Marked Variation Research Articles

Chromosome-contiguous genome for the Haecon-5 strain of Haemonchus contortus reveals marked genetic variability and enables the discovery of essential gene candidates

Millions of livestock animals worldwide are infected with the haematophagous barber’s pole worm, Haemonchus contortus, the aetiological agent of haemonchosis. Despite the major significance of this parasite worldwide and its widespread resistance to current treatments, the lack of a high-quality genome for the well-defined strain of this parasite from Australia, called Haecon-5, has constrained research in a number of areas including host-parasite interactions, drug discovery and population genetics. To enable research in these areas, we report here a chromosome-contiguous genome (∼280 Mb) for Haecon-5 with high-quality models for 19,234 protein-coding genes. Comparative genomic analyses show significant genomic similarity (synteny) with a UK strain of H. contortus, called MHco3(ISE).N1 (abbreviated as “ISE”), but we also discover marked differences in genomic structure/gene arrangements, distribution of nucleotide variability (single nucleotide polymorphisms (SNPs) and indels) and orthology between Haecon-5 and ISE. We used the genome and extensive transcriptomic resources for Haecon-5 to predict a subset of essential single-copy genes employing a “cross-species” machine learning (ML) approach using a range of features from nucleotide/protein sequences, protein orthology, subcellular localisation, single-cell RNA-seq and/or histone methylation data available for the model organisms Caenorhabditis elegans and Drosophila melanogaster. From a set of 1,464 conserved single copy genes, transcribed in key life-cycle stages of H. contortus, we identified 232 genes whose homologs have critical functions in C. elegans and/or D. melanogaster, and prioritised 10 of them for further characterisation; nine of the 10 genes likely play roles in neurophysiological processes, germline, hypodermis and/or respiration, and one is an unknown (orphan) gene for which no detailed functional information exists. Future studies of these genes/gene products are warranted to elucidate their roles in parasite biology, host-parasite interplay and/or disease. Clearly, the present Haecon-5 reference genome and associated resources now underpin a broad range of fundamental investigations of H. contortus and could assist in accelerating the discovery of novel intervention targets and drug candidates to combat haemonchosis.

Observed Global Mean State Changes Modulating the Collective Influence of the Tropical Atlantic and Indian Oceans on ENSO

Abstract In the last decades, many efforts have been made to understand how different tropical oceanic basins are able to impact El Niño–Southern Oscillation (ENSO). However, the collective connectivity among the tropical oceans and their associated influence on ENSO are less understood. Using a complex network methodology, the degree of collective connectivity among the tropical oceans is analyzed focusing on the detection of periods when the tropical basins collectively interact and the Atlantic and Indian basins influence the equatorial Pacific sea surface temperatures (SSTs). The background state for the periods of strong collective connectivity is also investigated. Our results show a marked multidecadal variability in the tropical interbasin connection, with periods of stronger and weaker collective connectivity. These changes seem to be modulated by changes in the North Atlantic Ocean mean state a decade in advance. In particular, strong connectivity occurs in periods with colder than average tropical North Atlantic surface ocean. Associated with this cooling, an anomalous convergence of the vertical integral of total energy flux (VIEF) takes place over the tropical north–west Atlantic, associated with anomalous divergence of VIEF over the equatorial eastern Pacific. In turn, an anomalous zonal surface pressure gradient over the tropical Pacific weakens the trades over the western equatorial Pacific. Consequently, a shallower thermocline emerges over the western equatorial Pacific, which can enhance thermocline feedbacks, the triggering of ENSO events, and therefore, ENSO variability. By construction, our results put forward opposite conditions for periods of weak tropical basin connectivity. These results have important implications for seasonal to decadal predictions.

Developmental, Cognitive, Ocular Motor, and Neuroimaging Findings Related to SUFU Haploinsufficiency: Unraveling Subtle and Highly Variable Phenotypes

BackgroundBiallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. MethodsNine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. ResultsWe identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. ConclusionsOur data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.

