Cardiovascular risks and sociodemographic correlates of multidimensional sleep phenotypes in two samples of US adults.

Study Objectives: Sleep is a modifiable risk factor for cardiovascular conditions. Holistic examination of within-person, multidimensional sleep patterns may offer more detailed information about the sleep-cardiovascular condition link, including who is more vulnerable to both. This study aimed to identify common sleep phenotypes in adulthood, establish the validity of the phenotypes in relation to cardiovascular conditions, and explore sociodemographic and background characteristics of the phenotypes. Methods: Across two independent samples of adults (N 1 = 4600; N 2 = 2598) from the Midlife in the United States Study, latent class analysis (LCA) extracted sleep phenotypes using five key self-reported sleep dimensions. Log-binomial regression was used to determine whether sleep phenotypes differentially predicted cardiovascular conditions, adjusting for known risk factors. LCA with covariates was used to compare sociodemographic characteristics of the identified sleep phenotypes. Results: Four sleep phenotypes were identified consistently across the two samples: good sleepers, nappers, dissatisfied/inefficient sleepers, and irregular sleepers. Compared to good sleepers (reference), dissatisfied/inefficient sleepers exhibited a higher risk of cardiovascular conditions in both samples (RR Sample1: 29%, RR Sample2: 53%) and consisted of relatively more racial/ethnic minorities. Nappers exhibited a higher risk of cardiovascular conditions in one sample (RR Sample1: 38%) and consisted of more women and older adults. Irregular sleepers exhibited no significantly different cardiovascular risk and were relatively younger. Conclusions: Common sleep phenotypes in adulthood exhibit differential risks for cardiovascular conditions. Cooccurring sleep dissatisfaction and inefficiency, in particular, may relate to increased risk of cardiovascular conditions. Certain sociodemographic groups (racial minorities, women, older adults) disproportionately fit within high-risk sleep phenotypes.

Identifying diverse forms of (un)healthy sleep: Sleep profiles differentiate adults' psychological and physical well-being.

RATIONALE: Sleep health is best described by the co-occurrence of various dimensions (e.g., regularity, daytime alertness, satisfaction, efficiency, duration) but is rarely measured this way. Information is needed regarding common within-person patterns of sleep characteristics among adults and their relative healthiness. OBJECTIVE: To deepen understanding of healthy and unhealthy sleep, the present study aimed to uncover multidimensional sleep profiles in adults and their associations with a variety of psychological and physical well-being outcomes. METHODS: Survey data from 4622 adults who participated in the Midlife in the United States (MIDUS) project was used to identify latent sleep profiles across five core sleep dimensions. Adjusting for individual sleep dimensions and sociodemographic covariates, General Linear Models were used to test the associations of sleep profile membership with hedonic and eudemonic well-being and chronic physical conditions. RESULTS: Four latent sleep profiles were revealed, good sleepers, sufficient but irregular sleepers, nappers, and short, dissatisfied, and inefficient sleepers. The profiles differentially related to well-being outcomes above and beyond individual sleep dimensions and sociodemographic covariates. Good sleepers generally reported the best outcomes, and short, dissatisfied, and inefficient sleepers generally reported the worst outcomes. CONCLUSION: Four common sleep profiles describe adults' holistic sleep experiences and predict a variety of well-being outcomes beyond other known predictors. In adulthood, healthy sleep may involve sufficient sleep across all dimensions whereas unhealthy sleep may involve insufficient sleep across three key dimensions: duration, satisfaction, and efficiency.

Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.

BACKGROUND: Development of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies. METHODS: We describe an immunofluorescence screening method, enabled by extensive expansion of basal cells from PCD patients and the directed differentiation of these cells into ciliated epithelium in miniaturised 96-well transwell format ALI cultures. As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene. RESULTS: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures. The screening system in our proof-of-principal investigation allowed drugs that induce translational readthrough to be evaluated alone or in combination with nonsense-mediated decay inhibitors. We observed restoration of basal body formation but not the generation of cilia in the patient's nasal epithelial cells in vitro. CONCLUSION: Our study provides a platform for higher throughput analyses of airway epithelia that is applicable in a range of settings and suggests novel avenues for drug evaluation and development in PCD caused by nonsense mutations.

Bidirectional associations between sleep quality or quantity, and dietary intakes or eating behaviors in children 6-12 years old: a systematic review with evidence mapping.

