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Although it has been recognized for only two decades, parvovirus B19 is now known to be a ubiquitous, potentially lethal pathogen. Its clinical manifestations range from fifth disease to prolonged anemia and fetal death. [ABSTRACT FROM AUTHOR]

Purpose: Toxicities associated with stereotactic radiosurgery (SRS) are important when considering treatment and supportive management for patients with brain metastases. We herein assessed the association between brain metastasis location and risk of toxicity after SRS., Methods: We conducted a retrospective institutional review of patients treated with SRS for brain metastases between 2008 and 2023. Outcomes included radiation necrosis, seizure, local failure, and overall survival (OS)., Results: We reviewed 215 patients treated to 605 metastases (median diameter 10 mm, IQR 5-17 mm), in the frontal (34%), cerebellar (19%), parietal (16%), temporal (13%), and occipital (13%) regions. Median follow-up was 16 months (IQR 7-36). New-onset seizures developed in 11% (19/174) of patients without prior seizure and was higher in patients with motor or sensory cortex lesions (12/48, 25%) on multivariate analysis (MVA, P = 0.02). SRS-related grade ≥ 2 symptomatic radionecrosis occurred in 6% (33/605) of lesions and correlated with larger metastasis volume (P < 0.001) and renal cell carcinoma histology (P < 0.05), while supratentorial location was nearly significant (MVA, P = 0.06). Median OS across all patients was 16 months (95% CI 12-20). Patients with symptomatic radiation necrosis had a longer median survival compared to those who did not (43 vs. 14 months, P = 0.002), which remained significant alongside Karnofsky performance status and extracranial disease on MVA., Conclusion: Brain metastasis location in the motor or sensory cortex is associated with increased risk of new-onset seizure following SRS and may warrant consideration of steroid and/or anti-epileptic prophylaxis. Symptomatic radiation necrosis is uncommon in the cerebellum and may be increasing with improvements in survival., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval This is a retrospective observational study. The University of North Carolina at Chapel Hill Research Ethics Committee has confirmed that no ethical approval is required. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The authors affirm that human research participants provided informed consent., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hearing mediates many behaviours critical for survival in echolocating bats, including foraging and navigation. Although most mammals are susceptible to progressive age-related hearing loss, the evolution of biosonar, which requires the ability to hear low-intensity echoes from outgoing sonar signals, may have selected against the development of hearing deficits in bats. Many echolocating bats exhibit exceptional longevity and rely on acoustic behaviours for survival to old age; however, relatively little is known about the ageing bat auditory system. In this study, we used DNA methylation to estimate the ages of wild-caught big brown bats ( Eptesicus fuscus ) and measured hearing sensitivity in young and ageing bats using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We found no evidence for hearing deficits in bats up to 12.5 years of age, demonstrated by comparable thresholds and similar ABR and DPOAE amplitudes across age groups. We additionally found no significant histological evidence for cochlear ageing, with similar hair cell counts, afferent and efferent innervation patterns in young and ageing bats. Here, we demonstrate that big brown bats show minimal evidence for age-related hearing loss and therefore represent informative models for investigating mechanisms that may preserve hearing function over a long lifetime.

