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Abstract This study evaluates the effectiveness and safety of trientine dihydrochloride (TETA 2‐HCl) in patients with Wilson disease (WD) following a switch from trientine tetrahydrochloride (TETA 4‐HCl). A total of 30 WD patients with stable copper metabolism were identified for treatment with TETA 2‐HCl (Cufence™) after prior use of TETA 4‐HCl (Cuprior™). Biochemical markers including urinary copper, non‐ceruloplasmin bound copper (NCC) and liver function were analyzed at baseline and followed up over 12 months. Safety was assessed based on reported adverse events (AEs). Urinary copper levels and NCC remained stable across all follow‐ups, indicating adequate copper metabolism control. Reported AEs during TETA 2‐HCl treatment were mostly gastrointestinal discomfort (n = 6). In two patients, progressive elevation of transaminases occurred (despite stable copper metabolism). AEs led to discontinuation of treatment in five cases. Median baseline dose per day was 10.2 mg TETA 4‐HCl/kg bodyweight, whereas median baseline dose after therapeutic switch to TETA 2‐HCl was 12.8 mg/kg bodyweight. Median daily dose at 12 months did not differ significantly from TETA 2‐HCl dose at switching timepoint, with stable biochemical markers and markers of copper metabolism in most (25/30) of the patients. Transitioning from TETA 4‐HCl to TETA 2‐HCl maintained stable copper parameters and liver function in most of analyzed patients. TETA 2‐HCl treatment was generally well tolerated, suggesting that switching medications is safe and effective. In our real‐life cohort, adjustment factor of ~1.25× for the switch of TETA 4‐HCl to TETA 2‐HCl resulted in adequate copper metabolism control.

Abstract Diverse patterns of climate and edaphic factors challenge detection of soil property change in the US Great Plains. Because detectable soil change can take decades, insights into the trajectory of soil properties frequently require long‐term site monitoring and, where available, associated soil archives to enable comparisons with initial or baseline states. Unfortunately, few multi‐decadal soil change investigations have been conducted in this region. Here, we document effects of dryland cropping on a suite of soil properties by comparing matched historic (1947) and contemporary (2018) soil samples from the Haas Soil Archive at three sites in the US Great Plains: Moccasin, MT, Akron, CO, and Big Spring, TX. Current analytical methods were used to provide insight into changes in soil texture, pH, carbon, and micronutrients at 0‐ to 15.2‐cm and 15.2‐ to 30.5‐cm depths. Changes in direction and magnitude of soil properties over 71 years were site specific. Changes in textural class occurred at all sites, with Moccasin and Akron transitioning from loam to clay loam and Big Spring from sandy clay loam to sandy loam. The soil pH reaction class changed from slightly alkaline to moderately acid at Akron and slightly alkaline to moderately alkaline at Big Spring. At 0–15.2 cm, soil organic carbon decreased by 15% and 36% at Moccasin and Big Spring, respectively, but increased by 15% at Akron. Soil micronutrients generally declined at all sites. Weather‐related variables derived from air temperature and precipitation records were not correlated with soil change. Inferred factors contributing to soil change included on‐site management, inherent soil features, weather metrics not evaluated, or a combination thereof.

Abstract Background Statins, metformin, and aspirin have been reported to reduce the incidence of hepatocellular carcinoma (HCC). However, the effect of their perioperative use on survival outcomes of HCC patients following curative liver resection still remains unclear. Method Three hundred and fifty three patients with a first diagnosis of HCC who underwent curative liver resection were included. Propensity score matching analysis with a users: nonusers ratio of 1:2 were performed for each of the medications (statins, metformin, and aspirin). Overall survival (OS) and recurrence‐free survival (RFS) were evaluated and multivariable Cox proportional hazard analysis was performed. Results Sixty two patients received statins, 48 patients used metformin, and 53 patients received aspirin for ≥90 days before surgery. None of the medications improved OS. RFS of statin users was significantly longer than that of nonusers (p = 0.021) in the matched cohort. Users of hydrophilic statins, but not lipophilic ones had a significantly longer RFS than nonusers. Multivariable analysis showed that statin use significantly improved RFS (hazard ratio [HR]: 0.41, 95% confidence interval [CI]: 0.17–0.97, p = 0.044). No difference was seen in RFS between metformin users and nonusers. Among patients with diabetes, RFS was nonsignificantly longer in metformin users than in non‐metformin users (84.1% vs. 60.85%, p = 0.069) in the matched cohort. No difference in postoperative RFS was seen between aspirin users and nonusers. Conclusion Preoperative use of statins in patients with HCC can increase RFS after curative liver resection, but metformin and aspirin were not associated with improved survival. Randomized controlled trials are needed to confirm the findings of the present study.

