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Aim: Brensocatib is an oral, selective, competitive and reversible dipeptidyl peptidase 1 inhibitor in development for the treatment of bronchiectasis. This study evaluated the pharmacokinetics (PKs), safety and tolerability of brensocatib in participants with varying degrees of renal impairment and normal renal function., Methods: In this phase 1, multicentre, open-label study, 28 participants with mild, moderate or severe renal impairment (estimated glomerular filtration rate [eGFR] 60 to <90, 30 to <60 and 15 to <30 mL/min/1.73 m 2 , respectively) or normal renal function (≥90 mL/min/1.73 m 2 ) received a single oral 25-mg dose of brensocatib. Blood samples were collected to measure brensocatib PKs at predetermined time points over the 14-day study period. PK parameters were derived using noncompartmental methods., Results: Demographic and baseline characteristics were similar across groups. There were no significant differences between groups in brensocatib PK parameters. The mean coefficient of variation (CV) of elimination half-life of brensocatib was 37.0 (15.3), 42.8 (21.7), 36.3 (22.9) and 39.1 (17.8) h for mild, moderate, severe and normal renal function groups, respectively. Single-dose brensocatib was quickly absorbed; all groups had a median time to maximum observed plasma concentration of 1 h. Regression model analyses indicated no significant relationships between selected brensocatib PK parameters and eGFR. No treatment-emergent adverse events were reported during the study., Conclusion: Single-dose brensocatib was well tolerated. The study data do not indicate a significant effect of renal impairment on brensocatib elimination and systemic exposure, suggesting that dose adjustment of brensocatib is not necessary in participants with renal impairment., Clinical Trial Registration Number: NCT05673603., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Study Objectives: To evaluate the concordance between visual scoring and automated detection of REM sleep without atonia (RSWA) and the validity and reliability of in-home automated-RSWA detection in REM sleep behavior disorder (RBD) patients and a control group (CG)., Methods: Sleep Profiler signals were acquired during simultaneous in-laboratory polysomnography in 24 isolated RBD patients. Chin and arm RSWA measures visually scored by an expert sleep technologist were compared to algorithms designed to automate RSWA detection. In a second cohort, the accuracy of automated-RSWA detection for discriminating between RBD and CG (n = 21 and 42, respectively) was assessed in multi-night in-home recordings., Results: For the in-laboratory studies, agreement between visual and auto-scored RSWA from the chin and arm were excellent, with intra-class correlations of 0.89 and 0.95, respectively, and substantial, based on Kappa scores of 0.68 and 0.74, respectively. For classification of iRBD patients versus controls, specificities derived from auto-detected RSWA densities obtained from in-home recordings were 0.88 for the chin, 0.93 for the arm, and 0.90 for the chin or arm, while the sensitivities were 0.81, 0.81 and 0.86, respectively. The night-to-night consistencies of the respective auto-detected RSWA densities were good based on intra-class correlations of 0.81, 0.79 and 0.84, however some night-to-night disagreements in abnormal RSWA detection were observed., Conclusions: When compared to expert visual RSWA scoring, automated RSWA detection demonstrates promise for detection of RBD. The night-to-night reliability of chin- and arm-RSWA densities acquired in-home were equivalent., (© 2024 American Academy of Sleep Medicine.)

Background: The lack of dermatological knowledge by non-dermatologists is exposed by the increasing number of requests made for inpatient dermatological consultations. Patients have been commenced on inappropriate treatment because of poor dermatology training., Objectives: To determine the burden and accuracy of inpatient dermatology referrals., Methods: A retrospective cohort study using paper inpatient dermatology referrals from one Health Board between June 2007 and July 2021. Data analysis included timing of referrals; referring speciality; diagnosis and treatment. Descriptive statistics, using Excel, were used for analyses., Results: The average number of referrals per year was 106 (79-166). The most frequent day of referral was Monday (26%). Most referrals were from medical teams (73%).Differential diagnosis was suggested by the referring team in 59% of referrals. In only 29% of referrals the dermatology team agreed with the differential diagnosis. There was discrepancy in the correctness of diagnosis in all categories, however the paediatricians were most likely to offer a correct differential (44%). In 44% of referrals treatment was commenced by the referring team, most commonly antibiotics., Conclusions: There is an extra burden on dermatology teams to cover inpatients. Our figures highlight two important issues - the need for better dermatological education in medical schools to improve diagnosis accuracy and management of conditions as well as the need to recognise the need for an inpatient dermatology service to review inpatient referrals and advise in diagnosis and management of dermatology cases on the wards, and to protect the service from being uncoupled from the main hospital., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease., Competing Interests: Declaration of interests M.Z.L. is an inventor on a patent for the earlier ASAP1 voltage indicator., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Recovery models of care for intensive care unit (ICU) survivors are limited by availability, accessibility, and efficacy. Digital health interventions represent an alternative mode of service delivery. The primary aim of this systematic review was to describe implementation factors (Reach, Effectiveness, Adoption, Implementation, and Maintenance) for digital health interventions for ICU survivors. The secondary aim was to describe any effect on patient-reported health outcomes., Data Sources: A systematic search of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excertpa Medica Database (EMBASE), Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central Register of Systematic Reviews (CENTRAL) databases was undertaken in March 2023., Study Selection: Two independent reviewers screened abstracts and full texts against eligibility criteria. Studies of adult survivors with any post-ICU discharge care, delivered via a digital mode, were included. Studies were excluded if published before 1990 or not in English., Data Extraction: Quantitative data were extracted using predefined data fields. Risk of bias was assessed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias Tool 2.0. Implementation factors were reported according to the Reach, Effectiveness, Adoption, Implementation and Maintenance framework., Data Synthesis: A total of 6482 studies were screened. Ten studies, with 686 participants, were included. Implementation factors were reported in all studies. Acceptability (reported in six studies) was high, with high satisfaction and usability scores, defined a priori by investigators. Eight studies reported intervention adherence rates between 46% and 100%. Nine studies report final outcome measurement retention rates up to 12 months, between 52% and 100%. Five studies included the primary outcome as the difference in a patient-reported health outcome. Appraisal of efficacy and digital health literacy was limited due to substantial methodological variation and a lack of reporting in included studies. There was some risk of bias in 50% of studies., Conclusions: Digital health interventions can be successfully implemented for critical care survivors and have varying intervention adherence and retention rate success. To broaden reach, future research should include cultural diversity and investigate digital health access, literacy, and cost-effectiveness. INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS REGISTRATION: CRD42022348252., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

The impact of warming on zooxanthellate corals is widespread, from tropical to temperate seas, with its associated mortalities causing global concern. The temperate coral Cladocora caespitosa is the only zooxanthellate coral with reef building capacity in the Mediterranean Sea, a climate change hotspot with warming rates triple the global average. During the past two decades, C. caespitosa populations have suffered severe mortality events associated with marine heatwaves (MHWs). However, with monitoring efforts beginning, at best, in the 2000s, the occurrence of MHWs before that period, as well as the sublethal effects of these events remain poorly understood. Here, we use sclerochronology to reconstruct the histories of past stress events and long-term sublethal effects on C. caespitosa in three locations along a latitudinal gradient within the NW Mediterranean Sea, each with different environmental conditions. Skeletal extension, density and calcification rates were compared with the in situ seawater temperature of each site to assess their relationship. Furthermore, we assessed the occurrence of skeletal growth anomalies to reconstruct stress events between 1991 and 2021, a period that encompasses the onset and evolution of warming-related mass mortality events in the NW Mediterranean Sea. Our results reveal a positive association between calcification and temperature, following a latitudinal temperature gradient. However, the evolution of the likelihood distribution of growth rates in the warmest site (Columbretes Islands) since the 1990s indicates a decrease in linear extension and calcification rates during the most recent years. With the increase in the frequency of MHWs and growth anomalies during the last decade, this decline suggests recurrent physiological stress events. These results unravel information on the long-term impacts of warming on coral growth and highlight the potential of applying sclerochronology to reconstruct the sublethal effects of warming using C. caespitosa., (© 2024 The Author(s). Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.)

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins, combined with the exposure of their residues, accounts for this sensitivity. One context in which IDPs play important roles that are concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat-soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet the mechanisms underlying this synergy differ between IDP families., Competing Interests: SK, KN, VN, AW, TT, EG, PR, SS, TB No competing interests declared, AH Scientific consultant with Dewpoint Therapeutics and is on the Scientific Advisory Board of Prose Foods. The work reported here was not influenced by these affiliations, (© 2024, KC et al.)

