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Abstract Objective To report the interim results of the PERPRISE study (Study 509; NCT04202159), which is evaluating perampanel as the only adjunctive anti‐seizure medication (ASM) in adults with focal to bilateral tonic–clonic seizures (FBTCS) or primary generalized tonic–clonic seizures (GTCS). Methods PERPRISE is an ongoing 12‐month multicenter, prospective, observational, non‐interventional study of perampanel in a real‐world setting in Germany. Patients are aged ≥18 years with FBTCS or GTCS due to focal or idiopathic generalized epilepsy. Perampanel, as an adjunctive therapy to ASM monotherapy (‘add‐on therapy’) or as a substitute for one ASM in dual therapy (‘substitution therapy’), is prescribed in line with its SmPC. The Interim Analysis Set comprises the first 100 patients who received ≥1 dose of perampanel and attended or discontinued prior to the ~6‐month visit. Interim endpoints include retention rate, measures of effects on seizure frequency, and treatment‐emergent adverse events (TEAEs). Results One hundred patients were included in the Interim Analysis Set (add‐on, n = 43 [43.0%]; substitution, n = 55 [55.0%]; unknown, n = 2). The 6‐month retention rate was 78.0% (add‐on, 83.7%; substitution, 72.7%). For the overall population with GTCS and/or FBTCS, seizure‐freedom rate at 6 months was 58.8% (add‐on, 72.2%; substitution, 47.9%) and 50% responder rate at 6 months was 82.6% (add‐on, 89.2%; substitution, 76.6%). Retention rates and seizure outcomes were better with perampanel as an early‐line treatment than as a late‐line treatment. TEAEs were reported by 48 patients (48.0%), most commonly dizziness (n = 9), fatigue (n = 7), and irritability (n = 7). Sixteen patients (16.0%) withdrew from perampanel treatment due to TEAEs. Significance The interim analysis of PERPRISE offers insight into the real‐world use of perampanel in Germany, including for the first time, clinical practice data from patients with GTCS and switching ASMs within a dual therapy. Further data from PERPRISE will be of value to inform clinical decision‐making in this patient cohort. Plain Language Summary Patients with epilepsy often take more than one medication for seizure control. This 12month study looked at patients in Germany receiving perampanel as only add‐on medication. The interim analysis shows, that at 6 months, over 70% of the 100 patients continued to use perampanel; 59% experienced no seizures during treatment with perampanel, and in 83%, seizure frequency was reduced by half. Side effects occurred in 48% of patients (most commonly dizziness, fatigue, and irritability) and caused 16% to withdraw from the study. Overall, perampanel was a suitable as only add‐on medication for patients with epilepsy.

Abstract Aims Many heart failure (HF) patients do not receive optimal guideline‐directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator‐initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open‐label trial to evaluate efficacy and safety of DC in patients on HF treatment. Methods and results Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home‐measured vital signs), (ii) patient education via an e‐learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. Conclusions The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient‐ and clinician‐targeted DC for GDMT optimization.

Key Clinical Message Serum carbohydrate antigen 19‐9 (CA19‐9) is used for recurrence surveillance in patients with resected pancreatic ductal adenocarcinoma (PDAC). This report describes the association of increasing CA19‐9 in a male PDAC survivor with presence of prostatic hyperplasia. Unexplained elevation of CA19‐9 in male PDAC survivors might be attributable to benign prostatic conditions.

