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Background As future cardiovascular disease mortality trends have public health implications, we aimed to project ischemic heart disease (IHD), cerebrovascular disease (CeVD), and heart failure (HF) mortality rates for adults (40–79 years). Methods and Results In this population‐level study, we linked the yearly mortality rates (per 100 000 US residents) (2000–2019) with IHD, CeVD, or HF as the primary cause of death from the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research with the midyear US population estimates (2000–2035) for adults (40–79 years). We calculated the observed age‐standardized mortality rates (2000–2019) (per 100 000 residents) (aSMR) and fitted Bayesian age‐period‐cohort models to project aSMR for IHD, CeVD, and HF up to 2035 in the United States. Between 2019 (last year of observed data) and 2035 (last year of projected results), the US population (40–79 years) will increase by 16% and age. The IHD aSMR will reduce from 111.9 (in 2019) to 81.8 (66.7–96.9) in 2035, an effect observed for all age groups. The CeVD aSMR will remain comparable between 2019 (37.4) and 2035 (38.6 [30.7–46.5]). The HF aSMR will increase from 16.5 in 2019 to reach 30.9 (13–48.8) in 2035; such increases were observed in all age groups. Conclusions In the United States, between 2020 and 2035, the aSMR for IHD is expected to decrease, for CeVD will remain stable, and for HF will increase substantially. These data can inform resource allocation for future public health initiatives.

Abstract Epidemiological studies have established a link between air pollution and an elevated risk of type 2 diabetes mellitus (T2DM). This study aims to measure the impact of T2DM related to fine particulate matter (PM2.5) pollution by examining death rates and disability‐adjusted life years (DALYs) from 1990 to 2019 in the United States of America. Using data from the Global Burden of Disease (GBD) database, we examined death and DALY rates per 100,000 populations in T2DM patients, specifically focusing on ambient particulate matter pollution (APMP) and household air pollution (HAP). We assessed average annual percentage change (AAPC) across various age and gender groups, states, and socio‐demographic index (SDI) categories. Our findings reveal a significant decline in death rates and DALYs in the United States of America over the last 30 years, with more pronounced decreases among females and older adults. Despite national progress, state‐level variations indicate complex interactions between environmental regulations, healthcare access, and socio‐economic factors. Some states, such as Oregon, Idaho, and Alaska, exhibited increased AAPC. Our study emphasizes the need for targeted policies and interventions to reduce PM2.5 exposure and further address regional disparities, ensuring continued improvement in public health outcomes.

Abstract Purpose The purpose of this study was to quantify and compare the clinical relevance of the different intra‐articular corticosteroids (CS) effects in vivo for osteoarthritis (OA) treatment. Methods The search was conducted on PubMed, Cochrane, and Web of Science in October 2023. The PRISMA guidelines were used. Inclusion criteria: animal or human randomized controlled trials (RCTs), English language and no time limitation, on the comparison of different intra‐articular CS for OA treatment. The articles' quality was assessed using the Cochrane RoB2 and GRADE guidelines for human RCTs, and SYRCLE's tool for animal RCTs. Results Eighteen RCTs were selected (16 human and 2 animal studies), including 1577 patients (1837 joints) and 31 animals (51 joints). The CS used were triamcinolone (14 human and 2 animal studies), methylprednisolone (7 human and 1 animal study), betamethasone (3 human studies) and dexamethasone (1 human study). All studies addressed knee OA except for three human and one animal study. A meta‐analysis was performed on the comparison of methylprednisolone and triamcinolone in humans with knee OA analysing VAS pain at very short‐ (≤2 weeks), short‐ (>2 and ≤4 weeks), mid‐ (>4 and ≤8 weeks), long‐ (>8 and ≤ 12 weeks), and very long‐term (>12 and ≤24 weeks). Triamcinolone showed better post‐injection values compared to methylprednisolone at very short‐term (p = 0.028). No difference in terms of VAS improvement was observed at any follow‐up. Conclusions The available preclinical and clinical literature provides limited evidence on the comparison of different CS, hindering the possibility of determining the best CS approach in terms of molecule and dose for the intra‐articular injection of OA joints. Level of Evidence Level I.