CONTEXT: Although dietary advice has long been a cornerstone of a healthy lifestyle, how sleep quality and quantity may interact with dietary intake or eating behaviors remains unclear. OBJECTIVE: To consider a bidirectional relationship between sleep and diet in children aged 6-12 years via a systematic review following PRISMA guidelines. DATA SOURCES: Relevant trials and observational studies were identified by searching the PubMed, Medline, Embase, and CENTRAL databases up to June 1, 2019, without language or date restrictions and supplemented with hand searching. Recognized procedures and reporting standards were applied. DATA EXTRACTION: Data on participant characteristics, study parameters, diet measures, sleep measures, and findings of study quality assessment criteria were collected. DATA ANALYSIS: Forty-five articles involving 308 332 participants on a diverse range of topics were included. Meta-analyses were planned but were impossible to perform due to high study heterogeneity. Most studies (82%) were cross-sectional, which prevented examining directionality of the observed associations. Risk of bias was assessed for trial, cohort studies, and cross-sectional studies, using the Cochrane Risk of Bias Tool or Newcastle Ottawa Scale. RESULTS: Of 16 studies in which the effect of sleep on dietary intake was investigated, 81% (n = 13) reported a significant association. All studies (n = 8) of sugar-sweetened or caffeinated beverages reported a negative association with sleep, and in 6 of 7 studies in which eating behaviors were investigated, associations with sleep were reported. The use of objective measures of sleep and diet were scarce, with most trials and studies relying on subjective measures of sleep (68%) or diet (93%). CONCLUSION: Because most studies investigating the relationship between sleep and diet in this age group are cross-sectional, temporality could not be determined. Additional randomized controlled trials and long-term cohort studies in middle childhood, particularly those using objective rather than questionnaire measures of sleep, are required to better understand interactions between diet and sleep. SYSTEMATIC REVIEW REGISTRATION: Prospectively registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42018091647).

The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids.

BACKGROUND & AIMS: Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). METHODS: Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18-65 years with type-2 diabetes mellitus and body mass index 30-50 kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group. RESULTS: Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. CONCLUSION: One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02459561.

Discovery of an Orally Bioavailable Pan αv Integrin Inhibitor for Idiopathic Pulmonary Fibrosis.

The heterodimeric transmembrane αv integrin receptors have recently emerged as potential targets for the treatment of idiopathic pulmonary fibrosis. Herein, we describe how subtle modifications of the central aromatic ring of a series of phenylbutyrate-based antagonists of the vitronectin receptors αvß3 and αvß5 significantly change the biological activities against αvß6 and αvß8. This resulted in the discovery of a pan αv antagonist (compound 39, 4-40 nM for the integrin receptors named above) possessing excellent oral pharmacokinetic properties in rats (with a clearance of 7.6 mL/(min kg) and a bioavailability of 97%).

Bacteriophage Delivery by Nebulization and Efficacy Against Phenotypically Diverse Pseudomonas aeruginosa from Cystic Fibrosis Patients.

BACKGROUND: The rise in antibiotic-resistant Pseudomonas aeruginosa and the considerable difficulty in eradicating it from patients has re-motivated the study of bacteriophages as a therapeutic option. For this to be effective, host range and viability following nebulization need to be assessed. Host-range has not previously been assessed for the Liverpool Epidemic Strain (LES) isolates that are the most common cystic fibrosis-related clone of P. aeruginosa in the UK. Nebulization studies have not previously been linked to clinically relevant phages. METHODS: 84 phenotypically variable isolates of the LES were tested for susceptibility to seven bacteriophages known to have activity against P. aeruginosa. Five of the phages were from the Eliava Institute (IBMV) and 2 were isolated in this study. The viability of the two bacteriophages with the largest host ranges was characterized further to determine their ability to be nebulized and delivered to the lower airways. Phages were nebulized into a cascade impactor and the phage concentration was measured. RESULTS: The bacteriophages tested killed between 66%-98% of the 84 Liverpool Epidemic Strain isolates. Two isolates were multi phage resistant, but were sensitive to most first line anti-Pseudomonal antibiotics. The amount of viable bacteriophages contained in particles that are likely to reach the lower airways (<4.7 µm) was 1% for the Omron and 12% AeroEclipse nebulizer. CONCLUSIONS: Individual P. aeruginosa bacteriophages can lyse up to 98% of 84 phenotypically diverse LES strains. High titers of phages can be effectively nebulized.

Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice.

OBJECTIVES: Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1(-/-) mouse by combining three therapies that each targets unique aspects of the pathogenic cascade. METHODS: We have treated Npc1(-/-) mice with miglustat that targets sphingolipid synthesis and storage, curcumin that compensates for the lysosomal calcium defect by elevating cytosolic calcium, and the non-steroidal anti-inflammatory drug ibuprofen to reduce central nervous system inflammation. RESULTS/INTERPRETATION: We have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1(-/-) mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease.