Abstract Background Investment in mobile devices to support primary or elementary education is increasing and must be informed by robust evidence to demonstrate impact. This systematic review of randomised controlled trials sought to identify the overall impact of mobile devices to support literacy and numeracy outcomes in mainstream primary classrooms. Objectives The aim of this systematic review was to understand how mobile devices are used in primary/elementary education around the world, and in particular, determine how activities undertaken using mobile devices in the primary classroom might impact literacy and numeracy attainment for the pupils involved. Within this context, mobile devices are defined as tablets (including iPads and other branded devices), smartphones (usually those with a touchscreen interface and internet connectivity) and handheld games consoles (again usually with touchscreen and internet‐enabled). The interventions of interest were those aimed at improving literacy and/or numeracy for children aged 4–12 within the primary/elementary school (or equivalent) classroom. Specifically, the review aimed to answer the following research questions: ‐ What is the effect of mobile device integration in the primary school classroom on children's literacy and numeracy outcomes? ‐ Are there specific devices which are more effective in supporting literacy and numeracy? (Tablets, smartphones, or handheld games consoles) ‐ Are there specific classroom integration activities which moderate effectiveness in supporting literacy and numeracy? ‐ Are there specific groups of children for whom mobile devices are more effective in supporting literacy and numeracy? (Across age group and gender). ‐ Do the benefits of mobile devices for learning last for any time beyond the study? ‐ What is the quality of available evidence on the use of mobile devices in primary/elementary education, and where is further research needed in this regard? An Expert Advisory Group supported the review process at key stages to ensure relevance to current practice. Search Methods The search strategy was designed to retrieve both published and unpublished literature, and incorporated relevant journal and other databases with a focus on education and social sciences. Robust electronic database searches were undertaken (12 databases, including APA PsychInfo, Web of Science, ERIC, British Education Index and others, and relevant government and other websites), as well as a hand‐search of relevant journals and conference proceedings. Contact was also made with prominent authors in the field to identify any ongoing or unpublished research. All searches and author contact took place between October and November 2020. The review team acknowledges that new studies will likely have emerged since and are not captured at this time. A further update to the review in the future is important and would build on the evidence reflected here. Selection Criteria The review included children within mainstream primary/elementary/kindergarten education settings in any country (aged 4–12), and interventions or activities initiated within the primary school classroom (or global equivalent) that used mobile devices (including tablets, smartphones, or hand‐held gaming devices) to intentionally support literacy or numeracy learning. In terms of study design, only Randomised Controlled Trials were included in the review. Data Collection and Analysis A total of 668 references were identified through a robust search strategy including published and unpublished literature. Following duplicate screening, 18 relevant studies, including 11,126 participants, 14 unique interventions, and 46 relevant outcome measures were synthesised using Robust Variance Estimation and a random effects meta‐analysis model. Risk of Bias assessment was undertaken by three reviewers using the ROB2 tool to assess the quality of studies, with 13 studies rated as having some concerns, and 5 as having high risk of bias. Qualitative data was also extracted and analysed in relation to the types of interventions included to allow a comparison of the key elements of each. Main Results A positive, statistically significant combined effect was found (Cohen's d = 0.24, CI 0.0707 to 0.409, p

Abstract The mechanisms driving catchment nitrogen storage and release operate at multiple spatiotemporal scales. Consequently, analyses grounded in different observational timescales can yield discrepant interpretations of underlying mechanisms. To assess the consistency of nitrate export patterns between event‐ and inter‐annual scales, we evaluated multiple years of high‐frequency observations of nitrate concentrations (C) and discharge (Q) including 3,480 discrete discharge events from 28 dominantly agricultural catchments. We observed consistent and often drastic divergence between long‐term and median event‐specific C‐Q patterns. Most catchments showed long‐term enrichment patterns (positive C‐Q slope), but events were, on average, more chemostatic (close‐to‐zero C‐Q slopes). C‐Q slope variability was high for small events but decreased with event magnitude, approaching chemostatic patterns during the largest storms, yielding compelling evidence against nitrate source limitation. We conclude that nitrate export patterns observed at different temporal scales and event magnitudes are controlled by different processes, therefore embedding complementary information.

Abstract Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing “immune classes” among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune “risk factors.” By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Abstract Background Cardiovascular diseases with increased right ventricular (RV) afterload induce RV diastolic and systolic dysfunction, and myocardial fibrosis in humans. Studies in dogs with pulmonary stenosis (PS) evaluating RV diastolic function and markers of myocardial fibrosis are lacking. Hypothesis/Objectives Dogs with PS have echocardiographic evidence of RV diastolic and systolic dysfunction and increased serum concentrations of galectin‐3 (Gal‐3), a surrogate biomarker for myocardial fibrosis. Animals Forty client‐owned dogs (10 controls, 30 with PS). Methods Prospective study. All dogs had systemic blood pressure measurement, serum biochemical analysis, echocardiography, and measurement of serum Gal‐3 concentration performed. Results Variables of RV diastolic function were obtained in 39/40 dogs. Trans‐tricuspid flow velocity in early diastole to trans‐tricuspid flow velocity in late diastole ratios (RV E/A) were lower (P