Abstract Tricuspid annular plane systolic excursion (TAPSE) is usually measured with M‐mode using sector line, however, this may not align with the anatomical shortening of the right ventricular (RV). In this study, we compared the different methods to measure TAPSE using three different reference lines (sector line, anatomical line, and apico‐annular line). We included 148 patients diagnosed with pulmonary arterial hypertension (PAH) who underwent TTE and right heart catheterization within 2 weeks of each other. TAPSE was measured by M‐mode (sector, anatomical), 2D (sector, anatomical), or as tricuspid apico‐annular displacement (TAAD). Agreement between measures was assessed using coefficient of variation (COV), Spearman's correlation, and Bland–Altman analysis. Receiver–operating characteristics and Kaplan–Meier analysis were used to explore associations with the combined outcome of death or lung transplantation at 5 years. There was a good concordance between anatomical and sector M‐mode with a COV of 15.5 ± 1.6% and a bias of −0.6 ± 3.2 mm. In contrast, anatomical M‐mode TAPSE and TAAD differed significantly with the mean difference of 3.3 ± 3.8 mm (COV 30.5 ± 6.1%; p

Abstract Electrochemical nitrogen reduction (E‐NRR) is one of the most promising approaches to generate green NH3. However, scarce ammonia yields and Faradaic efficiencies (FE) still limit their use on a large scale. Thus, efforts are focusing on different E‐NRR catalyst structures and formulations. Among present strategies, molecular electrocatalysts such as metal‐porphyrins emerge as an encouraging option due to their planar structures which favor the interaction involving the metal center, responsible for adsorption and activation of nitrogen. Nevertheless, the high hydrophobicity of porphyrins limits the aqueous electrolyte–catalyst interaction lowering yields. This work introduces a new class of metal‐porphyrin based catalysts, bearing hydrophilic tris(ethyleneglycol) monomethyl ether chains (metal = Cu(II) and CoII)). Experimental results show that the presence of hydrophilic chains significantly increases ammonia yields and FE, supporting the relevance of fruitful catalyst‐electrolyte interactions. This study also investigates the use of hydrophobic branched alkyl chains for comparison, resulting in similar performances with respect to the unsubstituted metal‐porphyrin, taken as a reference, further confirming that the appropriate design of electrocatalysts carrying peripheral hydrophilic substituents is able to improve device performances in the generation of green ammonia.

Abstract Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1‐year mortality risk. PAH patients (n = 223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R2 = 0.82, p

Abstract Intravenous immunoglobulin (IVIG) (2000 mg/kg) increased the clearance of the mouse monoclonal antibody 7E3, directed against platelet integrin IIb/IIIa (alpha IIb beta 3, CD41/CD61) in rodents. We wanted to investigate the effect of IVIG on clearance of monoclonal antibodies in humans as there is extremely limited data regarding this interaction in the literature. Using the tyrosine protein kinase KIT anti‐cluster of differentiation 117 (c‐Kit) humanized monoclonal antibody (JSP191) as a case study, we used physiologically‐based pharmacokinetic (PBPK) modeling to evaluate the pharmacokinetic interaction between monoclonal antibodies and IVIG at doses (300–600 mg/kg) administered to patients with primary human immunodeficiency (PI). We first characterized the interaction between monoclonal antibodies and IVIG in PK‐Sim®/MoBi® using published literature data, including the following: IVIG plus 7E3 in mice and rats and IVIG plus the human anti‐C5 monoclonal antibody tesidolumab in adults with end‐stage renal disease. We next developed a PBPK model using digitized data for JSPI91 alone in older adults with myelodysplastic syndrome and acute myeloid leukemia and in pediatric patients with severe combined immunodeficiency (SCID). Finally, we simulated the impact of IVIG (300–2000 mg/kg) coadministration with JSP191 on the area under the curve of JSP191 in patients with SCID. Model predictions were within 1.5‐fold of observed values for 7E3 plus IVIG and tesidolumab plus IVIG as well as for JSP191 administered alone. Based on our simulations, IVIG doses ≥500 mg exceeded the 80%–125% no‐effect boundaries. IVIG treatment with monoclonal antibodies in patients with PI may result in a clinically significant interaction depending on the IVIG dose administered and the exposure–response relationship for the specific monoclonal antibody.