Abstract Wound healing and prevention of bacterial infections are critical aspects of modern medical care. In this work, antibacterial films were produced by creating composites of polycaprolactone with inorganic peroxides. Calcium, magnesium, and zinc peroxide were incorporated in a biocompatible polymeric film. Iron oxide, sodium bicarbonate, and calcium phosphate were added to reduce hydrogen peroxide and to maintain pH in a less alkaline range, allowing for optimization of the material's antibacterial efficacy while minimizing cytotoxicity toward human fibroblasts. Experiments with common wound pathogens, Staphylococcus aureus and Pseudomonas aerugonisa, confirmed significant and prolonged antibacterial effects of peroxide‐doped films. Findings showed that the addition of CaO2 and MgO2 within the film increased cytotoxicity toward human fibroblasts after 48 h (30%–40% decrease compared to control), whereas ZnO2‐based films exhibited a minimal cytotoxicity consistently maintaining over 70% cell viability throughout the course of the experiment. We examined the materials’ sustained release of reactive oxygen species and oxygen, and pH variation correlated with antibacterial activity. Given the unique combination of antibacterial efficacy and mammalian biocompatibility, these peroxides have value as components to sustain hydrogen peroxide release when appropriately compounded to reduce pH variation and avoid excessive hydrogen peroxide levels.

Abstract Objective Evaluation of the role of indicator pathogens in equine surgical site infection (SSI) and other infection‐promoting factors. Study design Cross‐sectional study. Animals Horses presenting with an open injury or surgical colic during 1.5 years. Methods A nasal swab and a faecal sample were collected from every patient upon admission. Furthermore, a wound swab was collected from wounds of injured horses. Details on the wounds and procedures were documented. Laparotomy incisions and injuries were monitored for signs suggesting infection. Results In total, 156 horses presented because of a surgical colic (n = 48) or open injuries (n = 108). Thirteen surgical colic patients and three injured horses did not survive beyond 24 h, and four injured horses were discharged from the clinic at the day of admission. SSIs occurred in 31 (30.7%) injured horses and 11 (31.4%) horses after laparotomy. Regarding injuries, general anaesthesia increased the risk of developing a WI compared to sedation. Indicator pathogens were cultured from 29/42 SSI. In total, 10/11 infected laparotomy incisions and 19/31 injuries with SSI tested positive for multidrug‐resistant pathogens (MDRPs) . Indicator pathogens were not detected at admission in any of the horses that developed incisional SSIs after laparotomy but were detected in two of the injured horses that developed SSIs. Conclusion MDRPs were identified in almost 70% of the SSI. Less than 5% of the affected animals were colonized with the same pathogen before admission, indicating that colonization with MDR pathogens is only one of the crucial factors for the development of SSI. Clinical significance Colonization with MDRP seems not to predispose horses to MDR SSIs.

Abstract Objectives The Estonian National Mental Health Study (EMHS) was conducted in 2021–2022 to provide population‐wide data on mental health in the context of COVID‐19 pandemic. The main objective of this paper is to describe the rationale, design, and methods of the EMHS and to evaluate the survey response. Methods Regionally representative stratified random sample of 20,000 persons aged 15 years and older was drawn from the Estonian Population Register for the study. Persons aged 18 years and older at the time of the sampling were enrolled into three survey waves where they were invited to complete an online or postal questionnaire about mental well‐being and disorders, and behavioral, cognitive, and other risk factors. Persons younger than 18 years of age were invited to fill an anonymous online questionnaire starting from wave 2. To complement and validate survey data, data on socio‐demographic, health‐related, and environmental variables were collected from six national administrative databases and registries. Additionally, a subsample was enrolled into a validation study using ecological momentary assessment. Results In total, 5636 adults participated in the survey wave 1, 3751 in wave 2, and 4744 in wave 3. Adjusted response rates were 30.6%, 21.1%, and 27.6%, respectively. Women and older age groups were more likely to respond. Throughout the three survey waves, a considerable share of adult respondents screened positive for depression (27.6%, 25.1%, and 25.6% in waves 1, 2, and 3, respectively). Women and young adults aged 18 to 29 years had the highest prevalence of depression symptoms. Conclusions The registry‐linked longitudinal EMHS dataset comprises a rich and trustworthy data source to allow in‐depth analysis of mental health outcomes and their correlates among the Estonian population. The study serves as an evidence base for planning mental health policies and prevention measures for possible future crises.