WITHDRAWN: Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum is a patented, commercially available homoeopathic medicine. The rationale for its use in influenza comes from the homoeopathic principle of 'let like be cured by like'. This medicine is manufactured from wild duck heart and liver, which are said to be reservoirs for influenza viruses. OBJECTIVES: To determine whether homoeopathic Oscillococcinum or similar medicines are more effective than placebo in the prevention and treatment of influenza and influenza-like syndromes. SEARCH STRATEGY: We updated the electronic searches on the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006); MEDLINE (January 1966 to February 2006) and EMBASE (1980 to February 2006). The manufacturers of Oscillococcinum were contacted for information. SELECTION CRITERIA: Placebo-controlled trials of Oscillococcinum or homeopathically-prepared influenza virus, influenza vaccine or avian liver in the prevention and treatment of influenza and influenza-like syndromes. DATA COLLECTION AND ANALYSIS: Two authors extracted data and assessed methodological quality independently. MAIN RESULTS: Seven studies were included in the review, three prevention trials (number of participants (n) = 2265) and four treatment trials (n = 1194). Only two studies reported sufficient information to complete data extraction fully. There was no evidence that homoeopathic treatment can prevent influenza-like syndrome (relative risk (RR) 0.64, 95% confidence interval (CI) 0.28 to 1.43). Oscillococcinum treatment reduced the length of influenza illness by 0.28 days (95% CI 0.50 to 0.06). Oscillococcinum also increased the chances that a patient considered treatment to be effective (RR 1.08; 95% CI 1.17 to 1.00). AUTHORS' CONCLUSIONS: Though promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted but the required sample sizes are large. Current evidence does not support a preventative effect of Oscillococcinum-like homeopathic medicines in influenza and influenza-like syndromes.

Improvements in performance following optometric vision therapy in a child with dyspraxia.

SS, an 8-year-old boy with dyspraxia, presented for behavioural optometry assessment. He had been diagnosed with a subtle form of dyspraxia by his paediatric occupational therapist, based on poor proprioception, delayed bilateral integration and poor visual perception. A full visual assessment was carried out. SS was given a programme of reflex inhibition exercises for 3 months. Then, a programme of optometric vision therapy (OVT) exercises was prescribed at home and in practice for a period of 8 months. SS was assessed using a battery of occupational therapy Sensory Integration and Praxis Tests (SIPT) before optometric intervention, and after OVT. There were significant improvements in fusional reserves, accommodative facility and oculomotor control of pursuit and saccadic eye movements. His reading level had changed by 4 years in 11 months. The SIPT results showed improvements in the visual and motor/visual perception subtests, confirming the significant changes in visual perceptual performance. Consideration is given to treatment modalities for dyspraxia, and the studies confirming their effectivity of approach. This case study provides evidence supporting the use of OVT eye exercises in dyspraxia, ocular motility, accommodative dysfunction, learning difficulties and sports performance. The need for further research and inter-professional working is discussed.

Acupuncture for chronic headache in primary care: large, pragmatic, randomised trial.

OBJECTIVE: To determine the effects of a policy of "use acupuncture" on headache, health status, days off sick, and use of resources in patients with chronic headache compared with a policy of "avoid acupuncture." DESIGN: Randomised, controlled trial. SETTING: General practices in England and Wales. PARTICIPANTS: 401 patients with chronic headache, predominantly migraine. Interventions Patients were randomly allocated to receive up to 12 acupuncture treatments over three months or to a control intervention offering usual care. MAIN OUTCOME MEASURES: Headache score, SF-36 health status, and use of medication were assessed at baseline, three, and 12 months. Use of resources was assessed every three months. RESULTS: Headache score at 12 months, the primary end point, was lower in the acupuncture group (16.2, SD 13.7, n = 161, 34% reduction from baseline) than in controls (22.3, SD 17.0, n = 140, 16% reduction from baseline). The adjusted difference between means is 4.6 (95% confidence interval 2.2 to 7.0; P = 0.0002). This result is robust to sensitivity analysis incorporating imputation for missing data. Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year (8 to 38). SF-36 data favoured acupuncture, although differences reached significance only for physical role functioning, energy, and change in health. Compared with controls, patients randomised to acupuncture used 15% less medication (P = 0.02), made 25% fewer visits to general practitioners (P = 0.10), and took 15% fewer days off sick (P = 0.2). CONCLUSIONS: Acupuncture leads to persisting, clinically relevant benefits for primary care patients with chronic headache, particularly migraine. Expansion of NHS acupuncture services should be considered.