'Why did nobody ask us?': A mixed-methods co-produced study in the United Kingdom exploring why some children are unvaccinated or vaccinated late.

OBJECTIVE: Childhood vaccine uptake in the United Kingdom (UK) is sub-optimal leading to outbreaks of preventable diseases. We aimed to explore UK parents' perspectives on why some children are unvaccinated or vaccinated late. METHODS: We undertook a mixed-methods, co-production study involving a survey using a questionnaire followed by focus groups. We partnered with The Mosaic Community Trust (Mosaic) who are based in a more deprived, ethnically diverse, low vaccine uptake area of London. Targeted recruitment to complete the questionnaire (either on paper or online) was done through Mosaic, community networks and social media promotion. We collected demographic data alongside parents' views on routine childhood vaccination, their vaccine decisions, and experiences of accessing childhood vaccine appointments We report descriptive findings from the questionnaire and thematic analysis of free-text questionnaire answers and focus groups guided by the COM-B model of Capability, Opportunity, and Motivation. RESULTS: Between June-October 2022, 518 parents were surveyed of whom 25% (n = 130), were from ethnic minorities (13%, n = 68-unknown ethnicity). In 2023 we held four focus groups with 22 parents (10 from ethnic minorities). Only 15% (n = 78) parents had delayed or refused a vaccine for their child. A quarter of parents felt they had not been given enough information nor an opportunity to ask questions before their children's vaccinations. Inconsistent reminders and difficulties booking or attending appointments impacted vaccine uptake with negative experiences influencing future vaccine decisions. Parents had mixed views on vaccinations being given in different locations and wanted trusted health professionals to vaccinate their children. CONCLUSION: To reverse declining vaccine uptake and prevent future outbreaks it needs to be easier for UK parents to speak to health professionals to answer their childhood vaccine questions, alongside simplified booking systems and easier access to routine childhood vaccine appointments.

Impact of pregnancy vaccine uptake and socio-demographic determinants on subsequent childhood Measles, Mumps and Rubella vaccine uptake: A UK birth cohort study.

BACKGROUND: We examined the association between socio-demographic determinants and uptake of childhood Measles, Mumps & Rubella (MMR) vaccines and the association between pregnant women's pertussis vaccine uptake and their children's MMR vaccine uptake. METHODS: We used nationally-representative linked mother-baby electronic records from the United Kingdom's Clinical-Practice-Research-Datalink. We created a birth cohort of children born between 01.01.2000 and 12.12.2020. We estimated the proportion vaccinated with first MMR vaccine by age 2 years and first and second MMR vaccines by age 5 years. We used survival-analysis and Cox proportional hazard models to examine the association between deprivation, ethnicity and maternal age and pertussis vaccination in pregnancy and children's MMR uptake. RESULTS: Overall, 89.4 % (710,797/795,497) of children had first MMR by age 2 years and 92.6 % (736,495/795,497) by age 5 years. Among children still in the cohort when second MMR was due, 85.9 % (478,480/557,050) had two MMRs by age 5 years. Children from the most-deprived areas, children of Black ethnicity and children of mothers aged < 20 years had increased risk of being unvaccinated compared with children from the least-deprived areas, White children and children of mothers aged 31-40 years: first MMR by 5 years, adjusted Hazard Ratios (HR):0.86 (CI:0.85-0.87), HR:0.87 (CI:0.85-0.88) & HR:0.89 (CI:0.88-0.90) respectively. Deprivation was the determinant associated with the greatest risk of missed second MMR: adjusted HR:0.82 (CI:0.81-0.83). Children of mothers vaccinated in pregnancy were more likely than children of unvaccinated mothers to have MMR vaccines after adjusting for ethnicity, deprivation, and maternal age (First and Second MMRs adjusted HRs:1.43 (CI:1.41-1.45), 1.49 (CI:1.45-1.53). CONCLUSION: Children from most-deprived areas are less likely to have MMR vaccines compared with children from least-deprived areas. Mothers who take up pregnancy vaccines are more likely to have their children vaccinated with MMR. Healthcare services should promote and facilitate access to both maternal and childhood vaccines during pregnancy.

Paediatric TB care in the United Kingdom.