Abstract Background Cross‐matching is performed to determine the serological compatibility of donor and recipient blood. Current guidelines recommend that cross‐matching should be performed in dogs when an initial transfusion was performed more than 4 days ago or when the transfusion history is unknown. Hypothesis Determination at what time point alloantibodies are detected in dogs after transfusion. The hypothesis was that dogs would form alloantibodies within 4 days after a transfusion. Animals Twenty‐one anemic dogs were transfused and monitored for at least 4 subsequent days. Exclusion criteria were persistent red blood cell (RBC) agglutination and a previous transfusion. Methods Prospective observational study. Cross‐matching was performed before the initial DEA 1‐compatible transfusion and on days 1, 2, 3, and 4 and if possible, between day 5 and 28, using the tube method without enhancement (major cross‐match, recipient controls); recipients were monitored for transfusion reactions. Results In 12/21 dogs a positive cross‐match (microscopic degree of agglutination [AD] 1+ to 2+) was observed within 4 days after the transfusion. In a nonlinear regression model, no significant association was detected between type of anemia (P = .41), RBC storage time (P = .44), immunosuppressive treatment (P = .75) nor transfusion volume (P = .70) and the occurrence of positive cross‐matches within 4 days after transfusion. Another 4 dogs developed a positive cross‐match (microscopic AD 1+ to 2+) after 6 to 13 days. Conclusions and Clinical Importance Because production of alloantibodies was detected as early as 1 day after transfusion, cross‐matching should be performed before every subsequent transfusion.

Abstract Objectives Both positive and negative including psychotic‐like cannabis intoxication effects are well‐established. Yet, consequences for consumption patterns, addictive behavior or psychotic developments are poorly researched in general, in Germany not at all. Thus, objective was to develop the first German‐language questionnaire operationalizing acute cannabis intoxication effects, based on the original “Cannabis Experience Questionnaire” (CEQ). Methods After expert translation of the CEQ, items related to acute intoxication effects were presented to a sample of 537 cannabis users. Four‐ and five‐factorial solutions of explorative factor analysis with a randomly split sub‐sample 1 were cross‐validated by confirmatory factor analysis on sub‐sample 2. Results After content review of factors and analysis of external validity, a 17 item four‐factorial model was approved. Factors are (1) “paranoia/dysphoria”, (2) “confusion/disorientation”, (3) “euphoria/creativity”, (4) “psychosis‐like/loss of reality”. Model fit is satisfactory (RMSEA = 0.058, SRMR = 0.065, CFI = 0.929, TLI = 0.914). Correlations with corresponding external measures support construct validity. Conclusions The present questionnaire is a time‐efficient, valid and reliable instrument. Thus, predictors of different cannabis intoxication effects can be analysed for the first time in German‐speaking area, as well as their significance for substance use or psychosis risk.

