Prevalence, incidence and treatment patterns of prurigo nodularis in England: a retrospective database analysis.

BACKGROUND: Prurigo nodularis (PN) is a pruritic skin disease characterized by multiple intensely itchy skin nodules in symmetrically distributed areas of the extremities. There are limited studies on the epidemiology and treatment pathways of PN, especially moderate-to-severe PN, from England. OBJECTIVES: To assess the epidemiology and treatment pathways of mild and moderate-to-severe PN in England. METHODS: This retrospective cohort study used data from the Clinical Practice Research Datalink and Hospital Episode Statistics in England. Adult patients (aged ≥ 18 years) with a PN-specific diagnosis code allocated any time between 1 April 2007 and 1 March 2019 (patient identification period) were selected. Patients were included if their first PN diagnostic code (index diagnosis date; IDD) was recorded during the identification period, with data available 6 months before and ≥ 12 months after the IDD. Patients were classified as having moderate-to-severe PN (MSPN) or mild PN (MiPN), based on the presence or absence of a prescription record, post-IDD, for either a systemic immunosuppressant or a gabapentinoid. Patients with MSPN and MiPN were matched 1 : 1 according to age, sex and IDD. Prevalence and incidence were calculated for each year from 2007 to 2019. Drugs prescribed post-IDD were analysed. RESULTS: A total of 8933 patients (MSPN, n = 2498; MiPN, n = 6435) were included in the study; 2462 patients with MiPN and 2462 with MSPN were included for the comparative analysis. The presence of atopic dermatitis, asthma and eosinophilic oesophagitis were significantly higher (all P < 0.001) in patients with MSPN compared with those with MiPN. The overall prevalence of cases of PN increased during the study period. The incidence rate also showed a similar trend. The rates of prescription of potent and super-potent topical corticosteroids (TCS), topical calcineurin inhibitors, first- and second-generation antihistamines, oral and injectable systemic corticosteroids, methotrexate, antidepressants and tacrolimus were significantly higher (all P < 0.001) in patients with MSPN compared with those with MiPN. CONCLUSIONS: The epidemiology of PN was consistent with that found in other European studies. Patients with MSPN received a significantly higher number of prescriptions for potent TCS and systemic drugs compared with patients with MiPN.

Prurigo nodularis is an itchy skin disease that can affect a person's daily life and sleep, and is often accompanied by other diseases. Skin ointments are used to treat the disease. If these are not effective, the disease is treated with oral medicine. The severity of prurigo nodularis is not well established. People with prurigo nodularis and treated with skin ointments are generally considered to have a milder form of the disease. Patients with severe disease most often require oral medicine that target the immune system. In England, there are no estimates of how often prurigo nodularis has affected the population over the last 10 years. In this study, we looked at cases of mild and moderate-to-severe prurigo nodularis in England and the treatments used by patients. We found that cases of prurigo nodularis (both mild and moderate-to-severe) increased during the study period, which was 2007 to 2019. Patients with the more severe form of the disease were more often treated with drugs that were not approved for treating it. Overall, our findings suggest that the number of patients with prurigo nodularis is increasing in England. A new and approved treatment option might be required to manage moderate-to-severe disease.

A real-world retrospective observational study exploring NHS resource use in England for the management of moderate-to-severe atopic dermatitis in secondary care for children and adolescents.