Looking at the modern landscape of submediterranean Greece through a palaeoecological lens

The importance of understanding the long-lasting legacy of past land use on modern ecosystems has long been acknowledged. However, the magnitude and persistence of such legacies have been assessed only occasionally. Northern Greece has been a gateway of farming into mainland Europe during the Neolithic, thus providing a perfect setting to assess the potential impact of land-use history on present-day ecosystems. Additionally, the marked Holocene climatic variability of the southern Balkans makes it possible to investigate climate-vegetation-land use interactions over long timescales. Here, we have studied a sediment record from Limni Vegoritis (Northern Greece) spanning the past ∼9000 years using palaeoecological proxies (pollen, spores, stomata, microscopic charcoal). We aimed to reconstruct long-term vegetation dynamics in submediterranean Greece, to assess the environmental factors controlling them and to establish the legacies of the long history of land use in the modern landscape. We found that the Early Holocene afforestation, mainly oak woodlands, was delayed because of suboptimal moisture conditions. Later, colder and drier conditions during the rapid climate change centred around the ‘8.2 ka event’ triggered woodland opening and the spread of wooded (Juniperus) steppe vegetation. First indicators of farming activities are recorded during this period, but their abundances are too low to explain the concurrent large deforestation episode. Later, pinewoods (probably dominated by Pinus nigra) with deciduous Quercus spread and dominated the landscape for several millennia. These forests experienced repeated multi-centennial setback-recovery episodes associated with land-use intensification, but pines eventually declined ∼2500–2000 years ago during Classical times under heavy land use comprising intense pastoralism. This was the starting point for the present-day landscape, where the main ‘foundation’ taxon of the ancient forests (Pinus cf. nigra) is missing, therefore attesting to the strong imprint that historical land use has left on the modern landscape.

Spatial proteomics of human diabetic kidney disease, from health to class III.

Diabetic kidney disease (DKD) is the leading cause of chronic and end-stage kidney disease in the USA and worldwide. Animal models have taught us much about DKD mechanisms, but translation of this knowledge into treatments for human disease has been slowed by the lag in our molecular understanding of human DKD. Using our Spatial TissuE Proteomics (STEP) pipeline (comprising curated human kidney tissues, multiplexed immunofluorescence and powerful analysis tools), we imaged and analysed the expression of 21 proteins in 23 tissue sections from individuals with diabetes and healthy kidneys (n=5), compared to those with DKDIIA, IIA-B and IIB (n=2 each) and DKDIII (n=1). These analyses revealed the existence of 11 cellular clusters (kidney compartments/cell types): podocytes, glomerular endothelial cells, proximal tubules, distal nephron, peritubular capillaries, blood vessels (endothelial cells and vascular smooth muscle cells), macrophages, myeloid cells, other CD45+ inflammatory cells, basement membrane and the interstitium. DKD progression was associated with co-localised increases in inflammatory cells and collagen IV deposition, with concomitant loss of native proteins of each nephron segment. Cell-type frequency and neighbourhood analyses highlighted a significant increase in inflammatory cells and their adjacency to tubular and αSMA+ (α-smooth muscle actin-positive) cells in DKD. Finally, DKD progression showed marked regional variability within single tissue sections, as well as inter-individual variability within each DKD class. Using the STEP pipeline, we found alterations in protein expression, cellular phenotypic composition and microenvironment structure with DKD progression, demonstrating the power of this pipeline to reveal the pathophysiology of human DKD.

Several outstanding issues concerning the ionosphere of Mars

Several outstanding issues concerning the ionosphere of Mars can be addressed with the support of radio occultation observations acquired near the solar zenith angle limit of 45∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document}. First, two fundamentally different types of instruments (topside radar sounding, radio occultations) have been used to characterize how the subsolar peak density changes over the solar cycle. Here we find that their results for solar minimum and solar maximum values of peak density are consistent. This verifies that systematic errors do not affect peak density measurements from either type of instrument. Second, reported descriptions of how the peak altitude changes with solar zenith angle are inconsistent. Specifically, values reported by radio occultation and radar sounder instruments for the characteristic lengthscale used to describe changes in peak altitude with solar zenith angle vary by a factor of two. We find that the change in peak altitude with solar zenith angle is governed by a lengthscale that is close to the thermospheric scale height, as predicted theoretically. However, this behavior is only apparent when the Mars–Sun distance is held fixed. Reported smaller values of this lengthscale, which are not consistent with theoretical expectations, were adversely affected by using near-terminator peak altitude values only, which display marked variability. Third, Viking Lander entry science data have been interpreted to suggest that the M1 layer is not present in the ionosphere at solar zenith angles of 45∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document} or smaller. We show radio occultation observations at 45∘\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^{\\circ }$$\\end{document} in which the M1 layer is present. This suggests that the basic structure of the dayside ionosphere remains the same at all solar zenith angles.Graphical

Lung Adenocarcinoma Systems Biomarker and Drug Candidates Identified by Machine Learning, Gene Expression Data, and Integrative Bioinformatics Pipeline.