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by an intense trafficking of the leukemic cells between the peripheral blood and lymphoid tissues. It is known that the ability of lymphocytes to recirculate strongly depends on their capability to rapidly rearrange their cytoskeleton and adapt to external cues; however, little is known about the differences occurring between CLL and healthy B cells during these processes. To investigate this point, we applied a single-cell optical (super resolution microscopy) and nanomechanical approaches (atomic force microscopy, real-time deformability cytometry) to both CLL and healthy B lymphocytes and compared their behavior. We demonstrated that CLL cells have a specific actomyosin complex organization and altered mechanical properties in comparison to their healthy counterpart. To evaluate the clinical relevance of our findings, we treated the cells in vitro with the Bruton’s tyrosine kinase inhibitors and we found for the first time that the drug restores the CLL cells mechanical properties to a healthy phenotype and activates the actomyosin complex. We further validated these results in vivo on CLL cells isolated from patients undergoing ibrutinib treatment. Our results suggest that CLL cells’ mechanical properties are linked to their actin cytoskeleton organization and might be involved in novel mechanisms of drug resistance, thus becoming a new potential therapeutic target aiming at the normalization of the mechanical fingerprints of the leukemic cells.

Abstract Aims Heart transplantation involves many factors such as donor selection, recipient management, multidisciplinary assessment, coordination with other organ teams, and transportation. Because of some unpredictable factors, heart transplantation can be conducted at any time of day. The purpose of this study is to investigate if outcomes differ between heart transplants taking place inside or outside of normal working hours. Methods and results We reviewed patients who underwent heart transplantation at our institution from January 2010 to July 2020 (n = 329). Based on the documented start time of the recipient surgeries, the cohort was divided into two groups: working hours (Group A: 7:30 to 17:00; n = 92) and after hours (Group B: 17:00 to 7:30; n = 237). We compared these groups using propensity score matching analysis. After propensity score matching, 78 pairs of patients were successfully matched. We reviewed early and late clinical outcomes including survival. Long‐term survival was compared using the Kaplan–Meier method. In the propensity‐score matched patients, there were no significant differences in the baseline characteristics between two groups. In‐hospital mortality was not significantly different between the two groups (Group A: 6.4% vs. Group B: 2.6%, P = 0.44). Ischaemic time and cross‐clamp time did not differ between the groups. In terms of postoperative complications, there were no significant differences between two groups in stroke (6.4% vs. 3.9%, P = 0.72), primary graft dysfunction requiring extracorporeal membrane oxygenation (5.1% vs. 7.7%, P = 0.75), re‐exploration for bleeding (9.0% vs. 12.8%, P = 0.44), and newly required haemodialysis (7.7% vs. 6.4%, P = 0.75). The survival rate in Group A (88.1% at 1 year, 81.3% at 3 years) was not significantly different from Group B (90.5% at 1 year, 82.3% at 3 years, log rank = 0.96). Conclusion There was no significant difference in clinical outcomes between heart transplants taking place inside or outside of working hours. A high quality of care can be provided for heart transplant patients even during after hours.

Abstract Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement (“transverse shortening”) of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross‐sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post‐PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p

Abstract Breast cancer cell colonization of the lungs is associated with a dismal prognosis as the distributed nature of the disease and poor permeability of the metastatic foci challenge the therapeutic efficacy of small molecules, antibodies, and nanomedicines. Taking advantage of the unique physiology of the pulmonary circulation, here, micro‐combinatorial hydrogel particles (µCGP) are realized via soft lithographic techniques to enhance the specific delivery of a cocktail of cytotoxic nanoparticles to metastatic foci. By cross‐linking short poly(ethylene glycol) (PEG) chains with erodible linkers within a shape‐defining template, a deformable and biodegradable polymeric skeleton is realized and loaded with a variety of therapeutic and imaging agents, including docetaxel‐nanoparticles. In a model of advanced breast cancer lung metastasis, µCGP amplified the colocalization of docetaxel‐nanoparticles with pulmonary metastatic foci, prolonged the retention of chemotoxic molecules at the diseased site, suppressed lesion growth, and boosted survival beyond 20 weeks post nodule engraftment. The flexible design and modular architecture of µCGP would allow the efficient deployment of complex combination therapies in other vascular districts too, possibly addressing metastatic diseases of different origins.

