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Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the CFTR gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.

BackgroundThere have been dramatic clinical improvements in cystic fibrosis (CF) patients commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in people with CF.MethodsSputum samples from 21 CF subjects pre- and post-ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry.ResultsPost-ETI, mean FEV1% increased by 13.7% (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value ConclusionsSputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti-inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.

Mantle-derived noble gases in volcanic gases are powerful tracers of terrestrial volatile evolution, as they contain mixtures of both primordial (from Earth’s accretion) and secondary (e.g., radiogenic) isotope signals that characterize the composition of deep Earth. However, volcanic gases emitted through subaerial hydrothermal systems also contain contributions from shallow reservoirs (groundwater, crust, atmosphere). Deconvolving deep and shallow source signals is critical for robust interpretations of mantle-derived signals. Here, we use a novel dynamic mass spectrometry technique to measure argon, krypton, and xenon isotopes in volcanic gas with ultrahigh precision. Data from Iceland, Germany, United States (Yellowstone, Salton Sea), Costa Rica, and Chile show that subsurface isotope fractionation within hydrothermal systems is a globally pervasive and previously unrecognized process causing substantial nonradiogenic Ar-Kr-Xe isotope variations. Quantitatively accounting for this process is vital for accurately interpreting mantle-derived volatile (e.g., noble gas and nitrogen) signals, with profound implications for our understanding of terrestrial volatile evolution.

Funding: W. Hutchison is funded by a UKRI Future Leaders Fellowship (MR/S033505/1). E.R.D. Ogilvie was supported by a St Andrews Research Internship Scheme (StARIS) grant from the University of St Andrews. East Africa hosts significant reserves of untapped geothermal energy. Exploration has focused on geologically young (

Microbial communities in terrestrial geothermal systems often contain chemolithoautotrophs with well-characterized distributions and metabolic capabilities. However, the extent to which organic matter produced by these chemolithoautotrophs supports heterotrophs remains largely unknown. Here we compared the abundance and activity of peptidases and carbohydrate active enzymes (CAZymes) that are predicted to be extracellular identified in metagenomic assemblies from 63 springs in the Central American and the Andean convergent margin (Argentinian backarc of the Central Volcanic Zone), as well as the plume-influenced spreading center in Iceland. All assemblies contain two orders of magnitude more peptidases than CAZymes, suggesting that the microorganisms more often use proteins for their carbon and/or nitrogen acquisition instead of complex sugars. The CAZy families in highest abundance are GH23 and CBM50, and the most abundant peptidase families are M23 and C26, all four of which degrade peptidoglycan found in bacterial cells. This implies that the heterotrophic community relies on autochthonous dead cell biomass, rather than allochthonous plant matter, for organic material. Enzymes involved in the degradation of cyanobacterial- and algal-derived compounds are in lower abundance at every site, with volcanic sites having more enzymes degrading cyanobacterial compounds and non-volcanic sites having more enzymes degrading algal compounds. Activity assays showed that many of these enzyme classes are active in these samples. High temperature sites (> 80°C) had similar extracellular carbon-degrading enzymes regardless of their province, suggesting a less well-developed population of secondary consumers at these sites, possibly connected with the limited extent of the subsurface biosphere in these high temperature sites. We conclude that in < 80°C springs, chemolithoautotrophic production supports heterotrophs capable of degrading a wide range of organic compounds that do not vary by geological province, even though the taxonomic and respiratory repertoire of chemolithoautotrophs and heterotrophs differ greatly across these regions.

The complex conductivity of a superconducting thin film is related to the quasiparticle density, which depends on the physical temperature and can also be modified by external pair breaking with photons and phonons. This relationship forms the underlying operating principle of Kinetic Inductance Detectors (KIDs), where the detection threshold is governed by the superconducting energy gap. We investigate the electromagnetic properties of thin-film aluminum that is proximitized with either a normal metal layer of copper or a superconducting layer with a lower $T_C$, such as iridium, in order to extend the operating range of KIDs. Using the Usadel equations along with the Nam expressions for complex conductivity, we calculate the density of states and the complex conductivity of the resulting bilayers to understand the dependence of the pair breaking threshold, surface impedance, and intrinsic quality factor of superconducting bilayers on the relative film thicknesses. The calculations and analyses provide theoretical insights in designing aluminum-based bilayer kinetic inductance detectors for detection of microwave photons and athermal phonons at the frequencies well below the pair breaking threshold of a pure aluminum film., Comment: Submitted as a proceeding for Applied Superconductivity Conference 2022