PURPOSE: To describe secondary care health care resource utilization (HCRU) for children and adolescents with atopic dermatitis (AD). PATIENTS AND METHODS: This UK chart review of patients with moderate-to-severe AD was conducted in four National Health Service hospitals. Cohorts were defined by age (children 6-11 years, adolescents 12-17) at first consultation. Eligible patients were selected consecutively, starting with the most recently consulting patient. At least 12 months' data were abstracted from medical records. Data were collected on HCRU, demographics/clinical characteristics, treatment, and patient-reported outcomes. RESULTS: Data were abstracted for 55 patients. Most patients (80%) had severe AD at first referral, a mean (SD) of 3.2 (10.7) patient-reported flare episodes/patient/year-of-observation, and 18.5 (16.7) tests/scans/procedures/patient/year. Mean (SD) observation duration was 3.6 (1.8) years. Patients had tried mean (SD) 7.9 (5.3) treatments/patient/year of observation. Topical corticosteroids (TCS; 24.5% of prescriptions) were most frequently prescribed. Mean (SD) use of emollients/moisturizers, TCS, systemic corticosteroids, and systemic immunosuppressants was 30.9 (21.3), 21.1 (23.4), 1.7 (8.3), and 7.8 (8.2) months. There was a mean (SD) of 5.3 (2.9) consultations/patient/year-of-observation; 116 (10.7%) for flare. Most hospitalizations (87.5%) were for children; the 8/55 (15%) hospitalized patients (mean 2.0 hospitalizations/patient during observation period) spent 6.2 (SD: 5.1) nights in hospital/hospitalization. Earliest mean (SD) Children's Dermatology Life Quality Index score was 15.3 (7.2); latest was 12.9 (7.5). CONCLUSION: Children and adolescents with moderate-to-severe AD had a high HCRU burden and small changes in quality of life, indicating that current treatments may provide suboptimal AD control in most cases.

A population genetic interpretation of GWAS findings for human quantitative traits.

Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10-3.

The long-term maintenance of a resistance polymorphism through diffuse interactions.

Plant resistance (R) genes are a crucial component in plant defence against pathogens. Although R genes often fail to provide durable resistance in an agricultural context, they frequently persist as long-lived balanced polymorphisms in nature. Standard theory explains the maintenance of such polymorphisms through a balance of the costs and benefits of resistance and virulence in a tightly coevolving host-pathogen pair. However, many plant-pathogen interactions lack such specificity. Whether, and how, balanced polymorphisms are maintained in diffusely interacting species is unknown. Here we identify a naturally interacting R gene and effector pair in Arabidopsis thaliana and its facultative plant pathogen, Pseudomonas syringae. The protein encoded by the R gene RPS5 recognizes an AvrPphB homologue (AvrPphB2) and exhibits a balanced polymorphism that has been maintained for over 2 million years (ref. 3). Consistent with the presence of an ancient balanced polymorphism, the R gene confers a benefit when plants are infected with P. syringae carrying avrPphB2 but also incurs a large cost in the absence of infection. RPS5 alleles are maintained at intermediate frequencies in populations globally, suggesting ubiquitous selection for resistance. However, the presence of P. syringae carrying avrPphB is probably insufficient to explain the RPS5 polymorphism. First, avrPphB homologues occur at very low frequencies in P. syringae populations on A. thaliana. Second, AvrPphB only rarely confers a virulence benefit to P. syringae on A. thaliana. Instead, we find evidence that selection for RPS5 involves multiple non-homologous effectors and multiple pathogen species. These results and an associated model suggest that the R gene polymorphism in A. thaliana may not be maintained through a tightly coupled interaction involving a single coevolved R gene and effector pair. More likely, the stable polymorphism is maintained through complex and diffuse community-wide interactions.

Inferring the model and onset of natural selection under varying population size from the site frequency spectrum and haplotype structure.

A fundamental question about adaptation in a population is the time of onset of the selective pressure acting on beneficial alleles. Inferring this time, in turn, depends on the selection model. We develop a framework of approximate Bayesian computation (ABC) that enables the use of the full site frequency spectrum and haplotype structure to test the goodness-of-fit of selection models and estimate the timing of selection under varying population size scenarios. We show that our method has sufficient power to distinguish natural selection from neutrality even if relatively old selection increased the frequency of a pre-existing allele from 20% to 50% or from 40% to 80%. Our ABC can accurately estimate the time of onset of selection on a new mutation. However, estimates are prone to bias under the standing variation model, possibly due to the uncertainty in the allele frequency at the onset of selection. We further extend our approach to take advantage of ancient DNA data that provides information on the allele frequency path of the beneficial allele. Applying our ABC, including both modern and ancient human DNA data, to four pigmentation alleles in Europeans, we detected selection on standing variants that occurred after the dispersal from Africa even though models of selection on a new mutation were initially supported for two of these alleles without the ancient data.