Nitric oxide synthase 3 (NOS3) is a major vasoprotective enzyme that catalyzes the conversion of l‐arginine to nitric oxide (NO) in response to a significant number of signaling pathways. Here, we provide evidence that NOS3 interactions with MAP kinases have physiological relevance. Binding interactions of NOS3 with c‐Jun N‐terminal kinase (JNK1α1), p38α, and ERK2 were characterized using optical biosensing with full‐length NOS3 and NOS3 specific peptides and phosphopeptides. Like p38α and ERK2, JNK1α1 exhibited high‐affinity binding to full‐length NOS3 (KD 15 nm). Rate constants exhibited fast‐on, slow‐off binding (kon = 4106 m−1s−1; koff = 6.2 × 10‐5 s−1). Further analysis using synthetic NOS3 peptides revealed two MAP kinase binding sites unique to NOS3. p38α evinced similar affinity with both NOS3 binding sites. For ERK2 and JNK1α1, the affinity at the two sites differed. However, NOS3 peptides with a phosphate at either S114 or S633 did not meaningfully interact with the kinases. Immunoblotting revealed that each kinase phosphorylated NOS3 with a unique pattern. JNK1α1 predominantly phosphorylated NOS3 at S114, ERK2 at S600, and p38α phosphorylated both residues. In vitro production of NO was unchanged by phosphorylation at these sites. In human microvascular endothelial cells, endogenous interactions of all the MAP kinases with NOS3 were captured using proximity ligation assay in resting cells. Our results underscore the importance of MAP kinase interactions, identifying two unique NOS3 interaction sites with potential for modulation by MAP kinase phosphorylation (S114) and other signaling inputs, like protein kinase A (S633).

Abstract Aim To investigate the extent of post‐traumatic growth, and the correlation between post‐traumatic growth and self‐perceived stress, post‐traumatic growth and self‐perceived burden among CAPD patients. Design A cross‐sectional study. Methods This was a multi‐centre study including 752 patients from 44 hospitals. Self‐perceived stress, self‐perceived burden and post‐traumatic growth were measured using the post‐traumatic growth inventory (PTGI), the Chinese version of the perceived stress questionnaire (CPSQ) and the self‐perceived burden scale (SPBS). A multiple stepwise regression analysis was fit with the total PTGI score as the outcome of interest. Results Patients concurrently experienced post‐traumatic growth and stress following peritoneal dialysis. The initiation of patients’ education level, employment status and self‐perceived stress were all found to relate to growth among Chinese CAPD patients. There was not sufficient evidence to suggest that self‐perceived burden was related to experiencing growth.

Hypertrophic cardiomyopathy is the most common genetic heart disease. Biomarkers, molecules measurable in the blood, could inform the clinician by aiding in diagnosis, directing treatment, and predicting outcomes. We present an updated review of circulating biomarkers in hypertrophic cardiomyopathy representing key pathologic processes including wall stretch, myocardial necrosis, fibrosis, inflammation, hypertrophy, and endothelial dysfunction, in addition to their clinical significance.

After FDA and EMA approval of the regimen containing polatuzumab vedotin plus rituximab and bendamustine (PolaBR), eligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients in Italy were granted early access through a Named Patient Program. A multicentric observational retrospective study was conducted focusing on the effectiveness and safety of PolaBR in everyday clinical practice. Fifty-five patients were enrolled. There were 26 females (47.3%), 32 patients were primary refractory and 45 (81.8%) resulted refractory to their last therapy. The decision to add or not bendamustine was at physician’s discretion. Thirty-six patients underwent PolaBR, and 19 PolaR. The 2 groups did not differ in most of baseline characteristics. The final overall response rate was 32.7% (18.2% complete response rate), with a best response rate of 49.1%. Median disease-free survival was reached at 12 months, median progression-free survival at 4.9 months and median overall survival at 9 months, respectively. Overall, 88 adverse events (AEs) were registered during treatment in 31 patients, 22 of grade ≥3. Eight cases of neuropathy occurred, all of grades 1–2 and all related to polatuzumab. The two groups of treatment did not differ for effectiveness endpoints but presented statistically significant difference in AEs occurrence, especially in hematological AEs, in AEs of grade equal or greater than 3 and in incidence of neuropathy. Our data add useful information on the effectiveness of Pola(B)R in the setting of heavily pretreated DLBCL and may also suggest a better tolerability in absence of bendamustine without compromise of efficacy.