A detailed analysis of ptychography for three-dimensional (3D) phase reconstructions of thick specimens is performed. We introduce multi-focus ptychography, which incorporates a 4D-STEM defocus series to enhance the quality of 3D reconstructions along the beam direction through a higher overdetermination ratio. This method is compared with established multi-slice ptychography techniques, such as conventional ptychography, regularized ptychography, and multi-mode ptychography. Additionally, we contrast multi-focus ptychography with an alternative method that uses virtual optical sectioning through a reconstructed scattering matrix (S-matrix), which offers more precise 3D structure information compared to conventional ptychography. Our findings from multiple 3D reconstructions based on simulated and experimental data demonstrate that multi-focus ptychography surpasses other techniques, particularly in accurately reconstructing the surfaces and interface regions of thick specimens., Competing Interests: Conflict of Interest The authors declare that they have no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To evaluate whether abnormal sleep is associated with adverse outcomes for children who survived acute provoked neonatal seizures, and their parents' well-being., Study Design: This 9-center study prospectively followed newborns with acute provoked seizures. When children reached age 5 years, parents completed the Children's Sleep Habits Questionnaire (CSHQ), the Pediatric Sleep Questionnaire-Sleep Related Breathing Disorders (PSQ-SRBD) subscale, Vineland Adaptive Behavior Scales-3, and the Hospital Anxiety Depression Scale (HADS). Children were also assessed with the Wechsler Preschool and Primary Scale of Intelligence-IV (WPPSI-IV). Spearman correlations and multivariable analyses were used to evaluate risk factors for sleep problems., Results: The mean CSHQ score was 45±7; 77/118 (65%) scored abnormally above the healthy sleep threshold of 41. On the PSQ-SRBD, 32/119 (27%) screened positive for sleep-disordered breathing (SDB). SDB symptoms were more common among children with cerebral palsy (42% with vs. 22% without, p=0.03) and epilepsy (54% with vs. 24% without, p=0.02). Children with lower scores on the Vineland-3 (rho=-0.25, p=0.01) and WPPSI-IV (rho=-0.31, p=0.004) at age 5 years were more likely to have symptoms of SDB. Worse CSHQ and PSQ-SRBD scores were associated with higher parental anxiety (rho=0.28, p=0.002, and rho=0.34, p=0.0002, respectively) and depression scores on the HADS (rho=0.16, p=0.08, and rho=0.17, p=0.07, respectively)., Conclusions: Two-thirds of early school-aged survivors of acute provoked neonatal seizures had parent-reported sleep abnormalities and one quarter screened positive for SDB. Early screening and effective treatment for sleep disorders could be an innovative, practice-changing approach to improve outcomes after neonatal seizures., (Copyright © 2024. Published by Elsevier Inc.)

Multiple respiratory viruses lead to high morbidity and mortality, yet global surveillance platforms focus primarily on seasonal influenza viruses. The COVID-19 pandemic and new RSV vaccines highlight the importance of a broader approach. Upper respiratory tract swabs from children aged 24-59 months presenting with influenza-like illness in The Gambia were collected during follow-up of a live-attenuated influenza vaccine randomised controlled trial in 2017-18. A microfluidic quantitative polymerase chain reaction (qPCR) assay was established and used to detect 21 respiratory viruses. 76.6% of samples had one or more viruses detected (n = 121/158). The viruses detected most frequently were rhinovirus (n = 37/158, 23.4%) and adenovirus (n = 34/158, 21.5%), followed by parainfluenza virus 3, influenza B and human metapneumovirus B. A third of positive samples had multiple viruses detected (two n = 31/121, 25.6%; three n = 9/121, 7.4%). Our data demonstrates how microfluidic qPCR is a useful tool for high-throughput, comprehensive detection of multiple respiratory viruses in surveillance platforms. Rapidly changing epidemiology exemplifies the need for new, broader approaches to virus surveillance in low-resource settings to respond to future epidemics and to guide the need for and use of new prevention and therapeutic measures., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Subarachnoid haemorrhage is a potentially fatal consequence of intracranial aneurysm rupture, however, it is difficult to predict if aneurysms will rupture. Prophylactic treatment of an intracranial aneurysm also involves risk, hence identifying rupture-prone aneurysms is of substantial clinical importance. This systematic review aims to evaluate the performance of machine learning algorithms for predicting intracranial aneurysm rupture risk., Methods: MEDLINE, Embase, Cochrane Library and Web of Science were searched until December 2023. Studies incorporating any machine learning algorithm to predict the risk of rupture of an intracranial aneurysm were included. Risk of bias was assessed using the Prediction Model Risk of Bias Assessment Tool (PROBAST). PROSPERO registration: CRD42023452509., Results: Out of 10,307 records screened, 20 studies met the eligibility criteria for this review incorporating a total of 20,286 aneurysm cases. The machine learning models gave a 0.66-0.90 range for performance accuracy. The models were compared to current clinical standards in six studies and gave mixed results. Most studies posed high or unclear risks of bias and concerns for applicability, limiting the inferences that can be drawn from them. There was insufficient homogenous data for a meta-analysis., Conclusions: Machine learning can be applied to predict the risk of rupture for intracranial aneurysms. However, the evidence does not comprehensively demonstrate superiority to existing practice, limiting its role as a clinical adjunct. Further prospective multicentre studies of recent machine learning tools are needed to prove clinical validation before they are implemented in the clinic., Competing Interests: Conflict of interest K. Daga, S. Agarwal, Z. Moti, M.B.K. Lee, M. Din, D. Wood, M. Modat and T.C. Booth declare that they have no competing interests., (© 2024. The Author(s).)

Vast alteration of the biosphere by humans is causing a sixth mass extinction, driven in part by an increase in infectious diseases. The emergence of the lethal fungal pathogen Batrachochytrium dendrobatidis (Bd) has devastated global amphibian biodiversity. Given the lack of any broadly applicable methods to reverse these impacts, the future of many amphibians appears grim. The Sierra Nevada yellow-legged frog (Rana sierrae) is highly susceptible to Bd infection and most R. sierrae populations are extirpated following disease outbreaks. However, some populations persist and eventually recover, and frogs in these recovering populations have increased resistance against infection. Here, we conduct a 15-year reintroduction study and show that frogs collected from recovering populations and reintroduced to vacant habitats can reestablish populations despite the presence of Bd. In addition, the likelihood of establishment is influenced by site, cohort, and frog attributes. Results from viability modeling suggest that many reintroduced populations have a low probability of extinction over 50 years. These results provide a rare example of how reintroduction of resistant individuals can allow the landscape-scale recovery of disease-impacted species, and have broad implications for amphibians and other taxa that are threatened with extinction by novel pathogens., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Motivation: Biomedical visualizations are key to accessing biomedical knowledge and detecting new patterns in large datasets. Interactive visualizations are essential for biomedical data scientists and are omnipresent in data analysis software and data portals. Without appropriate descriptions, these visualizations are not accessible to all people with blindness and low vision, who often rely on screen reader accessibility technologies to access visual information on digital devices. Screen readers require descriptions to convey image content. However, many images lack informative descriptions due to unawareness and difficulty writing such descriptions. Describing complex and interactive visualizations, like genomics data visualizations, is even more challenging. Automatic generation of descriptions could be beneficial, yet current alt text generating models are limited to basic visualizations and cannot be used for genomics., Results: We present AltGosling, an automated description generation tool focused on interactive data visualizations of genome-mapped data, created with the grammar-based genomics toolkit Gosling. The logic-based algorithm of AltGosling creates various descriptions including a tree-structured navigable panel. We co-designed AltGosling with a blind screen reader user (co-author). We show that AltGosling outperforms state-of-the-art large language models and common image-based neural networks for alt text generation of genomics data visualizations. As a first of its kind in genomic research, we lay the groundwork to increase accessibility in the field., Availability and Implementation: The source code, examples, and interactive demo are accessible under the MIT License at https://github.com/gosling-lang/altgosling. The package is available at https://www.npmjs.com/package/altgosling., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2024. Published by Oxford University Press.)

Great Salt Lake is a critical habitat for migratory birds that is threatened by elevated metal concentrations, including mercury (Hg) and lead (Pb), and is subject to severe hydrologic changes, such as declining lake level. When assessing metal profiles recorded in Great Salt Lake sediment, a large data gap exists regarding the sources of metals within the system, which is complicated by various source inputs to the lake and complex biogeochemistry. Here, we leverage Hg and Pb stable isotopes to track relative changes in metal source contributions to Great Salt Lake over time. Mercury and Pb concentrations increase in sediments deposited after 1920 and peak between 1965 and 1995, following closure of several local smelters and the onset of increased emission controls. The nominal associations above are confirmed via Hg stable isotopes in pre-1920 background sediments, which reflect atmospheric inputs from regional and global origin, whereas Hg and Pb stable isotopes together indicate that elevated metal concentrations in mid-late 20th century sediments reflect increased mining/smelting inputs. The observed minimal rebound towards pre-1920 Pb isotope signatures in 21st century sediments indicates that mining/smelting inputs, though reduced, remain a primary source of Pb to Great Salt Lake. In contrast, the more pronounced rebound of Hg stable isotope signatures to pre-1920 values indicate a greater contribution of atmospheric inputs of regional/global origin to current Hg inputs, though Hg concentrations are ∼10 times greater than pre-1920 background values due to global increases in atmospheric Hg concentrations or possibly slow recovery from local contamination. The importance of regional/global Hg sources to the system suggests that reductions in Hg bioaccumulation in the open water food webs of Great Salt Lake are more dependent on national and global reductions in Hg emissions and management strategies to limit methylmercury production within system. This work highlights the utility of using coupled Hg and Pb stable isotope values to assess trace metal pollution sources and pathways in aquatic systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Interessenkonflikt C. Becker und C. Thomas geben an, dass kein Interessenkonflikt besteht.

