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Abstract Knee ligament sprains are common during change-of-direction (COD) maneuvers in multidirectional team sports. This study aimed to compare the effects of an 8-week injury prevention exercise program containing COD-specific exercises and a similar program containing linear sprint exercises on injury- and performance-related variables during a 135° COD task. We hypothesized that the COD-specific training would lead to (H1) stronger reductions in biomechanical variables associated with anterior cruciate ligament (ACL) injury risk during COD, i.e. knee abduction moment and angle, hip internal rotation angle and lateral trunk lean, and (H2) more effective improvements in COD performance according to the COD completion time, executed angle, ground contact time, and approach speed. Twenty-two sports science students (40% female) completed biomechanical assessments of COD movement strategies before and after participating in two supervised 25-min training sessions per week over 8 weeks. We observed significant ‘training x group’ interaction effects in support of H1: the COD-specific training but not the linear sprint training led to reduced peak knee abduction moments (interaction, p = 0.027), initial knee abduction (interaction, p

In the 2022 summer, western–central Europe and several other regions in the northern extratropics experienced substantial soil moisture deficits in the wake of precipitation shortages and elevated temperatures. Much of Europe has not witnessed a more severe soil drought since at least the mid-20th century, raising the question whether this is a manifestation of our warming climate. Here, we employ a well-established statistical approach to attribute the low 2022 summer soil moisture to human-induced climate change using observation-driven soil moisture estimates and climate models. We find that in western–central Europe, a June–August root zone soil moisture drought such as in 2022 is expected to occur once in 20 years in the present climate but would have occurred only about once per century during preindustrial times. The entire northern extratropics show an even stronger global warming imprint with a 20-fold soil drought probability increase or higher, but we note that the underlying uncertainty is large. Reasons are manifold but include the lack of direct soil moisture observations at the required spatiotemporal scales, the limitations of remotely sensed estimates, and the resulting need to simulate soil moisture with land surface models driven by meteorological data. Nevertheless, observation-based products indicate long-term declining summer soil moisture for both regions, and this tendency is likely fueled by regional warming, while no clear trends emerge for precipitation. Finally, our climate model analysis suggests that under 2 ∘C global warming, 2022-like soil drought conditions would become twice as likely for western–central Europe compared to today and would take place nearly every year across the northern extratropics.

Purpose: To determine proportion of eyes with neovascular age-related macular degeneration (nAMD) with retinal fluid and/or central subfield thickness (CST) fluctuations and evaluate their impact on best-corrected visual acuity (BCVA) in eyes treated with the Port Delivery System with ranibizumab (PDS) versus monthly intravitreal ranibizumab injections., Design: Post-hoc analyses of phase 3 Archway trial (NCT03677934)., Participants: Adults with nAMD responsive to anti-vascular endothelial growth factor therapy., Intervention: 418 patients randomized 3:2 to the PDS (100 mg/mL) with refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab (0.5 mg) for 96 weeks., Outcomes: Proportion of eyes in each treatment arm with subretinal and/or intraretinal fluid (SRF/IRF) overall and in central 1-mm; BCVA changes from baseline by treatment arm and fluid presence/location; proportion of eyes with CST fluctuations from baseline to week 48, week 48 to 96, and baseline to week 96; effects of CST fluctuations on BCVA., Results: 415 eyes were assessed. In the PDS versus monthly ranibizumab arm, proportion of eyes with SRF/IRF, central SRF, and central IRF were 47.6% versus 50.9%, 29.0% versus 19.2%, and 11.7% versus 12.6% at baseline, and 57.8% versus 56.1%, 21.6% versus 14.8%, and 7.0% versus 8.4% at week 96. BCVA changes from baseline to week 96 were -1.1 letters with the PDS versus -1.4 with monthly ranibizumab in eyes with SRF/IRF, and -1.9 versus -1.8 in eyes with central SRF. In eyes with central IRF, BCVA changes from baseline to week 96 were -2.1 with the PDS versus -6.9 with monthly ranibizumab, respectively (mean BCVA at 96 weeks 68.9 [20/40] versus 64.6 [20/50]). CST fluctuations occurred in 32.1% and 29.7% of PDS versus monthly ranibizumab eyes; corresponding BCVA changes from baseline to week 96 were -2.5 versus -2.6 (mean BCVA at 96 weeks 72.7 [20/35] versus 71.5 [20/38])., Conclusions: PDS Q24W maintained BCVA to 96 weeks regardless of SRF/IRF, central SRF, central IRF, or CST fluctuations, comparable with monthly ranibizumab, thus supporting the use of the PDS in stabilizing retinal anatomy without the need for monthly treatment in patients with nAMD., (Copyright © 2024. Published by Elsevier Inc.)

Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC., Methods: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1., Results: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects., Conclusions: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab., Clinical Trial Registration: ClinicalTrials.gov; NCT03260894 ., (© 2023. The Author(s).)