BACKGROUND: Care of patients with paediatric TB is delivered in a variety of settings by different clinicians in the United Kingdom. Paediatric practices vary in size. Guidelines on managing children with TB differ in recommendations. These factors contribute to variations in practice.OBJECTIVE: To describe practice among UK professionals caring for children exposed to or infected with TB, and their investigation and treatment.METHODS: From 81 NHS (National Health Service) clinical services, 114 individuals responded to a web-based questionnaire.RESULTS: We describe variation in several areas of practice, with important differences between smaller and larger centres. Most respondents go beyond National Institute for Health & Care Excellence guidance and screen child contacts of extrapulmonary TB. Most respondents would presume pulmonary TB exposed children aged under 2 years to be infected. They would not rely on immunological investigations to rule out infection. There was wide variety in approaches to microbiological diagnosis, and in the use of laboratory investigations to monitor treatment. Many respondents felt unclear on how to manage newborns exposed to TB, or children exposed to multidrug-resistant TB.CONCLUSION: These findings support the case for further developing regional networks providing evidence and consensus-based care for children with TB.

Using behavioural science in public health settings during the COVID-19 pandemic: The experience of public health practitioners and behavioural scientists.

INTRODUCTION: The emergence of COVID-19 and the importance of behaviour change to limit its spread created an urgent need to apply behavioural science to public health. Knowledge mobilisation, the processes whereby research leads to useful findings that are implemented to affect positive outcomes, is a goal for researchers, policy makers and practitioners alike. This study aimed to explores the experience of using behavioural science in public health during COVID-19, to discover barriers and facilitators and whether the rapidly changing context of COVID-19 influenced knowledge mobilisation. METHODS: We conducted a semi-structured interview study, with ten behavioural scientists and seven public health professionals in England, Scotland, Wales, The Netherlands and Canada. We conducted an inductive thematic analysis. RESULTS: We report three key themes and 10 sub-themes: 1.Challenges and facilitators of translation of behavioural science into public health (Methods and frameworks supported translation, Lack of supportive infrastructure, Conviction and sourcing of evidence and Embracing behavioural science) 2. The unique context of translation (Rapid change in context, the multi-disciplinary team and the emotional toll). 3. Recommendations to support future behavioural science translation (Embedding experts into teams, Importance of a collaborative network and showcasing the role of behavioural science). DISCUSSION: Barriers and facilitators included factors related to relationships between people, such as networks and teams; the expertise of individual people; and those related to materials, such as the use of frameworks and an overwhelming amount of evidence and literature. CONCLUSION: People and frameworks were seen as important in facilitating behavioural science in practice. Future research could explore how different frameworks are used. We recommend a stepped competency framework for behavioural science in public health and more focus on nurturing networks to facilitate knowledge mobilisation in future emergencies.

Socio-economic differences in cardiovascular disease risk factor prevalence in people with type 2 diabetes in Scotland: a cross-sectional study.

AIM: To describe the association between socio-economic status and prevalence of key cardiovascular risk factors in people with type 2 diabetes in Scotland. METHODS: A cross-sectional study of 264 011 people with type 2 diabetes in Scotland in 2016 identified from the population-based diabetes register. Socio-economic status was defined using quintiles of the area-based Scottish Index of Multiple Deprivation (SIMD) with quintile (Q)1 and Q5 used to identify the most- and least-deprived fifths of the population, respectively. Logistic regression models adjusted for age, sex, health board, history of cardiovascular disease and duration of diabetes were used to estimate odds ratios (ORs) for Q1 compared with Q5 for each risk factor. RESULTS: The mean (sd) age of the study population was 66.7 (12.8) years, 56% were men, 24% were in Q1 and 15% were in Q5. Crude prevalence in Q1/Q5 was 24%/8.8% for smoking, 62%/49% for BMI ≥ 30 kg/m2 , 44%/40% for HbA1c ≥ 58 mmol/mol (7.5%), 31%/31% for systolic blood pressure (SBP) ≥ 140 mmHg, and 24%/25% for total cholesterol ≥ 5 mmol/l, respectively. ORs [95% confidence intervals (CI)] were 3.08 (2.95-3.21) for current smoking, 1.48 (1.44-1.52) for BMI ≥ 30 kg/m2 , 1.11 (1.08-1.15) for HbA1c ≥ 58 mmol/mol (7.5%), 1.03 (1.00-1.06) for SBP ≥ 140 mmHg and 0.87 (0.84-0.90) for total cholesterol ≥ 5 mmol/l. CONCLUSIONS: Socio-economic deprivation is associated with higher prevalence of smoking, BMI ≥ 30 kg/m2 and HbA1c ≥ 58 mmol/mol (7.5%), and lower prevalence of total cholesterol ≥ 5 mmol/l among people with type 2 diabetes in Scotland. Effective approaches to reducing inequalities are required as well as reducing risk factor prevalence across the whole population.