Abstract Objective Extraglandular neurological manifestations of Sjögren’s syndrome are increasingly recognized, defining the disease entity of Neuro‐Sjögren. Neuropsychological assessment of patients with Sjögren’s syndrome has hitherto been performed on predominantly rheumatological cohorts. These studies revealed a wide variety of prevalence rates for cognitive impairment (22–80%), while variable cut‐off criteria for detection of cognitive impairment were applied. Attentional functions have not yet been thoroughly investigated in these patients, although they clearly represent relevant aspects of cognitive functioning in daily life. Methods We therefore conducted extensive neuropsychological assessment based on two neuropsychological test batteries [i.e., the extended German version of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery (CERAD‐PLUS), and the test battery for attentional performance (TAP) as a well‐established assessment of attentional functions in the German‐speaking part of Europe]. Results Sixty‐four patients with Neuro‐Sjögren, who were treated at our university hospital between December 2016 and January 2019, were included. Evidence for the presence of cognitive impairment was found in 55% of patients with Neuro‐Sjögren. The degree of cognitive impairment ranged from mild (38%) to severe (17%). Attentional and mnemonic subtests showed pronounced cognitive impairment in patients with Neuro‐Sjögren. Interpretation Our results suggest that a substantial proportion of patients with Neuro‐Sjögren suffer from cognitive impairment, putatively as a corollary of attentional deficits, which might exert adverse effects on occupational abilities, other cognitive functions, and social role functioning.

Abstract Monitoring and surveillance of antimicrobial usage in animals is a public health concern and different methods are currently discussed widely in public, science and politics. The objective of the paper is to present the available methods of monitoring and to discuss possible differences in the assessment of the antibiotics treatment. Sales data are expressed as the average amount of substance per animal or kg live weight (e.g. population‐corrected unit, PCU). The number of Defined Daily Doses (nDDDvet) is calculated by extrapolating sales data with average animal weights and defined drug doses to a number of treatments theoretically applied to animals. In contrast, the number of Used Daily Doses (nUDDvet) displays the actual number of treatments which have been applied. As sales data are relatively easily obtained, they are frequently used. However, their results are influenced by the composition of the population and by the dose of the substances. As both may vary strongly between countries, direct comparison of sales data between countries may be misleading. The concept of analysing sales data is shown by exemplarily using the methods in the ESVAC report 2015. The presentation of usage data in terms of nDDDvet or of nUDDvet increases the comparability of the data from different countries or time periods. Furthermore, fluoroquinolones and third‐/fourth‐generation cephalosporins which, among other substances, bare a potential risk for human health, are used at low doses. Hence, their use contributes to a sales reduction while contrasting the guidelines of prudent use. nDDDvet or nUDDvet have the ability to better reflect the treatment frequency and thus to better link antibiotics use to public health concerns. Quantification of antibiotics should assist to focus on prudent use of antimicrobials to reduce the burden of resistant bacteria and, thus, enhance public health, animal health and animal welfare.

Abstract Methane gas plumes have been discovered to issue from the seafloor in the Puget Sound estuary. These gas emission sites are co‐located over traces of three major fault zones that fracture the entire forearc crust of the Cascadia Subduction Zone. Multibeam and single‐beam sonar data from cruises conducted in years 2011, 2018, 2019, 2020, and 2021 identified the acoustic signature of 349 individual bubble plumes. Dissolved CH4 gas from the plumes combines to elevate seawater methane concentrations of the entire Puget Sound estuary. Fluid samples from adjacent terrestrial hot springs and deep‐water wells surrounding the estuary contain a helium‐3 isotope signature, suggesting a deep fluid source located near the underlying Cascadia Subduction Zone plate interface. However, limited data from this pilot study suggest that Puget Sound seawater emission sites lack both similar chemical isotope signatures and elevated thermal anomalies that would be expected from association with a deep plate‐interface reservoir. A shallow reservoir within the Holocene sediments that cover the older Puget Sound basement with horizontal transfer to the thinly covered Alki Point and Kingston Arch anticlines is also a possibility, as has been suggested for other methane seep areas. The existence of vigorous marine methane plumes arising from areas of thin sediment cover associated with deeply penetrating forearc fault zones but presenting no thermal or chemical anomalies found in other similar forearc environments, remains an unresolved paradox.

Abstract Factors associated with the choice of oral versus intravenous CT are not clearly established. Our purpose was to evaluate the influence of social status and home distance to hospital on the use of oral CT in patients with metastatic colorectal cancer (mCRC). This retrospective single‐center study included mCRC patients between 2011 and 2017. Patient social status was assessed by European Deprivation Index (EDI) and home distance to the hospital was calculated. Univariable and multivariable logistic regression analyses were performed. One hundred and seventy‐five mCRC patients were included, with 71 receiving oral CT. Most deprived patients received less oral CT (OR 0.5 [0.26, 0.96], p = .039). No association was found for road distance. Previous use of adjuvant oral CT was associated with oral CT in mCRC (OR 2.65 [1.06, 6.66], p = .038). Our results suggest that deprived social status is a factor associated with decreased use of oral CT in patients with mCRC. Clinical trial registration: no registration.