The Code of Ethics and Professional Responsibilities for Healthcare Ethics Consultants instructs clinical ethics consultants to preserve their professional integrity by "not engaging in activities that involve giving an ethical justification or stamp of approval to practices they believe are inconsistent with agreed-upon standards" (ASBH, 2014, p. 2). This instruction reflects a larger model of how to address value uncertainty and moral conflict in healthcare, and it brings up some intriguing and as yet unanswered questions-ones that the drafters of the Code, and the profession more broadly, should seek to address in upcoming revisions. The objective of this article is to raise these questions as a way of urging greater clarification of the Code's overall approach to professional integrity, its meaning, and implications., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Several polygynous mammals exhibit reproductive skew in which only a few males reproduce. Successful males need strength, stamina and fighting ability to exclude competitors. Consequently, during the mating season their androgens and glucocorticoids are expected to increase to support spermatogenesis and aggressive behavior. But, during the nonmating season these hormones should decline to minimize deleterious effects, such as reduced immune function. Bats that exhibit harem polygyny in which males aggressively defend large groups of females year-round are ideal for assessing hormonal and other consequences of extreme polygyny. Here we use DNA methylation to estimate age and gas chromatography, tandem mass spectrometry to profile steroid metabolites in urine of wild greater spear-nosed bats, Phyllostomus hastatus, across seasons. We find that condition, measured by relative weight, is lower during the mating season for both sexes, although it remains high in harem males during the mating season. Average age of females is greater than males, and females exhibit substantial seasonal differences in androgens, estrogens and glucocorticoids with higher levels of all hormones during the mating season. Males, however, show little seasonal differences but substantial age-associated increases in most steroid metabolites. Harem males have larger, persistently scrotal testes and are older than bachelor males. While cortisone generally declines with age, harem males maintain higher amounts of biologically active cortisol than bachelor males all year and cortisol levels increase more quickly in response to restraint in males than in females. Taken together, these results suggest that attaining reproductive dominance requires hormone levels that reduce lifespan., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In forensic anthropology, osteological sex estimation methods are continuously reevaluated and updated to improve classification accuracies. Therefore, to gain a comprehensive understanding of recent trends in sex estimation research in forensic anthropology, a content analysis of articles published between 2000 and 2022 in Forensic Science International, the Journal of Forensic Sciences, the International Journal of Legal Medicine, the American Journal of Biological Anthropology, and Forensic Anthropology, was performed. The main goals of this content analysis were to (1) examine trends in metric versus morphological research, (2) examine which areas of the skeleton have been explored, (3) examine which skeletal collections and population affinities have been most frequently utilized, and (4) determine which statistical methods were commonly implemented. A total of 440 articles were coded utilizing MAXQDA and the resulting codes were exported for analysis. Statistical analyses were conducted utilizing the Cochran-Armitage and Jonckheere-Terpstra tests for trends, as well as Fisher-Freeman-Halton tests. The results demonstrate that sex estimation research published in these journals has prioritized metric over morphological methods. Further, the most utilized skeletal regions continue to be the skull and pelvis, while the most popular classification statistics continue to be discriminant function analysis and logistic regression. This study also demonstrates that a substantial portion of research has been conducted utilizing U.S. and Europe-based collections and limited populations. Based on these results, future sex estimation research must continue exploring the use of long bones and other postcranial elements, testing newer methods of analysis, as well as developing population-inclusive methods., (© 2024 American Academy of Forensic Sciences.)

Background: Angiopoietin-2 (Ang-2) is increased in the blood of patients with kaposiform lymphangiomatosis (KLA) and kaposiform hemangioendothelioma (KHE). While the genetic causes of KHE are not clear, a somatic activating NRAS Q61R mutation has been found in the lesions of KLA patients., Procedure: Our study tested the hypothesis that the NRAS Q61R mutation drives elevated Ang-2 expression in endothelial cells. Ang-2 was measured in human endothelial progenitor cells (EPC) expressing NRAS Q61R and a genetic mouse model with endothelial targeted NRAS Q61R . To determine the signaling pathways driving Ang-2, NRAS Q61R EPC were treated with signaling pathway inhibitors., Results: Ang-2 levels were increased in EPC expressing NRAS Q61R compared to NRAS WT by Western blot analysis of cell lysates and ELISA of the cell culture media. Ang-2 levels were elevated in the blood of NRAS Q61R mutant mice. NRAS Q61R mutant mice also had reduced platelet counts and splenomegaly with hypervascular lesions, like some KLA patients. mTOR inhibitor rapamycin attenuated Ang-2 expression by NRAS Q61R EPC. However, MEK1/2 inhibitor trametinib was more effective blocking increases in Ang-2., Conclusions: Our studies show that the NRAS Q61R mutation in endothelial cells induces Ang-2 expression in vitro and in vivo. In cultured human endothelial cells, NRAS Q61R drives elevated Ang-2 through MAP kinase and mTOR-dependent signaling pathways., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations., (© 2024. The Author(s).)