East Africa hosts significant reserves of untapped geothermal energy. Most exploration has focused on geologically young (

Future cosmic microwave background (CMB) experiments will deploy increasing numbers of superconducting detectors with requirements for increased sensitivity and reduced systematics. We report on the ongoing development of OMT-coupled CMB detectors at Argonne National Laboratory. Key areas of development include bolometers with dual Transition Edge Sensors (TES) for easier lab characterization, a hybrid SiN membrane fabrication process, a chemical vapor deposition (CVD) SiN dielectric process, and a new pixel design for improved compatibility with large scale fabrication. These developments enhance our ability to fabricate large-scale (150 mm diameter wafers) detector arrays with the performance necessary for future CMB experiments.

The episodic growth of high-elevation orogenic plateaux is controlled by a series of geodynamic processes. However, determining the underlying mechanisms that drive plateau growth dynamics over geological history and constraining the depths at which growth originates, remains challenging. Here we present He-CO2-N2 systematics of hydrothermal fluids that reveal the existence of a lithospheric-scale fault system in the southeastern Tibetan Plateau, whereby multi-stage plateau growth occurred in the geological past and continues to the present. He isotopes provide unambiguous evidence for the involvement of mantle-scale dynamics in lateral expansion and localized surface uplift of the Tibetan Plateau. The excellent correlation between 3He/4He values and strain rates, along the strike of Indian indentation into Asia, suggests non-uniform distribution of stresses between the plateau boundary and interior, which modulate southeastward growth of the Tibetan Plateau within the context of India-Asia convergence. Our results demonstrate that deeply-sourced volatile geochemistry can be used to constrain deep dynamic processes involved in orogenic plateau growth., Deeply-sourced volatiles are releasing from orogenic plateau regions, providing windows to plateau growth dynamics occurring at variable depths. Here the authors show that mantle-derived volatiles reveal the involvement of mantle dynamics in southeastward growth of the Tibetan Plateau.

Rhesus macaques are natural hosts to multiple viruses including rhesus cytomegalovirus (RhCMV), rhesus rhadinovirus (RRV), and Simian Foamy Virus (SFV). While viral infections are ubiquitous, viral transmissions to uninfected animals are incompletely defined. Management procedures of macaque colonies include cohorts that are Specific Pathogen Free (SPF). Greater understanding of viral transmission would augment SPF protocols. Moreover, vaccine/challenge studies of human viruses would be enhanced by leveraging transmission of macaque viruses to recapitulate expected challenges of human vaccine trials.This study characterizes viral transmissions to uninfected animals following inadvertent introduction of RhCMV/RRV/SFV-infected adults to a cohort of uninfected juveniles. Following co-housing with virus-positive adults, juveniles were serially evaluated for viral infection.Horizontal viral transmission was rapid and absolute, reaching 100% penetrance between 19 and 78 weeks.This study provides insights into viral natural histories with implications for colony management and modeling vaccine-mediated immune protection studies.

The endangered mountain gorilla (Gorilla beringei beringei) in Rwanda, Uganda, and the Democratic Republic of Congo is frequently in contact with humans through tourism, research activities, and illegal entry of people into protected gorilla habitat. Herpesviruses, which are ubiquitous in primates, have the potential to be shared in any setting where humans and gorillas share habitat. Based on serological findings and clinical observations of orofacial ulcerated lesions resembling herpetic lesions, an alpha-herpesvirus resembling human herpes simplex virus type 1 (HSV-1) has long been suspected to be present in human-habituated mountain gorillas in the wild. While the etiology of orofacial lesions in the wild has not been confirmed, HSV-1 has been suspected in captively-housed mountain gorillas and confirmed in a co-housed confiscated Grauer's gorilla (Gorilla beringei graueri). To better characterize herpesviruses infecting mountain gorillas and to determine the presence/absence of HSV-1 in the free-living population, we conducted a population-wide survey to test for the presence of orally shed herpesviruses. DNA was extracted from discarded chewed plants collected from 294 individuals from 26 groups, and samples were screened by polymerase chain reaction using pan-herpesvirus and HSV-1-specific assays. We found no evidence that human herpesviruses had infected free-ranging mountain gorillas. However, we found gorilla-specific homologs to human herpesviruses, including cytomegaloviruses (GbbCMV-1 and 2), a lymphocryptovirus (GbbLCV-1), and a new rhadinovirus (GbbRHV-1) with similar characteristics (i.e., timing of primary infection, shedding in multiple age groups, and potential modes of transmission) to their human counterparts, human cytomegalovirus, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, respectively.