Abstract Intravenous remdesivir (RDV) is US Food and Drug Administration–approved for hospitalized and nonhospitalized individuals with coronavirus disease 2019. RDV undergoes intracellular metabolic activation to form the active triphosphate, GS‐443902, and other metabolites. Alternative administration routes, including localized pulmonary delivery, can lower systemic exposure and maximize exposure at the site of action. This study evaluated the pharmacokinetics (PK) and safety of inhaled RDV in healthy adults. This phase Ia, randomized, placebo‐controlled study evaluated inhaled RDV in healthy participants randomized 4:1 to receive RDV or placebo as single doses (4 cohorts) or multiple once‐daily doses (3 cohorts). Doses in cohorts 1–6 were administered as an aerosolized solution for inhalation through a sealed facemask; doses in cohort 7 were administered as an aerosolized solution for inhalation through a mouthpiece. Safety was assessed throughout the study. Seventy‐two participants were enrolled (inhaled RDV, n = 58 and placebo, n = 14). Following single RDV doses, RDV, GS‐704277, and GS‐441524 plasma PK parameters indicated dose‐proportional increases in area under the concentration‐time curve (AUC) extrapolated to infinite time, AUC from time zero to last quantifiable concentration, and maximum observed concentration. Analyte plasma concentrations after multiple RDV doses were consistent with those for single‐dose RDV. Analyte plasma exposures were lower when RDV was administered with a mouthpiece versus a sealed facemask. The most common adverse events included nausea, dizziness, and cough. Single‐ and multiple‐dose inhaled RDV exhibited linear and dose‐proportional plasma PK. Administration of RDV via inhalation was generally safe and well‐tolerated.

Key Clinical Message Virtual height exposure coupled with motion capture is feasible to elicit changes in spatiotemporal, kinematic, and kinetic gait parameters in a child with cerebral palsy and should be considered when investigating gait in real‐world‐scenarios.

Abstract While aquaculture is increasingly considered a globally important source of protein, growing fish for human consumption is not new. Indigenous aquaculture systems, such as loko i‘a (fishponds), were successfully implemented in ancient Hawai‘i and represent a technological advancement designed to sustain a growing human population while maintaining—instead of supplanting—natural ecosystem function in the process of increasing food availability. Biocultural restoration efforts in Hawai‘i, aimed at revitalizing Indigenous stewardship, have included restoration of loko i‘a to sustainably increase the availability of local seafood. While it is clear from historical accounts that loko i‘a can augment fish within estuaries, their role as a nursery ground that supplements surrounding fish populations and fisheries harvest (i.e., providing spillover) remains unstudied in the current literature. This study aimed to test the extent to which loko i‘a restoration can supplement fish populations and fisheries harvest both inside the loko i‘a and in the surrounding waters. A food web model was constructed representing nutrients, phytoplankton, fish, and fisheries in three distinct habitats. The model, set in Kāne‘ohe Bay, O‘ahu, Hawai‘i, revealed that there were interactive effects of the area under loko i‘a management, bay fishing effort, and fish dispersal rates on fish density and fisheries harvest. We found that increasing the area under loko i‘a management not only increased loko i‘a fish density and fisheries harvest but also created the potential to supplement bay fish populations and fisheries harvest under certain scenarios. We also identified a trade‐off whereby at high fish dispersal rates, a larger area under loko i‘a management provided maximal benefits to the bay fish population and fisheries harvest, while at low fish dispersal rates, a smaller area under loko i‘a management was more beneficial to bay fish populations and harvest. As expected, loko i‘a also created a surplus of fish within the pond. Our results support the idea that restoration of Indigenous aquaculture systems can positively impact conservation efforts and food security by increasing local fish availability, through both direct production and supplementation of surrounding fish stocks.

Abstract The antibody‐drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) model, developed using dosing data from four clinical TV studies, was used to estimate individual exposure and explore safety and efficacy exposure‐response (ER) relationships. Because PK analysis showed no appreciable accumulation of TV and monomethyl auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted average concentrations from time zero until end of the cycle in which an event occurred (CavgLast) were used for ER analyses. The probability of achieving objective response increased significantly as the ADC cycle 1 maximum serum concentration (Cmax) increased. The probability of treatment‐related adverse events (AEs) leading to dose modification increased significantly as ADC cycle 1 area under the concentration‐time curve (AUC) increased. Number of grade 2+ ocular AEs increased significantly as ADC cycle 1 AUC, Cmax, and ADC CavgLast increased. MMAE cycle 1 AUC predicted risk of serious treatment‐related AEs. The relationship between ADC exposure and efficacy end points suggests ADC treatment was associated with clinically meaningful response across the observed exposures; greater exposure was associated with increased efficacy. The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC.

Abstract Full exhaustion in specific energy/energy density of state‐of‐the‐art LiNixCoyMnzO2 (NCM)‐based Li‐ion batteries (LIB) is currently limited for reasons of NCM stability by upper cut‐off voltages (UCV) below 4.3 V. At higher UCV, structural decomposition triggers electrode crosstalk in the course of enhanced transition metal dissolution and leads to severe specific capacity/energy fade; in the worst case to a sudden death phenomenon (roll‐over failure). The additive lithium difluorophosphate (LiDFP) is known to suppress this by scavenging dissolved metals, but at the cost of enhanced toxicity due to the formation of organofluorophosphates (OFPs). Addition of film‐forming electrolyte additives like vinylene carbonate (VC) can intrinsically decrease OFP formation in thermally aged LiDFP‐containing electrolytes, though the benefit of this dual‐additive approach can be questioned at higher UCVs. In this work, VC is shown to decrease the formation of potentially toxic OFPs within the electrolyte during cycling at conventional UCVs but triggers OFP formation at higher UCVs. The electrolyte contains soluble VC‐polymerization products. These products are formed at the cathode during VC oxidation (and are found within the cathode electrolyte interphase (CEI), suggesting an OFP electrode crosstalk of VC decomposition species, as the OFP‐precursor molecules are shown to be formed at the anode.

