Has the COVID-19 pandemic changed existing patterns of non-COVID-19 health care utilization? A retrospective analysis of six regions in Europe.

BACKGROUND: Resilience of national health systems in Europe remains a major concern in times of multiple crises and as more evidence is emerging relating to the indirect effects of the COVID-19 pandemic on health care utilization (HCU), resulting from de-prioritization of regular, non-pandemic healthcare services. Most extant studies focus on regional, disease specific or early pandemic HCU creating difficulties in comparing across multiple countries. We provide a comparatively broad definition of HCU across multiple countries, with potential to expand across regions and timeframes. METHODS: Using a cross-country federated research infrastructure (FRI), we examined HCU for acute cardiovascular events, elective surgeries and serious trauma. Aggregated data were used in forecast modelling to identify changes from predicted European age-standardized counts via fitted regressions (2017-19), compared against post-pandemic data. RESULTS: We found that elective surgeries were most affected, universally falling below predicted levels in 2020. For cardiovascular HCU, we found lower-than-expected cases in every region for heart attacks and displayed large sex differences. Serious trauma was the least impacted by the COVID-19 pandemic. CONCLUSION: The strength of this study comes from the use of the European Population Health Information Research Infrastructure's (PHIRI) FRI, allowing for rapid analysis of regional differences to assess indirect impacts of events such as pandemics. There are marked differences in the capacity of services to return to normal in terms of elective surgery; additionally, we found considerable differences between men and women which requires further research on potential sex or gender patterns of HCU during crises.

Delayed treatment in breast cancer patients during the COVID-19 pandemic: a population health information research infrastructure (PHIRI) case study.

BACKGROUND: The indirect impact of the coronavirus disease 2019 pandemic on healthcare services was studied by assessing changes in the trend of the time to first treatment for women 18 or older who were diagnosed and treated for breast cancer between 2017 and 2021. METHODS: An observational retrospective longitudinal study based on aggregated data from four European Union (EU) countries/regions investigating the time it took to receive breast cancer treatment. We compiled outputs from a federated analysis to detect structural breakpoints, confirming the empirical breakpoints by differences between the trends observed and forecasted after March 2020. Finally, we built several segmented regressions to explore the association of contextual factors with the observed changes in treatment delays. RESULTS: We observed empirical structural breakpoints on the monthly median time to surgery trend in Aragon (ranging from 9.20 to 17.38 days), Marche (from 37.17 to 42.04 days) and Wales (from 28.67 to 35.08 days). On the contrary, no empirical structural breakpoints were observed in Belgium (ranging from 21.25 to 23.95 days) after the pandemic's beginning. Furthermore, we confirmed statistically significant differences between the observed trend and the forecasts for Aragon and Wales. Finally, we found the interaction between the region and the pandemic's start (before/after March 2020) significantly associated with the trend of delayed breast cancer treatment at the population level. CONCLUSIONS: Although they were not clinically relevant, only Aragon and Wales showed significant differences with expected delays after March 2020. However, experiences differed between countries/regions, pointing to structural factors other than the pandemic.

Uptake of COVID-19 vaccinations amongst 3,433,483 children and young people: meta-analysis of UK prospective cohorts.

SARS-CoV-2 infection in children and young people (CYP) can lead to life-threatening COVID-19, transmission within households and schools, and the development of long COVID. Using linked health and administrative data, we investigated vaccine uptake among 3,433,483 CYP aged 5-17 years across all UK nations between 4th August 2021 and 31st May 2022. We constructed national cohorts and undertook multi-state modelling and meta-analysis to identify associations between demographic variables and vaccine uptake. We found that uptake of the first COVID-19 vaccine among CYP was low across all four nations compared to other age groups and diminished with subsequent doses. Age and vaccination status of adults living in the same household were identified as important risk factors associated with vaccine uptake in CYP. For example, 5-11 year-olds were less likely to receive their first vaccine compared to 16-17 year-olds (adjusted Hazard Ratio [aHR]: 0.10 (95%CI: 0.06-0.19)), and CYP in unvaccinated households were less likely to receive their first vaccine compared to CYP in partially vaccinated households (aHR: 0.19, 95%CI 0.13-0.29).