Purpose: To determine the proportion and characteristics of eyes with neovascular age-related macular degeneration (nAMD) treated with the Port Delivery System (PDS) with ranibizumab that receive supplemental intravitreal ranibizumab injections because of changes in best-corrected visual acuity (BCVA) or central subfield thickness (CST), or both, and to investigate the safety and efficacy of supplemental injections in eyes with the PDS., Design: Post hoc analyses of data from the phase III, randomized, multicenter, open-label, active-comparator Archway trial (NCT03677934)., Participants: Adults with nAMD diagnosed within 9 months of screening previously responsive to anti-VEGF therapy., Intervention: Four hundred eighteen patients were randomized to the PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab 0.5 mg for 96 weeks., Results: Of the 246 eyes treated with the PDS Q24W and assessed for supplemental treatment criteria, the vast majority (94.6%-98.4%) did not receive supplemental treatment during each retreatment interval, with 87.4% not receiving supplemental treatment at any point during the trial. Of the 31 eyes receiving supplemental treatment, 58.1% received 1 injection and 32.3% received 2. At baseline, eyes receiving supplemental treatment were significantly more likely to have thicker retinas (mean CST, 370.5μm vs. 304.4μm; P = 0.0001), subretinal fluid (54.8% vs. 21.2%; P < 0.0001), and larger pigment epithelial detachment height (215.7 μm vs. 175.9 μm; P = 0.003). These features have previously been associated with difficult-to-treat nAMD. Although BCVA and CST generally remained constant throughout the trial in eyes without supplemental treatment, the small number of eyes receiving supplemental treatment on average lost 1 line of vision from baseline to week 96 (mean, -5.7 ETDRS score letters) and CST continued to increase over time. Absolute BCVA at week 96 was similar irrespective of supplemental treatment status (71.1 and 73.7 letters). Best-corrected visual acuity and CST generally improved within 28 days of supplemental treatment., Conclusions: Although the PDS Q24W effectively maintains vision and retinal stability in most eyes with nAMD, a small proportion of patients with features of difficult-to-treat nAMD may benefit from supplemental intravitreal anti-VEGF injections and initial close monitoring is recommended., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To investigate the effects of simultaneous cortisol cosecretion (CCS) on body composition in computed tomography (CT)-imaging and metabolic parameters in patients with primary aldosteronism (PA) with the objective of facilitating early detection., Design: Retrospective cohort study., Patients: Forty-seven patients with PA and CCS confirmed by 1-mg dexamethasone suppression test (DST) with a cutoff of ≥1.8 µg/dL were compared with PA patients with excluded CCS (non-CCS, n = 47) matched by age and sex., Methods: Segmentation of the fat compartments and muscle area at the third lumbar region was performed on non-contrast-enhanced CT images with dedicated segmentation software. Additionally, liver, spleen, pancreas and muscle attenuation were compared between the two groups., Results: Mean cortisol after DST was 1.2 µg/dL (33.1 nmol/L) in the non-CCS group and 3.2 µg/dL (88.3 nmol/L) in the CCS group with mild autonomous cortisol excess (MACE). No difference in total, visceral and subcutaneous fat volumes was observed between the CCS and non-CCS group (p = .7, .6 and .8, respectively). However, a multivariable regression analysis revealed a significant correlation between total serum cholesterol and results of serum cortisol after 1-mg DST (p = .026). Classification of the patients based on visible lesion on CT and PA-lateralization via adrenal venous sampling also did not show any significant differences in body composition., Conclusion: MACE in PA patients does not translate into body composition changes on CT-imaging. Therefore, early detection of concurrent CCS in PA is currently only attainable through biochemical tests. Further investigation of the long-term clinical adverse effects of MACE in PA is necessary., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Pathogenic platelet factor 4 (PF4) antibodies contributed to the abnormal coagulation profiles in COVID-19 and vaccinated patients. However, the mechanism of what triggers the body to produce these antibodies has not yet been clarified. Similar patterns and many comparable features between the COVID-19 virus and heparin-induced thrombocytopenia (HIT) have been reported. Previously, we identified a new mechanism of autoimmunity in HIT in which PF4-antibodies self-clustered PF4 and exposed binding epitopes for other pathogenic PF4/eparin antibodies. Here, we first proved that the SARS-CoV-2 spike protein (SP) also binds to PF4. The binding was evidenced by the increase in mass and optical intensity as observed through quartz crystal microbalance and immunosorbent assay, while the switching of the surface zeta potential caused by protein interactions and binding affinity of PF4-SP were evaluated by dynamic light scattering and isothermal spectral shift analysis. Based on our results, we proposed a mechanism for the generation of PF4 antibodies in COVID-19 patients. We further validated the changes in zeta potential and interaction affinity between PF4 and SP and found that their binding mechanism differs from ACE2-SP binding. Importantly, the PF4/SP complexes facilitate the binding of anti-PF4/Heparin antibodies. Our findings offer a fresh perspective on PF4 engagement with the SARS-CoV-2 SP, illuminating the role of PF4/SP complexes in severe thrombotic events.

Knee ligament sprains are common during change-of-direction (COD) maneuvers in multidirectional team sports. This study aimed to compare the effects of an 8-week injury prevention exercise program containing COD-specific exercises and a similar program containing linear sprint exercises on injury- and performance-related variables during a 135° COD task. We hypothesized that the COD-specific training would lead to (H1) stronger reductions in biomechanical variables associated with anterior cruciate ligament (ACL) injury risk during COD, i.e. knee abduction moment and angle, hip internal rotation angle and lateral trunk lean, and (H2) more effective improvements in COD performance according to the COD completion time, executed angle, ground contact time, and approach speed. Twenty-two sports science students (40% female) completed biomechanical assessments of COD movement strategies before and after participating in two supervised 25-min training sessions per week over 8 weeks. We observed significant 'training x group' interaction effects in support of H1: the COD-specific training but not the linear sprint training led to reduced peak knee abduction moments (interaction, p = 0.027), initial knee abduction (interaction, p < 0.001), and initial lateral trunk lean angles (interaction, p < 0.001) compared to baseline. Although the COD-specific training resulted in sharper executed angles (interaction, p < 0.001), the sprint-specific training group showed reduced COD completion (interaction, p = 0.037) and ground contact times (interaction, p < 0.001). In conclusion, a combination of generic and COD-specific injury prevention training resulted in COD technique adaptations that can help to avoid ACL injury-prone COD movements but may negatively affect COD speed., (© 2024. The Author(s).)

What Is This Summary About?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide., What Is Metastatic Castration-Resistant Prostate Cancer?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer., What Are the Aims of the Talapro-2 Trial?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study., What Are the Key Takeaways?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients). Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

For most applications, 2D keypoint detection works well and offers a simple and fast tool to analyse human movements. However, there remain many situations where even the best state-of-the-art algorithms reach their limits and fail to detect human keypoints correctly. Such situations may occur especially when individual body parts are occluded, twisted, or when the whole person is flipped. Especially when analysing injuries in alpine ski racing, such twisted and rotated body positions occur frequently. To improve the detection of keypoints for this application, we developed a novel method that refines keypoint estimates by rotating the input videos. We select the best rotation for every frame with a graph-based global solver. Thereby, we improve keypoint detection of an arbitrary pose estimation algorithm, in particular for 'hard' keypoints. In the current proof-of-concept study, we show that our approach outperforms standard keypoint detection results in all categories and in all metrics, in injury-related out-of-balance and fall situations by a large margin as well as previous methods, in performance and robustness. The Injury Ski II dataset was made publicly available, aiming to facilitate the investigation of sports accidents based on computer vision in the future., (© 2023. The Author(s).)

Background: Distinguishing primary and secondary pulmonary neoplasms can be challenging via cytology, and a rapid, inexpensive diagnostic tool to differentiate these neoplasms is unavailable. Alkaline phosphatase cytochemistry (ALP-CC) has been used to identify primary pulmonary carcinomas in human patients, and we hypothesized it could be applied to canine lung aspirates., Objective: We aimed to characterize ALP-CC expression in fine-needle aspirate (FNA) samples of canine pulmonary neoplastic and non-neoplastic tumors., Methods: A retrospective case search was conducted to identify cases with contemporaneous cytology and histopathology reports from pulmonary lesions, including neoplastic and non-neoplastic etiologies. Slides prepared from pulmonary aspirates were stained for ALP-CC activity, and the percentage of ALP-CC-positive primary pulmonary epithelial tumors was determined. To characterize the ALP-CC expression in non-neoplastic cellular constituents of pulmonary FNA samples, mesothelial cells were also evaluated., Results: Forty-eight canine cases met the inclusion criteria. ALP-CC-positive cells were seen in both neoplastic and non-neoplastic lesions. In non-neoplastic lesions, pulmonary epithelial cells were ALP-CC positive. Eighty-nine percent of primary pulmonary epithelial neoplasms were ALP-CC positive, and no ALP-CC positivity was noted in mesothelial cells. ALP-CC-positive neoplastic cells were seen in a metastatic amelanotic melanoma., Conclusions: Primary pulmonary epithelial neoplasms are frequently ALP-CC positive, but such positivity is not restricted to this tumor type. Non-neoplastic pulmonary epithelial cells can be ALP-CC positive, whereas mesothelial cells are negative., (© 2023 The Authors. Veterinary Clinical Pathology published by Wiley Periodicals LLC on behalf of American Society for Veterinary Clinical Pathology.)