Lung adenocarcinoma (LUAD) is a significant planetary health challenge with its high morbidity and mortality rate, not to mention the marked interindividual variability in treatment outcomes and side effects. There is an urgent need for robust systems biomarkers that can help with early cancer diagnosis, prediction of treatment outcomes, and design of precision/personalized medicines for LUAD. The present study aimed at systems biomarkers of LUAD and deployed integrative bioinformatics and machine learning tools to harness gene expression data. Predictive models were developed to stratify patients based on prognostic outcomes. Importantly, we report here several potential key genes, for example, PMEL and BRIP1, and pathways implicated in the progression and prognosis of LUAD that could potentially be targeted for precision/personalized medicine in the future. Our drug repurposing analysis and molecular docking simulations suggested eight drug candidates for LUAD such as heat shock protein 90 inhibitors, cardiac glycosides, an antipsychotic agent (trifluoperazine), and a calcium ionophore (ionomycin). In summary, this study identifies several promising leads on systems biomarkers and drug candidates for LUAD. The findings also attest to the importance of integrative bioinformatics, structural biology and machine learning techniques in biomarker discovery, and precision oncology research and development.

A Reconstruction of May–June Mean Temperature since 1775 for Conchos River Basin, Chihuahua, Mexico, Using Tree-Ring Width

Currently there are several precipitation reconstructions for northern Mexico; however, there is a lack of temperature reconstructions to understand past climate change, the impact on ecosystems and societies, etc. The central region of Chihuahua is located in a transition zone between the Sierra Madre Occidental and the Great Northern Plain, characterized by extreme temperatures and marked seasonal variability. The objectives of this study were (1) to generate a climatic association between variables from reanalysis models and the earlywood series for the center of Chihuahua, (2) to generate a reconstruction of mean temperature, (3) to determine extreme events, and (4) to identify the influence of ocean–atmosphere phenomena. Chronologies were downloaded from the International Tree-Ring Data Bank and climate information from the NLDAS-2 and ClimateNA reanalysis models. The response function was performed using climate models and regional dendrochronological series. A reconstruction of mean temperature was generated, and extreme periods were identified. The representativeness of the reconstruction was evaluated through spatial correlation, and low-frequency events were determined through multitaper spectral analysis and wavelet analysis. The influence of ocean–atmosphere phenomena on temperature reconstruction was analyzed using Pearson correlation, and the influence of ENSO was examined through wavelet coherence analysis. Highly significant correlations were found for maximum, minimum, and mean temperature, as well as for precipitation and relative humidity, before and after the growth year. However, the seasonal period with the highest correlation was found from May to June for mean temperature, which was used to generate the reconstruction from 1775 to 2022. The most extreme periods were 1775, 1801, 1805, 1860, 1892–1894, 1951, 1953–1954, and 2011–2012. Spectral analysis showed significant frequencies of 56.53 and 2.09 years, and wavelet analysis from 0 to 2 years from 1970 to 1980, from 8 to 11 years from 1890 to 1910, and from 30 to 70 years from 1860 to 2022. A significant association was found with the Multivariate ENSO Index phenomenon (r = 0.40; p = 0.009) and Pacific Decadal Oscillation (r = −0.38; p = 0.000). Regarding the ENSO phenomenon, an antiphase association of r = −0.34; p = 0.000 was found, with significant periods of 1 to 4 years from 1770 to 1800, 1845 to 1850, and 1860 to 1900, with periods of 6 to 10 years from 1875 to 1920, and from 6 to 8 years from 1990 to 2000. This study allowed a reconstruction of mean temperature through reanalysis data, as well as a historical characterization of temperature for central Chihuahua beyond the observed records.

The Efficacy of Story Champs for Improving Oral Language in Third-Grade Spanish-English Bilingual Students With Developmental Language Disorder.