Background We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high‐sensitivity cardiac troponin T, N‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long‐term mortality risk. Methods and Results BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high‐frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker‐based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all‐cause death were evaluated using accelerated failure time models (median follow‐up, 9.1 years; 141 deaths). Three biomarker‐based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long‐term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44–0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39–1.32; P=0.281) compared with patients with a repeat ACS. Conclusions Patients with subphenotypes of post‐ACS with different all‐cause mortality risks during long‐term follow‐up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Abstract Chronic nonbacterial osteomyelitis (CNO) is a rare disease spectrum affecting children and adults. Adult CNO may occur as isolated bone inflammation, or with a broad range of extraskeletal features. CNO pathophysiology, including the key drivers of inflammation, remains largely unknown. For pediatric CNO, a role for pro‐inflammatory cytokine dysregulation has been proposed, but studies in adults are scarce. We therefore provide immunological characterization of adult CNO. Cross‐sectional study in our referral center including adult CNO patients (n = 172) and healthy controls (n = 65). Inflammation parameters and systemic inflammatory based scores(SIBS, including neutrophil/lymphocyte ratio [NLR] and systemic immune inflammation index [SII]) were compared between groups. Cytokine expression was explored with electrochemiluminescent immunoassays in 33 patients, eight healthy controls and 21 osteoporosis patients. Routine inflammation markers were higher in patients than in controls, but generally remained within reference range. Systemic inflammation was more pronounced in patients with additional vertebral involvement as compared to those osteitis in the anterior chest wall alone, in patients with comorbid pustulosis palmoplantaris or psoriasis, and in patients with strongly rather than moderately increased lesional uptake on nuclear imaging. SII was elevated in CNO patients too, but NLR was not. Cytokine expression was generally nondifferential between patients and both control groups, and patients displayed low absolute concentrations of pro‐inflammatory cytokines. In this adult CNO cohort, systemic inflammation was generally subtle, but more pronounced in patients with vertebral lesions, associated skin disease, and strongly increased uptake on nuclear imaging. SII was increased in patients compared to healthy controls. Contrasting pediatric studies, we found no increased expression of the pro‐inflammatory cytokines that have been proposed to drive the inflammatory cascade, like interleukin‐6, ‐8, and ‐17 (IL‐6, IL‐8, and IL‐17), and tumor necrosis α (TNF‐α). Further studies are needed to evaluate the use of SII in diagnosis and monitoring of CNO, and elucidate the role of cytokine dysregulation in adult disease. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

ABSTRACT Introduction Subclinical epileptiform activity (SEA) and sleep disturbances are frequent in Alzheimer's disease (AD). Both have an important relation to cognition and potential therapeutic implications. We aimed to study a possible relationship between SEA and sleep disturbances in AD. Methods In this cross‐sectional study, we performed a 24‐h ambulatory EEG and polysomnography in 48 AD patients without diagnosis of epilepsy and 34 control subjects. Results SEA, mainly detected in frontotemporal brain regions during N2 with a median of three spikes/night [IQR1–17], was three times more prevalent in AD. AD patients had lower sleep efficacy, longer wake after sleep onset, more awakenings, more N1%, less REM sleep and a higher apnea‐hypopnea index (AHI) and oxygen desaturation index (ODI). Sleep was not different between AD subgroup with SEA (AD‐Epi+) and without SEA (AD‐Epi–); however, compared to controls, REM% was decreased and AHI and ODI were increased in the AD‐Epi+ subgroup. Discussion Decreased REM sleep and more severe sleep‐disordered breathing might be related to SEA in AD. These results could have diagnostic and therapeutic implications and warrant further study at the intersection between sleep and epileptiform activity in AD.

Abstract The Kunming‐Montreal Global Biodiversity Framework (GBF) calls for a 50% reduction in rates of invasive alien species establishment by 2030. However, estimating changes in rates of introduction and establishment is far from straightforward, particularly on a national scale. Variation in survey effort over time, the absence of data on survey effort, and aspects of the invasion process itself interact in ways that make rate estimates from naive models of invasion trends inaccurate. To support progress toward robust global and national reporting against the GBF invasions target, we illustrate this problem using a combination of simulations, and global and national scale case studies. We provide recommendations and a clear set of steps that are needed for progress. These include routine collection of survey effort data as part of surveillance and monitoring protocols and working closely with researchers to develop meaningful estimates of change in biological invasions. Better awareness of this challenge and investment in developing robust approaches will be required from Parties if progress on Target 6 of the GBF is to be tracked and achieved.