Process utilities for topical treatment in atopic dermatitis.

PURPOSE: Management of atopic dermatitis (AD) typically requires application of topical treatments, often multiple times a day. The cosmetic properties and burdensome application of these treatments can be detrimental to quality of life (QoL). Patients who achieve good disease control through use of systemic therapies may reduce the frequency and amount of topical applications, improving QoL. This study aimed to quantify the utility and disutility for topical AD treatment processes. METHODS: Seven vignettes describing different skincare regimens for people with moderate-to-severe AD were developed with input from healthcare professionals. 484 respondents from the general population completed time trade-off items for each vignette. Utility values for each regimen, and disutilities associated with the impact of changes to skincare regimens, were calculated. Analysis of variance assessed differences between skincare regimens. RESULTS: As skincare regimens increased in intensity (0.7968 for the most intense; 0.9999 for the least), utility values decreased. There were no statistically significant differences between skincare regimens followed by patients with good disease control (0.9862 to 0.9999); however, when compared to those involving topical corticosteroids and emollient combinations (0.7968 to 0.8835), significant differences were observed (p < 0.001). The largest disutilities (0.1521 to 0.1705) were between skincare regimens describing the use of topical corticosteroids plus emollient and those followed by patients with good disease control. CONCLUSIONS: The application of topical treatments has a detrimental effect on QoL, which increases with the duration and frequency of applications. Further research is needed to investigate how health and process utilities interact and both can be integrated into medical decision-making.

Extremely high genetic diversity in a single tumor points to prevalence of non-Darwinian cell evolution.

The prevailing view that the evolution of cells in a tumor is driven by Darwinian selection has never been rigorously tested. Because selection greatly affects the level of intratumor genetic diversity, it is important to assess whether intratumor evolution follows the Darwinian or the non-Darwinian mode of evolution. To provide the statistical power, many regions in a single tumor need to be sampled and analyzed much more extensively than has been attempted in previous intratumor studies. Here, from a hepatocellular carcinoma (HCC) tumor, we evaluated multiregional samples from the tumor, using either whole-exome sequencing (WES) (n = 23 samples) or genotyping (n = 286) under both the infinite-site and infinite-allele models of population genetics. In addition to the many single-nucleotide variations (SNVs) present in all samples, there were 35 "polymorphic" SNVs among samples. High genetic diversity was evident as the 23 WES samples defined 20 unique cell clones. With all 286 samples genotyped, clonal diversity agreed well with the non-Darwinian model with no evidence of positive Darwinian selection. Under the non-Darwinian model, MALL (the number of coding region mutations in the entire tumor) was estimated to be greater than 100 million in this tumor. DNA sequences reveal local diversities in small patches of cells and validate the estimation. In contrast, the genetic diversity under a Darwinian model would generally be orders of magnitude smaller. Because the level of genetic diversity will have implications on therapeutic resistance, non-Darwinian evolution should be heeded in cancer treatments even for microscopic tumors.

Estimating the Ages of Selection Signals from Different Epochs in Human History.

Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs.

Structural priming supports grammatical networks.

As Branigan & Pickering (B&P) argue, structural priming has important implications for the theory of language structure, but these implications go beyond those suggested. Priming implies a network structure, so the grammar must be a network and so must sentence structure. Instead of phrase structure, the most promising model for syntactic structure is enriched dependency structure, as in Word Grammar.

A reduced representation approach to population genetic analyses and applications to human evolution.

Second-generation sequencing technologies allow surveys of sequence variation on an unprecedented scale. However, despite the rapid decrease in sequencing costs, collecting whole-genome sequence data on a population scale is still prohibitive for many laboratories. We have implemented an inexpensive, reduced representation protocol for preparing resequencing targets, and we have developed the analytical tools necessary for making population genetic inferences. This approach can be applied to any species for which a draft or complete reference genome sequence is available. The new tools we have developed include methods for aligning reads, calling genotypes, and incorporating sample-specific sequencing error rates in the estimate of evolutionary parameters. When applied to 19 individuals from a total of 18 human populations, our approach allowed sampling regions that are largely overlapping across individuals and that are representative of the entire genome. The resequencing data were used to test the serial founder model of human dispersal and to estimate the time of the Out of Africa migration. Our results also represent the first attempt to provide a time frame for the colonization of Australia based on large-scale resequencing data.

Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes.

Mutation hotspots are commonly observed in genomic sequences and certain human disease loci, but general mechanisms for their formation remain elusive. Here we investigate the distribution of single-nucleotide changes around insertions/deletions (indels) in six independent genome comparisons, including primates, rodents, fruitfly, rice and yeast. In each of these genomic comparisons, nucleotide divergence (D) is substantially elevated surrounding indels and decreases monotonically to near-background levels over several hundred bases. D is significantly correlated with both size and abundance of nearby indels. In comparisons of closely related species, derived nucleotide substitutions surrounding indels occur in significantly greater numbers in the lineage containing the indel than in the one containing the ancestral (non-indel) allele; the same holds within species for single-nucleotide mutations surrounding polymorphic indels. We propose that heterozygosity for an indel is mutagenic to surrounding sequences, and use yeast genome-wide polymorphism data to estimate the increase in mutation rate. The consistency of these patterns within and between species suggests that indel-associated substitution is a general mutational mechanism.

Two evolutionary histories in the genome of rice: the roles of domestication genes.

Genealogical patterns in different genomic regions may be different due to the joint influence of gene flow and selection. The existence of two subspecies of cultivated rice provides a unique opportunity for analyzing these effects during domestication. We chose 66 accessions from the three rice taxa (about 22 each from Oryza sativa indica, O. sativa japonica, and O. rufipogon) for whole-genome sequencing. In the search for the signature of selection, we focus on low diversity regions (LDRs) shared by both cultivars. We found that the genealogical histories of these overlapping LDRs are distinct from the genomic background. While indica and japonica genomes generally appear to be of independent origin, many overlapping LDRs may have originated only once, as a result of selection and subsequent introgression. Interestingly, many such LDRs contain only one candidate gene of rice domestication, and several known domestication genes have indeed been "rediscovered" by this approach. In summary, we identified 13 additional candidate genes of domestication.

The relationship between prescription rates of oral corticosteroids for respiratory diseases and deprivation in England.

Respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), are common in England with the worst respiratory outcomes observed in the most deprived areas. There is limited published research to establish whether the rate of oral corticosteroid (OCS) prescribing for asthma and COPD is linked to levels of deprivation. This study carried out a multivariable regression analysis of publicly available data and found that deprivation is associated with a statistically significant increase in the proportion of patients receiving an OCS prescription for asthma or COPD at a GP practice level (p < 0.001). The model estimated that the proportion of prescriptions is 1.88% (95% CI 1.83% to 1.92%) and 2.84% (95% CI 2.70% to 2.98%) for the least deprived GP practice and the most deprived GP practice, respectively. This study lays the groundwork for future research using individual patient level data to consider the impact of variation in OCS prescribing rates.

Disease Burden Associated with All Infants in Their First RSV Season in the UK: A Static Model of Universal Immunization with Nirsevimab Against RSV-Related Outcomes.