We investigated the efficacy of Story Champs for improving oral language in third-grade Spanish-English bilingual children with developmental language disorder (DLD). We implemented a concurrent multiple-baseline across-participants single-case design with four bilingual Spanish-English third-grade students with DLD. Treatment was carried out over 12 sessions with approximately two sessions per week. Maintenance sessions were conducted 1, 2, and 4 weeks postintervention. Participants were explicitly taught story grammar elements, causal and temporal connections, and modifiers within story retells and personal narratives. Dependent variables were story grammar, grammatical complexity, modifiers and listening comprehension within story retells, and story grammar and grammatical complexity within personal narratives. Outcome measures were assessed at the end of every baseline, intervention, and maintenance session using the Narrative Language Measures-Listening (NLM-L). Visual analyses for outcome measures suggested slight increases in scores on the NLM-L during intervention accompanied by marked variability. Within-case analyses of story retell performance suggested an intervention effect on story grammar for two participants and on grammatical complexity and modifier use for one participant. For personal narratives, within-case analyses of personal narrative performance suggested an intervention effect on story grammar for one participant. Overall, Story Champs demonstrated efficacy for improving story grammar use in story retells for three out of four participants. It did not show efficacy for improving grammatical complexity, modifier use, or listening comprehension within story retells, nor did it show efficacy for improving story grammar and grammatical complexity within personal narratives. https://doi.org/10.23641/asha.26053033.

Near-surface wind speed trends and variability over the Antarctic Peninsula, 1979–2022

Near-Surface Wind Speed (SWS) is a crucial but less studied climate variable in the northern Antarctic Peninsula (AP). This research evaluates, for the first time, 44 years (i.e., 1979–2022) of SWS trends and variability across the AP using two data sources: (i) observational data from quality-controlled and homogenized meteorological stations, and (ii) reanalysis data from ERA5; the accuracy of this product strongly depends on each station with an overall underestimation of observed SWS. Annual trends in observed SWS exhibit a positive trend, being statistically significant in autumn and spring, with a marked intraanual and spatial variability in the sign and magnitudes across the AP. In addition, the multidecadal variability of observed SWS showed a general positive trend until ∼2001 (varying between 1993 and 2007 depending on each season), followed by a period of slowdown in the last two decades. Over the AP, SWS changes are mainly driven by two principal modes of atmospheric variability: i.e., mainly the Southern Annular Mode (SAM) and, secondarily, by the El Niño-Southern Oscillation (ENSO). Overall, positive trends in SWS could be partly associated with the increase and poleward shift of the westerlies due to the positive trend of the SAM index. However, as previous studies pointed out for air temperature and precipitation, we found a non-stationary and complex relationship of these modes with SWS changes. This research addresses the gap in SWS changes and variability in the AP and surrounding Southern Ocean and the influence of the atmospheric circulation, a hotspot area in climate change research.

Trends in incidence of pneumothorax in England before, during and after the COVID-19 pandemic (2017–2023): a population-based observational study

COVID-19 is a risk factor for pneumothorax. The pandemic may have influenced healthcare-seeking behaviour for pneumothorax. This study aimed to investigate recent trends in the incidence of pneumothorax in England. A population-based epidemiological study was conducted using an English national dataset of hospital admissions (Hospital Episode Statistics) from 2017 to 2023. Record-linkage was used to identify multiple admissions per person and co-morbidity. Pneumothoraces co-occurring with COVID-19 were identified by concurrent COVID-19 diagnostic coding. The pre-pandemic (January 2017-February 2020), pandemic (March-2020-February-2021) and post-pandemic periods (March 2021-March 2023) were compared. From 2017 to 2023, there were 72,275 hospital admissions for spontaneous pneumothorax among 59,130 patients. Admissions showed marked variability, peaking in January 2021 when the rate of admissions was about two-thirds higher than that of the pre-pandemic level (Incidence rate ratio [IRR] 1.65, 95% CI: 1.48-1.84). However, when excluding patients with a concurrent COVID-19 diagnosis, the overall trend shifted to a reduction during the pandemic period. Post-pandemic rates were not significantly different from pre-pandemic levels (IRR=0.96, 95% CI: 0.89-1.04). The incidence of spontaneous pneumothorax was significantly higher in males (rate ratio compared to females: 2.29, 95% CI: 2.19-2.39). However, the trends were consistent in both males and females. This study highlights a significant peak in COVID-19 related cases but a corresponding trough in non-COVID-related cases (end 2020, early 2021). Despite a previous report of increasing incidence of (non-COVID-related) hospitalised spontaneous pneumothorax over the long-term between 1968 and 2016, we did not observe any continued increase throughout this study period, prompting further investigation into the impact of recent guidelines. Authors are supported by the NIHR Oxford BRC, Li Ka Shing and Robertson Foundations, MRC, and HDR UK.