Objectives: The aim of this study was to investigate an integrated diagnostics approach for prediction of the source of aldosterone overproduction in primary hyperaldosteronism (PA)., Methods: 269 patients from the prospective German Conn Registry with PA were included in this study. After segmentation of adrenal glands in native CT images, radiomic features were calculated. The study population consisted of a training (n = 215) and a validation (n = 54) cohort. The k = 25 best radiomic features, selected using maximum-relevance minimum-redundancy (MRMR) feature selection, were used to train a baseline random forest model to predict the result of AVS from imaging alone. In a second step, clinical parameters were integrated. Model performance was assessed via area under the receiver operating characteristic curve (ROC AUC). Permutation feature importance was used to assess the predictive value of selected features., Results: Radiomics features alone allowed only for moderate discrimination of the location of aldosterone overproduction with a ROC AUC of 0.57 for unilateral left (UL), 0.61 for unilateral right (UR), and 0.50 for bilateral (BI) aldosterone overproduction (total 0.56, 95% CI: 0.45-0.65). Integration of clinical parameters into the model substantially improved ROC AUC values (0.61 UL, 0.68 UR, and 0.73 for BI, total 0.67, 95% CI: 0.57-0.77). According to permutation feature importance, lowest potassium value at baseline and saline infusion test (SIT) were the two most important features., Conclusion: Integration of clinical parameters into a radiomics machine learning model improves prediction of the source of aldosterone overproduction and subtyping in patients with PA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mansour, Mittermeier, Walter, Schachtner, Rudolph, Erber, Schmidt, Heinrich, Bruedgam, Tschaidse, Nowotny, Bidlingmaier, Kunz, Adolf, Ricke, Reincke, Reisch, Wildgruber and Ingrisch.)

Background: Although biosimilar uptake has increased (at a variable pace) in many countries, there have been recent concerns about the long-term sustainability of biosimilar markets. The aim of this manuscript is to assess the sustainability of policies across the biosimilar life cycle in selected countries with a view to propose recommendations for supporting biosimilar sustainability. Methods: The study conducted a comparative analysis across 17 countries from North America, South America, Asia-Pacific, Europe and the Gulf Cooperation Council. Biosimilar policies were identified and their sustainability was assessed based on country-specific reviews of the scientific and grey literature, validation by industry experts and 23 international and local non-industry experts, and two advisory board meetings with these non-industry experts. Results: Given that European countries tend to have more experience with biosimilars and more developed policy frameworks, they generally have higher sustainability scores than the other selected countries. Existing approaches to biosimilar manufacturing and R&D, policies guaranteeing safe and high-quality biosimilars, exemption from the requirement to apply health technology assessment to biosimilars, and initiatives counteracting biosimilar misconceptions are considered sustainable. However, biosimilar contracting approaches, biosimilar education and understanding can be ameliorated in all selected countries. Also, similar policies are sometimes perceived to be sustainable in some markets, but not in others. More generally, the sustainability of the biosimilar landscape depends on the nature of the healthcare system and existing pharmaceutical market access policies, the experience with biosimilar use and policies. This suggests that a general biosimilar policy toolkit that ensures sustainability does not exist, but varies from country to country. Conclusion: This study proposes a set of elements that should underpin sustainable biosimilar policy development over time in a country. At first, biosimilar policies should guarantee the safety and quality of biosimilars, healthy levels of supply and a level of cost savings. As a country gains experience with biosimilars, policies need to optimise uptake and combat any misconceptions about biosimilars. Finally, a country should implement biosimilar policies that foster competition, expand treatment options and ensure a sustainable market environment., Competing Interests: GC-H has received consultancy and speaker fees from AbbVie, Amgen, Janssen-Cilag, Libbs, Novartis, Pfizer, Roche, Sanofi, Takeda, and UCB. OM and GH work at Nile, secretary general of the French think tank “Biosimilaires” and have links of interest with Accord Healthcare, Amgen, Biogen, and Sandoz. MT has received personal honoraria for lectures and participation in advisory boards from Amgen, Medscape, Jörg Eickeler, Onkowissen, Organon, Pfizer, Viatris, Vifor. He received manuscript support by Amgen, Roche, Servier and travel expenses by Amgen, Hexal, I-Med-Institute, Pfizer, Roche. Congress support was given by Amgen, Hexal, Pfizer, Roche. TW, MP, and RS were commissioned to support the project that informed this analysis and they assume editorial responsibility as contributors to the study. Charles River Associates is an economic consultancy company. SS is one of the founding members of the KU Leuven Fund on Market Analysis of Biologics and Biosimilars following Loss of Exclusivity (MABEL Fund). SS was involved in a stakeholder roundtable on biologics and biosimilars sponsored by Amgen, Pfizer and MSD, and he has participated in advisory board meetings for Amgen, Pfizer, Organon and Sandoz. He has contributed to studies on biologics and biosimilars for Hospira, Celltrion, Mundipharma and Pfizer; and he has had speaking engagements for Amgen, Celltrion, Organon and Sandoz. Author AB was employed by Matrix Global Advisors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (Copyright © 2023 Alnaqbi, Bellanger, Brill, Castañeda-Hernández, Clopés Estela, Delgado Sánchez, García-Alfonso, Gyger, Heinrich, Hezard, Kakehasi, Koehn, Mariotte, Mennini, Mayra Pérez-Tapia, Pistollato, Saada, Sasaki, Tambassis, Thill, Werutsky, Wilsdon and Simoens.)