Note: Electrical resolution during conductive atomic force microscopy measurements under different environmental conditions and contact forces.

Conductive atomic force microscopy experiments on gate dielectrics in air, nitrogen, and UHV have been compared to evaluate the impact of the environment on topography and electrical measurements. In current images, an increase of the lateral resolution and a reduction of the conductivity were observed in N(2) and, especially, in UHV (where current depends also on the contact force). Both effects were related to the reduction/elimination of the water layer between the tip and the sample in N(2)/UHV. Therefore, since current measurements are very sensitive to environmental conditions, these factors must be taken into consideration when comparisons between several experiments are performed.

Interferon-gamma release assays do not identify more children with active tuberculosis than the tuberculin skin test.

Data are lacking on the performance of interferon-gamma release assays (IGRAs) in children. Although IGRAs are recommended for screening for latent tuberculosis infection (LTBI), many clinicians wish to employ them as a diagnostic test for active tuberculosis (TB). The objective of the present study was to compare the performance of the two commercially available IGRAs and the tuberculin skin test (TST) side-by-side in children with active TB and LTBI. In a prospective study, 209 children were investigated for active (n = 91) or latent TB (n = 118). TST, QuantiFERON-TB Gold In-tube (QFG-IT; Cellestis, Carnegie, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK) assays were simultaneously used. For culture-confirmed active TB, the sensitivity of the TST was 83%, compared with 80% for QFG-IT and 58% for T-SPOT.TB. IGRAs did not perform significantly better than TST, although QFG-IT was significantly better than T-SPOT.TB. The agreement between QFG-IT and T-SPOT.TB in culture-confirmed TB was poor at 66.7%. In LTBI, the agreement between QFG-IT and T-SPOT.TB was very good (92%) with moderate agreement between TST and T-SPOT.TB (75%) and QFG-IT and TST (77%). A negative interferon-gamma release assay should not dissuade paediatricians from diagnosing and treating presumed active tuberculosis. If used for diagnosis of latent tuberculosis infection, interferon-gamma release assays could significantly reduce the numbers of children receiving chemoprophylaxis. Very good concordance between both tests was found.

Presentation, diagnosis and management of tuberculosis in HIV-infected children in the UK.

OBJECTIVES: Management of HIV-infected children with tuberculosis (TB) is challenging. The objective of this study was to assess current treatment and outcomes in a resource-rich setting in the era of highly active antiretroviral therapy (HAART). METHODS: A retrospective case-note review of coinfected children was carried out in a large UK-based HIV family clinic. RESULTS: Of 328 HIV-infected children, 18 were diagnosed and treated for active TB. TB presentation led to HIV diagnosis in eight of these 18 children. TB was confirmed microbiologically in 33% of children. Fifteen of the 18 children presented with pulmonary TB, and three with extrapulmonary TB (EPTB). Immunological status at TB diagnosis did not predict EPTB. The mean CD4 T-cell count at TB presentation was 402 cells/microL (mean CD4 percentage 16%), with a range of 0-790 cells/microL (0-34%). In seven children concurrently treated with HAART and anti-tuberculous therapy (ATT), therapeutic drug monitoring (TDM) guided management. No immune reconstitution disease occurred. There was one death, unrelated to TB, 2 years after completion of ATT. CONCLUSIONS: An HIV test should be considered in all children diagnosed with TB, especially if there are epidemiological risk factors. Our experience shows that, even with deferral of HAART in concurrently infected children, good therapeutic responses to ATT can be achieved. Where necessary, TDM guiding concurrent HAART and ATT can facilitate good clinical and virological responses.

Evaluating education in palliative care with link nurses in nursing homes.