PurposeThis paper aims to use coordinated financial statements' system properties that include exogenous and endogenous variables to answer important questions. These questions include the following: What is the financial condition of the firm? What if there is a change in the firm's exogenous variable(s) – how will the financial condition of the firm change? And, how much of a change in the firm's exogenous variable(s) is required for the firm to reach its financial goal(s)?Design/methodology/approachThis paper uses coordinated financial statements to construct solvency, profitability, efficiency, liquidity and leverage (SPELL) ratios to answer the question: what is the financial condition of the firm? It answers what-if questions by changing an exogenous variable(s) and recalculating SPELL ratios. It answers how-much questions by using Excel's Goal Seek algorithm to find the required change in an exogenous variable to reach a firm's goal.FindingsThe authors find that coordinated financial statements' system properties can be used to answer important what-is, what-if and how-much questions about the firm.Research limitations/implicationsThe usefulness of coordinated financial statements' system properties to answer what-is, what-if and how-much questions about the firm depends – mostly on the accuracy of exogenous data used to represent the firm's external financial environment. Furthermore, the usefulness of what-if and how-much analysis depends on how appropriate the changes are in exogenous variables used to represent alternative scenarios.Practical implicationsUsing coordinated financial statements' system properties to answer what-is, what-if and how-much questions provides the firm's financial manager the tools to not only asses the firm's current financial condition but also to assess its ability to respond to opportunities and threats posed by future scenarios.Social implicationsThe ability to assess the financial condition of a firm and to assess its strengths and weaknesses in key to making sound financial decisions. In addition, the consistency imposed on coordinated financial statements makes it an effective tool for discovering errors in its data.Originality/valueThe authors know of no similar work.

Volatile elements (water, carbon, nitrogen, sulfur, halogens, and noble gases) played an essential role in the secular evolution of the solid Earth and emergence of life. Here we provide an overview of Earth's volatile inventories and describe the mechanisms by which volatiles are conveyed between Earth's surface and mantle reservoirs, via subduction and volcanism. Using literature data, we compute volatile concentration and flux estimates for Earth's major volatile reservoirs and provide an internally balanced assessment of modern global volatile recycling. Using a nitrogen isotope box model, we show that recycling of N (and possibly C and S) likely began before 2 Ga and that ingassing fluxes have remained roughly constant since this time. In contrast, our model indicates recycling of H2O(and most likely noble gases) was less efficient in the past. This suggests a decoupling of major volatile species during subduction through time, which we attribute to the evolving thermal regime of subduction zones and the different stabilities of the carrier phases hosting each volatile. ▪ This review provides an overview of Earth's volatile inventory and the mechanisms by which volatiles are transferred between Earth reservoirs via subduction. ▪ The review frames the current thinking regarding how Earth acquired its original volatile inventory and subsequently evolved through subduction processes and volcanism.

The subsurface is among Earth’s largest biomes, but the extent to which microbial communities vary across tectonic plate boundaries or interact with subduction-scale geological processes remains unknown. Here we compare bacterial community composition with deep-subsurface geochemistry from 21 hot springs across the Costa Rican convergent margin. We find that cation and anion compositions of the springs reflect the dip angle and position of the underlying tectonic structure and also correlate with the bacterial community. Co-occurring microbial cliques related to cultured chemolithoautotrophs that use the reverse tricarboxylic acid cycle (rTCA) as well as abundances of metagenomic rTCA genes correlate with concentrations of slab-volatilized carbon. This, combined with carbon isotope evidence, suggests that fixation of slab-derived CO2 into biomass may support a chemolithoautotrophy-based subsurface ecosystem. We calculate that this forearc subsurface biosphere could sequester 1.4 × 109 to 1.4 × 1010 mol of carbon per year, which would decrease estimates of the total carbon delivered to the mantle by 2 to 22%. Based on the observed correlations, we suggest that distribution and composition of the subsurface bacterial community are probably affected by deep tectonic processes across the Costa Rican convergent margin and that, by sequestering carbon volatilized during subduction, these chemolithoautotrophic communities could in turn impact the geosphere. The subsurface biosphere across a convergent margin may reflect tectonic processes and reduce carbon transfer to the mantle, according to bacterial and geochemical correlations from hot springs across the Costa Rican margin.