Abstract Aim The study aimed to investigate the current status of reproductive concerns and explore the associated factors among young female chronic kidney disease (CKD) patients. Design A multi‐center cross‐sectional study was designed. Methods The study was conducted in six representative tertiary hospitals across southwest China. A total of 295 female Chronic kidney disease patients between 18–45 years of age completed a 20 min, web‐based survey, which included demographics and disease‐related information questionnaire, Reproductive Concerns Scale, Generalized Anxiety Disorder 7 (GAD‐7) instrument and Patient Health Questionnaire 9 (PHQ‐9) instrument. Result The survey total collected 270 valid questionnaires. The mean reproductive concern score was 54.39 ± 10.90 (out of a maximum of 90), with the mean scores for sub‐scales ranging from 7.80 ± 1.69 to 10.44 ± 1.85. Multiple regression analysis showed that those with higher reproductive concerns were more likely to have pregnancy intentions, to be in Chronic kidney disease stages 1–3, and to have a higher GAD‐7 score. This study offered further evidence of the need for improved education and emotional support surrounding reproductive concerns among young Chinese women with Chronic kidney disease.

Background Holter analysis requires significant clinical resources to achieve a high‐quality diagnosis. This study sought to assess whether an artificial intelligence (AI)‐based Holter analysis platform using deep neural networks is noninferior to a conventional one used in clinical routine in detecting a major rhythm abnormality. Methods and Results A total of 1000 Holter (24‐hour) recordings were collected from 3 tertiary hospitals. Recordings were independently analyzed by cardiologists for the AI‐based platform and by electrophysiologists as part of clinical practice for the conventional platform. For each Holter, diagnostic performance was evaluated and compared through the analysis of the presence or absence of 5 predefined cardiac abnormalities: pauses, ventricular tachycardia, atrial fibrillation/flutter/tachycardia, high‐grade atrioventricular block, and high burden of premature ventricular complex (>10%). Analysis duration was monitored. The deep neural network–based platform was noninferior to the conventional one in its ability to detect a major rhythm abnormality. There were no statistically significant differences between AI‐based and classical platforms regarding the sensitivity and specificity to detect the predefined abnormalities except for atrial fibrillation and ventricular tachycardia (atrial fibrillation, 0.98 versus 0.91 and 0.98 versus 1.00; pause, 0.95 versus 1.00 and 1.00 versus 1. 00; premature ventricular contractions, 0.96 versus 0.87 and 1.00 versus 1.00; ventricular tachycardia, 0.97 versus 0.68 and 0.99 versus 1.00; atrioventricular block, 0.93 versus 0.57 and 0.99 versus 1.00). The AI‐based analysis was >25% faster than the conventional one (4.4 versus 6.0 minutes; P

Abstract Search image formation, a proximal mechanism to maintain genetic polymorphisms by negative frequency‐dependent selection, has rarely been tested under natural conditions. Females of many nonterritorial damselflies resemble either conspecific males or background vegetation. Mate‐searching males are assumed to form search images of the majority female type, sexually harassing it at rates higher than expected from its frequency, thus selectively favoring the less common morph. We tested this and how morph coloration and behavior influenced male perception and intersexual encounters by following marked Ischnura elegans and noting their reactions to conspecifics. Contrary to search image formation and associative learning hypotheses, although males encountered the minority, male‐like morph more often, sexual harassment and clutch size were similar for both morphs. Prior mating attempts or copula with morphs did not affect a male's subsequent reaction to them; males rarely attempted matings with immature females or males. Females mated early in the day, reducing the opportunity for males to learn their identity beforehand. Once encountered, the male‐like morph was more readily noticed by males than the alternative morph, which once noticed was more likely to receive mating attempts. Flexible behavior gave morphs considerable control over their apparency to males, influencing intersexual encounters. Results suggested a more subtle proximal mechanism than male learning maintains these color polymorphisms and call for inferences of learning to be validated by behavior of wild receivers and their signalers.