BACKGROUND: Palliative care is recognized as an important component of care for everyone with advanced illness. Historically, it has been provided in specialist settings, but it has been suggested that best practice in palliative care should be transferred to non-specialist settings, including care homes. Care homes require particular support for this and link nurses have been recruited to develop palliative care in these settings. AIM: To assess the palliative care education received and consequently cascaded by designated nursing home staff. METHOD: Questionnaire administered to private nursing home nurses who attended a palliative care training programme in one UK region. FINDINGS: Thirty questionnaires were returned (response rate 77%). There was a high satisfaction with course content, facilitation and benefits accrued from participation. Many respondents (83%) had not commenced cascading training within their nursing homes due to lack of time and competing mandatory demands. CONCLUSION: Extending palliative care practice to non-specialist settings with the help of link nurses is possible and welcomed by nursing home staff. However, more substantive and on-going support is needed post-training from both nursing home management and training facilitator to enable and empower link nurses to undertake palliative care education with their peers.

mRNA and protein expression of dog liver cytochromes P450 in relation to the metabolism of human CYP2C substrates.

1. Interpretation of novel drug exposure and toxicology data from the dog is tempered by our limited molecular and functional knowledge of dog cytochromes P450 (CYPs). The aim was to study the mRNA and protein expression of hepatic dog CYPs in relation to the metabolism of substrates of human CYP, particularly those of the CYP2C subfamily. 2. The rate of 7-hydroxylation of S-warfarin (CYP2C9 in humans) by dog liver microsomes (mean +/- SD from 12 (six male and six female) dogs = 10.8 +/- 1.9 fmol mg(-1) protein min(-1)) was 1.5-2 orders of magnitude lower than that in humans. 3. The rate of 4'-hydroxylation of S-mephenytoin, catalysed in humans by CYP2C19, was also low in dog liver (4.6 +/-1.5 pmol mg(-1) protein min(-1)) compared with human liver. In contrast, the rate of 4'-hydroxylation of the R-enantiomer of mephenytoin by dog liver was much higher. The kinetics of this reaction (range of K(m) or K(0.5) 15-22 micro M, V(max) 35-59 pmol mg(-1) protein min(-1), n = 4 livers) were consistent with the involvement of a single enzyme. 4. In contrast to our findings for S-mephenytoin, dog liver microsomes 5'-hydroxylated omeprazole (also catalysed by CYP2C19 in humans) at considerably higher rates (range of K(m) 42-64 micro M, V(max) 22-46 pmol mg(-1) protein min(-1), n = 4 livers). 5. For all the substrates except omeprazole, a sex difference in their metabolism was observed in the dog (dextromethorphan N-demethylation: female range = 0.7-0.9, male = 0.4-0.8 nmol mg(-1) protein min(-1) (p < 0.02); S-warfarin 7-hydroxylation: female = 9-15.5, male = 8-12 fmol mg(-1) protein min(-1) (p < 0.02); R-mephenytoin 4'-hydroxylation: female = 16-35, male = 11.5-19 pmol mg(-1) protein min(-1) (p < 0.01); omeprazole 5'-hydroxylation: female = 15-20, male 13-22 pmol mg(-1) protein min(-1) (p < 0.2)). 6. All dog livers expressed mRNA and CYP3A12, CYP2B11, CYP2C21 proteins, with no sex differences being found. Expression of CYP2C41 mRNA was undetectable in the livers of six of 11 dogs. 7. Correlation analysis suggested that CYP2B11 catalyses the N-demethylation of dextromethorphan (mediated in humans by CYP3A) and the 4'-hydroxylation of mephenytoin (mediated in humans by CYP2C19) in the dog, and that this enzyme and CYP3A12 contribute to S-warfarin 7-hydroxylation (mediated in humans by CYP2C9). 8. In conclusion, we have identified a distinct pattern of hepatic expression of the CYP2C41 gene in the Alderley Park beagle dog. Furthermore, marked differences in the metabolism of human CYP2C substrates were observed in this dog strain compared with humans with respect to rate of reaction, stereoselectivity and CYP enzyme selectivity.

The anti-inflammatory cytokine, interleukin (IL)-10, blocks the inhibitory effect of IL-1 beta on long term potentiation. A role for JNK.