Commercial helium systems have been found to date as a serendipitous by-product of petroleum exploration. There are nevertheless significant differences in the source and migration properties of helium compared with petroleum. An understanding of these differences enables prospects for helium gas accumulations to be identified in regions where petroleum exploration would not be tenable. Here we show how the basic petroleum exploration playbook (source, primary migration from the source rock, secondary longer distance migration, trapping) can be modified to identify helium plays. Plays are the areas occupied by a prospective reservoir and overlying seal associated with a mature helium source. This is the first step in identifying the detail of helium prospects (discrete pools of trapped helium). We show how these principles, adapted for helium, can be applied using the Rukwa Basin in the Tanzanian section of the East African Rift as a case study. A thermal hiatus caused by rifting of the continental basement has resulted in a surface expression of deep crustal gas release in the form of high-nitrogen gas seeps containing up to 10%4He. We calculate the total likely regional source-rock helium generative capacity, identify the role of the Rungwe volcanic province in releasing the accumulated crustal helium and show the spatial control of helium concentration dilution by the associated volcanic CO2. Nitrogen, both dissolved and as a free-gas phase, plays a key role in the primary and secondary migration of crustal helium and its accumulation into what might become a commercially viable gas pool. This too is examined. We identify and discuss evidence that structures and seals suitable for trapping hydrocarbon and CO2 gases will likely also be efficient for helium accumulation on the timescale of the Rukwa Basin activity. The Rukwa Basin prospective recoverable P50 resources of helium have been independently estimated to be about 138 BSCF (billion standard cubic ft: 2.78 × 109 m3 at STP). If this volume is confirmed it would represent about 25% of the current global helium reserve. Two exploration wells, Tai 1 and Tai 2, completed by August 2021 have proved the presence of seal and reservoir horizons with the reservoirs containing significant helium shows.

Long-lived ‘memory-like’ NK cells, characterized by FcRγ-deficiency and enhanced responsiveness to antibody-bound virus-infected cells, have been found in certain human cytomegalovirus (HCMV)-seropositive individuals. Because humans are exposed to numerous microbes and environmental agents, specific relationships between HCMV and FcRγ-deficient NK cells (also known as g-NK cells) have been challenging to define. Here, we show that a subgroup of rhesus cytomegalovirus (RhCMV)-seropositive macaques possesses FcRγ-deficient NK cells that stably persist and display phenotype resembling human FcRγ-deficient NK cells. Moreover, these macaque NK cells resembled human FcRγ-deficient NK cells with respect to functional characteristics, including enhanced responsiveness to RhCMV-infected target in an antibody-dependent manner and hypo-responsiveness to tumor and cytokine stimulation. These cells were not detected in specific-pathogen-free (SPF) macaques free of RhCMV and six other viruses; however, experimental infection of SPF animals with RhCMV strain UCD59, but not RhCMV strain 68-1 or SIV, led to induction of FcRγ-deficient NK cells. In non-SPF macaques, co-infection by RhCMV with other common viruses was associated with higher frequencies of FcRγ-deficient NK cells. These results support a causal role for specific cytomegalovirus strain(s) in the induction of FcRγ-deficient NK cells, and suggest that co-infection by other viruses further expands this memory-like NK cell pool.

Introduction. The black yeast Exophiala dermatitidis has been isolated in respiratory samples from people with cystic fibrosis (CF). However, adequate detection may require longer incubation periods than the current UK national standard for CF respiratory samples. Furthermore, it is unclear whether isolation of E. dermatitidis is associated with poorer clinical outcomes in CF. Hypothesis/gap statement. E. dermatitidis does not cause clinically significant lung disease in CF adults. Aim. To evaluate differences in clinical outcomes over a 12 month period and during acute pulmonary exacerbations between CF adults with and without untreated E. dermatitidis. Methodology. Incubation times for respiratory samples on Sabouraud dextrose agar with chloramphenicol (SABC) plates at a large regional adult CF centre were extended from 2 to 7 days over a 1 month period. The number of patients from whom E. dermatitidis was isolated, and the length of incubation time prior to isolation, were recorded. Outcomes of treatment of exacerbations with intravenous antibiotics but in the absence of concomitant antifungal therapy were compared between those with and without E. dermatitidis, as were changes in lung function and body mass index (BMI) over a 12 month period. Results. Extended incubation unmasked the presence of E. dermatitidis in 22 of 132 patients; all isolations occurred after >48 h of incubation. Patients who isolated E. dermatitidis had lower rates of Pseudomonas aeruginosa isolation (P=0.02) and higher rates of non-tuberculous mycobacteria isolation (P=0.03), and were more likely to be prescribed a long-term antifungal medication (P=0.03), but had no differences in age, sex, baseline lung function or body mass index (BMI). There were no differences in response to treatment of acute exacerbations between patients with and without E. dermatitidis, or in change in forced expiratory volume in 1 s (FEV1), BMI and number of exacerbations over 12 months of follow-up. Conclusion. E. dermatitidis is not associated with worse clinical outcomes in CF. Given potential side effects and drug interactions, routine targeting of E. dermatitidis with antifungals during acute exacerbations is not advised.