Background: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing., Findings: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group., Interpretation: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations., Funding: Pfizer., Competing Interests: Declaration of interests NA has received an honorarium for consultancy since May, 2020, from the following: Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma, and research funding (institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON. AAA reports honoraria from Aculeus Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix Pharmaceuticals, and Tolmar; consulting fees from Aculeus Therapeutics, Astellas Pharma, Janssen, and Novartis; participation on advisory boards for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, and Tolmar; participation on a data safety monitoring board for OncoSec; research funding (institution unless stated otherwise) from Aptevo Therapeutics, Astellas Pharma (investigator), AstraZeneca (investigator), Bionomics, Bristol Myers Squibb, Exelixis, Gilead Sciences, GlaxoSmithKline, Hinova Pharmaceuticals, Ipsen, Janssen, Lilly, MedImmune, Merck Serono (investigator), MSD, Novartis, Pfizer, Sanofi, and Synthorx; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, Janssen, Merck Serono, Novartis, Pfizer, and Tolmar; and receiving medical writing services from Astellas Pharma, Exelixis, and Pfizer; he is Chair of the Urologic Oncology Group for the Clinical Oncology Society of Australia, and Chair of the Translational Research Subcommittee and on the Scientific Advisory Committee for the ANZUP Cancer Trials Group. JC reports a consulting or advisory role for Advanced Accelerator Applications/Novartis, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Pfizer, Roche, and Sanofi; participation in speakers' bureau for Astellas Pharma, Bayer, and Johnson & Johnson; research funding (institution) from AB Science, Aragon Pharmaceuticals, AROG Pharmaceuticals, Astellas Pharma, AstraZeneca, AVEO Pharmaceuticals, Bayer, Blueprint Medicines, BN ImmunoTherapeutics, Boehringer Ingelheim España, Bristol Myers Squibb International Corporation, Clovis Oncology, Cougar Biotechnology, Deciphera, Exelixis, Genentech, GlaxoSmithKline, Incyte, Janssen-Cilag International, Karyopharm Therapeutics, Laboratoires Leurquin Mediolanum, Lilly, MedImmune, Millennium Pharmaceuticals, Nanobiotix, Novartis Farmacéutica, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis, SFJ Pharmaceuticals Group, and Teva; and travel, accommodations, and/or expenses from AstraZeneca, BMS, Ipsen, and Roche. APF reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; a consulting or advisory role for Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; stock or stock options in Brazilian Information Oncology; and research funding from AstraZeneca, Bristol Myers Squibb, CAPES – CNPq, Foundation Medicine, Ipsen, MSD, and Roche; and travel, accommodations and/or expenses from Astellas Pharma, AstraZeneca, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. NM reports honoraria (personal) from Sanofi; research funding (institution) from Amgen, Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Eisai, Janssen, Lilly, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, and Takeda; and travel, accommodations, and/or expenses (personal) from Pfizer. DH reports honoraria (personal) from Advanced Accelerator Applications/Novartis, Astellas Pharma, Bayer, Bristol Myers Squibb, EUSA Pharma, Ferring, Ipsen, Janssen, MSD, and Novartis; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, Eisai, Ipsen, Janssen, Novartis, Organon, Pfizer, and Roche; and research funding (institution) from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, MSD, Pfizer, and Roche. UDG reports a consulting or advisory role for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Clovis Oncology, Dompé Farmaceutici, Eisai, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, and PharmaMar; research funding (institution) from AstraZeneca, Roche, and Sanofi; and travel, accommodations, and/or expenses from Ipsen and Pfizer. PCCF reports a consulting or advisory role for MSD and travel, accommodations, and/or expenses from Pfizer. RJJ reports honoraria from Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; a consulting or advisory role for Astellas Pharma, Bayer, Bristol Myers Squibb, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, and Roche; research funding from Astellas Pharma, Bayer, Clovis Oncology, Exelixis, and Roche; and travel, accommodations, and/or expenses from Bayer and Janssen. NDS reports a consulting or advisory role for AbbVie, Alessa Therapeutics, Akido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Ferring, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. CD reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. SZ reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen (personal and institution), Bayer, (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); participation on a data safety monitoring board or advisory board for Amgen (personal and institution), Bayer (personal and institution), Bristol Myers Squibb (institution), Eisai (personal), Janssen (personal), MSD (institution), Novartis (personal), and Pfizer (institution); research funding (institution) from Eisai; and travel, accommodations, and/or expenses from Amgen, Astellas Pharma, AstraZeneca, Ipsen, Janssen, Merck, MSD, and Pfizer. JO reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, AstraZeneca, Bayer, BMS Norway, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; participation on a data safety monitoring board or advisory board for Astellas Pharma, AstraZeneca, Bayer, BMS, Eisai, Ipsen, Janssen-Cilag, Merck, and Roche; and travel, accommodations, and/or expenses from Astellas Pharma. XL, CGH, NDiS, and FZ are employees of Pfizer and may hold Pfizer stock/stock options. KF reports honoraria (institution) for participation in advisory boards and talks from Advanced Accelerator Applications/Novartis, Amgen, Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, MSD, Novartis, Pfizer, and Sanofi; and honoraria (personal) for participation in advisory boards from Arvinas, CureVac, MacroGenics, and Orion. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In vivo, cells navigate through complex environments filled with obstacles such as other cells and the extracellular matrix. Recently, the term "topotaxis" has been introduced for navigation along topographic cues such as obstacle density gradients. Experimental and mathematical efforts have analyzed topotaxis of single cells in pillared grids with pillar density gradients. A previous model based on active Brownian particles (ABPs) has shown that ABPs perform topotaxis, i.e., drift toward lower pillar densities, due to decreased effective persistence lengths at high pillar densities. The ABP model predicted topotactic drifts of up to 1% of the instantaneous speed, whereas drifts of up to 5% have been observed experimentally. We hypothesized that the discrepancy between the ABP and the experimental observations could be in 1) cell deformability and 2) more complex cell-pillar interactions. Here, we introduce a more detailed model of topotaxis based on the cellular Potts model (CPM). To model persistent cells we use the Act model, which mimics actin-polymerization-driven motility, and a hybrid CPM-ABP model. Model parameters were fitted to simulate the experimentally found motion of Dictyostelium discoideum on a flat surface. For starved D. discoideum, the topotactic drifts predicted by both CPM variants are closer to the experimental results than the previous ABP model due to a larger decrease in persistence length. Furthermore, the Act model outperformed the hybrid model in terms of topotactic efficiency, as it shows a larger reduction in effective persistence time in dense pillar grids. Also pillar adhesion can slow down cells and decrease topotaxis. For slow and less-persistent vegetative D. discoideum cells, both CPMs predicted a similar small topotactic drift. We conclude that deformable cell volume results in higher topotactic drift compared with ABPs, and that feedback of cell-pillar collisions on cell persistence increases drift only in highly persistent cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

In alpine skiing, estimation of the muscle forces and joint loads such as the forces in the ACL of the knee are essential to quantify the loading pattern of the skier during turning maneuvers. Since direct measurement of these forces is generally not feasible, non-invasive methods based on musculoskeletal modeling should be considered. In alpine skiing, however, muscle forces and ACL forces have not been analyzed during turning maneuvers due to the lack of three dimensional musculoskeletal models. In the present study, a three dimensional musculoskeletal skier model was successfully applied to track experimental data of a professional skier. During the turning maneuver, the primary activated muscles groups of the outside leg, bearing the highest loads, were the gluteus maximus, vastus lateralis as well as the medial and lateral hamstrings. The main function of these muscles was to generate the required hip extension and knee extension moments. The gluteus maximus was also the main contributor to the hip abduction moment when the hip was highly flexed. Furthermore, the lateral hamstrings and gluteus maximus contributed to the hip external rotation moment in addition to the quadratus femoris. Peak ACL forces reached 211 N on the outside leg with the main contribution in the frontal plane due to an external knee abduction moment. Sagittal plane contributions were low due to consistently high knee flexion (> 60[Formula: see text]), substantial co-activation of the hamstrings and the ground reaction force pushing the anteriorly inclined tibia backwards with respect to the femur. In conclusion, the present musculoskeletal simulation model provides a detailed insight into the loading of a skier during turning maneuvers that might be used to analyze appropriate training loads or injury risk factors such as the speed or turn radius of the skier, changes of the equipment or neuromuscular control parameters., (© 2023. The Author(s).)

Competitive skiers encounter a high risk of sustaining an ACL injury during jump-landing in downhill ski racing. Facing an injury-prone landing manoeuvre, there is a lack of knowledge regarding optimum control strategies. So, the purpose of the present study was to investigate possible neuromuscular control patterns to avoid injury during injury-prone jump-landing manoeuvres. A computational approach was used to generate a series of 190 injury-prone jump-landing manoeuvres based on a 25-degree-of-freedom sagittal plane musculoskeletal skier model. Using a dynamic optimization framework, each injury-prone landing manoeuvre was resolved to identify muscle activation patterns of the lower limbs and corresponding kinematic changes that reduce peak ACL force. In the 190 injury-prone jump-landing simulations, ACL forces peaked during the first 50 ms after ground contact. Optimized muscle activation patterns, that reduced peak ACL forces, showed increased activation of the monoarticular hip flexors, ankle dorsi- and plantar flexors as well as hamstrings prior to or during the early impact phase (<50 ms). The corresponding kinematic changes were characterized by increased hip and knee flexion and less backward lean of the skier at initial ground contact and the following impact phase. Injury prevention strategies should focus on increased activation of the monoarticular hip flexors, ankle plantar flexors and rapid and increased activation of the hamstrings in combination with a flexed landing position and decreased backward lean to reduce ACL injury risk during the early impact phase (<50 ms) of jump landing. Highlights First study investigating advantageous control strategies during injury-prone jump-landing manoeuvres in downhill skiing using a musculoskeletal simulation model and dynamic optimization framework.The simulation results predicted high injury risk during the first 50 ms after initial ground contact.Optimized neuromuscular control patterns showed adapted activation patterns (timing and amplitude) of muscles crossing the knee as well as the hip and ankle joints prior to and after initial ground contact, respectively.An optimized control strategy during an injury-prone landing manoeuvre was characterized kinematically by increasing hip and knee flexion and less backward lean of the skier at initial ground contact and the following impact phase.

