AbstractObjectiveTo determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on ...risk of all cause acute respiratory tract infection and covid 19.DesignPhase 3 open label randomised controlled trial.SettingUnited Kingdom.Participants6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.InterventionsOffer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.Main outcome measuresThe primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.ResultsOf 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).ConclusionsAmong people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.Trial registrationClinicalTrials.gov NCT04579640.
Neutrophils contain antimicrobial peptides with antituberculous activity, but their contribution to immune resistance to tuberculosis (TB) infection has not been previously investigated to our ...knowledge. We determined differential white cell counts in peripheral blood of 189 adults who had come into contact with patients diagnosed with active TB in London, United Kingdom, and evaluated them for evidence of TB infection and capacity to restrict mycobacterial growth in whole-blood assays. Risk of TB infection was inversely and independently associated with peripheral blood neutrophil count in contacts of patients diagnosed with pulmonary TB. The ability of whole blood to restrict growth of Mycobacterium bovis bacille Calmette Guérin and Mycobacterium tuberculosis was impaired 7.3- and 3.1-fold, respectively, by neutrophil depletion. In microbiological media, human neutrophil peptides (HNPs) 1-3 killed M. tuberculosis. The neutrophil peptides cathelicidin LL-37 and lipocalin 2 restricted growth of the organism, the latter in an iron-dependent manner. Black African participants had lower neutrophil counts and lower circulating concentrations of HNP1-3 and lipocalin 2 than south Asian and white participants. Neutrophils contribute substantially to innate resistance to TB infection, an activity associated with their antimicrobial peptides. Elucidation of the regulation of neutrophil antimicrobial peptides could facilitate prevention and treatment of TB.
Abstract
It is challenging for conventional top-down lithography to fabricate reproducible devices very close to atomic dimensions, whereas identical molecules and very similar nanoparticles can be ...made bottom-up in large quantities, and can be self-assembled on surfaces. The challenge is to fabricate electrical contacts to many such small objects at the same time, so that nanocrystals and molecules can be incorporated into conventional integrated circuits. Here, we report a scalable method for contacting a self-assembled monolayer of nanoparticles with a single layer of graphene. This produces single-electron effects, in the form of a Coulomb staircase, with a yield of 87 ± 13% in device areas ranging from < 800 nm
2
to 16
μ
m
2
, containing up to 650,000 nanoparticles. Our technique offers scalable assembly of ultra-high densities of functional particles or molecules that could be used in electronic integrated circuits, as memories, switches, sensors or thermoelectric generators.
Prospective population-based studies investigating multiple determinants of pre-vaccination antibody responses to SARS-CoV-2 are lacking.
We did a prospective population-based study in SARS-CoV-2 ...vaccine-naive UK adults recruited between May 1 and November 2, 2020, without a positive swab test result for SARS-CoV-2 prior to enrolment. Information on 88 potential sociodemographic, behavioural, nutritional, clinical and pharmacological risk factors was obtained through online questionnaires, and combined IgG/IgA/IgM responses to SARS-CoV-2 spike glycoprotein were determined in dried blood spots obtained between November 6, 2020, and April 18, 2021. We used logistic and linear regression to estimate adjusted odds ratios (aORs) and adjusted geometric mean ratios (aGMRs) for potential determinants of SARS-CoV-2 seropositivity (all participants) and antibody titres (seropositive participants only), respectively.
Of 11,130 participants, 1696 (15.2%) were seropositive. Factors independently associated with higher risk of SARS-CoV-2 seropositivity included frontline health/care occupation (aOR 1.86, 95% CI 1.48-2.33), international travel (1.20, 1.07-1.35), number of visits to shops and other indoor public places (≥ 5 vs. 0/week: 1.29, 1.06-1.57, P-trend = 0.01), body mass index (BMI) ≥ 25 vs. < 25 kg/m
(1.24, 1.11-1.39), South Asian vs. White ethnicity (1.65, 1.10-2.49) and alcohol consumption ≥15 vs. 0 units/week (1.23, 1.04-1.46). Light physical exercise associated with lower risk (0.80, 0.70-0.93, for ≥ 10 vs. 0-4 h/week). Among seropositive participants, higher titres of anti-Spike antibodies associated with factors including BMI ≥ 30 vs. < 25 kg/m
(aGMR 1.10, 1.02-1.19), South Asian vs. White ethnicity (1.22, 1.04-1.44), frontline health/care occupation (1.24, 95% CI 1.11-1.39), international travel (1.11, 1.05-1.16) and number of visits to shops and other indoor public places (≥ 5 vs. 0/week: 1.12, 1.02-1.23, P-trend = 0.01); these associations were not substantially attenuated by adjustment for COVID-19 disease severity.