Abstract Background Colorectal cancer is the second most common cause of cancer‐related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes. Methods To model the heterogeneous nature of colorectal cancer, we used patient‐derived scaffolds (PDS), which were obtained via decellularization of surgically resected tumor material, as a growth substrate for standardized cell lines. Results After confirmation of native cell absence and validation of the structural and compositional integrity of the matrix, 89 colorectal PDS were repopulated with colon cancer cell line HT29. After 3 weeks of PDS culture, HT29 cells varied their gene and protein expression profiles considerably compared to 2D‐grown HT29 cells. Markers associated with proliferation were consistently decreased, while markers associated with pluripotency were increased in PDS‐grown cells compared to their 2D counterparts. When comparing the PDS‐induced changes in HT29 cells with clinically relevant tumor information from individual patients, we observed significant associations between stemness/pluripotency markers and tumor location, and between epithelial‐to‐mesenchymal transition (EMT) markers and cancer mortality. Kaplan–Meier analysis revealed that low PDS‐induced EMT correlated with worse cancer‐specific survival. Conclusions The colorectal PDS model can be used as a simplified personalized tool that can potentially reveal important diagnostic and pathophysiological information related to the TME.

Abstract Partial and/or heterogeneous irradiation of established (i.e., large, vascularized) tumors by α‐particles that exhibit only a 4–5 cell‐diameter range in tissue, limits the therapeutic effect, since regions not being hit by the high energy α‐particles are likely not to be killed. This study aims to mechanistically understand a delivery strategy to uniformly distribute α‐particles within established solid tumors by simultaneously delivering the same α‐particle emitter by two diverse carriers, each killing a different region of the tumor: (1) the cancer‐agnostic, but also tumor‐responsive, liposomes engineered to best irradiate tumor regions far from the vasculature, and (2) a separately administered, antibody, targeting any cancer‐cell's surface marker, to best irradiate the tumor perivascular regions. We demonstrate that on a prostate specific membrane antigen (PSMA)‐expressing prostate cancer xenograft mouse model, for the same total injected radioactivity of the α‐particle emitter Actinium‐225, any radioactivity split ratio between the two carriers resulted in better tumor growth inhibition compared to the tumor inhibition when the total radioactivity was delivered by any of the two carriers alone. This finding was due to more uniform tumor irradiation for the same total injected radioactivity. The killing efficacy was improved even though the tumor‐absorbed dose delivered by the combined carriers was lower than the tumor‐absorbed dose delivered by the antibody alone. Studies on spheroids with different receptor‐expression, used as surrogates of the tumors' avascular regions, demonstrated that our delivery strategy is valid even for as low as 1+ (ImmunoHistoChemistry score) PSMA‐levels. The findings presented herein may hold clinical promise for those established tumors not being effectively eradicated by current α‐particle radiotherapies.

Abstract Rapid, widespread changes in public perceptions and behaviors have the potential to influence conservation outcomes. However, few studies have documented whether and how such shifts occur throughout the span of a conservation initiative. We examined the 2020 ballot initiative to reintroduce wolves into Colorado, which passed with less support than prior surveys had estimated. We conducted a postelection survey of Colorado residents using the same methods as our preelection survey to compare responses between surveys and to official election results. Reported voting in favor of wolf reintroduction in the postelection survey decreased in comparison to voting intentions shared in the preelection survey, but not enough to reflect the actual vote. While bias from survey methods and/or sampling contributed to differences, we also found evidence that public perception changed. Specifically, beliefs about the potential for negative impacts of wolves increased, while beliefs about the potential for positive impacts of wolves decreased. Our findings highlight the need to conduct longitudinal monitoring of public perception given perceptions may be highly fluid as different entities attempt to sway voters. In addition, to better understand evolving perceptions, survey methods and sampling need to be improved.