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence., Objective: To present the voting results of the APCCC 2022., Design, Setting, and Participants: The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions., Results and Limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer., Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer., Twitter Summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer., Take-Home Message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aurelis Omlin: Advisory role (compensated, institutional): Astra Zeneca, Astellas, Bayer, Janssen, Molecular Partners, MSD, Pfizer, Roche, Sanofi Aventis. Research support (institutional): TEVA, Janssen. Travel support: Astellas, Bayer, Janssen, Sanofi Aventis. Speakers Bureau (compensated, institutional): Bayer, Astellas, Janssen. Fizazi Karim: Participation to advisory boards or talks for: Amgen, Astellas, Astrazeneca, Bayer, Clovis, Janssen, MSD, Novartis, Pfizer, Sanofi. Honoraria are provided to Gustave Roussy, my institution. Participation to advisory boards with personal honorarium for: CureVac, Orion. Bossi Alberto: Honoraria: Astellas, Ipsen, Janssen, Myovant. Consulting or advisory role: Astellas, Ipsen, Janssen, Myovant. Speakers’ bureau: Astellas, Ipsen, Elketa. Research funding: Astellas, Ipsen, Myovant. Travel, accommodations, expenses: Janssen. Tombal Bertrand: Advisor for Astellas, Amgen, Bayer, Curium, Ferring, Myovant, Janssens, MSD, Novartis (AAA), Pfizer, Sanofi. Gillessen Silke: SG received personal honoraria for participation in advisory boards for Sanofi, Orion, Roche, Amgen, MSD; other honoraria from RSI (Televisione Svizzera Italiana); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary oncology (SAMO), Orikata academy research group, China Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU); Speaker’s bureau for Janssen Cilag; travel grant from ProteoMEdiX; institutional honoraria for advisory boards for Bayer, Janssen Cilag, Roche, AAA International including Indipendent Data Monitoring Committee and IDMC and Steering Committee member for Amgen, Menarini Silicon Biosystems, Astellas Pharma, Tolero Pharmaceutcials, MSD, Pfizer, Telixpharma, BMS and Orion; patent royalties and other intellectual property for a research method for biomarker WO2009138392. Ian Davis: Research Funding: Company: Astellas Pharma, Recipient: Your Institution; Company: Pfizer, Recipient: Your Institution; Company: Roche/Genentech, Recipient: Your Institution; Company: MSD Oncology, Recipient: Your Institution; Company: AstraZeneca, Recipient: Your Institution; Company: Janssen Oncology, Recipient: Your Institution; Company: Eisai, Recipient: Your Institution; Company: Bayer, Recipient: Your Institution; Company: Amgen, Recipient: Your Institution; Company: Bristol-Myers Squibb, Recipient: Your Institution; Company: Movember Foundation, Recipient: Your Institution; Company: Exelixis, Recipient: Your Institution; Company: Ipsen, Recipient: Your Institution; Company: Medivation, Recipient: Your Institution; Company: Seagen, Recipient: Your Institution. Patents, Royalties, Other Intellectual Property: Please describe: International Patent Application No: PCT /US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research; Recipient: You. Christopher Sweeney: Receipt of grants/research supports: Astellas, Bayer, Janssen, Pfizer, Sanofi, Dendreon; Receipt of honoraria or consultation fees: Astellas, Bayer, Janssen, Pfizer, Sanofi, Lilly, Genentech. Eric J. Small: Receipt of honoraria or consultation fees: Jannsen, Johnson & Johnson; Participation in a company sponsored speaker’s bureau: Jannsen, Fortis, Teon, Ulgragenyx, Fortis, Harpoon Johann de Bono: Receipt of grants/research supports: Professor De Bono is an employee of The Institute of Cancer Research, which has received funding or other support for his research work from Astellas, Astra Zeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income); Receipt of honoraria or consultation fees: Professor De Bono has served on advisory boards and received fees from Amgen, Astellas, Astra Zeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon. Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Participation in a company sponsored speaker’s bureau: AstraZeneca, MSD. Matthew Smith: Receipt of grants/research supports: Clinical trial funding to my institution from: Amgen, Bayer, ESSA, Janssen, ORIC, Pfizer; Receipt of honoraria or consultation fees: Amgen, Astellas, Astrazeneca, Bayer, Janssen, ORIC, Pfizer. Neal Shore: Receipt of honoraria or consultation fees: Abbvie, Amgen, Astellas, Astrazeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, MDxhealth, Merck, Myvovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, Sanofi, Genzyme, Sesen Bio, Tolmar, Urogen; Partecipation in a company sponsored speaker's bureau: Astellas, Astrazeneca, Bayer, Clovis Oncology, Foundation Medicina, Janssen, Merck, Pfizer, Guardant Health. Nicholas James: Receipt of grants/research supports: • Funding for STAMPEDE trial – Coordinating PI – financial interest, Institutional. Name of commercial company: Astellas. • Funding for RADIO trial bladder cancer – Coordinating. PI – financial interest, Institutional. Name of commercial company: AstraZeneca. • Funding for STAMPEDE trial – Coordinating PI – No. financial interest, Institutional. Name of commercial company: Janssen; Receipt of honoraria or consultation fees: • Advisory Board – Advice around PARP inhibitors, Personal,<€5000. Name of commercial company: AstraZeneca dvisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Clovis. Expert Testimony – Assisted with submissions. regarding licensing for abiraterone, Institutional>€100,001. Name of commercial company: Janssen. Advisory Board – Prostate cancer therapies, Personal, €5001–€10,000. Name of commercial company: Janssen. Advisory Board – Bladder cancer therapy, Personal,<€5000. Name of commercial company: Merck. Advisory Board – Prostate cancer therapies, Personal,<€5000. Name of commercial company: Novartis Expert Testimony – Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel, Institutional,>€100,001. Name of commercial company: Sanofi. Advisory Board - Docetaxel, Personal,<€5000. Name of commercial company: Sanofi. Participation in a company sponsored speaker’s bureau: Bayer, Novartis. Nicolas MOTTET: Receipt of grants/research supports: Astellas, Sanofi Pasteur, Pierre Fabre; Receipt of honoraria or consultation fees: Astellas, Jansen, BMS, Bayer, IPSEN, Ferring, Sanofi, Steba, Astra Zeneca, Carrik, Arquer. diagnostics, GE, Takeda. Thomas ZILLI. AFFILIATION: Geneva University Hospital, Geneva, Switzerland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Varian Medical Systems International AG; Debiopharm. Receipt of honoraria or consultation fees: Janssen, Astellas, Debiopharm, Ferring, Varian Medical Systems International AG. Participation in a company sponsored speaker’s bureau: Janssen, Astellas, Debiopharm. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Geneva 07.02.2022. Christopher Logothetis. AFFILIATION: MD Anderson Cancer Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, ORIC Pharmaceuticals, Novartis, Aragon Pharmaceuticals. Receipt of honoraria or consultation fees: Merck, Sharp & Dohme, Bayer, Amgen. Participation in a company sponsored speakers bureau: None. Stock shareholder: None. Spouse/partner: None. Other support (please specify): None. Signature: Date: February 7, 2022. William Oh. AFFILIATION: Chief Medical Officer at Sema4 and Clinical Professor of Medicine, Div. of Hematology/Medical Oncology at Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Receipt of honoraria or consultation fees: GSK, Janssen, Merck, Pfizer. Participation in a company sponsored speakers bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 7, 2022. Himisha Beltran. AFFILIATION: Dana Farber Cancer Institute. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, AbbVie/Stemcentrx, Eli Lilly, Millennium Pharmaceuticals, Bristol Myers Squibb. Receipt of honoraria or consultation fees: Janssen, Astellas, Astra Zeneca, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, Oncorus, LOXO. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify): Signature: Date: Feb 7, 2022. Pirkko-Liisa Kellokumpu-Lehtinen. AFFILIATION: Tampere University and Tampere University Hospital, Tampere, Finland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Only directly to my hospital; Lilly, Merck and Finnish Cancer Society. Receipt of honoraria or consultation fees: BMS, Merck. Participation in a company sponsored speaker’s bureau: NONE. Stock shareholder: NONE. Spouse/partner: NONE. Other support (please specify):reimbursement of expenses to attend conference; Sanofi. Signature: Date: Feb 7, 2022. Prof. Mark A. Rubin, MD. AFFILIATION: University of Bern, Department for BioMedical Research (DBMR). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Janssen, Roche, Novartis. Receipt of honoraria or consultation fees: NeoGenomics Labs. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Dr. Thomas Steuber. AFFILIATION: Martini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: NONE. Receipt of honoraria or consultation fees: Astellas, Amgen, Bayer, Janssen, ProteoMedix, Sanofi, Merck, Astra Zeneca. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: Feb 8, 2022. Prof. Rob Bristow. AFFILIATION: University of Manchester. I have no potential conflict of interest to report. IGNACIO DURAN. AFFILIATION: HOSPITAL UNIVERSITARIO MARQUES DE VALDECILLA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Roche and Astra-Zeneca. Receipt of honoraria or consultation fees: Bristol Myers Squibb, MSD, Ipsen, Roche- Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. FERNANDO MALUF. AFFILIATION: ONCOLOGIST. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Hiroyoshi Suzuki. AFFILIATION: Department of Urology, Toho University Sakura Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Takeda, AsahiKasei, Taiho, Ono, Chugai, Sanofi, Daiichi-Sankyo, Nihon, Nippon Shinyaku. Receipt of honoraria or consultation fees: Bayer, Janssen, AstraZeneca, Astellas, Chuga-Roche, MSD. Participation in a company sponsored speaker’s bureau:Takeda, Bayer, Janssen, AstraZeneca, Astellas, Sanofi. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 8th 2022. Danny M. Rabah. AFFILIATION: King Saud University and king Faisal specialist hospital and research centre. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. LEVENT TÜRKERİ. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Mark Frydenberg. AFFILIATION: ACIBADEM M.A. AYDINLAR UNIVERSITY, ISTANBUL, TURKEY. I have no potential conflict of interest to report. Signature: Date: February 8th 2022. Anders Bjartell. AFFILIATION: Dept. Of Urology, Skane University Hospital Malmö, Sweden. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Ferring, Bayer, Astellas. Receipt of honoraria or consultation fees: Astellas, AstraZeneca, Bayer, Janssen, Merck, Recordati, Sandoz. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, IPSEN, Janssen, Recordati, Sandoz. Stock shareholder: LIDDS Pharma, Glactone Pharma, WntResearch. Spouse/partner: NONE. Other support (please specify): Signature: Date: February 9th 2022. Dingwei Ye. AFFILIATION: Fudan University Shanghai Cancer Center. I have no potential conflict of interest to report. Signature: Date: February 9th 2022. Ros Eeles. AFFILIATION: ………………………………………. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: GU-ASCO, The Royal Marsden NHS Foundation Trust, University of Chicago, ESMO, AstraZeneca UK Limited. Receipt of honoraria or consultation fees: Honorarium as speaker. Participation in a company sponsored speaker’s bureau: Stock shareholder: Spouse/partner: Other support (please specify): January 2016. Signature: Date: February 15th 2022. Inge van Oort. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas, Bayer, Janssen. Receipt of honoraria or consultation fees: Astellas, Bayer, MSD-Astra Zeneca, Janssen. Participation in a company sponsored speaker’s bureau: Bayer, Astellas. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Ravindran Kanesvaran. AFFILIATION: Urology, Radboudumc, Nijmegen, The Netherlands. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Sanofi, Eisai. Receipt of honoraria or consultation fees: MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Participation in a company sponsored speaker’s bureau:MSD, BMS, AstraZeneca, Amgen, Astellas, Johnson&Johnson, Novartis, Merck, Pfizer. Stock shareholder: Spouse/partner: Other support (please specify): Signature: Date: February 22nd 2022. Signature: Date: February 9th 2022. Nicola Fossati. AFFILIATION: Urology, Ente Ospedaliero Cantonale (EOC), Lugano, CH. I have no potential conflict of interest to report. Signature: Date: February 1st March 2022. Hiroji Uemura. AFFILIATION: Department of Urology and Renal Transplantation, Yokohama City University Medical Center. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: none. Receipt of honoraria or consultation fees: Bayer, Janssen, Sanofi, Takeda, Astellas, AstraZeneca, Amgen, Dai-ichi Sankyo, Pfizer, MSD, Chugai. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: Date: March 7th 2022. Lisa Horvath. AFFILIATION: Chris O′Brien Lifehouse. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: Astellas. Receipt of honoraria or consultation fees: Astellas, Janssen, Bayer, Imagion Biosystems. Participation in a company sponsored speaker’s bureau:Astellas, Janssen, Bayer. Stock shareholder: Imagion Biosystems. Spouse/partner: Connected Medicine Solutions (Employee, stocks). Other support (please specify): none. Signature: Date: March 9th 2022. Robert Reiter. AFFILIATION: UCLA Urology. X I have no potential conflict of interest to report. Signature: Date: March 11th 2022. Daniel Castellano. AFFILIATION: MEDICAL ONCOLOGIST HEAD GU UNIT HOSPITAL UNIVERSITARIO 12 DE OCTUBRE. MADRID-UNIVERSIDAD COMPLUTENSE. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports: JANSSEN. Receipt of honoraria or consultation fees:ASTELLAS, ROCHE, MERCK, PFIZER, NOVARTIS, MSD, BMS, IPSEN, GILEAD, JANSSEN, BAYER. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: none. Spouse/partner: none. Other support (please specify): none. Signature: 28th March 2022. Sandy Srinivas. AFFILIATION: Stanford University, CA. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:BAYER, JANSSEN, MERCK, NOVARTIS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31ST March 2022. Matthew Sydes. AFFILIATION: MRC Clinical Trials Unit at UCL. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASTELLAS, CLOVIS ONCOLOGY, JANSSEN, NOVARTIS, PFIZER, SANOFI AVENTIS. Receipt of honoraria or consultation fees:ELI LILLY, JANSSEN. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Ekeke, Onyanunam Ngozi. AFFILIATION: DEPARTMENT OF SURGERY, UNIVERSITY OF PORT HARCOURT TEACHING HOSPITAL, PORT HARCOUT, NIGERIA. X I have no potential conflict of interest to report. Signature: Date: March 30 h 2022. Susan Halabi, PhD. AFFILIATION: Duke University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:ASCO TAPUR, Astellas. Receipt of honoraria or consultation fees:Sanofi, Aveo Oncology. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Cora N. Sternberg, MD, FACP. AFFILIATION: Eeill Cornell Medicine, New York Presbyterian. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas Pharma, Astrazeneca, Bayer, Genzyme, Gilead, Incyte, Medscape, Janssen, Bristol Myers Squibb, Merck, Msd, Pfizer, Roche, Impact Pharma, Sanofi-Genzyme, Urotoday, Cco Clinical, Nci. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3Oth March 2022. Hirotsugu Uemura. AFFILIATION:. Kindai University Faculty of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:AstraZeneca, Janssen, Takeda, Astellas, Sanofi, Taiho, Ono pharm, Kissei. Receipt of honoraria or consultation fees:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Participation in a company sponsored speaker’s bureau:Bayer, Sanofi, Janssen, MSD, Ono, BMS, Pfizer. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Orazio Caffo. AFFILIATION: Santa Chiara Hospital – Trento (Italy). Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:AAA, Astella, Bayer, Janssen, MSD, Pfizer. Participation in a company sponsored speaker’s bureau:Astellas, Bayer, Janssen, Ipsen, MSD. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Valérie Fonteyne. AFFILIATION:Ghent University Hospital. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Ipsen. Receipt of honoraria or consultation fees:Ipsen, Astellas, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Muhammad Bulbul. AFFILIATION: American University of Beirut. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. Claire Vale. AFFILIATION: MRC Clinical Trials Unit at UCL. X I have no potential conflict of interest to report. Signature: Date: March 31st 2022. MRABTI Hind. AFFILIATION: Institut National d′oncologie, Mohamed V University. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, Sanofi, Janssen, AstraZeneca, Ipsen, MSD, Pfizer, Amgen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Deborah Mukherji. AFFILIATION: American University of Beirut. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas. Receipt of honoraria or consultation fees:Astellas, Janssen, MSD, Ipsen, BMS. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Howard I. Scher, MD, FASCO. AFFILIATION: Memorial Sloan Kettering Cancer Center. Howard I. Scher, MD, FASCO - Disclosure Form. March 31, 2022. Honoraria. Sidney Kimmel Cancer Center, Jefferson Health. Elsevier, LTD. Arsenal Capital. Consultancy/Advisory Board. Ambry Genetics Corporation, Konica Minolta,Inc. Amgen. Bayer. Janssen Research & Development, LLC. Pfizer Inc. Sun Pharmaceuticals Industries, Inc. WCG Oncology. Research Funding to Memorial Sloan Kettering Cancer Center. AIQ Pharma. Epic Sciences. Janssen. Menarini Silicon Biosystems. ThermoFisher. Evan Y. Yu, M.D. AFFILIATION: Fred Hutchinson Cancer Center and University of Washington. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Lantheus, Merck, Seagen. Receipt of honoraria or consultation fees:Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Exelixis, Janssen, Merck, Sanofi. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Gedske Daugaard. AFFILIATION: Rigshospitalet, Copenhagen. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Bayer, Sanofi, Astellas, MSD, Bristol Myers. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Celestia S. Higano, MD, FACP. AFFILIATION: University of Columbia. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None last 24 months. Receipt of honoraria or consultation fees:AstraZeneca, Astellas, Genentech, Merck Sharp & Dohme, Myovant, Tolmar, Vaccitech, Verity. Participation in a company sponsored speaker’s bureau:none. Stock shareholder: CTI Biopharma. Spouse/partner: none. Other support (please specify): Expert testimony, Ferring. Signature: 31st March 2022. Dr. Vedang Murthy. AFFILIATION: Radiotion Oncology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Varian Medical Systems. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau: Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Gero Kramer. AFFILIATION: Department of Urology, Medical University of Vienna. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:None. Receipt of honoraria or consultation fees:Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Sanofi Genzyme, Takeda, Ferring. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 31st March 2022. Niven Mehra. AFFILIATION: Radboudumc. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Astrazeneca, BMS. Receipt of honoraria or consultation fees:Astellas, Astrazeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Juan Pablo Sade. AFFILIATION: Instituto Alexnder Fleming, Buenos Aires, Argentina. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen, Astellas, AtraZeneca, MSD, BMS. Receipt of honoraria or consultation fees:Janssen, Bayer, Pfizer, Astellas. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 3rd April 2022. Dr Maria De Santis. AFFILIATION: Charité Universitätsmedizin Berlin, Department of Urology. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:AAA, Amgen, Astellas, AstraZeneca, Basilea, Bayer, Bioclin, BMS, EISAI, Ferring, Immunomedics, Ipsen, Janssen, MSD, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Iwona Skoneczna. AFFILIATION: Maria Sklodowska-Curie National Research Institute of Oncology, Szpital Grochowski, Warsaw, Poland. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Astellas, Bayer, BMS, Janssen, Roche. Receipt of honoraria or consultation fees:Astellas, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 1st April 2022. Laurence Klotz. AFFILIATION: University of Toronto. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:miR Scientific, Exact Imaging. Receipt of honoraria or consultation fees:miR Scientific, Antev. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 30th March 2022. Yüksel Ürün. AFFILIATION: Ankara University School of Medicine. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Astellas, AtraZeneca, BMS, Janssen Oncology, MSD, Pfizer, Roche. Participation in a company sponsored speaker’s bureau:Astellas, Amgen, AtraZeneca, BMS, Janssen Oncology, Pfizer, Roche. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 01st April 2022. Howard R. Soule. AFFILIATION: Prostate Cancer Foundation. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:. Receipt of honoraria or consultation fees:Compugen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 4th April 2022. Simon Chowdhury. AFFILIATION:. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:Janssen Oncology, Beigene, Clovis Oncology, Pfizer,. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:Janssen Oncology, AstraZeneca, Bayer, Pfizer, Sandoz. Stock shareholder:. Spouse/partner:. Other support (please specify): Janssen Oncology (Advisory board). Novartis (advisory board, consultancy). Bayer (Advisory board). Astellas (advisory board, consultancy). Athenex (advisory board). Beigene (advisory board). Clovis Oncology (Advisory board). Telix (advisory board, consultancy). Curve.Life (founder and stock). Huma (consulting fees and Stock). Remedy Bio: consulting fees, Stock. Signature: 4th April 2022. Daniel Heinrich. AFFILIATION: Innlandet Hospital, Department of Oncology and Radiotherapy, Gjøvik, Norway. X I have no potential conflict of interest to report. Signature: Date: 28th February 2022. Raya Leibowitz. AFFILIATION: Shamir Medical Center, Zerifin, Be’er Yaakov, Israel. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:MSD, BMS, Isotopia, Bayer, AstraZeneca, Astellas, Janssen, Pfizer. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Signature: 05th April 2022. Raja Khauli. AFFILIATION: American University of Beirut Medical Ctr Clinical. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): honoraria: Astellas, Janssen, Algorithm SAL. Signature: 06th April 2022. Axel Merseburger. AFFILIATION: Campus Lübeck, University Hospital Schleswig-Holstein. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify):. Lectures/Speaker/Honoraria:. Astra Zeneca, Bristol-Myers Squibb, Eisai, Ferring, Ipsen, MSD, Merck Serono, Janssen, Takeda, TEVA, Astellas, Novartis, Pfizer, Recordati and Roche. Consultant:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ferring, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer, Recordati and Roche. Research and clinical trials:. AstraZeneca, Astellas, Bristol-Myers Squibb, Ipsen, Janssen, EUSAPharm, MSD, Merck Serono, Novartis, Takeda, Teva, Pfizer und Roche. Signature: 06th April 2022. Carmel Pezaro. AFFILIATION: Sheffield Teaching Hospitals NHS Foundation Trust. Type of affiliation / financial interest Name of commercial company. Receipt of grants/research supports:none. Receipt of honoraria or consultation fees:Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer, Janssen. Participation in a company sponsored speaker’s bureau:. Stock shareholder:. Spouse/partner:. Other support (please specify): Bayer, Ipsen (travel support). Signature: 06th April 2022. All remaining authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management., Objective: To present consensus voting results for select questions from APCCC 2022., Design, Setting, and Participants: Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members ("panellists") who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1-3., Outcome Measurements and Statistical Analysis: Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement., Results and Limitations: The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis., Conclusions: These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Heparin-induced thrombocytopenia (HIT), a severe autoimmune disorder, occurs in patients undergoing heparin therapy. The presence of platelet-activating antibodies against platelet factor 4/Heparin in the blood confirms patients suffering from HIT. The most widely used methods for HIT diagnosis are immunoassays but the results only suit to rule out HIT as the assays provide only around 50% specificity. To confirm HIT, samples with positive results in immunoassays are retested in functional assays (>98% specificity) that track platelet-activating antibodies via platelet aggregation. However, the protocols in functional assays are either time-consuming (due to the requirement of the detection of serotonin release) or require highly trained staff for the visualization of platelets. Here, we applied a cheap and easy-to-use contactless sensor, which employs high-frequency microwaves to detect the changes in the resonant frequency caused by platelet aggregation/activation. Analysis of change in conductivity and permittivity allowed us to distinguish between HIT-like (KKO) and non-HIT-like (RTO) antibodies. KKO caused a stronger reduction of conductivity of platelet samples than RTO. Our results imply that the high-frequency contactless sensor can be a promising approach for the development of a better and easier method for the detection of HIT.