Auto-Diacritization and Stylistic Realization of Arabic Text using Deep Neural Networks

This paper presents QRDiaRec, an advanced diacritization system for Arabic Quranic texts. In Arabic, linguistic style refers to the variations in diacritic markings used to convey different pronunciations, dialects, meanings, and contextual understandings.QRDiaRec addresses the challenge of interpreting Arabic diacritics across multiple linguistic styles, which is crucial for accurate language processing. Unlike traditional systems that generate only one correct form of diacritics, QRDiaRec can recognize and produce multiple valid diacritic forms. This capability is due to its training on a dataset that encompasses seven Quranic linguistic styles.The Qur'an is an ideal case study because it is one text with multiple linguistic patterns, allowing us to recognize different forms of correct diacritization. QRDiaRec employs bidirectional LSTM, GRU, and transformer-based models to convert non-diacritic texts into annotated formats, achieving up to 94.2%accuracy. The system enhances Arabic language processing, impacting NLP, machine translation, and Arabic linguistics.

Marked interannual variability in the relative dominance of phytoplankton over submerged macrophytes rather than regime shifts in a shallow eutrophic lake: Evidence from long-term observations

The theory of regime shift is rooted in the concept of fold catastrophe and posits the existence of alternative stable states, such as a lake dominated by phytoplankton or macrophytes under similar environmental conditions. Although regime shifts have been reported in many shallow lakes, recent evidence has revealed that a linear rather than dual relationship between chlorophyll-a (Chla) and nutrients is more common, indicating that regime shifts are rare in nature. Here, long-term field observations and the coverage of the submerged macrophyte area (SMA) retrieved from remote sensing (RS) images of Yilong Lake, in which regime shifts have been reported, were used to re-examine the presence or absence of regime shifts and to explore the drivers of abrupt changes. During the past three decades, Yilong Lake has experienced three abrupt changes in water quality, phytoplankton biomass (Chla) and the SMA. However, the relationship between Chla and nutrients was significantly linear, and the state variables (Chla, Secchi depth and SMA) changed along the gradient of environmental stress, which demonstrates the absence of regime shifts and instead highlights the presence of marked interannual changes. Moreover, we found that nutrients and water depth are the main environmental factors driving the establishment/collapse of the SMA and shaping the relative dominance of phytoplankton over the SMA, further inducing rapid changes in nutrient cycling and water quality in Yilong Lake. The significant interannual variability in the SMA and Chla in Yilong Lake reflects a pronounced weakening of resilience. To enhance resilience, an adaptive strategy involving external nutrient loading reduction, water level management and biodiversity restoration is proposed.

Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia.

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Trajectories of improvement with repetitive transcranial magnetic stimulation for treatment-resistant major depression in the BRIGhTMIND trial

Repetitive transcranial magnetic stimulation (rTMS) is an established non-invasive brain stimulation treatment for major depressive disorder, but there is marked inter-individual variability in response. Using latent class growth analysis with session-by-session patient global impression ratings from the recently completed BRIGhTMIND trial, we identified five distinct classes of improvement trajectory during a 20-session treatment course. This included a substantial class of patients noticing delayed onset of improvement. Contrary to prior expectations, members of a class characterised by early and continued improvement showed greatest inter-session variability in stimulated location. By relating target locations and inter-session variability to a well-studied atlas, we estimated an average of 3.0 brain networks were stimulated across the treatment course in this group, compared to 1.1 in a group that reported symptom worsening (p < 0.001, d = 0.893). If confirmed, this would suggest that deliberate targeting of multiple brain networks could be beneficial to rTMS outcomes.