The lymphatic system is one of the most essential and complex systems in the human body. Disorders that affect the development or function of the lymphatic system can lead to multi-system complications and life-long morbidity. The past two decades have seen remarkable progress in our knowledge of the basic biology and function of the lymphatic system, the molecular regulators of lymphatic development, and description of disorders associated with disrupted lymphangiogensis. In this chapter we will touch on the clinical features of complex lymphatic anomalies, new molecular knowledge of the drivers of these disorders, and novel developmental therapeutics for lymphatic disease., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The rational use of medicines offers a cost-saving strategy to maximize therapeutic outcomes for developing and developed countries. The aim of this study was to evaluate the rational use of medicines for selected noncommunicable diseases (NCDs) at three pharmacies at public hospitals in Jamaica using the World Health Organization's (WHO's) prescribing indicators., Methods: In this retrospective cross-sectional study, prescriptions for adult outpatients containing at least one medicine for cardiovascular disease, diabetes, cancer, chronic obstructive pulmonary disease or asthma that were filled between January and July 2019 were reviewed using WHO's prescribing indicators for the rational use of medicines. Data were analyzed and expressed as descriptive and inferential statistics. For all analyses conducted, significance was determined at P < 0.05., Results: A total of 1 500 prescriptions covering 5 979 medicines were reviewed; prescriptions were mostly written for female patients aged 42-60 years. Polypharmacy was observed in 35.6% (534) of prescriptions, and there was an average of 4 medicines per prescription, with a maximum of 17. Most of the prescriptions at each site were filled, with the main reason for not dispensing a medicine being that it was out of stock. Generic prescribing was high for all sites, accounting for more than 95% (5 722) of prescribed medicines. There was full compliance with prescribing according to the WHO Model List of Essential Medicines at two of the sites, but it was just off the target at Site 1, by 1.4%., Conclusions: The WHO guidelines for the rational use of medicines were followed with respect to the proportion of medicines prescribed from the WHO Model List and the proportion of antibiotics prescribed. The number of medicines per prescription and the proportion of medicines prescribed by generic name did not meet the WHO criteria. However, prescribing was aligned with treatment guidelines for the selected NCDs., Competing Interests: Conflicts of interest. None declared.

Background and Objectives: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials., Methods: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated., Results: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus., Conclusions: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors., (© 2023 Wiley Periodicals LLC.)

The use of real-time magnetic resonance imaging (rt-MRI) of speech is increasing in clinical practice and speech science research. Analysis of such images often requires segmentation of articulators and the vocal tract, and the community is turning to deep-learning-based methods to perform this segmentation. While there are publicly available rt-MRI datasets of speech, these do not include ground-truth (GT) segmentations, a key requirement for the development of deep-learning-based segmentation methods. To begin to address this barrier, this work presents rt-MRI speech datasets of five healthy adult volunteers with corresponding GT segmentations and velopharyngeal closure patterns. The images were acquired using standard clinical MRI scanners, coils and sequences to facilitate acquisition of similar images in other centres. The datasets include manually created GT segmentations of six anatomical features including the tongue, soft palate and vocal tract. In addition, this work makes code and instructions to implement a current state-of-the-art deep-learning-based method to segment rt-MRI speech datasets publicly available, thus providing the community and others with a starting point for developing such methods., (© 2023. The Author(s).)