Abstract Background Ingrowing toenails are a common and painful condition often requiring surgical management. Practitioners who perform surgery on ingrowing toenails include orthopaedic surgeons, general practitioners, podiatrists and podiatric surgeons. There has been limited investigation into the specific surgical approaches used by Australian podiatric surgeons for ingrowing toenails, or the associated infection rates for these procedures. The aim of this study was to assess the frequency and type of ingrowing toenail surgery performed by podiatric surgeons, and identify risk factors for post-operative infection. Methods Data was entered into the Australian College Podiatric Surgeons (ACPS) National Audit Tool for all patients who underwent foot and ankle surgery performed by podiatric surgeons in Australia between January 2014 and December 2017. Infection within the first 30 days following surgery was recorded according to the ACPS national audit descriptors. Infection rates, risk ratios (RR) and 95% Confidence Intervals (CI) were calculated to determine postoperative infection risk. Results Of 7682 records, 1831 reported 2712 diagnoses of ingrowing nails. Patients with a diagnosis of ingrowing toenails were younger, less likely to have systemic disease, and a lower proportion were female compared to those without ingrowing toenails. Furthermore, they were more likely to be diagnosed with a post-operative infection than those without ingrowing toenails (RR = 2.72; CI = 2.00–3.69; P

Abstract Purpose To use serial PET/MRI imaging to radiographically evaluate the metabolic activity of the ACL graft over the first post-operative year. Methods Six patients undergoing primary ACL reconstruction were recruited in this prospective study in an inpatient university hospital. All patients underwent femoral and tibial suspensory cortical fixation with quadrupled semitendinosus autograft hamstring ACL reconstruction by an orthopaedic surgeon. Simultaneous 18F-FDG PET and MRI of both the operative and non-operative knee was performed at three, six, and 12 months post-operatively. Quantification of the mean standardized uptake value (SUV) within the whole-knee, as well as tibial tunnel, femoral tunnel, and intra-articular graft regions of interest (ROIs). Results PET whole-knee activity was increased at all time-points post-operatively compared to the control, non-operative knee. Activity decreased over time, yet considerable generalized activity remained 1 year post-operatively, with relative intensity 34% percent higher than control. When the operative knee was divided into three whole-regions, there was greater activity in the tibia at three than 12 months, the femur at six than 12 months, and in the tibia compared to the intra-articular region at 3 months. When they were separated into sub-regions, results demonstrated greater activity closer to the joint surface. Conclusions PET/MRI evaluation of ACL graft reconstructions demonstrates evolving biologic activity within the graft and both tunnels. Focal areas of increased activity within the tunnels may indicate of ligamento-osseous morphologic changes. These data suggest that graft incorporation continues well beyond 1 year post-operatively. Level of evidence Level IV.

Abstract Aims The aim of this study was to investigate prospectively the effect of sacubitril/valsartan in advanced heart failure (HF) patients in waiting list for heart transplantation (HT) and the effect on physical frailty (PF). Methods and results We treated 37 consecutive patients with advanced HF with sacubitril/valsartan. Patients were followed up until HT, device implant, or last follow‐up visit after 2 years of follow‐up. At baseline, mean New York Heart Association (NYHA) class was 3.1 ± 0.4, with 64.9% in NYHA III and 35.1% NYHA IIIB. Left ventricular ejection fraction was 23.5 ± 5.8%, VO2 max was 10.3 ± 2.3 mL/kg/min, cardiac index was 2.3 ± 0.5 L/min/m2, and N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) was 4943.0 ± 5326.8 pg/mL. After a mean follow‐up of 17.1 ± 4.4 months, no deaths were observed, but NYHA class improved significantly with 56.8% in NYHA II, 40.5% in NYHA III, and 2.7% in NYHA IIIB (P < 0.001). VO2 max and 6 min walk test (6MWT) increased, whereas pulmonary systolic blood pressure, E/E′, VE/VCO2 slope, and NT‐pro‐BNP decreased. At right heart catheterization performed after 1 year of follow‐up, cardiac index and pulmonary vascular resistance remained stable, while a decrease in systolic pulmonary artery pressure and pulmonary capillary wedge pressure is observed. Furosemide dosage decrease from 102.7 ± 69.4 to 78.7 ± 66.3 mg (P = 0.040). PF decreased from 3.35 ± 1.0 at baseline to 1.57 ± 1.3 at the end of follow‐up (P < 0.001), with a reduction in all PF domains. Conclusions Our study showed a rapid improvement in PF in HT waiting list patients treated with sacubitril/valsartan. The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together with an NT‐pro‐BNP reduction constant over the follow‐up.