Malignant Progression of an Ancestral Bone Marrow Clone Harboring a CIC-NUTM2A Fusion in Isolated Myeloid Sarcoma.

Myeloid sarcoma is a rare condition consisting of extramedullary myeloid blasts found in association with acute myeloid leukemia or, in the absence of bone marrow involvement. We identified an infant with isolated myeloid sarcoma whose bone marrow was negative for involvement by flow cytometry. Sequencing revealed the fusion oncogene CIC-NUTM2A and identified the sarcoma to be clonally evolved from the bone marrow, which carried the fusion despite the absence of pathology. Murine modeling confirmed the ability of the fusion to transform hematopoietic cells and identified receptor tyrosine kinase (RTK) signaling activation consistent with disruption of the CIC transcriptional repressor. These findings extend the definition of CIC-rearranged malignancies to include hematologic disease, provide insight into the mechanism of oncogenesis, and demonstrate the importance of molecular analysis and tracking of bone marrow involvement over the course of treatment in myeloid sarcoma, including patients that lack flow cytometric evidence of leukemia at diagnosis. IMPLICATIONS: This study illustrates molecular involvement of phenotypically normal bone marrow in myeloid sarcoma, which has significant implications in clinical care. Further, it extends the definition of CIC-rearrangements to include hematologic malignancies and shows evidence of RTK activation that may be exploited therapeutically in cancer(s) driven by these fusions.

The commutability of enzyme linked immunosorbent assays for the quantification of serum eosinophil-derived neurotoxin (EDN).

Eosinophil-derived neurotoxin (EDN) is a surrogate biomarker of eosinophil activation and has considerable potential as a precision medicine biomarker in diseases where eosinophils may play a causative role. Clinical data for EDN have been generated using different quantitative immunoassays, but comparisons between these individual data sets are challenging as no internationally recognised EDN standards or orthogonal methods exist. In this study we aimed to compare commercial EDN assays from ALPCO, MBL, LSBio and CUSABIO for sample commutability. Firstly, we analytically validated the ALPCO enzyme linked immunosorbent assay (ELISA) and demonstrated appropriate analytical characteristics, including an intra/inter-assay precision coefficient-of-variation of between 1.9 and 6.8%. EDN purified from blood proved to be a good quality control material, whereas recombinant EDN, expressed in E.coli, did not react in the ALPCO immunoassay. Using healthy and asthma patient serum samples we confirmed that the ALPCO assay correlated well with the MBL assay, with a coefficient of determination (R2) of 0.92. However, the results from LSBio and CUSABIO assays were not commutable to the other assays.

A narrow ear canal reduces sound velocity to create additional acoustic inputs in a microscale insect ear.

Located in the forelegs, katydid ears are unique among arthropods in having outer, middle, and inner components, analogous to the mammalian ear. Unlike mammals, sound is received externally via two tympanic membranes in each ear and internally via a narrow ear canal (EC) derived from the respiratory tracheal system. Inside the EC, sound travels slower than in free air, causing temporal and pressure differences between external and internal inputs. The delay was suspected to arise as a consequence of the narrowing EC geometry. If true, a reduction in sound velocity should persist independently of the gas composition in the EC (e.g., air, [Formula: see text]). Integrating laser Doppler vibrometry, microcomputed tomography, and numerical analysis on precise three-dimensional geometries of each experimental animal EC, we demonstrate that the narrowing radius of the EC is the main factor reducing sound velocity. Both experimental and numerical data also show that sound velocity is reduced further when excess [Formula: see text] fills the EC. Likewise, the EC bifurcates at the tympanal level (one branch for each tympanic membrane), creating two additional narrow internal sound paths and imposing different sound velocities for each tympanic membrane. Therefore, external and internal inputs total to four sound paths for each ear (only one for the human ear). Research paths and implication of findings in avian directional hearing are discussed.