Purpose: PIK3CA-related overgrowth spectrum (PROS) encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS., Methods: EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary end point assessed patient response to treatment at Week 24 (6 months)., Results: Twenty-four weeks (6 months) after treatment initiation, 12 of 32 (37.5%) patients with complete case records included in the analysis of the primary end point experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred., Conclusion: EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management., Competing Interests: Conflict of Interest Guillaume Canaud reports consulting fees from Novartis, BridgeBio, Fresenius Medical Care, Alkernes, and Vaderis; support for attending meetings and/or travel from Novartis; patent with Novartis (WO2017140828A1); and participation on data safety/advisory board for Novartis. Juan Carlos Lopez Gutierrez reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pierre Fabre Pharmaceuticals and support for attending meetings and/or travel from Pierre Fabre Pharmaceuticals. Alan D. Irvine reports consulting fees from Sanofi, Regeneron, Novartis, AbbVie, Menlo, Leo Pharma, Eli Lilly, Dermavant, Benevolent AI, Pfizer, and Almirall; speaker fees from Leo Pharma, Regeneron, Sanofi, Eli Lilly, and AbbVie; royalties from UpToDate; participation on data safety/advisory board for Novartis and OM Pharma; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for International Eczema Council (Director- unpaid). Pierre Vabres reports honoraria from Novartis. Jordan R. Hansford reports consulting fees from Bayer Pharmaceuticals Australia, Alexion Pharmaceuticals, and Boxer Capital; payment for expert testimony from Bayer Pharmaceuticals Australia; and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for ANZCHOG (Director). Nii Ankrah reports being an employee of Novartis and stock ownership in Novartis. Fabrice Branle reports being an employee of Novartis Pharma AG Switzerland and stock ownership in Novartis. Athanasia Papadimitriou reports being an employee of Novartis Pharma AG Switzerland and stock ownership in Novartis. Antonia Ridolfi reports being an employee of Novartis. Paul O’Connell reports being an employee of Novartis and stock ownership in Novartis. Stuart Turner reports being an employee of Novartis and stock ownership in Novartis. Denise M. Adams reports consulting fees from Novartis and Venthera; royalties from UpToDate; and participation on data safety/advisory board for Novartis., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Women with obesity have higher risk of adverse pregnancy outcomes, including preeclampsia (PE). Late-gestational hypertension, aberrant fetoplacental development, and fetal growth restriction (FGR), hallmarks of PE, are observed spontaneously in BPH/5 mice. Similar to obese preeclamptic women, BPH/5 mice have higher visceral white adipose tissue (WAT) and circulating leptin. We hypothesized that attenuation of maternal obesity and serum leptin in pregnant BPH/5 mice will improve fetoplacental development by decreasing hypoxia markers and leptin expression at the maternal-fetal interface., Methods: To test this hypothesis, BPH/5 mice were fed ad libitum (lib) and pair-fed (PF) to C57 ad lib controls beginning at embryonic day (e) 0.5. Hypoxia-related genes, hypoxia inducible factor (Hif) 1α, stem cell factor (Scf), heme oxygenase-1 (Ho-1), leptin (Lep), and leptin receptor (LepR) were assessed in e7.5 implantation sites., Results: BPH/5 ad lib had 1.5 to 2-fold increase in Hif1α , Scf , and Ho-1 mRNA and a greater than 3-fold increase in leptin mRNA vs . C57 that was attenuated with PF. Exogenous leptin promoted Hif1α and Ho-1 mRNA expression in e7.5 decidua in vitro . While hypoxic conditions in vitro did not change decidual leptin mRNA. Furthermore, BPH/5 PF mice demonstrated improved fetal and placental outcomes later in gestation, with greater placental vascular area by e18.5 and attenuation of FGR., Conclusion: In conclusion, pair-feeding BPH/5 mice beginning at conception may improve placental vasculature formation via decreased leptin and hypoxia-associated markers in this model. Future investigations are needed to better determine the effect of hypoxia and leptin on pregnancy outcomes in obese pregnant women., Competing Interests: Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals., (© 2023. The Author(s).)

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.