Abstract A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

Abstract Cell‐free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™‐epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next‐generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non‐small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first‐line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™‐EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™‐EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™‐EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™‐EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™‐EGFR assay achieved higher sensitivity for detection of clinically actionable mutations.

Abstract The Macquarie Ridge Complex (MRC) on the Australia‐Pacific plate boundary south of New Zealand is an extinct mid‐ocean ridge that has experienced a complex tectonic history and produced highly heterogeneous mid‐ocean ridge basalts (MORBs). When and how seafloor spreading ceased along the proto‐Macquarie mid‐ocean ridge remain elusive, and it is unclear how the mantle source of MORBs is affected by the gradual cessation of seafloor spreading at mid‐ocean ridges. To constrain the tectonic evolution of the MRC, the mantle source variations for MORBs at dying mid‐ocean ridges, and the mechanisms of mantle enrichment and asthenospheric heterogeneities, we report 11 pyroxene, plagioclase, basaltic glass, groundmass, and sericite 40Ar/39Ar and one zircon U‐Pb ages for the MRC MORBs. Our data reveal that basalts from the MRC seamounts were erupted between 25.9 and 1.6 Ma and Macquarie Island at ∼10 Ma. Combined age and plate reconstruction results reveal that the cessation of seafloor spreading at the MRC generally propagated from south to north along the ridge. Basalts produced by the then dying Macquarie mid‐ocean ridge at different times on different seamounts/island show a large variation in isotopic compositions and there is no clear correlation between ages and isotopic ratios. The heterogeneity of mantle source for MORBs from the proto‐Macquarie mid‐ocean ridge suggests that the upper asthenospheric mantle is heterogeneous, and such heterogeneity becomes most obvious at dying mid‐ocean ridges where the degrees of partial melting are low and a large range of melt compositions are produced.

Abstract. Iron metabolism might play a crucial role in cytokine release syndrome in COVID-19 patients. Therefore, we assessed iron metabolism markers in COVID-19 patients for their ability to predict disease severity. COVID-19 patients referred to the Heidelberg University Hospital were retrospectively analyzed. Patients were divided into outpatients (cohort A, n = 204), inpatients (cohort B, n = 81), and outpatients later admitted to hospital because of health deterioration (cohort C, n = 23). Iron metabolism parameters were severely altered in patients of cohort B and C compared to cohort A. In multivariate regression analysis including age, gender, CRP and iron-related parameters only serum iron and ferritin were significantly associated with hospitalization. ROC analysis revealed an AUC for serum iron of 0.894 and an iron concentration

Abstract Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (

Abstract Strategies to protect biodiversity in the face of a global crisis must be place‐based and sensitive to context. A failure to consider the socioeconomic and political circumstances, as well as wellbeing needs and lived realities of those most directly reliant upon biodiversity will further undermine progress on Aichi targets and subsequent goals for the post‐2020 framework. How communities experience the benefits or costs of conservation action is influenced in large measure by the principles that guide conservation governance, and the subsequent institutional structures and processes that frame conservation action (at local to global scales). In this article, we define and critically reflect on core principles of community‐centered conservation governance needed to yield desirable and long‐term conservation outcomes—both ecological and social (i.e., equitable and just). In doing so, we emphasize a conception of community‐centered conservation that we argue is relevant to guide implementation of a post‐2020 biodiversity framework, and which is based on a foundation of well‐established evidence. Core principles of community‐centered conservation governance include: (a) building multilevel networks and collaborative relationships needed to coproduce conservation solutions; (b) promoting equity and recognizing the central role of women as agents of positive change in conservation efforts across scales; (c) reframing conservation action through the lens of reconciliation and redress (e.g., responding to injustices from land grabs and territorial enclosures); (d) ensuring a rights‐based approach to conservation action in which community agency, access and decision making autonomy are supported; and (e) revitalizing the customary and local institutions that provide legitimate and adaptive strategies for the stewardship of biodiversity.