Complex wing motion during stridulation in the katydid Nastonotus foreli (Orthoptera: Tettigoniidae: Pseudophyllinae).

Male Katydids (Orthoptera: Tettigoniidae) rub together their specialised forewings to produce sound, a process known as stridulation. During wing closure, a lobe on the anal margin of the right forewing (a scraper), engages with a tooth-covered file on the left forewing. The movement of the scraper across the file produces vibrations which are amplified by a large wing cell adjacent to the scraper, the mirror. Katydids are known to stridulate with either sustained or interrupted sweeps of the file, generating resonant pure-tone (narrowband frequency) or non-resonant (broadband frequency) calls. However, some species can conserve some purity in their calls despite incorporating discrete pulses and silent intervals. This mechanism is exhibited by many Pseudophyllinae, such as Nastonotus spp., Cocconotus spp., Triencentrus spp. and Eubliastes spp. This study aims to measure and quantify the mechanics of wing stridulation in Nastonotus foreli, a Neotropical katydid that can produce, relatively narrowband calls at ≈20 kHz. It was predicted that this species will use a stridulatory mechanism involving elastic energy whereby the scraper bends and flicks along the file in periodic bursts. The calling behaviour and wing mechanics of seven males were studied using a combination of technologies (e.g. micro-scanning laser Doppler vibrometry, advanced microscopy, ultrasound-sensitive equipment and optical motion detectors) to quantify wing mechanics and structure. Analysis of recordings revealed no clear relationship between wing velocity and carrier frequency, and a pronounced distinction between wing velocity and scraper velocity during wing closure, suggesting that the scraper experiences considerable deformation. This is characteristic of the elastic scraper mechanism of stridulation. Curiously, N. foreli might have evolved to employ elastic energy to double the duration of the call, despite possessing muscles that can reach velocities high enough to produce the same frequency without the help of elastic energy.

Growth of patients with congenital adrenal hyperplasia due to 21-hydroxylase in infancy, glucocorticoid requirement and the role of mineralocorticoid therapy.

Background The dose of hydrocortisone therapy required to maintain normal growth in infants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is lower than in later childhood. This reflects the presence of excess non-aromatisable rather than aromatisable androgen but there has been relatively little focus on the role of mineralocorticoid therapy. Methods Growth data of infants with CAH due to 21-hydroxylase deficiency (2008-2016) were reviewed and information regarding hydrocortisone and fludrocortisone regimen was collected. Change in height standard deviation (SD) and height velocity standard deviation score (SDS) were analysed during the first year of life. Results Growth data from 13 children (8 M) were analysed. Height (length) declined from a median of -0.69 SD at 3 months to -1.23 SD at 12 months with a reduction in height velocity SDS from 0.02 between 3 and 6 months to -2.22 between 9 and 12 months (p=0.017) despite a hydrocortisone dose at the lower end of the range as recommended in consensus guidelines. The glucocorticoid activity of hydrocortisone and fludrocortisone was negatively associated with growth velocity (r=-0.55; p=0.049) although renin activity was not suppressed. Conclusions Infants with 21-hydroxylase deficiency can be managed with replacement hydrocortisone. The reasons for this paradigm are now understood although our data confirm that the glucocorticoid activity of fludrocortisone needs to be taken into consideration as well.

Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes.

Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, we identified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 and 6 million yr ago, but that are absent in the Hominidae. Hominidae show between four- and sevenfold lower rates of nucleotide change and feature turnover in both neutral and functional sequences, suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. Recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli, which resulted in thousands of novel, species-specific CTCF binding sites. Our results show that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology.

Introduction of novel 3D-printed superficial applicators for high-dose-rate skin brachytherapy.