Vascular anomalies are malformations or tumors of the blood or lymphatic vasculature and can be life-threatening. Although molecularly targeted therapies can be life-saving, identification of the molecular etiology is often impeded by lack of accessibility to affected tissue samples, mosaicism or insufficient sequencing depth. In a cohort of 356 participants with vascular anomalies, including 104 with primary complex lymphatic anomalies (pCLAs), DNA from CD31+ cells isolated from lymphatic fluid or cell-free DNA from lymphatic fluid or plasma underwent ultra-deep sequencing thereby uncovering pathogenic somatic variants down to a variant allele fraction of 0.15%. A molecular diagnosis, including previously undescribed genetic causes, was obtained in 41% of participants with pCLAs and 72% of participants with other vascular malformations, leading to a new medical therapy for 63% (43/69) of participants and resulting in improvement in 63% (35/55) of participants on therapy. Taken together, these data support the development of liquid biopsy-based diagnostic techniques to identify previously undescribed genotype-phenotype associations and guide medical therapy in individuals with vascular anomalies., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Complex lymphatic anomalies are debilitating conditions characterized by aberrant development of the lymphatic vasculature (lymphangiogenesis). Diagnosis is typically made by history, examination, radiology, and histologic findings. However, there is significant overlap between conditions, making accurate diagnosis difficult. Recently, genetic analysis has been offered as an additional diagnostic modality. Here, we describe four cases of complex lymphatic anomalies, all with PIK3CA variants but with varying clinical phenotypes. Identification of PIK3CA resulted in transition to a targeted inhibitor, alpelisib. These cases highlight the genetic overlap between phenotypically diverse lymphatic anomalies., (© 2023 Wiley Periodicals LLC.)

Kaposiform lymphangiomatosis (KLA) is a life-threatening rare disease that can cause substantial morbidity, mortality, and social burdens for patients and their families. Diagnosis often occurs long after initial symptoms, and there are few centers in the world with the expertise to diagnose and care for patients with the disease. KLA is a lymphatic anomaly and significant advancements have been made in understanding its pathogenesis and etiology since its first description in 2014. This review provides multidisciplinary, comprehensive, and state-of-the-art information on KLA patient presentation, diagnostic imaging, pathology, organ involvement, genetics, and pathogenesis. Finally, we describe current therapeutic approaches, important areas for research, and challenges faced by patients and their families. Further insights into the pathogenesis of KLA may advance our understanding of other vascular anomalies given that similar signaling pathways may be involved., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: To describe the dynamic contrast magnetic resonance lymphangiography (DCMRL) findings of three patients with complicated lymphatic anomaly (CLA) and protein losing enteropathy. We further discuss the importance of a multicompartment (intrahepatic [IH], intramesenteric [IM], and intranodal [IN]) DCMRL in delineating central lymphatic flow pathologies. Methods and Results: This is a retrospective study of three patients-one adult and two children who individually underwent the three-compartment DCMRL, namely IN-DCMRL, IH-DCMRL, and IM-DCMCRL. Findings from the results of the DCMRL for these three patients were obtained from the medical records and compared. Using the multicompartment imaging modalities, chylous fluid leakage into the peritoneum was observed using IM-DCMRL and IH-DCMRL but not IN-DCMRL for one of the patients in the case series. In contrast, leakage of chyle into the mediastinum was noted using IN-DCMRL but not IH-DCMRL and IM-DCMRL on another patient in this case series. Conclusion: Owing to the variability in outlining lymphatic flow pathologies, multicompartment imaging gives a more global picture of individual conduction disorders, has the potential to improve clinical assessment, and in some cases leads to a diagnosis of the abnormality and thus provides a better understanding of lymphatic flow anomalies in patients with CLAs.