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically‐based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24–50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24–33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration‐time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.

Abstract The success rate of weed biological control programs is difficult to evaluate and the factors affecting it remain poorly understood. One aspect which is still unclear is whether releases of multiple, genetically distinct populations of a biological control agent increase the likelihood of success, either by independent colonization of different environmental niches or by hybridization that may increase the agent's fitness and adaptive ability. Since hybridization is often invoked to explain the success of unintentionally introduced exotic species, hybridization among biocontrol agents may be similarly important in shaping the effectiveness of biological control programs. In this study, we first evaluated intraspecific hybridization among populations of a weed biological control agent, the ragwort flea beetle, Longitarsus jacobaeae. These insects were introduced as part of a classical biological control program from Italy and Switzerland. We genotyped 204 individuals from 15 field sites collected in northwest Montana, and an additional 52 individuals that served as references for Italian and Swiss populations. Bayesian analysis of population structure assigned seven populations as pure Swiss and one population as pure Italian, while intraspecific hybrid individuals were detected in seven populations at frequencies of 5%–69%. Subsequently, we conducted a 2‐year exclusion experiment using six sites with Swiss beetles and three with hybrid beetles to evaluate the impact of biological control. We found that biological control by Swiss beetles and by hybrid beetles is effective, increasing mortality of the target plant, Jacobaea vulgaris, by 42% and 45%, and reducing fecundity of surviving plants by 44% and 72%, respectively. Beetle densities were higher and mortality of larger plants was higher at sites with hybrids present. These results suggest that hybridization of ragwort flea beetles at high‐elevation sites may improve biological control of tansy ragwort and that intraspecific hybridization of agents could benefit biological control programs.

Abstract Largely absent from the current scientific dialog is recognition of which voices should contribute to decisions on the future of Africa's elephants, particularly those living in the Kavango‐Zambezi Transfrontier Conservation Area. We argue that elephant conservation policy must take into account the voices of the people bearing the cost of living with wildlife, as well as the nations with the responsibility of hosting elephant populations. Southern African elephant conservation is a 'wicked problem', which is best addressed through small wins approaches. Specifically, research on changes in local political and governance dynamics resulting from community conservation programs is needed, to identify new modalities for community level engagement. Additionally, research into policy implications, as well as seasonal resource needs of humans and wildlife, from zoning and corridor development to facilitate landscape level movement is needed. A modular approach to research for ensuring functional social–ecological landscapes within the KAZA context could help sustain both wildlife and communities in the region.

Abstract Gray wolves (Canis lupus) were eliminated from the state of Oregon in the middle of the 20th century. By the early 21st century, wolves had returned to the northeast corner of the state, dispersing from populations reintroduced in Idaho and Wyoming. On a series of random‐sample telephone surveys (2011–2018), we asked more than 3,000 northeast Oregon residents about their preferences concerning wolf management strategies. One‐third of the respondents said that wolves should be eliminated from this region. Sociopolitical identity dominated other individual characteristics including age, education, years resident, and forestland ownership in predicting wolf‐management views. Political effects appear even stronger when our indicator distinguishes the most conservative, and further intensify when most of the respondent's friends belong to the same party. This strong influence of sociopolitical identity echoes findings from the broader literature on environmental concern, but adds a new and policy‐relevant element to wolf‐attitude research. As wolves expand throughout the west, and new states consider reintroduction, state and federal wildlife managers face deeply rooted opposition. Managers must consider a range of strategies to manage wolves while working with community leaders in wolf‐occupied areas to determine management options.