Several effects of the proinflammatory cytokine, interleukin-1 beta (IL-1 beta), have been described in the central nervous system, and one area of the brain where marked changes have been reported is the hippocampus. Among these changes are an IL-1 beta-induced inhibition of long term potentiation (LTP) in perforant path-granule cell synapses and an attenuation of glutamate release in synaptosomes prepared from the hippocampus. Evidence suggests that, at least in circulating cells, the anti-inflammatory cytokine, IL-10, antagonizes certain effects of IL-1. We investigated the effect of IL-10 on IL-1 beta-induced inhibition of LTP and glutamate release. The evidence presented indicates that IL-1 beta stimulates the stress-activated protein kinase, c-Jun-activated protein kinase (JNK), and IL-1 receptor-associated kinase, which may explain its inhibitory effect on release and LTP, and that IL-10 reversed the IL-1 beta-induced stimulation of JNK activity and inhibition of release and LTP. We observed that IL-10 abrogated the stimulatory effect of IL-1 beta on superoxide dismutase activity and reactive oxygen species production, whereas the H(2)O(2)-induced inhibition of LTP was also blocked by IL-10. We present evidence that suggests that the action of IL-10 may be mediated by its ability to induce shedding of the IL-1 type I receptor.

Neuropeptide Y inhibits glutamate release and long-term potentiation in rat dentate gyrus.

The effect of intracerebroventricular injection of neuropeptide Y (NPY) was assessed on LTP in dentate gyrus. We report that NPY attenuated LTP and inhibited KCl-induced glutamate release in synaptosomes prepared from dentate gyrus. Activity of the stress-activated kinase, c-Jun NH2-terminal kinase (JNK) in synaptosomes was increased by incubation with NPY or following intracerebroventricular injection. Activation of JNK might underlie the inhibitory effect of NPY on LTP.

Sensitive absorption spectroscopy with a room-temperature distributed-feedback quantum-cascade laser.

We report what we believe are the first spectroscopic measurements to be made with a room-temperature quantum-cascade distributed-feedback laser. Using wavelength modulation spectroscopy, we detected N(2)O and CH(4) in the chemical fingerprint wavelength range near 8microm . The noise equivalent absorbance for our measurement was 5 parts in 10(5), limited by excess amplitude modulation on the laser output, which corresponds to a 1-Hz bandwidth detection limit of 250 parts N(2)O in 10(9) parts N(2) in a 1-m path length.

Interaction of the yeast splicing factor PRP8 with substrate RNA during both steps of splicing.

PRP8 protein of Saccharomyces cerevisiae interacts directly with pre-mRNA in spliceosomes, shown previously by UV-crosslinking. To analyse at which steps of splicing and with which precursor-derived RNA species the interaction(s) take place, UV-crosslinking was combined with PRP8-specific immunoprecipitation and the coprecipitated RNA species were analysed. Specific precipitation of intron-exon 2 and excised intron species was observed. PRP8 protein could be UV-crosslinked to pre-mRNA in PRP2-depleted spliceosomes stalled before initiation of the splicing reaction. Thus, the interaction of PRP8 protein with substrate RNA is established prior to the first transesterification reaction, is maintained during both steps of splicing and continues with the excised intron after completion of the splicing reaction. RNase T1 treatment of spliceosomes revealed that substrate RNA fragments of the 5' splice site region and the branchpoint-3' splice site region could be coimmunoprecipitated with PRP8 specific antibodies, indicating that these are potential sites of interaction for PRP8 protein with substrate RNA. Protection of the branch-point-3' splice site region was detected only after step 1 of splicing. The results allow a first glimpse at the pattern of PRP8 protein-RNA interactions during splicing and provide a fundamental basis for future analysis of these interactions.

Theoretical description of frequency modulation and wavelength modulation spectroscopy.

We present a comprehensive theory for heterodyne absorption spectroscopy with phase-modulated light. The general equations presented allow for an arbitrary modulation index and an arbitrary modulation frequency. We use this description for three purposes: First, we review the special cases of so-called frequency modulation and wavelength modulation spectroscopy. Second, we present the additional case of large-index, high-frequency modulation. Third, we present an overview of how the absorption signal depends on the experimental parameters of modulation frequency and modulation index. This overview may be helpful to experimentalists in choosing these parameters, for it provides a systematic understanding of how moving around in parameter space changes certain features of the signal, while leaving other features invariant.