(032) A REVIEW OF VESTIBULECTOMY PATHOLOGY FINDINGS AND A CALL TO ACTION TO STANDARDIZE PATHOLOGY REPORTING

Abstract Introduction There is no standardization for pathology reporting of vestibulectomy specimens. Our current understanding of neuroproliferative vestibulodynia is limited, but it is understood to be mediated by the accumulation c-afferent nociceptors and mast cells. Histopathology is fundamental to our understanding of disease mechanism and treatment. Given how much remains unknown about the histology, physiology, and neuroplasticity of the vestibule, it is imperative that we take every opportunity to fully examine this tissue and its complex role in pain. Objective Describe current pathology reporting practices for vestibulectomy specimens Methods Data was collected using Epic and Cerner report tools to identify any patients between 1/2017 to 10/2023 with a surgical history of vestibulectomy. Forty-five patients were identified &amp; confirmed to have a history of vestibulectomy. Charts were reviewed to locate surgical pathology reports (available through hospital EMR, CRISP, or Care Everywhere). Results Pathology reports were available for 37 patients. Thirty-one of these reports (84%) were from our own institution; six reports were from outside hospitals. Marked variability in pathology reporting was noted between pathologists and institutions. All but one pathology report notes inflammation. The one report that does not include language about inflammation only notes “negative for dysplasia or malignancy”. Twenty-nine reports comment on the absence of dysplasia, including two reports from other institutions. All pathology reports from our institution (100%), note lymphoid infiltrate; however, this is not noted on any of the 6 pathology reports from other hospitals. Nineteen of the 31 specimens (61%) examined at our institution included specific stains to test for mast cells and nerve fibers. Nineteen specimens were evaluated with Giemsa staining and 8 specimens were evaluated with CD117 staining to assess for mast cell density (measured in mast cells/hpf). The range of mast cell density was 1/hpf to 25/hpf, and the average mast cell density was 8.1/hpf. All 19 specimens stained with S100 noted a relative increase in nerve fibers in the superficial dermis. Conclusions Histopathology is a window of opportunity to better understand the pathophysiology of neuroproliferative vestibulodynia. There is no standard when it comes to examining and reporting on vestibulectomy specimens. This results in reporting inconsistencies, which limits our ability to compile data and draw clinical conclusions. As surgeons we can collaborate to advance our understanding of the pathophysiology of vestibulodynia. This starts with communicating with our pathology colleagues, requesting appropriate stains, and setting a standard for reporting. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Patty Brisben Foundation.

Paragangliomas of the head and neck

Paragangliomas represent a heterogeneous group of rare neuroendocrine tumors with marked variability in symptoms and disease course. Due to the close proximity to neurovascular structures, paragangliomas of the head and neck region can cause a variety of symptoms. To this day, there are no reliable prognostic factors that can predict apotentially malignant course. All patients with newly diagnosed paragangliomas should undergo an early diagnostic workup and regular follow-up examinations in specialized centers. While radical resection was previously regarded as standard treatment for paragangliomas, radiotherapy and active surveillance (watch-and-scan strategy) have become equally important over the years. Low-threshold techniques for molecular pathology analysis of the mutation-specific behavior of paragangliomas are nowadays available.

Post-market study requirements and associations with timely submission and regulatory action for oncology drugs receiving accelerated approval, 2011-2023.

11028 Background: For oncology drugs receiving accelerated approval (AA), the Food and Drug Administration (FDA) enforces Postmarketing Requirements (PMRs) to verify clinical benefit prior to regular approval. Although previous work has characterized the rigor and timeliness of confirmatory studies, the association between specificity and scope of PMR statements and the timeliness of PMR submission and ultimate approval status is not well understood. Methods: We identified 161 oncology indications granted AA between January 2011 and July 2023 using FDA’s Cancer AA database. We linked indications to 181 corresponding PMR statements using the Drugs@FDA database. We analyzed PMR statement scope and specificity based on the presence or requirement of eight characteristics: target population, comparator (active or placebo-controlled), randomization, multicenter trial, blinding (double-blind or open-label), enrollment target, follow-up duration, and endpoints. We used chi-square and t-tests to analyze associations between PMR characteristics and two primary outcomes: indication approval status (regular vs. withdrawn) and PMR timeliness (on time vs. late). We defined “late” submissions as PMRs submitted or withdrawals occurring after an expected PMR Final Report submission date. Ongoing PMRs were excluded from the timeliness analysis unless expected dates occurred before August 2023. Results: Among 181PMR statements, 98% percent specified target population, 81% endpoint (44% overall survival), 63% use of randomization, 54% comparator (40% active; 14% placebo-controlled), 30% follow-up duration 26% enrollment targets, 24% multicenter trial, and 13% double-blinding (and 8% open-label). Among AAs converted to regular approval, 82% of PMRs were submitted on time vs. 24% on-time for withdrawn AAs (p=0.001). Regular approval PMRs were submitted 10.2 months ahead of expected dates, whereas withdrawn AAs were submitted 14.5 months behind expected dates (p&lt;0.001). Compared late PMR submissions, on-time PMR submissions had lower enrollment (400 vs. 665, p=0.01), less blinding (19% vs. 40%, p=0.03), more frequent use of a single trial for both AA and PMR (38% vs. 8%, p=0.001), and primary endpoints other than overall or progression-free survival (36% vs. 5%, p&lt;0.001). Compared to late PMR submissions, on-time PMR submissions more often followed PMR statements that specified follow-up duration (39% vs. 13%, p=0.006) and non-survival primary endpoints (30% vs. 8%, p=0.01). Conclusions: There is marked variability in the contents of PMR statements for oncology AA drugs. Several characteristics of PMRs – including smaller enrollment size, surrogate endpoints, and single trials for AA and PMR – are associated with timely submission. These findings inform the specificity and scope of future FDA PMRs for oncology AA indications.