Abstract Many insects, including several orthopterans, undergo dramatic changes in body coloration during ontogeny. This variation is particularly intriguing in gomphocerine grasshoppers, where the green and brown morphs appear to be genetically determined (Schielzeth & Dieker, 2020, BMC Evolutionary Biology, 20, 63; Winter et al., 2021, Heredity, 127, 66). A better understanding of how these color morphs develop during ontogeny can provide valuable insights into the evolution and ecology of such a widespread color polymorphism. Here, we focus on the color development of two green–brown polymorphic species, the club‐legged grasshopper Gomphocerus sibiricus and the steppe grasshopper Chorthippus dorsatus. By following the color development of individuals from hatching to adulthood, we found that color morph differences begin to develop during the second nymphal stage, are clearly defined by the third nymphal stage, and remain stable throughout the life of an individual. Interestingly, we also observed that shed skins of late nymphal stages are identifiable by color morphs based on their yellowish coloration, rather than the green that marks green body parts. Furthermore, by assessing how these colors are perceived by different visual systems, we found that certain potential predators can chromatically discriminate between morphs, while others may not. These results suggest that the putative genes controlling color morph are active during the early stages of ontogeny, and that green color is likely composed of two components, one present in the cuticle and one not. In addition, the effectiveness of camouflage appears to vary depending on the specific predator involved.

Abstract Introduction Trials of CT‐based screening for lung cancer have shown a mortality advantage for screening in North America and Europe. Before introducing a nationwide lung cancer screening program in Germany, it is important to assess the criteria used in international trials in the German population. Methods We used data from 3623 lung cancer patients from the data warehouse of the German Center for Lung Research (DZL). We compared the sensitivity of the following lung cancer screening criteria overall and stratified by age and histology: the National Lung Screening Trial (NLST), the Danish Lung Cancer Screening Trial (DLCST), the 2013 and 2021 US Preventive Services Task Force (USPSTF), and an adapted version of the Prostate, Lung, Colorectal, and Ovarian no race model (adapted PLCOm2012) with 6‐year risk thresholds of 1.0%/6 year and 1.7%/6 year. Results Overall, the adapted PLCOm2012 model (1%/6 years), selected the highest proportion of lung cancer patients for screening (72.4%), followed by the 2021 USPSTF (70.0%), the adapted PLCOm2012 (1.7%/6 year) (57.4%), the 2013 USPTF (57.0%), DLCST criteria (48.7%), and the NLST (48.5%). The adapted PLCOm2012 risk model (1.0%/6 year) had the highest sensitivity for all histological types except for small‐cell and large‐cell carcinomas (non‐significant), whereas the 2021 USPTF selected a higher proportion of patients. The sensitivity levels were higher in males than in females. Conclusion Using a risk‐based selection score resulted in higher sensitivities compared to criteria using dichotomized age and smoking history. However, gender disparities were apparent in all studied eligibility criteria. In light of increasing lung cancer incidences in women, all selection criteria should be reviewed for ways to close this gender gap, especially when implementing a large‐scale lung cancer screening program.

Abstract Background: TAK‐659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B‐cell lymphoma (DLBCL). We report results of a phase I single‐institution escalation study of front‐line treatment with R‐CHOP and TAK‐659 in treatment‐naïve high‐risk DLBCL. Methods: Patients with high‐risk DLBCL were treated with R‐CHOP for 1 cycle, followed by combined R‐CHOP and TAK‐659 for an additional five cycles, with TAK‐659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK‐659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow‐up of 21 months, 92% of patients achieved complete response (CR). The most common treatment‐emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK‐659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R‐CHOP and TAK‐659 in patients with newly diagnosed high‐risk DLBCL produces promising CR rates.