INTRODUCTION: Respiratory syncytial virus (RSV) leads to significant morbidity in newborn infants in the United Kingdom (UK). Nirsevimab, a long-acting monoclonal antibody, received approval from the European Medicines Agency and has been licensed by the Medicines and Healthcare products Regulatory Agency for preventing RSV lower respiratory tract disease (LRTD) in neonates and infants during their first RSV season. The objective of this study was to assess the potential impact of nirsevimab on RSV-associated LRTDs, related costs, and loss of quality-adjusted life years (QALYs) in infants experiencing their first RSV season. METHODS: The impact of administering nirsevimab across all infant populations compared to palivizumab in the high-risk palivizumab-eligible population was assessed via a static decision-analytic model specified for a UK birth cohort experiencing their first RSV season. The RSV-related health events of interest included primary care (PC), accident and emergency (A&E) visits, hospitalizations [including hospitalizations alone and those resulting in intensive care unit (ICU) admissions], recurrent wheezing in infants who were previously hospitalized, and all-cause LRTD hospitalizations. RESULTS: Under the current standard of practice (SoP), RSV was estimated to result in 329,425 RSV LRTDs annually, including 24,381 hospitalizations and ICU admissions, representing £117.8 million (2024 GBP) in costs. Comparatively, universal immunization of all infants with nirsevimab could avoid 198,886 RSV LRTDs, including 16,657 hospitalizations and ICU admissions, resulting in savings of £77.2 million in RSV treatment costs. Considering the impact on all-cause LRTD of a universal immunization strategy, nirsevimab could be valued between £243 and £274, assuming willingness-to-pay (WTP) thresholds of £20,000 and £30,000 per QALY saved, respectively. CONCLUSIONS: This analysis demonstrated that the health and economic burden of RSV would be substantially reduced in all infants experiencing their first RSV season in the UK (including term, preterm, and palivizumab-eligible infants) as a result of a universal immunization strategy with nirsevimab.

Respiratory Syncytial Virus Hospital Admission Rates and Patients' Characteristics Before the Age of 2 Years in England, 2015-2019.

BACKGROUND: A granular understanding of respiratory syncytial virus (RSV) burden in England is needed to prepare for new RSV prevention strategies. We estimated the rates of RSV hospital admissions before the age of 2 years in England and described baseline characteristics. METHODS: A birth cohort of all infants born between March 1, 2015, and February 28, 2017 (n = 449,591) was established using Clinical Practice Research Datalink-Hospital Episode Statistics. Case cohorts included infants with admission for (1) RSV, (2) bronchiolitis, (3) any respiratory tract infection (RTI) <24 months and (4) RSV predicted by an algorithm <12 months. Baseline characteristics were described in the case and comparative cohorts (infants without corresponding admission). Cumulative incidence and admission rates were calculated. Multiple linear regression was used to estimate the proportion of RTI healthcare visits attributable to RSV. RESULTS: The RSV-coded/RSV-predicted case cohorts were composed of 4813/12,694 infants (cumulative incidence: 1.1%/2.8%). Case cohort infants were more likely to have low birth weight, comorbidities and to be born during RSV season than comparative cohort infants, yet >77% were term-healthy infants and >54% were born before the RSV season. During the first year of life, 11.6 RSV-coded and 34.4 RSV-predicted hospitalizations occurred per 1000 person-years. Overall, >25% of unspecified lower RTI admissions were estimated to be due to RSV. CONCLUSIONS: In England, 1 in 91 infants had an RSV-coded admission, likely underestimated by ~3-fold. Most infants were term-healthy infants born before the RSV season. To decrease the total burden of RSV at the population level, immunization programs need to protect all infants.

Healthcare Resource Utilization and Associated Costs in Patients With Chronic Graft-Versus-Host Disease Post-Allogeneic Hematopoietic Stem Cell Transplantation in England.

