match intervention strategies to each target. A patient and public involvement group helped to identify patient and caregiver needs, refine the intervention objectives and strategies and deliver training to the intervention facilitators. A feasibility study (ISRCTN25032672) involving 23 patients, 12 caregivers and seven trained facilitators at four sites assessed the feasibility and acceptability of the intervention and quality of delivery and generated ideas to help refine the intervention. RESULTS: The Rehabilitation Enablement in Chronic Heart Failure (REACH-HF) intervention is a comprehensive self-care support programme comprising the "Heart Failure Manual", a choice of two exercise programmes for patients, a "Family and Friends Resource" for caregivers, a "Progress Tracker" tool and a facilitator training course. The main targets for change are engaging in exercise training, monitoring for symptom deterioration, managing stress and anxiety, managing medications and understanding heart failure. Secondary targets include managing low mood and smoking cessation. The intervention is facilitated by trained healthcare professionals with specialist cardiac experience over 12 weeks, via home and telephone contacts. The feasibility study found high levels of satisfaction and engagement with the intervention from facilitators, patients and caregivers. Intervention fidelity analysis and stakeholder feedback suggested that there was room for improvement in several areas, especially in terms of addressing caregivers' needs. The REACH-HF materials were revised accordingly. CONCLUSIONS: We have developed a comprehensive, evidence-informed, theoretically driven self-care and rehabilitation intervention that is grounded in the needs of patients and caregivers. A randomised controlled trial is underway to assess the effectiveness and cost-effectiveness of the REACH-HF intervention in people with heart failure and their caregivers.

Endothelial Function in Hypertension: Victim or Culprit?

Far from simply lining the inner surface of blood vessels, the cellular monolayer that comprises the endothelium is a highly active organ that regulates vascular tone. In health, the endothelium maintains the balance between opposing dilator and constrictor influences, while in disease, it is the common ground on which cardiovascular risk factors act to initiate the atherosclerotic process. As such, it is the site at which cardiovascular disease begins and consequently acts as a barometer of an individual's likely future cardiovascular health. The vascular endothelium is a very active organ responsible for the regulation of vascular tone through the effects of locally synthesized mediators, predominantly nitric oxide (NO), endothelial NO synthase (eNOS), and superoxide. NO is abundantly evident in normally functioning vasculature where it acts as a vasodilator, inhibits inflammation, and has an antiaggregant effect on platelets. Its depletion is both a sign and cause of endothelial dysfunction resulting from reduced activity of eNOS and amplified production of nicotinamide adenine dinucleotide oxidase, which, in turn, results in raised levels of reactive oxygen species. This cascade is the basis for reduced vascular compliance through an imbalanced regulation of tone with a predominance of vasoconstrictive elements. Further, structural changes in the microvasculature are a critical early step in the loss of normal function. This microvascular dysfunction is known to be highly predictive of future macrovascular events and is consequently a very attractive target for intervention in the hypertensive population in order to prevent cardiovascular events.

Brief report: new legislation supports students with intellectual disabilities in post-secondary funding.

With the passage of the Higher Education Opportunities Act (HEAO) of 2008, students with intellectual disabilities who are enrolled in a federally approved Comprehensive Transition and Postsecondary Program on a college campus will be eligible for some forms of federal student financial aid. This Brief Report discusses the forms of aid available, the impact upon higher functioning students with ASDs, the impact upon colleges and the potential conflict between HEOA and Individuals with Disabilities Education Act.