Abstract Background While prior Micra trials demonstrated a high implant success rate and favorable safety and efficacy results, changes in implant populations and safety over time is not well studied. The objective of this analysis was to report the performance of Micra in European and Middle Eastern patients and compare to the Micra Investigational Device Exemption (IDE) and Micra Post Approval Registry (PAR) studies. Methods The prospective, single‐arm Micra Acute Performance European and Middle Eastern (MAP EMEA) registry was designed to further study the performance of Micra in patients from EMEA. The primary endpoint was to characterize acute (30‐day) major complications. Electrical performance was analyzed. The major complication rate through 12 months was compared with the IDE and PAR studies. Results The MAP EMEA cohort (n = 928 patients) had an implant success rate of 99.9% and were followed for an average of 9.7 ± 6.5 months. Compared to prior studies, MAP EMEA patients were more likely to have undergone dialysis and have a condition which precluded the use of a transvenous pacemaker (p

Abstract Marine historical ecology provides a means to establish baselines to inform current fisheries management. Groupers (Epinephelidae) are key species for fisheries in the Mediterranean, which have been heavily overfished. Species abundance and distribution prior to the 20th century in the Mediterranean remains poorly known. To reconstruct the past biogeography of Mediterranean groupers, we investigated whether Zooarchaeology by Mass Spectrometry (ZooMS) can be used for identifying intra‐genus grouper bones to species level. We discovered 22 novel, species‐specific ZooMS biomarkers for groupers. Applying these biomarkers to Kinet Höyük, a Mediterranean archaeological site, demonstrated 4000 years of regional Epinephelus aeneus dominance and resiliency through millennia of fishing pressures, habitat degradation and climatic changes. Combining ZooMS identifications with catch size reconstructions revealed the Epinephelus aeneus capacity for growing 30 cm larger than hitherto documented, revising the maximum Total Length from 120 to 150 cm. Our results provide ecological baselines for a key Mediterranean fishery which could be leveraged to define and assess conservation targets.

ABSTRACT Impact microindentation (IMI) is a technique to assess bone material properties of the cortical bone at the tibia in a transcutaneous, microinvasive, way. IMI is increasingly used in studies evaluating the contribution of tissue material properties to bone fragility in humans, and is approved for use in the clinic in Europe and the United States. Previous data show that IMI is well tolerated during and immediately after the procedure. The aim of this prospective observational study was to evaluate the longer‐term safety and acceptability of an IMI measurement using the handheld OsteoProbe device®. Included were patients who were scheduled for a measurement at the Leiden University Medical Center from September 2019 to December 2020 and willing to participate. Patients were asked to review the procedure right after the measurement, and by telephone interviews 1 week and 1 month thereafter. The primary outcome was the 30‐day complication rate after the measurement. Included were 106 patients (71 women) with a median age of 59 years (range, 20 to 86 years). Only three minor events were reported by 1‐week follow‐up, with an overall 30‐day event rate of 2.8%. These were a very small hematoma in two patients, and a small bruise in one patient, all of which resolved without medical intervention. No other safety‐related concerns were observed, and all 106 patients would undergo the measurement again if needed. The vast majority had no pain at baseline, 1‐week and 1‐month follow‐up (80.2%, 88.4% and 94.3%, respectively). In this first and large longitudinal study we demonstrated that although minimally‐invasive, IMI using the OsteoProbe® device at the tibia did not lead to any complications, and was well accepted by patients. Results strongly suggest that IMI can be safely used in studies as well as in the clinic in the hands of an experienced operator. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Abstract Objectives Myocardial infarction (MI) initiates a complex reparative response during which damaged cardiac muscle is replaced by connective tissue. While the initial repair is essential for survival, excessive fibrosis post‐MI is a primary contributor to progressive cardiac dysfunction, and ultimately heart failure. Currently, there are no approved drugs for the prevention or the reversal of cardiac fibrosis. Therefore, we tested the therapeutic potential of repurposed mesalazine as a post‐MI therapy, as distinct antifibrotic effects have recently been demonstrated. Methods At 8 weeks of age, MI was induced in male C57BL/6J mice by LAD ligation. Mesalazine was administered orally at a dose of 100 μg/g body weight in drinking water. Fluid intake, weight development, and cardiac function were monitored for 28 days post intervention. Fibrosis parameters were assessed histologically and via qPCR. Results Compared to controls, mesalazine treatment offered no survival benefit. However, no adverse effects on heart and kidney function and weight development were observed, either. While total cardiac fibrosis remained largely unaffected by mesalazine treatment, we found a distinct reduction of perivascular fibrosis alongside reduced cardiac collagen expression. Conclusions Our findings warrant further studies on mesalazine as a potential add‐on therapy post‐MI, as perivascular fibrosis development was successfully prevented.