PURPOSE: Custom-made surface mold applicators often allow more flexibility when carrying out skin brachytherapy, particularly for small treatment areas with high surface obliquity. They can, however, be difficult to manufacture, particularly if there is a lack of experience in superficial high-dose-rate brachytherapy techniques or with limited resources. METHODS AND MATERIALS: We present a novel method of manufacturing superficial brachytherapy applicators utilizing three-dimensional (3D)-printing techniques. We describe the treatment planning process and the process of applicator manufacture. RESULTS: The treatment planning process, with the introduction of a pre-plan, allows for an "ideal" catheter arrangement within an applicator to be determined, exploiting varying catheter orientations, heights, and curvatures if required. The pre-plan arrangement is then 3D printed to the exact specifications of the pre-plan applicator design. This results in improved target volume coverage and improved sparing of organs at risk. CONCLUSIONS: Using a pre-plan technique for ideal catheter placement followed by automated 3D-printed applicator manufacture has greatly improved the entire process of superficial high-dose-rate brachytherapy treatment. We are able to design and manufacture flexible, well-fitting, superior quality applicators resulting in a more efficient and improved patient pathway and patient experience.

Enhancer evolution across 20 mammalian species.

The mammalian radiation has corresponded with rapid changes in noncoding regions of the genome, but we lack a comprehensive understanding of regulatory evolution in mammals. Here, we track the evolution of promoters and enhancers active in liver across 20 mammalian species from six diverse orders by profiling genomic enrichment of H3K27 acetylation and H3K4 trimethylation. We report that rapid evolution of enhancers is a universal feature of mammalian genomes. Most of the recently evolved enhancers arise from ancestral DNA exaptation, rather than lineage-specific expansions of repeat elements. In contrast, almost all liver promoters are partially or fully conserved across these species. Our data further reveal that recently evolved enhancers can be associated with genes under positive selection, demonstrating the power of this approach for annotating regulatory adaptations in genomic sequences. These results provide important insight into the functional genetics underpinning mammalian regulatory evolution.

AHT-ChIP-seq: a completely automated robotic protocol for high-throughput chromatin immunoprecipitation.

ChIP-seq is an established manually-performed method for identifying DNA-protein interactions genome-wide. Here, we describe a protocol for automated high-throughput (AHT) ChIP-seq. To demonstrate the quality of data obtained using AHT-ChIP-seq, we applied it to five proteins in mouse livers using a single 96-well plate, demonstrating an extremely high degree of qualitative and quantitative reproducibility among biological and technical replicates. We estimated the optimum and minimum recommended cell numbers required to perform AHT-ChIP-seq by running an additional plate using HepG2 and MCF7 cells. With this protocol, commercially available robotics can perform four hundred experiments in five days.

Eating disorders and intrasexual competition: testing an evolutionary hypothesis among young women.

The sexual competition hypothesis (SCH) contends that intense female intrasexual competition (ISC) is the ultimate cause of eating disorders. The SCH explains the phenomenon of the pursuit of thinness as an adaptation to ISC in the modern environment. It argues that eating disorders are pathological phenomena that arise from the mismatch between the modern environment and the inherited female adaptations for ISC. The present study has two aims. The first is to examine the relationship between disordered eating behavior (DEB) and ISC in a sample of female undergraduates. The second is to establish whether there is any relationship between disordered eating behavior and life history (LH) strategy. Participants completed a battery of questionnaires examining eating-related attitudes and behaviors, ISC, and LH strategy. A group of 206 female undergraduates were recruited. A structural equation model was constructed to analyze the data. ISC for mates was significantly associated with DEB, as predicted by the SCH. DEB was found to be predicted by fast LH strategy, which was only partially mediated by the SCH. The results of this study are supportive of the SCH and justify research on a clinical sample.

Influences on Decision Making Identified by Parents of Children Receiving Pediatric Palliative Care.