Introduction: Dysregulated androgen receptor (AR) activity is central to various diseases, particularly prostate cancer (PCa), in which it drives tumour initiation and progression. Consequently, antagonising AR activity via anti-androgens is an indispensable treatment option for metastatic PCa. However, despite initial tumour remission, drug resistance occurs. Therefore, the AR signalling pathway has been intensively investigated. However, the role of AR protein stability in AR signalling and therapy resistance has not yet been deciphered. Therefore, this study aimed to investigate the role of AR protein changes in transactivity and assess its mechanism as a possible target in PCa., Methods: LNCaP, C4-2, and 22Rv1 cells were treated with R1881, enzalutamide, cycloheximide, and Rocaglamide. Mass spectrometry analyses were performed on LNCaP cells to identify the pathways enriched by the treatments. Western blotting was performed to investigate AR protein levels and localisation changes. Changes in AR transactivity were determined by qPCR., Results: Mass spectrometry analyses were performed on LNCaP cells to decipher the molecular mechanisms underlying androgen- and antiandrogen-induced alterations in the AR protein. Pathway analysis revealed the enrichment of proteins involved in different pathways that regulate translation. Translational and proteasome inhibitor experiments revealed that these AR protein changes were attributable to modifications in translational activity. Interestingly, the effects on AR protein levels in castration-resistant PCa (CRPC) cells C4-2 or enzalutamide-resistant cells 22Rv1 were less prominent and non-existent. This outcome was similarly observed in the alteration of AR transactivation, which was suppressed in hormone-sensitive prostate cancer (HSPC) LNCaP cells by translational inhibition, akin to the effect of enzalutamide. In contrast, treatment-resistant cell lines showed only a slight change in AR transcription., Conclusion: This study suggests that in HSPC, AR activation triggers a signalling cascade that increases AR protein levels by enhancing its translation rate, thereby amplifying AR activity. However, this mechanism appears to be dysregulated in castration-resistant PCa cells., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Human immunoglobulin G (IgG) antibodies are one of the most important classes of biotherapeutic agents and undergo glycosylation at the conserved N297 site in the C H 2 domain, which is critical for IgG Fc effector functions and anti-inflammatory activity. Hence, technologies for producing authentically glycosylated IgGs are in high demand. While attempts to engineer Escherichia coli for this purpose have been described, they have met limited success due in part to the lack of available oligosaccharyltransferase (OST) enzymes that can install N- linked glycans within the QYNST sequon of the IgG C H 2 domain. Here, we identified a previously uncharacterized single-subunit OST (ssOST) from the bacterium Desulfovibrio marinus that exhibited greatly relaxed substrate specificity and, as a result, was able to catalyze glycosylation of native C H 2 domains in the context of both a hinge-Fc fragment and a full-length IgG. Although the attached glycans were bacterial in origin, conversion to a homogeneous, asialo complex-type G2 N -glycan at the QYNST sequon of the E. coli -derived hinge-Fc was achieved via chemoenzymatic glycan remodeling. Importantly, the resulting G2-hinge-Fc exhibited strong binding to human FcγRIIIa (CD16a), one of the most potent receptors for eliciting antibody-dependent cellular cytotoxicity (ADCC). Taken together, the discovery of a unique ssOST from D. marinus provides previously unavailable biocatalytic capabilities to the bacterial glycoprotein engineering toolbox and opens the door to using E. coli for the production and glycoengineering of human IgGs and fragments derived thereof.

Objecive: To investigate temporal trends in the individual workload of nuclear medicine physicians at a large tertiary care academic center between 2008 and 2023., Methods: This study analyzed the reporting workload of nuclear medicine physicians in a large tertiary care academic center in The Netherlands on 36 unique (randomly sampled) calendar days, for each year between 2008 and 2023. The average daily departmental workload (measured with relative value units) was calculated for each year between 2008 and 2023. The individual workload was calculated by dividing the average daily departmental workload in each year by the available full-time equivalent nuclear medicine physicians in each year. Mann-Kendall tests were used to assess for any temporal monotonic trends in individual workload and types of nuclear medicine procedures performed., Results: Individual workload increased significantly between 2008 and 2023 (Mann-Kendall tau of 0.611, P = 0.001). Individual workload in 2023 was 86% higher than in 2008. The use of positron emission tomography (PET) increased significantly (Mann-Kendall tau of 0.912, P < 0.001) between 2008 and 2023. The use of diagnostic scintigraphy decreased significantly in the same period (Mann-Kendall tau of -0.817, P < 0.001). The use of DEXA also showed a significant decrease (Mann-Kendall tau of -0.467, P = 0.013), but this decrease was negligible on a relative scale. The number of therapeutic procedures (Mann-Kendall tau of -0.100, P = 0.626) remained statistically stable in this period., Conclusions: Our single-center study showed that the individual workload of nuclear medicine physicians has increased significantly between 2008 and 2023, driven by the rise in PET scans. The demand for both diagnostic and therapeutic nuclear medicine procedures and associated workload is expected to keep on increasing in the foreseeable future. This workload trend should be taken into account by policymakers involved in nuclear medicine staffing planning. A healthy balance between the nuclear medicine workforce and workload is necessary to maintain the quality of care, to be able to perform other important (academic) tasks such as research, educating and training medical students and residents, and management, and to prevent physician burnout and dropout., (© 2024. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

Coastal wetlands are crucial in climate change regulation due to their capacity to act as either sinks or sources of carbon, resulting from the balance between greenhouse gas (GHG) emissions, mainly methane (CH 4 ), and soil carbon sequestration. Despite the paramount role of wetlands in climate regulation few studies investigate both aspects. The Camargue is one of the largest wetlands in Europe, yet the ways in which environmental and anthropic factors drive carbon dynamics remain poorly studied. We examined GHG emissions and soil organic carbon (SOC) stocks and accumulation rates in twelve representative wetlands, including two rice fields, to gain insights into the carbon dynamics and how it is influenced by hydrology and salinity. Mean CH 4 rates ranged between - 87.0 and 131.0 mg m -2  h -1 and the main drivers were water conductivity and redox, water table depth and soil temperature. High emission rates were restricted to freshwater conditions during summer flooding periods whereas they were low in wetlands subjected to summer drought and water conductivity higher than 10 mS cm -1 . Nitrous oxide emissions were low, ranging from - 0.5 to 0.9 mg N 2 O m -2  h -1 . The SOC stocks in the upper meter ranged from 17 to 90 Mg OC ha -1 . Our research highlights the critical role of low-saline wetlands in carbon budgeting which potentially are large sources of CH 4 but also contain the largest SOC stocks in the Camargue. Natural hydroperiods, involving summer drought, can maintain them as carbon sinks, but altered hydrology can transform them into sources. Artificial freshwater supply during summer leads to substantial CH 4 emissions, offsetting their SOC accumulation rates. In conclusion, we advocate for readjusting the altered hydrology in marshes and for the search of management compromises to ensure the compatibility of economic and leisure activities with the preservation of the inherent climate-regulating capacity of coastal wetlands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Trofinetide, the first approved treatment for Rett syndrome (RTT), is primarily excreted unchanged in the urine; therefore, it is important to assess the extent to which the exposure is affected in patients with renal impairment. Pharmacokinetic modeling overcomes the challenge of dose finding in phase 1 studies that include special populations where there is the potential for increased exposure to study drug. The objectives of this phase 1 study were to evaluate trofinetide pharmacokinetics, safety, and tolerability in a population with moderate renal impairment and normal renal function. The observed pharmacokinetic profiles were used to validate the dosing adjustments in moderate renal impairment that were previously predicted using a physiologically-based pharmacokinetic (PBPK) model., Methods: The PBPK model was first used to predict dose adjustments that are necessary to achieve similar exposure in the four stages of renal impairment (mild, moderate, severe, end stage renal disease) as in healthy controls. The predicted dose adjustment from 12 to 6 g for the moderate renal impairment category was then applied to the phase 1 clinical study. Subsequent validation of the PBPK model was achieved by comparing the model-predicted and clinically observed exposures in subjects with moderate renal impairment. In a phase 1, open-label study, trofinetide exposure was assessed in healthy (n = 10) and moderate renal impairment (n = 10) participants receiving single oral doses of 12 g or 6 g, respectively. Observed exposures [area under the blood concentration-time curve from time 0 to infinity (AUC inf ) and maximum concentration (C max )] were compared with predicted exposures from simulations in virtual healthy and moderate renal impairment populations (n = 100) to validate a PBPK model of renal impairment that had previously predicted doses across renal impairment categories., Results: Dose-normalized geometric mean ratios for C max were comparable [1.02 (90% CI 0.69-1.50)] while AUC inf was approximately two-fold higher [1.81 (90% CI 1.31-2.50)] in moderate renal impairment participants compared with healthy controls. These observed values closely aligned with predicted distributions. Treatment-emergent adverse events were reported in two (20.0%) participants with moderate renal impairment and four healthy participants (40.0%)., Conclusion: PBPK modeling of trofinetide in a virtual population with moderate renal impairment predicted a 50% dose reduction compared to individuals with normal renal function. Comparison of observed pharmacokinetic results from a phase 1 study in subjects with moderate renal impairment and matched healthy participants to the model-predicted exposures validated this dose reduction. No new safety concerns for trofinetide emerged., (© 2024. The Author(s).)