Objectives: To develop a single-slice numerical phantom with known myocardial motion, at several temporal and in-plane spatial resolutions, for testing and comparison of Cardiovascular Magnetic Resonance (CMR) feature tracking (FT) software., Methods: The phantom was developed based on CMR acquisitions of one volunteer (acquired cine, tagging cine, T1 map, T2 map, proton density weighted image). The numerical MRI simulator JEMRIS was used, and the phantom was generated at several in-plane spatial resolutions (1.4 × 1.4 mm 2 to 3.0 × 3.0 mm 2 ) and temporal resolutions (20 to 40 cardiac phases). Two feature tracking software packages were tested: Medical Image Tracking Toolbox (MITT) and two versions of cvi42 (v5.3.8 and v5.13.7). The effect of resolution on strain results was investigated with reference to ground-truth radial and circumferential strain., Results: Peak radial strain was consistently undermeasured more for cvi42 v5.13.7 than for v5.3.8. Increased pixel size produced a trend of increased difference from ground-truth peak strain, with the largest changes for cvi42 obtained using v5.13.7 between 1.4 × 1.4 mm 2 and 3.0 × 3.0 mm 2 , at 9.17 percentage points (radial) and 8.42 percentage points (circumferential)., Conclusions: The results corroborate the presence of intervendor differences in feature tracking results and show the magnitude of strain differences between software versions., Advances in Knowledge: This study shows how temporal and in-plane spatial resolution can affect feature tracking with reference to the ground-truth strain of a numerical phantom. Results reaffirm the need for numerical phantom development for the validation and testing of FT software.

Background: Anorexia nervosa (AN) is a psychiatric disorder associated with marked morbidity. Whilst AN genetic studies could identify novel treatment targets, integration of functional genomics data, including transcriptomics and proteomics, would assist to disentangle correlated signals and reveal causally associated genes., Methods: We used models of genetically imputed expression and splicing from 14 tissues, leveraging mRNA, protein, and mRNA alternative splicing weights to identify genes, proteins, and transcripts, respectively, associated with AN risk. This was accomplished through transcriptome, proteome, and spliceosome-wide association studies, followed by conditional analysis and finemapping to prioritise candidate causal genes., Results: We uncovered 134 genes for which genetically predicted mRNA expression was associated with AN after multiple-testing correction, as well as four proteins and 16 alternatively spliced transcripts. Conditional analysis of these significantly associated genes on other proximal association signals resulted in 97 genes independently associated with AN. Moreover, probabilistic finemapping further refined these associations and prioritised putative causal genes. The gene WDR6 , for which increased genetically predicted mRNA expression was correlated with AN, was strongly supported by both conditional analyses and finemapping. Pathway analysis of genes revealed by finemapping identified the pathway regulation of immune system process (overlapping genes = MST1 , TREX1 , PRKAR2A , PROS1 ) as statistically overrepresented., Conclusions: We leveraged multiomic datasets to genetically prioritise novel risk genes for AN. Multiple-lines of evidence support that WDR6 is associated with AN, whilst other prioritised genes were enriched within immune related pathways, further supporting the role of the immune system in AN.

Kaposiform hemangioendothelioma is classified as a locally aggressive vascular tumor of childhood resulting from abnormal angiogenesis and lymphangiogenesis. Most commonly, KHE presents as a single tissue mass, ranging from an erythematous papule to a violaceous indurated tumor. Definitive diagnosis requires tissue sampling with the demonstration of ill-defined nodules and fascicles of spindle-shaped D2-40 positive endothelial cells, forming slit-like vascular channels. This newborn presented with multifocal cutaneous Kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon confirmed on histopathology with immunostaining., (Copyright © 2022 by the American Academy of Pediatrics.)