Introduction\ud \ud Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management.\ud \ud \ud \ud Methods\ud \ud UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy.\ud \ud \ud \ud Results\ud \ud 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February–August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%).\ud \ud \ud \ud For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure.\ud \ud \ud \ud For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy.\ud \ud \ud \ud Conclusion\ud \ud This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways.

Introduction: Indications for accurate removal of a previously identified, involved or highly suspicious axillary lymph node include: 1) after neoadjuvant chemotherapy (NACT) to ensure pathological assessment of the correct index node (targeted axillary dissection, TAD) 2) for women with an abnormal/indeterminate node on imaging who may be able to avoid axillary lymph node clearance (ALNC) because they meet Z0011 criteria or may be eligible for POSNOC trial inclusion 3) guided removal of a specific axillary lymph node (eg Rotter’s node recurrence, diagnostic biopsy, inclusion of specific node in ALNC). Dual localisation is either not viable or has an unacceptably high false negative rate in these scenarios and marking of the index node is advised. Although conventional markers are often used prior to NACT, finding that marked node at surgery can pose a challenge. Wire localisation has variable outcomes and scheduling constraints. Magnetic seed localisation, with MagseedTM, allows for easy placement and excision of targeted nodes. Seeds can be accurately placed, do not migrate and can now be placed many months prior to surgery, at the start of NACT. The aim of this study was to report our early experience. Methods: Patients were identified by searching an imaging database for women who had undergone ultrasound (US)-guided MagseedTM insertion into an abnormal axillary lymph node between August 2018 and July 2020. Data on intended use and surgical outcomes were collected retrospectively from electronic patient records (EPR). Patients were categorised into 3 groups as described above. Results: 37 patients were identified, 17 in group 1, 13 in group 2 and 7 in group 3. Only 1 patient had complications with MagseedTM insertion, requiring a second attempt to successfully mark the required node. In 1 patient the MagseedTM was found on the surgical drape, thought to have been lying adjacent to the node intended for excision, this patient was therefore excluded from further evaluation in the results, as were 3 patients with missing data. One patient has yet to come to surgery, all other MagseedsTM have been successfully retrieved. Group 3 indications were disparate, and this group will not be described further. Group 1 - in 10 of 15 patients post NACT the MagseedTM-marked node was found to be the sentinel node by routine mapping techniques (Technetium 99 +/- Patent V blue dye injection), identified as either hot or hot and blue. Of the 15 patients, 6 remained node positive on intra-operative assessment and underwent ALNC whilst 9 (60%) were spared ALNC. 2 patients avoided false negative results as the Magseed™-marked node contained residual disease yet was neither hot nor blue. Group 2 - Ten patients underwent sentinel lymph node biopsy using routine mapping techniques and MagseedTM-guided excision of a specifically targeted node. In 7 the MagseedTM-marked node was found to be a sentinel node (hot or hot and blue). Only 3 patients had sufficient disease to warrant completion ALNC. Conclusion: Insertion of a magnetic seed into a biopsy-proven positive node prior to planned TAD or into an abnormal node identified at diagnosis facilitates specific node retrieval for pathological assessment, with minimal associated complications, and has wide versatility. Magnetic seed localisation reduces the false negative rate and provides confidence in the correct assessment of the axilla thereby sparing patients unnecessary ALNC if they have had a complete pathological response to NACT or have limited axillary disease. The ability to insert the seed prior to the surgical date allows for flexibility with scheduling in comparison to wire localisation. Citation Format: Kathryn E Harborough, V Sinnett, K Downey, K Krupa, J E Rusby, P A Barry. Magnetic seeds to aid targeted axillary dissection [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-46.

IntroductionIvacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying aGly551Aspmutation were greater than previously seen in clinical trials for other therapies. Limited data are available regarding long-term outcomes and adherence to ivacaftor outside clinical trials.MethodsWe conducted a 5-year single-centre retrospective study of people with CF carrying theGly551Aspmutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR).Results35 people were included. After commencing ivacaftor, FEV1improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV1declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV1decline (1.57% pre vs 1.82% post, p=0.74). Body mass index (BMI) increased for 4 years. There was a significant reduction in inpatient and total intravenous antibiotic days sustained over 5 years. MPR remained high but declined over time (−2.5±0.9% per year, p=0.007). FEV1was better maintained in patients with higher MPRs.ConclusionThe addition of ivacaftor provides acute benefits for people with theGly551Aspmutation and established lung disease. We report a sustained reduction in intravenous antibiotic use but following acute improvement in lung function, decline continues, and patients will continue to require medical observation and optimisation. Strategies to maintain high adherence should be a priority to prolong the benefits of ivacaftor.

The starfish Tethyaster subinermis is documented from the south-western parts of British waters, with one specimen caught by trawl at 48° 27.5’N, 009° 35.3’W (208–250 m depth) in 2001 and a further two specimens caught by trawl at 48° 28.32’N, 009° 33.23’W (189–217 m depth) in 2020., Autori iznose novi nalaz morske zvijezdače Tethyaster subinermis iz jugozapadnih dijelova britanskih voda, s jednim primjerkom ulovljenim koćom na 48 ° 27,5 ‘N, 009 ° 35,3’ W (dubine 208–250 m) 2001. godine i dva primjerka koja su ulovljena povlačnom mrežom na 48 ° 28,32’N, 009 ° 33,23’W (dubina 189–217 m) u 2020. godini.

Rhesus cytomegalovirus (RhCMV) infection of rhesus macaques (Macaca mulatta) is a valuable nonhuman primate model of human CMV (HCMV) persistence and pathogenesis. In vivo studies predominantly use tissue culture-adapted variants of RhCMV that contain multiple genetic mutations compared to wild-type (WT) RhCMV. In many studies, animals have been inoculated by non-natural routes (e.g., subcutaneous, intravenous) that do not recapitulate disease progression via the normative route of mucosal exposure. Accordingly, the natural history of RhCMV would be more accurately reproduced by infecting macaques with strains of RhCMV that reflect the WT genome using natural routes of mucosal transmission. Herein, we tested two WT-like RhCMV strains, UCD52 and UCD59, and demonstrated that systemic infection and frequent, high-titer viral shedding in bodily fluids occurred following oral inoculation. RhCMV disseminated to a broad range of tissues, including the central nervous system and reproductive organs. Commonly infected tissues included the thymus, spleen, lymph nodes, kidneys, bladder, and salivary glands. Histological examination revealed prominent nodular hyperplasia in spleens and variable levels of lymphoid lymphofollicular hyperplasia in lymph nodes. One of six inoculated animals had limited viral dissemination and shedding, with commensurately weak antibody responses to RhCMV antigens. These data suggest that long-term RhCMV infection parameters might be restricted by local innate factors and/or de novo host immune responses in a minority of primary infections. Together, we have established an oral RhCMV infection model that mimics natural HCMV infection. The virological and immunological parameters characterized in this study will greatly inform HCMV vaccine designs for human immunization. IMPORTANCE Human cytomegalovirus (HCMV) is globally ubiquitous with high seroprevalence rates in all communities. HCMV infections can occur vertically following mother-to-fetus transmission across the placenta and horizontally following shedding of virus in bodily fluids in HCMV infected hosts and subsequent exposure of susceptible individuals to virus-laden fluids. Intrauterine HCMV has long been recognized as an infectious threat to fetal growth and development. Since vertical HCMV infections occur following horizontal HCMV transmission to the pregnant mother, the nonhuman primate model of HCMV pathogenesis was used to characterize the virological and immunological parameters of infection following primary mucosal exposures to rhesus cytomegalovirus.

We demonstrate microwave-mediated distant magnon-magnon coupling on a superconducting circuit platform, incorporating chip-mounted single-crystal Y$_3$Fe$_5$O$_{12}$ (YIG) spheres. Coherent level repulsion and dissipative level attraction between the magnon modes of the two YIG spheres are demonstrated. The former is mediated by cavity photons of a superconducting resonator, and the latter is mediated by propagating photons of a coplanar waveguide. Our results open new avenues towards exploring integrated hybrid magnonic networks for coherent information processing on a quantum-compatible superconducting platform., Comment: 6 pages, 4 figures, Accepted in Phys. Rev. Lett