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common after traumatic events. We examined whether wrist-wearable devices could provide heart rate variability (HRV) biomarkers for recovery after traumatic stress exposure in a large socioeconomically disadvantaged cohort. Participants were enrolled in the emergency department within 72 hours after a traumatic event as part of the AURORA (Advancing Understanding of RecOvery afteR traumA) multicenter prospective observational cohort study and followed over 6 months. HRV biomarkers were derived and validated for associations with specific APNS symptoms at a point in time and changes in symptom severity over time. Sixty-four HRV characteristics were derived and validated as cross-sectional biomarkers of APNS symptoms, including pain (26), re-experiencing (8), somatic (7), avoidance (7), concentration difficulty (6), hyperarousal (5), nightmares (1), anxiety (1), and sleep disturbance (3). Changes in 22 HRV characteristics were derived and validated as biomarkers identifying changes in APNS symptoms, including reexperiencing (11), somatic (3), avoidance (2), concentration difficulty (1), hyperarousal (1), and sleep disturbance (4). Changes in HRV variables over time predicted symptom improvement (PPV 0.68-0.87) and symptom worsening (NPV 0.71-0.90). HRV biomarkers collected from wrist-wearable devices may have utility as screening tools for APNS symptoms that occur after traumatic stress exposure in high-risk populations., Competing Interests: Declaration of competing interest Dr. Neylan has received research support from NIH, VA, and Rainwater Charitable Foundation, and consulting income from Jazz Pharmaceuticals. In the last three years Dr Clifford has received research funding from the NSF, NIH and LifeBell AI, and unrestricted donations from AliveCor Inc, Amazon Research, the Center for Discovery, the Gates Foundation, Google, the Gordon and Betty Moore Foundation, MathWorks, Microsoft Research, Nextsense Inc, One Mind Foundation, and the Rett Research Foundation. Dr Clifford has financial interest in AliveCor Inc and Nextsense Inc. He also is the CTO of MindChild Medical with significant stock. These relationships are unconnected to the current work. Dr. Germine receives funding from the National Institute of Mental Health (R01 MH121617) and is on the board of the Many Brains Project. Her family also has equity in Intelerad Medical Systems, Inc. Dr. Rauch reported serving as secretary of the Society of Biological Psychiatry; serving as a board member of Community Psychiatry and Mindpath Health; serving as a board member of National Association of Behavioral Healthcare; serving as secretary and a board member for the Anxiety and Depression Association of America; serving as a board member of the National Network of Depression Centers; receiving royalties from Oxford University Press, American Psychiatric Publishing Inc, and Springer Publishing; and receiving personal fees from the Society of Biological Psychiatry, Community Psychiatry and Mindpath Health, and National Association of Behavioral Healthcare outside the submitted work. Dr. Jones has no competing interests related to this work, though he has been an investigator on studies funded by AstraZeneca, Vapotherm, Abbott, and Ophirex. Dr. Datner serves as a Medical Advisor and on the Board of Directors for Cayaba Care. Dr. Harte has no competing interest related to this work, though in the last three years he has received research funding from Aptinyx and Arbor Medical Innovations, and consulting payments from Memorial Sloan Kettering Cancer Center, Indiana University, The Ohio State University, and Dana Farber Cancer Institute. Dr. Ressler has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. Dr. Koenen's has been a paid scientific consultant for the US Department of Justice and Covington Burling, LLP over the last three years. She receives royalties from Guilford Press and Oxford University Press. In the past 3 years, Dr. Kessler was a consultant for Cambridge Health Alliance, Canandaigua VA Medical Center, Holmusk, Partners Healthcare, Inc., RallyPoint Networks, Inc., and Sage Therapeutics. He has stock options in Cerebral Inc., Mirah, PYM, and Roga Sciences. Dr. McLean has served as a consultant for Walter Reed Army Institute for Research, Arbor Medical Innovations, and BioXcel Therapeutics, Inc., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: As US hospital markets become increasingly consolidated, empirical evidence is needed on the clinical and financial impacts of mergers on care provided by rural hospitals. We identified characteristics of rural hospitals that underwent mergers or acquisitions and examined changes in profitability, clinical outcomes, and patient experience at acquired versus non-acquired rural hospitals., Methods: We identified 145 rural US hospitals that underwent merger or acquisition between 2009 and 2014 and 906 rural non-acquired control hospitals. For each acquisition year, we used a difference-in-differences design to compare that year's acquired hospitals to a randomly chosen set of non-acquired controls. Adjusted linear regression models were used to assess the relationship between acquisition and changes in profitability, patient experience, and clinical outcomes., Findings: Compared to non-acquired hospitals, acquired hospitals were more likely to be for-profit (18.6% vs. 4.6%, p<0.001) and tended to have lower total margins (-1.1% vs. 1.2%; p<0.05) despite higher average clinical volumes. Changes in acquired hospitals' total margins, patient satisfaction, and risk-adjusted 30-day mortality rates were not different than changes among control hospitals. However, acquisition was associated with lower improvement in 30-day risk-adjusted readmission rates (-0.58 percentage point [p.p.] difference-in-differences, 95% confidence interval -0.88 to -0.28 p.p., p<0.001)., Conclusions: Overall, mergers or acquisitions of rural hospitals were not associated with significant improvements in profitability, clinical outcomes, or patient experience. Policymakers may need to closely monitor rural hospital mergers in order to balance preserving access for rural patients with the consequences of health care consolidation., (© 2024 National Rural Health Association.)

In nuisance or vector mosquito management, effective sampling is a stepping stone to efficient use of resources, targeted control efforts, and successful reduction of disease transmission. Experimental evidence indicates that there are species biases for certain traps, which in turn implies that the traps used will influence the species make-up of samples collected. A comparative study between 3 CO2-baited light traps and 2 hay-infusion baited gravid traps-Centers for Disease Control and Prevention (CDC) light trap, American BioPhysics Company (ABC) light trap, Reiter-Cummings (RC) gravid trap, and a convertible gravid/light trap with a novel design-was conducted to test for species specificity of each trap type. It was found that different species of mosquitoes are more likely to be collected in greater numbers with certain traps compared to others, even between the different light traps or gravid traps. In particular, Coquillettidia perturbans tended to be collected in greater numbers with CDC light traps, Culex salinarius tended to be collected in greater numbers with the experimental convertible light traps, and Culex pipiens tended to be collected in greater numbers with the Reiters-Cummings gravid traps over the other traps included in the study (P ≤ 0.05). The overall species richness of samples was comparable among trap types, with similar performance of the new trap designs as established designs (P ≤ 0.05)., (Copyright © 2024 by The American Mosquito Control Association, Inc.)