Higher alcohol consumption and lower light physical exercise represent new modifiable risk factors for SARS-CoV-2 infection. Recognised associations between South Asian ethnic origin and obesity and higher risk of SARS-CoV-2 seropositivity were independent of other sociodemographic, behavioural, nutritional, clinical, and pharmacological factors investigated. Among seropositive participants, higher titres of anti-Spike antibodies in people of South Asian ancestry and in obese people were not explained by greater COVID-19 disease severity in these groups.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A number of mechanisms have been proposed to contribute to glucocorticoid-resistant asthma, including increased expression of nuclear factor kappa B and activating protein 1 (AP-1), increased ...expression of histone deacetylase, polymorphisms in IL-10, increased expression of the dominant negative isoform of the glucocorticoid receptor beta (GRβ), and vitamin D insufficiency.2-4 Our earlier data showed that peripheral blood CD4+ T cells from glucocorticoid-resistant as compared with glucocorticoid-sensitive asthmatic patients failed to synthesize the anti-inflammatory cytokine IL-10 in response to glucocorticoid in vitro.5 The active form of vitamin D (calcitriol; 1,25-dihydroxyvitamin D3 1,25(OH)2D3) when used in combination with glucocorticoid restored this IL-10 response both in vitro and ex vivo following patient ingestion of calcitriol.6 These data, together with epidemiologic evidence linking vitamin D insufficiency/deficiency with a poor clinical response to treatment in asthma,3,4 provided the rationale for this proof-of-concept clinical trial. On the one hand, the decision to study a well-characterized cohort of glucocorticoid-resistant asthmatic patients produced significant challenges with recruitment and retention, but on the other hand may have facilitated our ability to observe a clinical effect that may be manifest most clearly in this small but important subset of patients.\n Study subjects were asked to report any adverse events from the day of commencement of the first course of oral prednisolone until 4 weeks after the second course by telephone or e-mail or at study visits.
Asthma exacerbations are commonly precipitated by viral upper respiratory infections (URIs). Vitamin D insufficiency associates with susceptibility to URI in patients with asthma. Trials of vitamin D ...in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking.
To conduct a randomised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI (coprimary outcomes).
250 adults with asthma in London, UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 (n=125) or placebo (n=125) over 1 year. Secondary outcomes included asthma control test and St George's Respiratory Questionnaire scores, fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum. Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes.
206/250 participants (82%) were vitamin D insufficient at baseline. Vitamin D3 did not influence time to first severe exacerbation (adjusted HR 1.02, 95% CI 0.69 to 1.53, p=0.91) or first URI (adjusted HR 0.87, 95% CI 0.64 to 1.16, p=0.34). No clinically important effect of vitamin D3 was seen on any of the secondary outcomes listed above. The influence of vitamin D3 on coprimary outcomes was not modified by baseline vitamin D status or genotype.
Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency.
NCT00978315 (ClinicalTrials.gov).
Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25OHD) levels may represent a cause or a consequence of these ...conditions.
To determine whether vitamin D metabolism is altered in asthma or COPD.
We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D
, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D
, 25(OH)D
, and 1α,25-dihydroxyvitamin D
(1α,25OH
D
) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)
D
-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.
The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L;
= 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D
-to-vitamin D
and higher molar ratios of 1α,25(OH)
D
-to-25(OH)D
both presupplementation and postsupplementation (
≤ 0.005). Intergroup differences in 1α,25(OH)
D
-inducible gene expression signatures were modest and variable if statistically significant.
Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D
-to-vitamin D
and increased molar ratios of 1α,25(OH)
D
-to-25(OH)D
in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells ...from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna
HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.
Corticosteroids enhance the production of the antiinflammatory cytokine IL-10 by T cells in vitro, but notably this response is impaired in cultures from SR asthmatic patients, implying an ...association between impaired IL-10 response and poor asthma control.2 This defect in steroid-induced IL-10 can be restored by the addition of the active form of vitamin D3 (1,25-hydroxyvitamin D3) into the culture, thus suggesting that vitamin D may play a role in controlling steroid responsiveness.3 These data are complemented by a number of independent clinical studies that highlight a high prevalence of vitamin D deficiency and insufficiency worldwide and its association with an increased incidence, severity, and poor control of asthma.4,5 The importance and status of a well-defined subset of Treg cells, as defined by the expression of the transcription factor forkhead box P3 (Foxp3), in SS and SR asthma are less well understood.1,6 Although 1,25-hydroxyvitamin D3 has been shown to enhance the frequency of human Foxp3+ Treg cells in vitro, no in vivo correlates of these data exist.7 The aim of the present study was therefore to investigate whether differences exist in the frequency of Foxp3+ Treg cells in the peripheral blood of SS and SR adult asthma patients, and the relationship between vitamin D status and the Foxp3+ Treg-cell compartment.
This paper reports data from the evaluation of a coach education programme provided by a major national governing body of sport (NGB) in the UK. The programme was designed for youth sport coaches ...based on research evidence that suggests that CPD is most effective in supporting practitioner learning when it is interactive, collaborative and located in practice. At the same time, the NGB was keen to ensure that in order to meet the objectives of the organisation, there was some consistency in delivery across the various practice sites. The research aimed to investigate how the original CPD programme was enacted across eight professional sports clubs, and to understand how professional knowledge was interpreted and negotiated between participants at the NGB and sports club levels. Over a 2-year period, data were collected from a series of focus groups and extended individual semi-structured interviews. Participants were 7 senior managers, 8 coach educators, 8 Academy club directors and 12 sports club coaches. Data were initially analysed inductively and, drawing on the theoretical work of Bernstein (1999). Vertical and horizontal discourse: An essay. British Journal of Sociology of Education, 20(2), 157-173, (2000). Pedagogy, symbolic control and identity: Theory, research, critique (Rev. ed.). Lanham, MD: Rowman & Littlefield, illustrate the numerous ways in which programme knowledge was interpreted, facilitated and blocked at different levels of the organisation. The paper adds new insights into the complexities of coach education settings and the inherent challenges faced when attempting to 'roll out' a coach education intervention - even when it is 'evidence-based'.
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