Limited evidence suggests chronic graft-versus-host disease (cGvHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) increases healthcare resource utilization (HCRU) and costs. However, this burden has not been well characterized in England. This study assesses secondary care HCRU and costs for patients following allo HSCT in England with cGvHD and patients who did not develop graft-versus-host disease (GvHD). Further stratification was performed among patients who did or did not subsequently receive high-cost therapies for the treatment of cGvHD. This descriptive, retrospective cohort study used Hospital Episode Statistics (HES) data from April 2017 to March 2022. HES data captures information on reimbursed diagnoses and procedures from all National Health Service (NHS) secondary care admissions and attendances in England. High-cost drugs as defined by NHS England are recorded in HES, these drugs and other procedures including plasma exchange, were used to identify patients with cGvHD who were in receipt of high-cost therapies. HCRU and costs were described for patients with cGvHD following allo-HSCT (n = 721) and were matched with patients with no evidence of GvHD following allo-HSCT (n = 718). HCRU and costs were also described for the subset of patients with cGvHD (n = 198) following receipt of high-cost therapies and patients with cGvHD prior to or without such therapies (n = 523). A higher proportion of patients with cGvHD had at least one inpatient or intensive care unit (ICU) admission or emergency care attendance than patients without GvHD (inpatient: 74.6% versus 66.6%; emergency care: 39.3% versus 30.5%; ICU: 7.4% versus 4.7%; respectively); whilst the proportion of patients with an outpatient attendance were similar for both groups (outpatient: 80.3% versus 84.1%; respectively). The cost across all secondary care settings was higher for patients with cGvHD than patients without GvHD, with a mean cost of inpatient admissions of £17,339 per patient-year for those with cGvHD versus £8548 per patient-year in patients without GvHD. A higher proportion of patients who received high-cost therapies for the treatment of cGvHD had at least one secondary care admission or attendance, than patients who did not (inpatient: 85.4% versus 66.4%; ICU: 7.1% versus 5.4%; outpatient: 87.9% versus 76.7%; emergency care: 44.4% versus 36.5%; respectively). Patients who were treated with high-cost therapies for the treatment of cGvHD had a greater mean number (14.6 versus 8.2 per patient-year, respectively) for all-cause inpatient admissions after treatment than patients who did not. In all secondary care settings, the total cost per patient-year was higher for patients who received high-cost therapies for the treatment of cGvHD, than for those who did not. Patients who were treated with high-cost therapies for the treatment of cGvHD had a greater mean cost (£21,137 versus £15,956 per patient-year, respectively) for all-cause inpatient admissions than patients who did not. This study demonstrates that cGvHD and the use of associated high-cost therapies impacts healthcare activity and costs across various secondary care settings in England more than patients without GvHD and patients with cGvHD who received no high-cost therapies.

Estimating the healthcare burden of Prurigo Nodularis in England: a CPRD database study.

Purpose: Prurigo nodularis (PN) is a skin disease characterized by intensely itchy skin nodules and is associated with a significant healthcare resource utilization (HCRU). This study aimed to estimate the HCRU of patients in England with PN overall and moderate-to-severe PN (MSPN) in particular.Methods: This retrospective cohort study used data from the Clinical Practice Research Datalink and Hospital Episode Statistics in England. Patients with Mild PN (MiPN) were matched to patients with MSPN by age and gender for the primary analysis. Patients were enrolled in the study between 1st April 2007 and 1st March 2019. All-cause HCRU was calculated, including primary and secondary care contacts and costs (cost-year 2022).Results: Of 23,522 identified patients, 8,933 met the inclusion criteria, with a primary matched cohort of 2,479 PN patients. During follow up, the matched cohort's primary care visits were 21.27 per patient year (PPY) for MSPN group and 11.35 PPY for MiPN group. Any outpatient visits were 10.72 PPY and 4.87 PPY in MSPN and MiPN groups, respectively. Outpatient dermatology visits were 1.96 PPY and 1.14 PPY in MSPN and MiPN groups, respectively.Conclusion: PN, especially MSPN, has a high HCRU burden in England, highlighting the need for new and improved disease management treatments.

A genetic polymorphism evolving in parallel in two cell compartments and in two clades.