In this essay, I utilize a historical methodology into Catholic thought on abortion, looking toward the foundational viewpoint of original sin as justification for the need to baptize infants for the sake of their salvation. Then, I highlight how abortion has developed and shifted throughout the twentieth century vis-à-vis Papal Encyclicals and Vatican II. Strikingly, there is a resounding silence on the soteriology of aborted fetuses in Canon Law. Finally, I return to the clinical context to indicate the theological tension between the Catholic Church's foundational belief on the need to baptize and their procedural ethic on the soteriology of aborted fetuses, resulting in the uncertainty of the salvation for unbaptized aborted fetuses., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fluoridoargentates(II) represent a fascinating class of silver(II) compounds with structural and magnetic similarities to cuprate superconductors. However, their synthesis is challenging, leaving their properties largely underexplored and hindering the discovery of new phases. This study introduces mechanochemistry as a novel approach for the synthesis of fluoridoargentates(II), avoiding the use of anhydrous HF or elemental fluorine and employing readily available equipment. Notably, ball milling of commercially available precursors successfully produced the long-sought-after first two examples of binary mixed-valent silver(I,II) phases, Ag I 2 Ag II F 4 (Ag 3 F 4 ) and Ag I Ag II F 3 (Ag 2 F 3 ). While the Ag I 2 Ag II F 4 phase was obtained at room temperature, the Ag I Ag II F 3 phase is metastable and required milling under cryogenic conditions. Characterization by synchrotron powder X-ray and neutron diffraction revealed that Ag I 2 Ag II F 4 crystallizes in the P 2 1 / c space group and is isostructural to β-K 2 AgF 4 . In this crystal structure, [Ag II F 2 F 4/2 ] 2- distorted octahedral units with 4 + 2 coordination, extend parallel to a -crystallographic axis giving a quasi-one-dimensional canted antiferromagnetic character, as shown by magnetic susceptibility. The triclinic perovskite Ag I Ag II F 3 phase adopts the P 1̅ space group, is isostructural to AgCuF 3 and also shows features of a one-dimensional antiferromagnet. This mechanochemical approach, also successfully applied to synthesize β-K 2 AgF 4 , is expected to expand the field of silver(II) chemistry, accelerating the search for silver analogs to cuprate superconductors and potentially extending to other cations in unusual oxidation states.

Genome-wide association studies typically evaluate the autosomes and sometimes the X Chromosome, but seldom consider the Y or mitochondrial (MT) Chromosomes. We genotyped the Y and MT Chromosomes in heterogeneous stock (HS) rats (Rattus norvegicus), an outbred population created from 8 inbred strains. We identified 8 distinct Y and 4 distinct MT Chromosomes among the 8 founders. However, only 2 types of each nonrecombinant chromosome were observed in our modern HS rat population (generations 81-97). Despite the relatively large sample size, there were virtually no significant associations for behavioral, physiological, metabolome, or microbiome traits after correcting for multiple comparisons. However, both Y and MT Chromosomes were strongly associated with the expression of a few genes located on those chromosomes, which provided a positive control. Our results suggest that within modern HS rats there are no Y and MT Chromosomes differences that strongly influence behavioral or physiological traits. These results do not address other ancestral Y and MT Chromosomes that do not appear in modern HS rats, nor do they address effects that may exist in other rat populations, or in other species., Competing Interests: Conflicts of interest RK is a scientific advisory board member, and consultant for BiomeSense, Inc., has equity and receives income. He is a scientific advisory board member and has equity in GenCirq. He is a consultant for DayTwo, and receives income. He has equity in and acts as a consultant for Cybele. He is a co-founder of Biota, Inc., and has equity. He is a cofounder of Micronoma, and has equity and is a scientific advisory board member. The terms of these arrangements have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Objective: To assess utilization and perceptions of 2D synthesized mammography (SM) for digital breast tomosynthesis (DBT) among practicing U.S. breast radiologists., Methods: An IRB-exempt 23-question anonymized survey was developed by the Society of Breast Imaging (SBI) Patient Care and Delivery Committee and emailed to practicing U.S. radiologist SBI members on October 9, 2023. Questions assessed respondents' demographics, current mammographic screening protocol, confidence interpreting SM for mammographic findings, and perceived advantages and disadvantages of SM., Results: Response rate was 13.4% (371/2771). Of 371 respondents, 208 were currently screening with DBT/SM (56.1%), 98 with DBT/SM/digital mammography (DM) (26.4%), 61 with DBT/DM (16.4%), and 4 with DM (1.1%). Most respondents felt confident using DBT/SM to evaluate masses (254/319, 79.6%), asymmetries (247/319, 77.4%), and distortions (265/318, 83.3%); however, confidence was mixed for calcifications (agreement 130/320, 40.6%; disagreement 156/320, 48.8%; neutral 34/320, 10.6%). The most frequently cited disadvantage and advantage of SM were reconstruction algorithm false-positive results (199/347, 57.4%) and lower radiation dose (281/346, 81.2%), respectively. Higher confidence and fewer disadvantages were reported by radiologists who had more SM experience, screened with DBT/SM, or exclusively used Hologic vendor (all P <.05)., Conclusion: For most survey respondents (56.1%), SM has replaced DM in DBT screening. Radiologists currently screening with DBT/SM or with more SM experience reported greater confidence in SM with fewer perceived disadvantages., (© Society of Breast Imaging 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Results from multiple recent studies support further evaluation of 3,4-methylenedioxymethamphetamine (MDMA) in conjunction with psychotherapy (i.e., MDMA-Assisted Therapy) in the treatment of post-traumatic stress disorder (PTSD). In two Phase 3 trials, MDMA-Assisted Therapy comprised a short-term, intensive psychotherapy that included three sessions directly facilitated by MDMA (referred to as "experimental sessions"), as well as a number of non-drug psychotherapy sessions. This treatment model aimed to harness the potential of MDMA to facilitate recall and processing of traumatic memories, and to increase learning in a social context, integrating "top-down" and "bottom-up" approaches to trauma-focused care. To date, the conceptual framework for this treatment has not been described in the scientific literature. This omission has contributed to misunderstandings about both the theoretical underpinnings of this modality and the therapeutic approach that emerges from it. This paper delineates the psychotherapeutic concepts, theories, and historical antecedents underlying the inner-directed approach to MDMA-Assisted Therapy for PTSD. Broadly speaking, this therapeutic framework centered the concept of the participant's inner healing intelligence as the primary agent of change, with the therapeutic relationship being the core facilitative condition fostering the participant's self-directed movement toward recovery and growth. Corollaries to this holistic, self-directed, relational, and trauma-informed framework include a non-pathologizing approach to the participant's embodied experience (including the possibility of intense emotional and somatic expression, experiences of multiplicity, suicidal ideation, and multigenerational and transpersonal experiences), as well as the therapists' own psychodynamic, somatic, and transpersonal awareness, empathic attunement, relational skillfulness, and cultural humility. The use of MDMA in conjunction with this psychotherapy platform outperformed the use of placebo with psychotherapy in Phase 2 and 3 trials, as measured by symptom reduction in participants with PTSD. However, within-group comparisons also identified significant symptom reduction in participants who did not receive MDMA, lending empirical support to the psychotherapy model itself. In addition to comparative efficacy trials, future research should investigate which elements of the conceptual framework and therapeutic approach underlie the clinical benefit in individuals with PTSD., Competing Interests: LO was employed by Lykos Therapeutics, Inc. BP and MO’a were employed by Aguazul-Bluewater, Inc. KO’D has received funding from Lykos Therapeutics for contract work as a clinical trial investigator, MDMA-Assisted Therapy Trainer/Educator, and Presenter for the June 2024 FDA Advisory Committee Hearing. Authors MA, BP, CN, CT, AM, MM, and MO’a have received funding from Lykos Therapeutics for contract work as a clinical trial investigator and as an MDMA-Assisted Therapy Trainer/Educator. The authors declare that this study received funding from Lykos Therapeutics. The funder had the following involvement in this publication: sponsorship of the the phase 2 and 3 studies of MDMA-Assisted Therapy for PTSD, review by Medical, Regulatory, and Compliance, and payment of publication fees., (Copyright © 2024 O’Donnell, Okano, Alpert, Nicholas, Thomas, Poulter, Mithoefer, Mithoefer and Ot’alora G.)

Purpose: CLN3 Batten disease (also known as juvenile neuronal ceroid lipofuscinosis) is a lysosomal storage disorder that typically initiates with retinal degeneration but is followed by seizure onset, motor decline and premature death. Patient-derived CLN3 disease induced pluripotent stem cell-RPE cells show defective phagocytosis of photoreceptor outer segment (POS). Because modifier genes are implicated in CLN3 disease, our goal here was to investigate a direct link between CLN3 mutation and POS phagocytosis defect., Methods: Isogenic control and CLN3 mutant stem cell lines were generated by CRISPR-Cas9-mediated biallelic deletion of exons 7 and 8. A transgenic CLN3Δ7-8/Δ7-8 (CLN3) Yucatan miniswine was also used to study the impact of CLN3Δ7-8/Δ7-8 mutation on POS phagocytosis. POS phagocytosis by cultured RPE cells was analyzed by Western blotting and immunohistochemistry. Electroretinogram, optical coherence tomography and histological analysis of CLN3Δ7-8/Δ7-8 and wild-type miniswine eyes were carried out at 6, 36, or 48 months of age., Results: CLN3Δ7-8/Δ7-8 RPE (CLN3 RPE) displayed decreased POS binding and consequently decreased uptake of POS compared with isogenic control RPE cells. Furthermore, wild-type miniswine RPE cells phagocytosed CLN3Δ7-8/Δ7-8 POS less efficiently than wild-type POS. Consistent with decreased POS phagocytosis, lipofuscin/autofluorescence was decreased in CLN3 miniswine RPE at 36 months of age and was followed by almost complete loss of photoreceptors at 48 months of age., Conclusions: CLN3Δ7-8/Δ7-8 mutation (which affects ≤85% of patients) affects both RPE and POS and leads to photoreceptor cell loss in CLN3 disease. Furthermore, both primary RPE dysfunction and mutant POS independently contribute to impaired POS phagocytosis in CLN3 disease.