Biological rhythms that are mediated by exogenous factors, such as light and temperature, drive the physiology of organisms and affect processes ranging from cellular to population levels. For elasmobranchs (i.e. sharks, rays, and skates), studies documenting diel activity and movement patterns indicate that many species are crepuscular or nocturnal in nature. However, few studies have investigated the rhythmicity of elasmobranch physiology to understand the mechanisms underpinning these distinct patterns. Here, we assess diel patterns of metabolic rates in a small meso-predator, the epaulette shark ( Hemiscyllium ocellatum ), across ecologically relevant temperatures and upon acutely removing photoperiod cues. This species possibly demonstrates behavioral sleep during daytime hours, which is supported herein by low metabolic rates during the day and a 1.7-fold increase in metabolic rates at night. From spring to summer seasons, where average average water temperature temperatures for this species range 24.5 to 28.5 °C, time of day, and not temperature, had the strongest influence on metabolic rate. These results indicate that this species, and perhaps other similar species from tropical and coastal environments, may have physiological mechanisms in place to maintain metabolic rate on a seasonal time scale regardless of temperature fluctuations that are relevant to their native habitats.

Machine learning applications have become ubiquitous. Their applications range from embedded control in production machines over process optimization in diverse areas (e.g., traffic, finance, sciences) to direct user interactions like advertising and recommendations. This has led to an increased effort of making machine learning trustworthy. Explainable and fair AI have already matured. They address the knowledgeable user and the application engineer. However, there are users that want to deploy a learned model in a similar way as their washing machine. These stakeholders do not want to spend time in understanding the model, but want to rely on guaranteed properties. What are the relevant properties? How can they be expressed to the stake- holder without presupposing machine learning knowledge? How can they be guaranteed for a certain implementation of a machine learning model? These questions move far beyond the current state of the art and we want to address them here. We propose a unified framework that certifies learning methods via care labels. They are easy to understand and draw inspiration from well-known certificates like textile labels or property cards of electronic devices. Our framework considers both, the machine learning theory and a given implementation. We test the implementation's compliance with theoretical properties and bounds., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morik, Kotthaus, Fischer, Mücke, Jakobs, Piatkowski, Pauly, Heppe and Heinrich.)