USE OF VISCOELASTIC COAGULATION TESTING IN MEGACHIROPTERA (PTEROPUS HYPOMELANUS AND PTEROPUS VAMPYRUS) REVEALS HIGH VARIABILITY IN CLOT KINETICS.

Megachiroptera is a mammalian suborder that includes old world fruit bats. Common clinical problems among captive Megachiroptera, such as liver disease (e.g., iron storage disease), kidney disease (e.g., protein-losing nephropathy), and heart disease (e.g., dilated cardiomyopathy), carry elevated risk for hemostatic derangements. The assessment of viscoelastic coagulation assays, however, has not yet been reported in bats. The main objective of the study was to describe viscoelastography data using the Viscoelastic Coagulation Monitor (VCM) Vet in captive large flying foxes (Pteropus vampyrus) (n = 20) and variable flying foxes (Pteropus hypomelanus) (n = 10). Additional objectives were to compare viscoelastic and clotting parameters (1) between healthy P. vampyrus and P. hypomelanus bats and (2) between untreated bats and those treated with meloxicam or aspirin, and (3) to examine relationships between activated partial thromboplastin time (aPTT) and potentially homologous viscoelastic parameters clotting time (CT) and clot formation time (CFT). The results showed marked variability among clinically normal bats. The intrinsic pathway, as measured by aPTT, had prolonged times compared with most terrestrial mammals, but similar times to birds, marine mammals, and sea turtles. A search of P. vampyrus genome found stop codons present in two exons of the factor XI gene; alterations in factor XI expression would be expected to alter intrinsic coagulation. Because of the high variability, no statistically significant findings were noted in the secondary objectives. Correlation between aPTT and CT or CFT was not strong (rs = 0.406 or 0.192, respectively). The results from this study suggest that clot kinetics vary widely among Megachiroptera when using the VCM Vet with untreated blood. A prolonged intrinsic coagulation pathway, as has been found in other megachiropteran species, and activation of the extrinsic coagulation pathway during venipuncture may be responsible for the inconsistent results.

Beyond central-local relations: the introduction of a new perspective on China’s environmental governance model

In recent years, the Chinese government has initiated assertive centralization efforts in its approach to environmental governance. However, the efficacy of these initiatives demonstrates marked variability across different sectors. While the central-local relational framework has traditionally been employed to elucidate these disparities, its explanatory power is showing signs of strain. This paper, through policy analysis and field interviews, investigates regulatory conflicts in land use for ecological and agricultural purposes within China. The findings highlight instances of overlapping jurisdictions and discordant policy objectives among agencies responsible for delineating ecological spaces and agricultural zones. While these conflicts seem to stem from the dynamics between the central and local governments, they more accurately reflect the inherent characteristics of fragmented authoritarianism. This paper aims to expand the theory of fragmented authoritarianism by incorporating the dimension of inter-departmental competition into environmental governance, moving beyond the traditional binary analysis framework of central-local relations. It seeks to understand and critique its limitations from a broader perspective, emphasizing the role of departmental competition within fragmented authoritarianism. By analyzing this internal mechanism, the paper reveals a more nuanced governance landscape, essentially replacing the traditional central-local paradigm with a model that situates departmental competition within the overall context of fragmented authoritarianism. We propose two models for delineating competition among governmental institutions: the bureaucratic model and the charisma model, thereby advancing and deepening the application of fragmented authoritarianism theory in China’s environmental governance. This provides new theoretical insights for understanding the current challenges and developments in China’s environmental governance.