Combined wavelength and frequency modulation spectroscopy: a novel diagnostic tool for materials processing.

By applying both low-frequency wavelength modulation and high-frequency phase modulation to a laser diode, we develop a sensitive, high-bandwidth chemical diagnostic tool that is applicable to a variety of gas-phase processing environments. Specific chemical species are identified and monitored through their infrared absorption spectra, and the modulation methods allow for sensitive detection that is free of window and other reflection-driven interference fringes. Absorbance limits of 5.3 x 10(-8) and 1.9 x 10(-7) are obtained for an AlGaAs diode laser and a lead-salt diode laser, respectively. We discuss applications to plasma etching and chemical vapor deposition.

Frequency-modulation spectroscopy with a multimode dye laser.

A multimode laser in frequency-modulation spectroscopy gives a signal that is broader than the absorption line by an amount that is determined by how sharp the edges of the laser profile are, not by the total bandwidth of the laser. We have experimentally demonstrated that one can therefore obtain frequency-modulation signals that are narrower than the total bandwidth of the laser.

Novel étalon fringe rejection technique for laser absorption spectroscopy.

When used for trace-gas detection, laser absorption spectroscopy is usually limited by false absorption signals that are traceable to interferometric effects induced by windows and other pairs of optical surfaces. Here we introduce a new technique that can selectively reject these étalon fringes while preserving the true absorption signal over a wide range of étalon free spectral range to absorption linewidth ratios. We present a theoretical analysis and experimental verification by using a tunable lead salt diode laser.

The yeast PRP8 protein interacts directly with pre-mRNA.

The PRP8 protein of Saccharomyces cerevisiae is required for nuclear pre-mRNA splicing. Previously, immunological procedures demonstrated that PRP8 is a protein component of the U5 small nuclear ribonucleoprotein particle (U5 snRNP), and that PRP8 protein maintains a stable association with the spliceosome during both step 1 and step 2 of the splicing reaction. We have combined immunological analysis with a UV-crosslinking assay to investigate interaction(s) of PRP8 protein with pre-mRNA. We show that PRP8 protein interacts directly with splicing substrate RNA during in vitro splicing reactions. This contact event is splicing-specific in that it is ATP-dependent, and does not occur with mutant RNAs that contain 5' splice site or branchpoint mutations. The use of truncated RNA substrates demonstrated that the assembly of PRP8 protein into splicing complexes is not, by itself, sufficient for the direct interaction with the RNA; PRP8 protein only becomes UV-crosslinked to RNA substrates capable of participating in step 1 of the splicing reaction. We propose that PRP8 protein may play an important structural and/or regulatory role in the spliceosome.

Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus.

BACKGROUND: Restriction of dietary protein may slow the progression of renal failure in diverse renal diseases, but the extent to which such a diet is beneficial in patients with diabetic nephropathy is uncertain. METHODS: We studied the effect of reduced intake of protein and phosphorus on the progression of renal disease in 35 patients with insulin-dependent (Type I) diabetes mellitus and clinically evident nephropathy. The low-protein, low-phosphorus diet contained 0.6 g of protein per kilogram of ideal body weight per day, 500 to 1000 mg of phosphorus, and 2000 mg of sodium. The control diet consisted of the patient's prestudy diet with the stipulation that it contain 2000 mg of sodium and at least 1 g of protein per kilogram per day and 1000 mg of phosphorus. Renal function was assessed by measurement of iothalamate and creatinine clearances at intervals of 3 to 6 months, and the patients were followed for a minimum of 12 months (mean, 34.7). The declines in mean glomerular filtration rates were compared between groups by linear-regression analysis of the glomerular filtration rate as a function of time. RESULTS: The patients who followed the study diet for a mean of 37.1 months had declines in iothalamate clearance of 0.0043 ml per second per month and in creatinine clearance of 0.0055 ml per second per month. The comparable values in the control group were 0.0168 and 0.0135, respectively (P less than 0.05). Blood pressure was well controlled, and the degree of glycemic control was comparable in both groups. CONCLUSION: Dietary restriction of protein and phosphorus can retard the progression of renal failure in patients with Type I diabetes mellitus who have nephropathy. We believe that wider use of this treatment is indicated.