Background: Effective interprofessional teamwork is vital for ensuring high-quality patient care, especially in emergency medicine. However, interprofessional education often fails to facilitate meaningful interaction among health care disciplines. It is therefore imperative to afford early opportunities for cultivating interprofessional teamwork skills. While in-person simulation-based training has been shown to improve performance, this is resource-intensive, especially if it involves multiple professions. Virtual reality (VR)-based training is an innovative instructional approach that demands fewer resources and offers the flexibility of location-independent learning., Objective: This study aimed to develop and evaluate the acceptance, learning outcome, and feasibility of an interprofessional team (INTEAM) training course that included a VR simulation of a neurological emergency case., Methods: This 1-group study used a pre- and posttest design to evaluate the 2-hour INTEAM training course for nursing and medical students. The course included an e-learning part, VR simulation, and debriefing. The main learning objectives were derived from the entrustable professional activity 6, namely to handle a common problem in emergency medicine (headache due to subarachnoid hemorrhage and epileptic seizure) that requires interprofessional collaboration, including a structured handover. We used validated and self-constructed questionnaires, pre- and posttests, and open questions to assess the acceptance, learning outcome, and feasibility of the course., Results: The data of 42 students (21 nursing and 21 medical students) were analyzed and showed good usability in the System Usability Scale (median 72.5, IQR 65-80). The perception of usefulness (median 6, IQR 5.8-6.9) and ease of use (median 5.9, IQR 5.1-6.3) was good among all students. There was a significant increase in the handover performance from pre- (median 8, IQR 6-9) to posttraining (median 8, IQR 7-9; z=-2.01; P=.045; r=0.33) and of the confidence in caring for patients with seizures (median 3, IQR 2-3 and median 3.5, IQR 3-4, respectively; z=-3.8; P<.001; r=0.60). In 67% (14/21) of the simulations, technical issues occurred, but all simulations could be carried out completely., Conclusions: The new INTEAM training course was well received by nursing and medical students. The handover skills and confidence in caring for patients with seizures were improved after the course. Despite technical challenges with the VR simulations, none required termination, and this demonstrates that our approach is feasible. These promising results encourage the use of VR simulations for team training in the education of nursing and medical students., (© Andrea N Neher, Rafael Wespi, Benjamin D Rapphold, Thomas C Sauter, Juliane E Kämmer, Tanja Birrenbach. Originally published in JMIR Serious Games (https://games.jmir.org).)

Purpose: Postoperative delirium (POD) in patients with obstructive sleep apnea (OSA) is associated with increased mortality and healthcare costs. In this study, we investigated the association of OSA risk, serum biomarkers for central nervous ischemia (S100B and NSE), and POD., Methods: After research ethics approval, patients completed the STOP BANG assessment before undergoing elective surgery. Blood was drawn for S100B and NSE measurement, and cognitive performance was tested using the Montreal Cognitive Assessment (MoCA) at study admission and postoperatively at discharge. Delirium assessment was performed using the Nursing Delirium Screening Scale (NuDESC) and the Confusion Assessment Method (CAM)., Results: One hundred twenty-four enrolled patients were separated into three OSA-risk groups based on STOP BANG score testing (low risk, n = 22; intermediate risk, n = 67; high risk, n = 35). Preoperative NSE values increased with OSA risk (NSE in ng/ml; mean [range]; low risk: 15.6 [9.2-44.3]; intermediate risk: 21.8 [7.6-114.1]; high risk: 29.2 [10.1-151]; p = 0.039). Postoperative MoCA and NuDESC assessments were not different between the OSA-risk groups. We found a decreasing incidence for POD with increasing OSA risk (positive CAM: low risk: 18.1%, intermediate risk: 12.0%; high risk: 11.5%, p = 0.043). However, this was no longer detectable in a complete case analysis. In patients with POD, postoperative ischemic biomarker values were not different between OSA-risk groups., Conclusion: We found a trend of decreasing POD incidence with increasing OSA risk, which was not robust in a complete case analysis. Our results possibly support the phenomenon of hypoxic preconditioning., (© 2024. The Author(s).)

Background: Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV)., Methods: A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe., Results: The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV., Conclusions: In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Importance: Compared with traditional Medicare (TM), Medicare Advantage (MA) insurers have greater financial incentives to reduce the delivery of low-value services (LVS); however, there is limited evidence at a national level on the prevalence of LVS utilization among MA vs TM beneficiaries and whether LVS utilization rates vary among the largest MA insurers., Objective: To determine whether there are differences in the rates of LVS delivered to Medicare beneficiaries enrolled in MA vs TM, overall and by the 7 largest MA insurers., Design, Setting, and Participants: This cross-sectional study included Medicare beneficiaries aged 65 years and older residing in the US in 2018 with complete demographic information. Eligible TM beneficiaries were enrolled in Parts A, B, and D, and eligible MA beneficiaries were enrolled in Part C with Part D coverage. Data analysis was conducted between February 2022 and August 2024., Exposures: Medicare plan type., Main Outcomes and Measures: The primary outcome was utlization of 35 LVS defined by the Milliman Health Waste Calculator. An overdispersed Poisson regression model was used to calculate estimated margins comparing risk-adjusted rates of LVS in TM vs MA, overall and across the 7 largest MA insurers., Results: The study sample included 3 671 364 unique TM beneficiaries (mean [SD] age, 75.7 [7.7] years; 1 502 631 female [40.9%]) and 2 299 618 unique MA beneficiaries (mean [SD] age, 75.3 [7.3] years; 983 592 female [42.8%]). LVS utilization was lower among those enrolled in MA compared with TM (50.02 vs 52.48 services per 100 beneficiary-years; adjusted absolute difference, -2.46 services per 100 beneficiary-years; 95% CI, -3.16 to -1.75 services per 100 beneficiary-years; P < .001). Within MA, LVS utilization was lower among beneficiaries enrolled in HMOs vs PPOs (48.03 vs 52.66 services per 100 beneficiary-years; adjusted absolute difference, -4.63 services per 100 beneficiary-years; 95% CI, -5.53 to -3.74 services per 100 beneficiary-years; P < .001). While MA beneficiaries enrolled in UnitedHealth, Humana, Centene, and smaller MA insurers had lower rates of LVS compared with those in TM, beneficiaries enrolled in CVS, Cigna, and Anthem showed no differences. Blue Cross Blue Shield Association plans had higher rates of LVS compared with TM., Conclusions and Relevance: In this cross-sectional study of nearly 6 million Medicare beneficiaries, utilization of LVS was on average lower among MA beneficiaries compared with TM beneficiaries, possibly owing to stronger financial incentives in MA to reduce LVS; however, meaningful differences existed across some of the largest MA insurers, suggesting that MA insurers may have variable ability to influence LVS reduction.

Sarcomere activation in striated muscle requires both thin filament-based and thick filament-based activation mechanisms. Recent studies have shown that myosin heads on the thick filaments undergo OFF to ON structural transitions in response to calcium (Ca2+) in permeabilized porcine myocardium in the presence of a small molecule inhibitor that eliminated active force. The changes in X-ray diffraction signatures of OFF to ON transitions were interpreted as Ca2+ acting to activate the thick filaments. Alternatively, Ca2+ binding to troponin could initiate a Ca2+-dependent crosstalk from the thin filament to the thick filament via interfilament connections such as the myosin binding protein-C. Here, we exchanged native troponin in permeabilized porcine myocardium for troponin containing the cTnC D65A mutation, which disallows the activation of troponin through Ca2+ binding to determine if Ca2+-dependent thick filament activation persists in the absence of thin filament activation. After the exchange protocol, over 95% of the Ca2+-activated force was eliminated. Equatorial intensity ratio increased significantly in both WT and D65A exchanged myocardium with increasing Ca2+ concentration. The degree of helical ordering of the myosin heads decreased by the same amount in WT and D65A myocardium when Ca2+ concentration increased. These results are consistent with a direct effect of Ca2+ in activating the thick filament rather than an indirect effect due to Ca2+-mediated crosstalk between the thick and thin filaments., (© 2024 Mohran et al.)