Abstract Antibiotic resistance is a major global health threat. Agricultural use of antibiotics is considered to be a main contributor to the issue, influencing both animals and humans as defined by the One Health approach. The purpose of the present study was to determine the abundance of antibiotic‐resistant bacterial populations and the overall bacterial diversity of cattle farm soils that have been treated with animal manure compost. Soil and manure samples were collected from different sites at Tullimba farm, NSW. Cultures were grown from these samples in the presence of 11 commonly used antibiotics and antibiotic‐resistant bacteria (ARB) colonies were identified. Soil and manure bacterial diversity was also determined using 16S ribosomal RNA next‐generation sequencing. Results showed that ARB abundance was greatest in fresh manure and significantly lower in composted manure. However, the application of composted manure on paddock soil led to a significant increase in soil ARB abundance. Of the antibiotics tested, the number of ARB in each sample was greatest for antibiotics that inhibited the bacterial cell wall and protein synthesis. Collectively, these results suggest that the transfer of antibiotic resistance from composted animal manure to soil may not be solely mediated through the application of live bacteria and highlight the need for further research into the mechanism of antibiotic resistance transfer.

Abstract The process of standardizing taxon names, taxonomic name harmonization, is necessary to properly merge data indexed by taxon names. The large variety of taxonomic databases and related tools are often not well described. It is often unclear which databases are actively maintained or what is the original source of taxonomic information. In addition, software to access these databases is developed following non‐compatible standards, which creates additional challenges for users. As a result, taxonomic harmonization has become a major obstacle in ecological studies that seek to combine multiple datasets. Here, we review and categorize a set of major taxonomic databases publicly available as well as a large collection of R packages to access them and to harmonize lists of taxon names. We categorized available taxonomic databases according to their taxonomic breadth (e.g. taxon specific vs. multi‐taxa) and spatial scope (e.g. regional vs. global), highlighting strengths and caveats of each type of database. We divided R packages according to their function, (e.g. syntax standardization tools, access to online databases, etc.) and highlighted overlaps among them. We present our findings (e.g. network of linkages, data and tool characteristics) in a ready‐to‐use Shiny web application (available at: https://mgrenie.shinyapps.io/taxharmonizexplorer/). We also provide general guidelines and best practice principles for taxonomic name harmonization. As an illustrative example, we harmonized taxon names of one of the largest databases of community time series currently available. We showed how different workflows can be used for different goals, highlighting their strengths and weaknesses and providing practical solutions to avoid common pitfalls. To our knowledge, our opinionated review represents the most exhaustive evaluation of links among and of taxonomic databases and related R tools. Finally, based on our new insights in the field, we make recommendations for users, database managers and package developers alike.

Abstract Grading of squamous cell carcinomas (SCCs) based on tumour budding and cell nest size has been termed cellular dissociation grading (CDG) and was suggested as a robust outcome predictor when assessed in biopsies and resections of various extrapulmonary SCCs. In pulmonary SCC (pSCC), this has so far been shown only for resected cancers. As most lung cancers are inoperable, it is of utmost importance to clarify whether the prognostic impact of CDG is retained in the biopsy setting. Two independent pSCC biopsy cohorts from Munich (n = 134, non‐resected) and Heidelberg (n = 135, resected) were assessed. Tumour budding and cell nest size measures were assembled into the three‐tiered CDG system (G1–G3). Data were correlated with clinicopathological parameters and overall‐ (OS), disease‐specific‐ (DSS), and disease‐free survival (DFS). Interobserver variability and concordance between biopsy and resection specimen were also investigated. CDG was highly congruent between biopsy and resection specimens (κ = 0.77, p

Abstract Hematopoietic stem and progenitor cells (HSPCs) are desirable targets for gene therapy but are notoriously difficult to target and transfect. Existing viral vector‐based delivery methods are not effective in HSPCs due to their cytotoxicity, limited HSPC uptake and lack of target specificity (tropism). Poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs) are attractive, nontoxic carriers that can encapsulate various cargo and enable its controlled release. To engineer PLGA NP tropism for HSPCs, megakaryocyte (Mk) membranes, which possess HSPC‐targeting moieties, were extracted and wrapped around PLGA NPs, producing MkNPs. In vitro, fluorophore‐labeled MkNPs are internalized by HSPCs within 24 h and were selectively taken up by HSPCs versus other physiologically related cell types. Using membranes from megakaryoblastic CHRF‐288 cells containing the same HSPC‐targeting moieties as Mks, CHRF‐wrapped NPs (CHNPs) loaded with small interfering RNA facilitated efficient RNA interference upon delivery to HSPCs in vitro. HSPC targeting was conserved in vivo, as poly(ethylene glycol)–PLGA NPs wrapped in CHRF membranes specifically targeted and were taken up by murine bone marrow HSPCs following intravenous administration. These findings suggest that MkNPs and CHNPs are effective and promising vehicles for targeted cargo delivery to HSPCs.