Background: Rational use of medicines (RUM) offers a cost-saving strategy to maximize therapeutic outcomes. The aims of this study were to assess RUM for chronic non-communicable diseases (NCDs) using the World Health Organization's (WHO) prescribing indicators in a public access facility and to evaluate the alignment of the use of drugs with therapeutic recommendations/guidelines., Design and Methods: In this retrospective cross-sectional study, prescriptions of adult patients containing at least one drug for chronic NCDs, filled between January and July 2019 were reviewed using the WHO prescribing indicators for RUM. Data were analyzed and expressed as descriptive statistics. Associations were determined using chi-square tests, correlations using Pearson's correlation and medians compared using Mann-Whitney U test. For all analyses, significance was determined at p  < 0.05., Results: Of the 571 prescriptions reviewed, most were for female, elderly patients with mean age of 69 years, predominantly with hypertension and/or diabetes. Polypharmacy was noted for 53.6% of prescriptions, primarily in elderly patients ( p  < 0.001), with the median number of five drugs prescribed and three dispensed. Of the drugs prescribed, 76.6% used generic prescribing, 63.3% were dispensed as written and 3.9% were antibiotics prescribed mainly for asthmatic patients (χ 2  = 74.9, p  < 0.001). Drugs prescribed for NCDs were aligned to therapeutic guidelines, but a significantly higher proportion of diabetes medications, (metformin and gliclazide), and cardiovascular medications (enalapril and losartan), were not dispensed as written (χ 2  = 40.0, p  = 0.007)., Conclusion: This research indicates that there is positive alignment with recommended therapeutic guidelines, however, based on WHO prescribing factors, strategies to improve RUM in this setting are highly recommended., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

AbstractPreeclampsia (PE) is a hypertensive disorder that impacts 2-8% of pregnant women worldwide. It is characterized by new onset hypertension during the second half of gestation and is a leading cause of maternal and fetal morbidity/mortality. Maternal obesity increases the risk of PE and is a key predictor of childhood obesity and potentially offspring cardiometabolic complications in a sex-dependent manner. The influence of the maternal obesogenic environment, with superimposed PE, on offspring development into adulthood is unknown. Obese BPH/5 mice spontaneously exhibit late-gestational hypertension, fetal demise and growth restriction, and excessive gestational weight gain. BPH/5 females have improved pregnancy outcomes when maternal weight loss via pair-feeding is imposed beginning at conception. We hypothesized that phenotypic differences between female and male BPH/5 offspring can be influenced by pair feeding BPH/5 dams during pregnancy. BPH/5 pair-fed dams have improved litter sizes and increased fetal body weights. BPH/5 offspring born to ad libitum dams have similar sex ratios, body weights, and fecal microbiome as well as increased blood pressure that is reduced in the dam pair-fed offspring. Both BPH/5 male and female offspring born to pair-fed dams have a reduction in adiposity and an altered gut microbiome, while only female offspring born to pair-fed dams have decreased circulating leptin and white adipose tissue inflammatory cytokines. These sexually dimorphic results suggest that reduction in the maternal obesogenic environment in early pregnancy may play a greater role in female BPH/5 sex-dependent cardiometabolic outcomes than males. Reprograming females may mitigate the transgenerational progression of cardiometabolic disease., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Green turtle ( Chelonia mydas ) embryos are in an arrested state of development when the eggs are laid, but in the presence of oxygen, arrest is broken and development resumes within 12-16 h. However, the precise oxygen level at which embryos break arrest and continue development is not known. To better understand the impact of oxygen concentration on breaking of arrest and early embryonic development, we incubated freshly laid eggs of the green sea turtle for three days at each of six different oxygen concentrations (less than or equal to 1%, 3%, 5%, 7%, 9% and 21%) and monitored the appearance and growth of white spots on the shell, indicative of embryonic development. As reported previously, white spots did not develop on eggs incubated in anoxia (less than or equal to 1% oxygen). For all other treatments, mean time to white spot detection and white spot growth rate varied inversely with oxygen concentration. In nearly all cases the difference between eggs at different oxygen levels was statistically significant ( p ≤ 0.05). This suggests that sea turtle embryonic development may respond to oxygen in a dose-dependent manner. Our results indicate that the development of green turtle embryos may be slowed if they are exposed to the most hypoxic conditions reported in mature natural nests., (© 2022 The Authors.)