Background: The disease severity index (DSI) for inflammatory bowel disease (IBD) combines measures of disease phenotype, inflammatory activity, and patient-reported outcomes. We aimed to validate the DSI and assess its utility in predicting a complicated IBD course., Methods: A multicenter cohort of adults with IBD was recruited. Intraclass correlation coefficients (ICCs) and weighted Kappa assessed inter-rater reliability. Cronbach's alpha measured internal consistency of DSI items. Spearman's rank correlations compared the DSI with endoscopic indices, symptom indices, quality of life, and disability. A subgroup was followed for 24 months to assess for a complicated IBD course. Area under the receiver operating characteristics curve (AUROC) and multivariable logistic regression assessed the utility of the DSI in predicting disease progression., Results: Three hundred and sixty-nine participants were included (Crohn's disease [CD], n = 230; female, n = 194; mean age, 46 years [SD, 15]; median disease duration, 11 years [interquartile range, 5-21]), of which 171 (CD, n = 99; ulcerative colitis [UC], n = 72) were followed prospectively. The DSI showed inter-rater reliability for CD (ICC 0.93, n = 65) and UC (ICC 0.97, n = 33). The DSI items demonstrated inter-rater agreement (Kappa > 0.4) and internal consistency (CD, α > 0.59; UC, α > 0.75). The DSI was significantly associated with endoscopic activity (CDn=141, r = 0.65, P < .001; UCn=105, r = 0.80, P < .001), symptoms (CDn=159, r = 0.69, P < .001; UCn=132, r = 0.58, P < .001), quality of life (CDn=198, r = -0.59, P < .001; UCn=128, r = -0.68, P < .001), and disability (CDn=83, r = -0.67, P < .001; UCn=52, r = -0.74, P < .001). A DSI of 23 best predicted a complicated IBD course (AUROC = 0.82, P < .001) and was associated with this end point on multivariable analyses (aOR, 9.20; 95% confidence interval, 3.32-25.49)., Conclusions: The DSI reliably encapsulates factors contributing to disease severity and accurately prognosticates the longitudinal IBD course., (© 2023 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

HIV-1 Nef mediates immune evasion and viral pathogenesis in part through downregulation of cell surface cluster of differentiation 4 (CD4) and major histocompatibility complex class I (MHC-I) on infected cells. While Nef function of circulating viral populations found early in infection has been associated with reservoir size in early-treated cohorts, there is limited research on how its activity impacts reservoir size in people initiating treatment during chronic infection. In addition, there is little research on its role in persistence of viral variants during long-term antiretroviral therapy (ART). Phylogenetically distinct nef genes (n=82) with varying estimated times of reservoir entry were selected from viral outgrowth variants stimulated from the reservoir of South African women living with HIV who initiated ART during chronic infection (n=16). These nef genes were synthesized and used in a pseudovirus infection assay that measures CD4 and MHC-I downregulation via flow cytometry. Downregulation measures were compared to the size of the replication-competent viral reservoir (RC-VR), estimated by quantitative viral outgrowth assay (QVOA) at 5 years after treatment initiation, as well as proviral survival time. Maximum Nef-mediated MHC-I downregulation was significantly associated with RC-VR size (p=0.034), but this association was not observed for CD4 downregulation. Conversely, we did not find a consistent association between intraparticipant MHC-I or CD4 downregulation and the variant timing of entry into the reservoir. These data support a role for Nef-mediated MHC-I downregulation in determining RC-VR size, but more work is needed to determine Nef's role in the survival of individual viral variants over time.

Medicare Advantage (MA) plans are increasingly enrolling veterans. Because MA plans receive full capitated payments regardless of whether or not veterans use Medicare services, the federal government can incur substantial duplicative, wasteful spending if veterans in MA plans predominantly seek care through the Veterans Health Administration (VHA) system. The recent growth of MA plans that disproportionately enroll veterans could further exacerbate such wasteful spending. Using national data, we found that veterans increasingly enrolled in MA between 2016 and 2022, including in a growing number of MA plans in which 20 percent or more of the enrollees were veterans. Notably, about one in five VHA enrollees in these high-veteran MA plans did not incur any Medicare services paid by MA within a given year-a rate 2.5 times that of VHA enrollees in other MA plans and 5.7 times that of the general MA population. Meanwhile, VHA enrollees in high-veteran MA plans were significantly more likely to receive VHA-funded care. In 2020, the Centers for Medicare and Medicaid Services paid more than $1.32 billion to MA plans for VHA enrollees who did not use any Medicare services, with 19.1 percent going to high-veteran MA plans.

Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL and/or platelets <100 G/L and/or leukopenia (white blood cell count <4 G/L) and/or neutrophils <1.5 G/. Among the 2313 patients <18 years old enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis: 1 year); median follow-up lasted 8.1 years. Bone-marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis or myelofibrosis but never confirm the diagnosis. Fifty-eight (17%) patients developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 G/L, respectively) and severe HI (SHI; ≤7 g/dL and ≤20 G/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities and outcomes (respective MHI and SHI 10-year survival rates: 98% and 73%). Since 1998, mortality first declined with combination Cladribine-cytarabine therapy, and then with mitogen-activated protein-kinase inhibitors since 2014. Forty-one (12%) patients developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, as it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted-therapy approaches would be better adapted for these patients, while MHI can be managed with classic therapies., (Copyright © 2024 American Society of Hematology.)

Objective: Spinal cord ischemia (SCI) remains one of the most devastating complications in both open and endovascular stent graft repair of thoracoabdominal aortic aneurysms. The endovascular aortic aneurysm repair (EVAR) can be either thoracic (TEVAR) when it targets the thoracic aortic aneurysm or fenestrated branched when repair involves the visceral and/or renal arteries. Even though EVAR interventions are less invasive than open repair, they are still associated with a significant risk of SCI. The current primary strategy to prevent SCI after TEVAR is to increase and/or maintain spinal cord perfusion pressure (blood flow) by increasing the mean arterial pressure while simultaneously draining CSF. Although the benefit of CSF drainage in EVAR procedures remains uncertain, it provides an opportunity to study the changes in cytokine and oxidative stress markers that may signal the pathophysiology of SCI following EVAR. The aim of this study was to evaluate the temporal relationship between stent deployment and CSF cytokine and oxidative stress marker levels as predictors of delayed SCI in patients undergoing an EVAR procedure., Methods: There were 16 EVAR cases across 15 patients enrolled in this study, with 1 patient undergoing the procedure twice 1 year apart. The levels of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG], glial fibrillary acidic [GFAP], and lactic acid) and proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin (IL)-6, and IL-1β) and antiinflammatory (IL-4) markers were quantified at different time points between 0 and 48 hours after EVAR by enzyme-linked immunosorbent assay. The changes in protein levels of both oxidative stress and inflammatory markers were expressed as fold change from the time of the lumbar drain insertion prior to surgery., Results: Following the EVAR procedure, 8-OHdG resulted in the highest upregulation at later time points postoperatively (48 hours) and this increase was positively correlated with TNF-α level. The data also revealed that IL-6 peaked during the stent deployment intervention and this pattern of expression was positively correlated with the expression of lactic acid. No significant changes were noted in the expression levels of GFAP, lactic acid, and IL-1β., Conclusions: There appears to be a temporal relationship between lumbar CSF drainage and CSF cytokines and oxidative stress markers that may help 1) identify patients at risk for developing delayed SCI and 2) modify patient management to prevent the damage from delayed SCI.