Abstract Tisotumab vedotin is an investigational antibody–drug conjugate (ADC) for treatment of solid tumors expressing tissue factor with accelerated approval from the US Food and Drug Administration for treatment of recurrent or metastatic cervical cancer with disease progression during or after chemotherapy. This study describes development of a population pharmacokinetic (PK) model to assess the PK profile of tisotumab vedotin and microtubule‐disrupting agent monomethyl auristatin E (MMAE) using data from 399 patients with solid tumors across four phase I/II trials. The ADC–MMAE model describes ADC and MMAE concentrations following intravenous administration of tisotumab vedotin. This four‐compartment model comprises a two‐compartment ADC model with parallel linear and Michaelis–Menten elimination, a delay compartment, and a one‐compartment MMAE model. Nonspecific linear clearance of ADC was 1.42 L/day, central volume of distribution (Vc) was 3.10 L, and median terminal half‐life of ADC was 4.04 days. Apparent clearance of MMAE was 42.8 L/day, and apparent volume of distribution was 2.09 L. Terminal slope of the MMAE concentration–time curve was defined by the delay compartment rate with a half‐life of 2.56 days. Patients with higher body weight and lower albumin concentration had faster ADC clearance. Male patients and those with higher body weight and lower albumin concentration had higher Vc. Body weight was the most influential covariate influencing distribution and elimination of ADC and MMAE, thus supporting weight‐based dosing of tisotumab vedotin. Presence of antidrug antibodies (detected in 3.3% of patients) did not affect key PK parameters or exposures for ADC and MMAE.

Abstract Objective Activated astroglia is involved in the pathophysiology of neurodegenerative diseases and has also been described in animal models of spinal muscular atrophy (SMA). Given the urgent need of biomarkers for treatment monitoring of new RNA‐modifying and gene replacement therapies in SMA, we examined glial fibrillary acidic protein concentrations in cerebrospinal fluid (cGFAP) as a marker of astrogliosis in SMA. Methods 58 adult patients and 21 children with genetically confirmed 5q‐associated SMA from four German motor neuron disease specialist care centers and 30 age‐ and sex‐matched controls were prospectively included in this study. cGFAP was measured and correlated to motor performance and disease severity. Additionally, we compared cGFAP with neurofilament light chain concentrations in cerebrospinal fluid (cNfL). Results cGFAP concentrations did not differ from controls but showed higher levels in more severely affected patients after adjustment for patients' age. Normalized cNfL values were associated with disease severity. Within 14 months of nusinersen treatment, cGFAP concentrations did not change, while cNfL decreased significantly. Interpretation cGFAP is not an outstanding biomarker in SMA, but might support the hypothesis that glial activation is involved in SMA pathology. Unlike previously suggested, cNfL may be a promising biomarker also in adult patients with SMA, which should be subject to further investigations.

Abstract Reconciling conservation and socioeconomic development goals is key to sustainability but remains a source of fierce debate. Protected areas (PAs) are believed to play an essential role in achieving these seemingly conflicting goals. Yet, there is limited evidence as to whether PAs are actually achieving the two goals simultaneously. Here, we investigate when and to what extent synergies or trade‐offs between biodiversity conservation and local socioeconomic development occur. To explore these relationships, we collected data across a wide range of socioeconomic settings through face‐to‐face survey with PA managers from 114 African and European PAs using structured questionnaire. We found synergies between biodiversity conservation and socioeconomic development for 62% of the PAs, albeit with significant differences between African (55%) and European PAs (75%). Moreover, the sustainability of PAs in conserving biodiversity was strongly correlated with the empowerment of the PA management and the involvement of local communities in PA planning and decision‐making processes. Our results demonstrate that for PAs to promote synergies between biodiversity conservation and local socioeconomic development, and to enhance their long‐term sustainability, they should invest in the empowerment of their respective management and involvement of local communities in their planning and management activities. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Abstract Aims We aim to explore the relationship of heart failure (HF) and diabetes with cardiovascular (CV) death or hospitalization for HF (HHF) and to study the clinical utility of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in an unselected patient population with atrial fibrillation (AF). Methods and results Patients with AF admitted to a tertiary academic center between January 2005 and July 2019 were identified through a search of electronic health records. We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, coronary artery disease, hypertension, smoking, C‐reactive protein, and low‐density lipoprotein cholesterol. To select the most informative variables, we performed a least absolute shrinkage and selection operator Cox regression with 10‐fold cross‐validation. In total, 7412 patients (median age 70 years, 39.7% female) were included in this analysis and followed over a median of 4.5 years. Both diabetes [adjusted (Adj.) HR 1.87, 95% CI 1.55–2.25] and HF (Adj. HR 2.57, 95% CI 2.22–2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared with patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all‐cause death. NT‐proBNP showed good discriminatory performance (area under the curve 0.78, 95% CI 0.77–0.80) and the addition of NT‐proBNP to the covariates used for adjustment resulted in a significant area under the curve improvement (Δ = 0.04, P