Comparative analyses of bats indicate that hibernation is associated with increased longevity among species. However, it is not yet known if hibernation affects biological ageing of individuals. Here, we use DNA methylation (DNAm) as an epigenetic biomarker of ageing to determine the effect of hibernation on the big brown bat, Eptesicus fuscus . First, we compare epigenetic age, as predicted by a multi-species epigenetic clock, between hibernating and non-hibernating animals and find that hibernation is associated with epigenetic age. Second, we identify genomic sites that exhibit hibernation-associated change in DNAm, independent of age, by comparing samples taken from the same individual in hibernating and active seasons. This paired comparison identified over 3000 differentially methylated positions (DMPs) in the genome. Genome-wide association comparisons to tissue-specific functional elements reveals that DMPs with elevated DNAm during winter occur at sites enriched for quiescent chromatin states, whereas DMPs with reduced DNAm during winter occur at sites enriched for transcription enhancers. Furthermore, genes nearest DMPs are involved in regulation of metabolic processes and innate immunity. Finally, significant overlap exists between genes nearest hibernation DMPs and genes nearest previously identified longevity DMPs. Taken together, these results are consistent with hibernation influencing ageing and longevity in bats.

Vascular anomalies (VAs) are a heterogeneous group of primarily congenital tumors and malformations. The International Society for the Study of Vascular Anomalies (ISSVA) has developed a standard classification of these disorders, creating a uniform approach to their diagnosis. Recent discoveries evaluating the genetic causes of VAs have revealed that they are due to mutations in cancer pathways, including the PI3K/AKT/mTOR and RAS/MAPK/MEK pathways. These discoveries have led to improved phenotype-genotype correlation and have expanded medical therapy for this group of unique disorders., (© 2022 Wiley Periodicals LLC.)

Kaposiform lymphangiomatosis is an uncommon generalized lymphatic anomaly with distinctive clinical, radiologic, histopathologic, and molecular findings. Herein, we document the pathology in 43 patients evaluated by the Boston Children's Hospital Vascular Anomalies Center from 1999 to 2020. The most frequent presentations were respiratory difficulty, hemostatic abnormalities, and a soft tissue mass. Imaging commonly revealed involvement of some combination of mediastinal, pulmonary, pleural, and pericardial compartments and most often included spleen and skeleton. Histopathology was characterized by dilated, redundant, and abnormally configured lymphatic channels typically accompanied by dispersed clusters of variably canalized, and often hemosiderotic, spindled lymphatic endothelial cells that were immunopositive for D2-40, PROX1, and CD31. An activating lesional NRAS variant was documented in 9 of 10 patients. The clinical course was typically aggressive, marked by hemorrhage, thrombocytopenia, diminished fibrinogen levels, and a mortality rate of 21%., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Clinical manifestations of blue rubber bleb nevus syndrome (BRBNS) and multifocal venous malformation (MVM) vary depending on the location of the lesions. The aim of this study was to assess the risk of developing CSF leaks in patients with epidural venous malformations (VMs)., Methods: The authors retrospectively investigated the relationship between the development of a CSF leak and the presence of epidural VMs., Results: Nine patients (5 females) had epidural VMs and presentation that was confirmatory or suggestive of a CSF leak: 4 had BRBNS, 4 had MVMs, and 1 had a solitary VM. Of 66 patients with BRBNS, clinical and imaging features of CSF leak were noted in 3 (4.5%) with epidural VMs at the age of 11-44 years. A fourth patient had suggestive symptoms without imaging confirmation. An epidural blood patch was ineffective in 2 patients, both with more than one source of leakage, requiring surgical repair or decompression. Symptomatic downward displacement of the cerebellar tonsils was noted in 3 patients with MVM and 1 with a solitary VM; 3 required surgical decompression., Conclusions: These findings suggest an increased risk of CSF leak in patients with epidural VM, including BRBNS, MVMs, and solitary VMs. Awareness of the association between epidural VM and CSF leakage may facilitate earlier diagnosis and therapeutic intervention.