Technological advancements have enabled the extended investigation, development, and application of computational approaches in various domains, including health care. A burgeoning number of diagnostic, predictive, prognostic, and monitoring biomarkers are continuously being explored to improve clinical decision making in neuro-oncology. These advancements describe the increasing incorporation of artificial intelligence (AI) algorithms, including the use of radiomics. However, the broad applicability and clinical translation of AI are restricted by concerns about generalisability, reproducibility, scalability, and validation. This Policy Review intends to serve as the leading resource of recommendations for the standardisation and good clinical practice of AI approaches in health care, particularly in neuro-oncology. To this end, we investigate the repeatability, reproducibility, and stability of AI in response assessment in neuro-oncology in studies on factors affecting such computational approaches, and in publicly available open-source data and computational software tools facilitating these goals. The pathway for standardisation and validation of these approaches is discussed with the view of trustworthy AI enabling the next generation of clinical trials. We conclude with an outlook on the future of AI-enabled neuro-oncology., Competing Interests: Declaration of interests NG reported Blue Earth Diagnostics honorarium and Telix Pharmaceuticals participation on Advisory Board. TCB reported consulting fees from Microvention and fees for speakers bureaus of Siemens Healthineers, Bayer, and Medtronic. HJWLA reported receiving grants from the National Institutes of Health, European Union, and the US Department of Veterans Affairs, and consulting fees from Onc.AI, Sphera, and Love Health. WLB reported receiving an honorarium from Stryker. PL reported receiving a grant from the German Research Foundation. RJ reported receiving a grant from AIRS Medical. JML reported receiving grants from the National Institutes of Health, Department of Defense, and GE Healthcare. JCT reported receiving grants from Novocure and Munich Surgical Imaging; royalties from Springer Publishing; consulting fees from Novartis; an honorarium from the Italian Society for Neurology; and support to attend meetings of the Belgian Association for Neurooncology and Glioma Meeting Athens 2023. MV reported receiving grants from Infuseon Therapeutics, Oncosynergy, and DeNovo Pharma; drug delivery device royalties; consulting fees from Servier Pharma and BioDexa Pharma; and holds patents for drug delivery devices. RYH reported consulting fees from Nuvation Bio and Vysioneet. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The development, application, and benchmarking of artificial intelligence (AI) tools to improve diagnosis, prognostication, and therapy in neuro-oncology are increasing at a rapid pace. This Policy Review provides an overview and critical assessment of the work to date in this field, focusing on diagnostic AI models of key genomic markers, predictive AI models of response before and after therapy, and differentiation of true disease progression from treatment-related changes, which is a considerable challenge based on current clinical care in neuro-oncology. Furthermore, promising future directions, including the use of AI for automated response assessment in neuro-oncology, are discussed., Competing Interests: Declaration of interests JML received grants from the National Institutes of Health (NIH; P01CA118816), Department of Defense, and GE Healthcare. WLB reported receiving an honorarium from Stryker. PL received a grant from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; 428090865/SPP 2177). TCB received consulting fees from Microvention; is on speakers bureaus for Siemens Healthineers, Bayer, and Medtronic; and received grants from the Medical Research Council (MR/W021684/1) and the Wellcome Engineering and Physical Sciences Research Council Centre for Medical Engineering (WT 203,148/Z/16/Z). HJWLA received grants from the NIH (U24CA194354, U01CA190234, U01CA209414, R35CA22052, and U54CA27451), the European Research Council (866504), and the US Department of Veterans Affairs; and consulting fees from Onc.AI, Sphera, and Love Health. JCT received grants from Novocure and Munich Surgical Imaging; royalties from Springer Publishing; consulting fees from Novartis; an honorarium from the Italian Society for Neurology; and support to attend meetings of the Belgian Association for Neurooncology and Glioma Meeting Athens 2023. RJ received a grant from AIRS Medical. MAV received grants from Infuseon Therapeutics, Oncosynergy, and DeNovo Pharma; consulting fees from Servier Pharma and BioDexa Pharma; and holds patents and received royalties for drug delivery devices. RYH reported consulting fees from Nuvation Bio and Vysioneet. NG received a grant from the DFG (428090865/SPP 2177); honorarium from Blue Earth Diagnostics; and participated on an advisory board for Telix Pharmaceuticals. CD received grants from the NIH (U24CA189523, UL1TR001878, and R01NS042645). SB received grants from the NIH (U01CA242871 and UL1TR001878). RRC received grants from the NIH. MI received grants from the Musella Foundation Grant and the R&D Pilot Award from the University of Wisconsin-Madison. PT received grants from the NIH (U01CA248226, R01CA264017, and U01CA248226), the Veterans Affairs (VA) Merit Award (1I01BX005842-01A2), the DOD/PRCRP Career Development Award (W81XWH-18-1-0404), the Dana Foundation David Mahoney Neuroimaging Program, the V Foundation Translational Research Award, the Johnson & Johnson WiSTEM2D Award, the Ohio Third Frontier Technology Validation Fund, the Musella Foundation Grant, and the R&D Pilot Award from the University of Wisconsin-Madison. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Multidisciplinary Shock Teams have improved clinical outcomes for cardiogenic shock, but their implementation costs have not been studied. This study's objective was to compare costs between patients treated with and without a Shock Team and determine if the team's implementation is cost-effective compared with standard of care., Methods: We examined patients with refractory cardiogenic shock treated with or without a Shock Team at a tertiary academic hospital from 2009 to 2018. Real-world hospital data were used to compare costs and outcomes, including survival at discharge, 1-year survival, and quality-adjusted life years gained at 1 year. Incremental cost-effectiveness ratios were calculated over a 1-year time horizon, with parameter uncertainty evaluated through probabilistic sensitivity analysis using 1000 second-order Monte Carlo simulations., Results: The study involved 244 patients, with 123 treated by the Shock Team and 121 receiving standard of care. Patients were predominantly male (77.5%), with a mean age of 58 (18-92) years. The Shock Team approach improved survival rates at hospital discharge and 1-year follow-up (61.0% versus 47.9%; P =0.04 and 55.0% versus 40.5%; P =0.03, respectively). The incremental cost-effectiveness ratio for increases in survival probability at discharge for the multidisciplinary Shock Team compared with standard of care was $102 088. The incremental cost-effectiveness ratio for increases in survival probability at 1-year was estimated at $96 152 and at $127 862 per 1 quality-adjusted life year gained. Probabilistic sensitivity analysis estimates showed that the Shock Team was cost-effective in the majority of simulations using a willingness-to-pay threshold of $150 000, while it was also dominant in almost one-third of the simulations., Conclusions: The Shock Team approach for treating refractory cardiogenic shock may be a cost-effective alternative to traditional standard of care. These findings can help prioritize the implementation of Shock Team initiatives to further improve cardiogenic shock outcomes., Competing Interests: Dr Drakos serves as a consultant for Abbott Laboratories and Pfizer and has received research support from Novartis and Merck. Dr Ohsfeldt reports grant support from Bayer. Dr. Tonna is the Chair of the Extracorporeal Life Support Organization Registry. E.S. Davis serves as a consultant for Abbott Laboratories and Medtronic Inc. The other authors report no conflicts.

During ovulation, an egg is released from an ovarian follicle, ready for fertilization. Ovulation occurs inside the body, impeding direct studies of its progression. Therefore, the exact mechanisms that control ovulation have remained unclear. Here we devised live imaging methods to study the entire process of ovulation in isolated mouse ovarian follicles. We show that ovulation proceeds through three distinct phases, follicle expansion (I), contraction (II) and rupture (III), culminating in the release of the egg. Follicle expansion is driven by hyaluronic acid secretion and an osmotic gradient-directed fluid influx into the follicle. Then, smooth muscle cells in the outer follicle drive follicle contraction. Follicle rupture begins with stigma formation, followed by the exit of follicular fluid and cumulus cells and the rapid release of the egg. These results establish a mechanistic framework for ovulation, a process of fundamental importance for reproduction., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Many magic tricks rely solely on vision, but there are few, if any, that rely on auditory perception alone. Here, we question why this is so and argue that research focusing on this issue could provide deeper theoretical insights into the similarities and differences between our senses., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Cascade testing for hereditary cancer syndromes allows relatives to estimate cancer risk and pursue prevention and early detection strategies. The current paradigm relies on patient coordinated care, resulting in only one-third of relatives successfully completing testing. Studies suggest that team-based approaches, where clinicians facilitate testing, can increase uptake. As institutions consider implementing such programs, understanding patient characteristics associated with interest is crucial for resource allocation. We aim to assess interest in clinician-facilitated testing and evaluate barriers., Methods: Patients with cancer-associated pathogenic variants seen at a gynecologic oncology clinic were offered clinician-facilitated cascade testing. Patient interest and demographic variables were recorded and patients that declined were interviewed regarding the decision., Results: From 11/2023-4/2024, 139 patients were offered clinician-facilitated cascade testing. Median patient age was 43 years (IQR 17), 97 (69.8 %) self-identified as White and 101 (72.7 %) as non-Hispanic. Fifty-six (40.3 %) patients harbored a BRCA1 pathogenic variant, 37 (26.6 %) BRCA2, and 46 (33.1 %) other cancer-associated genes. Fifty-seven (41.0 %) patients expressed interest in the intervention. Interested patients were more likely to have been diagnosed in the prior year vs. patients who were not interested on univariate (OR 4.6, 95 % CI 2.0-10.2, P = 0.0002) and multivariable analyses (adjusted OR 3.8, 95 % CI 1.622-9.009, P = 0.0022)., Conclusions: Our study demonstrates that patients are almost five time more likely to be interested in cascade genetic testing within the first year of diagnosis of a pathogenic variant. Given the utility of such programs and their resource requirements, targeting this population could maximize effectiveness and uptake of cascade services., Competing Interests: Declaration of competing interest The authors have no financial or personal conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)