BACKGROUND: Parental decision making is a critical component in the provision of palliative and end-of-life care, yet factors that parents perceive as influencing this process, when they are making decisions for their children, have not been well characterized. METHODS: As part of a mixed-methods cohort study, we interviewed 73 parents of 50 pediatric patients who were referred to the hospital's pediatric palliative care service. The semistructured interviews focused on "decision making for your child"; the interviews were recorded and transcribed. A random sample (n = 13) was first coded and analyzed for core themes, and these themes were then cross-validated with a second random sample (n = 3) of interviews. RESULTS: Four dominant interrelated themes permeated parents' discussions about the decisions they were making for their children and the process of decision making. First, Orientation and Direction (including the subthemes of Goals and Hopes, Spirituality and Meaning, and Purposeful Effort) connotes the parents' effort to establish and clarify the broad context of decision making. Second, Defining What Is Good for the Child (including the subthemes of Quality of Life and Suffering, and Normalcy and Normalization) conveys how the parents posed questions and pondered what decisions would be in the child's best interests. Third, the entwined theme of Relationships, Communication, and Support reflects how parents reported the social and interactive nature of decision making. Fourth, the theme of Feelings and Personal Accountability focuses inward as parents report efforts to deal with their emotional responses and self-judgments. CONCLUSIONS: Parents report grappling with several influences upon their decision-making processes that extend well beyond the standard discussions of medical information exchanges and the evaluation of risks and benefits. Decision support for these parents should account for these diverse influences.

Introduction to miRNA profiling technologies and cross-platform comparison.

MicroRNA analysis has been widely adopted for basic and applied science. The tools and technologies available for quantifying and analysing miRNAs are still maturing. Here, we give an introductory overview of the main tools and the challenges in their use. We also discuss the importance of basic experimental design, sample handling and analysis methods as the impact of these can be as profound as the choice of miRNA analysis platform. Whether the reader is interested in a gene-by-gene or genome-wide approach choosing the platform to use is not trivial. Careful thought given before starting an experiment will make the execution much easier.

Males assessed by a specialized adult eating disorders service: Patterns over time and comparisons with females.

OBJECTIVE: In view of previous inconsistencies and the limited literature on males with eating disorders, we aimed to examine changes in presentation rates over time and any differences between males and females. METHOD: In a cohort of 2,554 new patients assessed by a specialized service for adults over a 21-year period, we examined rates by gender over time. We also carried out a detailed comparison of selected clinical and demographic variables on a series of 65 males and females matched by diagnosis and date of assessment. RESULTS: Approximately 5% of patients were male and there was no evidence of a change in presentation rate by gender over time. Males were more likely to be diagnosed as not having a clinical eating disorder and less likely to abuse laxatives, but otherwise there was little difference in clinical presentation. CONCLUSION: Eating disorders continue to present predominantly in females and the proportion of males remains broadly stable.

Easing of suffering in children with cancer at the end of life: is care changing?

PURPOSE: In the past decade studies have documented substantial suffering among children dying of cancer, prompting national attention on the quality of end-of-life care and the development of a palliative care service in our institutions. We sought to determine whether national and local efforts have led to changes in patterns of care, advanced care planning, and symptom control among children with cancer at the end of life. METHODS: Retrospective cohort study from a US tertiary level pediatric institution. Parent survey and chart review data from 119 children who died between 1997 and 2004 (follow-up cohort) were compared with 102 children who died between 1990 and 1997 (baseline cohort). RESULTS: In the follow-up cohort, hospice discussions occurred more often (76% v 54%; adjusted risk difference [RD], 22%; P < .001) and earlier (adjusted geometric mean 52 days v 28 days before death; P = .002) compared with the baseline cohort. Do-not-resuscitate orders were also documented earlier (18 v 12 days; P = .031). Deaths in the intensive care unit or other hospitals decreased significantly (RD, 16%; P = .024). Parents reported less child suffering from pain (RD, 19%; P = .018) and dyspnea (RD, 21%; P = .020). A larger proportion of parents felt more prepared during the child's last month of life (RD, 29%; P < .001) and at the time of death (RD, 24%; P = .002). CONCLUSION: Children dying of cancer are currently receiving care that is more consistent with optimal palliative care and according to parents, are experiencing less suffering. With ongoing growth of the field of hospice and palliative medicine, further advancements are likely.