BACKGROUND: The enzyme phosphoenolpyruvate carboxykinase, PEPCK, occurs in its guanosine-nucleotide-using form in animals and a few prokaryotes. We study its natural genetic variation in Colias (Lepidoptera, Pieridae). PEPCK offers a route, alternative to pyruvate kinase, for carbon skeletons to move between cytosolic glycolysis and mitochondrial Krebs cycle reactions. RESULTS: PEPCK is expressed in both cytosol and mitochondrion, but differently in diverse animal clades. In vertebrates and independently in Drosophila, compartment-specific paralogous genes occur. In a contrasting expression strategy, compartment-specific PEPCKs of Colias and of the silkmoth, Bombyx, differ only in their first, 5', exons; these are alternatively spliced onto a common series of following exons. In two Colias species from distinct clades, PEPCK sequence is highly variable at nonsynonymous and synonymous sites, mainly in its common exons. Three major amino acid polymorphisms, Gly 335 ↔ Ser, Asp 503 ↔ Glu, and Ile 629 ↔ Val occur in both species, and in the first two cases are similar in frequency between species. Homology-based structural modelling shows that the variants can alter hydrogen bonding, salt bridging, or van der Waals interactions of amino acid side chains, locally or at one another's sites which are distant in PEPCK's structure, and thus may affect its enzyme function. We ask, using coalescent simulations, if these polymorphisms' cross-species similarities are compatible with neutral evolution by genetic drift, but find the probability of this null hypothesis is 0.001 ≤ P ≤ 0.006 under differing scenarios. CONCLUSION: Our results make the null hypothesis of neutrality of these PEPCK polymorphisms quite unlikely, but support an alternative hypothesis that they are maintained by natural selection in parallel in the two species. This alternative can now be justifiably tested further via studies of PEPCK genotypes' effects on function, organismal performance, and fitness. This case emphasizes the importance, for evolutionary insight, of studying gene-specific mechanisms affected by natural genetic variation as an essential complement to surveys of such variation.

The burden of selected vaccine-preventable diseases on the secondary care health system in England: Results from a five-year administrative healthcare dataset.

OBJECTIVES: This study examined healthcare resource use (HCRU) for selected vaccine-preventable diseases (VPD) in secondary care in England. METHODS: The hospital episode statistics (HES) dataset covering all secondary care interactions within the English National Health Service (NHS) from 2015 to 2021 was used to identify and track HCRU for patients with a primary or secondary diagnosis for pertussis and Haemophilus influenzae type b (Hib), or a primary diagnosis only for hepatitis B, diphtheria, poliomyelitis, or tetanus. The first documented diagnosis during the study period (01/04/2015-31/03/2021) was the index event. RESULTS: 7,274 patients with a total of 5,554,343 patient-days (mean follow up 1,491 days) were included. The total number of hospital admissions was 27,092 and total inpatient cost was £4,987,770, with hepatitis B making up ∼80 % of this. Mean outpatient hospital appointments per patient were highest for tetanus (4.00), but total outpatient A&E cost burden was highest for Hib (£643,343 [mean per attendance £144.57]). For patients 0-9 years of age (n = 1,917), pertussis (n = 1,547) and Hib (n = 313) were by far the most commonly coded diseases. Hepatitis B was the most common disease in adults of working age and Hib was most prevalent in adults of retirement age. Surprisingly, poliomyelitis was observed in the database potentially due to historic diagnoses and/or coding inaccuracy. Other discrepancies with surveillance data were noted. CONCLUSIONS: VPDs impose a large burden on the NHS, but there is potential to reduce this and improve public health by optimising vaccination schedules, improving access and ensuring high coverage rates.

A Real-World Data Study on the Healthcare Resource Use for Uncontrolled Moderate-to-Severe Atopic Dermatitis in Secondary Care in the United Kingdom Prior to the Introduction of Biologic Treatment.

Background: Whilst there is international evidence around the high healthcare resource utilization (HRU) associated with atopic dermatitis (AD), there is a lack of published data from the United Kingdom (UK). Methods: A retrospective, descriptive, observational study was conducted to evaluate the burden of moderate-to-severe AD on the National Health Service (NHS) in an adult UK population treated with traditional standard of care prior to the introduction of biologics. Patients (n=59) were recruited from 6 UK NHS Hospital Trusts and observed over three years. Results: 707 dermatology clinic visits were recorded over the observation period, amounting to 6.6 visits per patient-year, most commonly for routine check-ups most of which involved dermatology consultants (n=469, 66%). Physicians were the most consulted healthcare professional (n=652, 92%); emollients were the most common treatment (n=80 courses). 174 flares requiring additional medical advice were recorded in total (1.6 per patient-year). Discussion/Conclusions: Complex treatment pathways for adult patients in the UK with moderate-to-severe AD incur considerable HRU, particularly for those patients non-responsive to systemic therapies with broad immunosuppressant action. Recent advances in biologics-based AD management could possibly have a significant positive impact on HRU through significant reduction in the number of NHS touch points identified in this study.