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence., Objective: To present the voting results from APCCC 2021., Design, Setting, and Participants: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions., Outcome Measurements and Statistical Analysis: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process., Results and Limitations: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material., Conclusions: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials., Patient Summary: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Patients with advanced prostate cancer (APC) may be at greater risk for severe illness, hospitalisation, or death from coronavirus disease 2019 (COVID-19) due to male gender, older age, potential immunosuppressive treatments, or comorbidities. Thus, the optimal management of APC patients during the COVID-19 pandemic is complex. In October 2021, during the Advanced Prostate Cancer Consensus Conference (APCCC) 2021, the 73 voting members of the panel members discussed and voted on 13 questions on this topic that could help clinicians make treatment choices during the pandemic. There was a consensus for full COVID-19 vaccination and booster injection in APC patients. Furthermore, the voting results indicate that the expert's treatment recommendations are influenced by the vaccination status: the COVID-19 pandemic altered management of APC patients for 70% of the panellists before the vaccination was available but only for 25% of panellists for fully vaccinated patients. Most experts (71%) were less likely to use docetaxel and abiraterone in unvaccinated patients with metastatic hormone-sensitive prostate cancer. For fully vaccinated patients with high-risk localised prostate cancer, there was a consensus (77%) to follow the usual treatment schedule, whereas in unvaccinated patients, 55% of the panel members voted for deferring radiation therapy. Finally, there was a strong consensus for the use of telemedicine for monitoring APC patients. PATIENT SUMMARY: In the Advanced Prostate Cancer Consensus Conference 2021, the panellists reached a consensus regarding the recommendation of the COVID-19 vaccine in prostate cancer patients and use of telemedicine for monitoring these patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

In alpine skiing, estimation of the joint moments acting onto the skier is essential to quantify the loading of the skier during turning maneuvers. In the present study, a novel forward dynamics optimization framework is presented to estimate the joint moments acting onto the skier incorporating a three dimensional musculoskeletal model (53 kinematic degrees of freedom, 94 muscles). Kinematic data of a professional skier performing a turning maneuver were captured and used as input data to the optimization framework. In the optimization framework, the musculoskeletal model of the skier was applied to track the experimental data of a skier and to estimate the underlying joint moments of the skier at the hip, knee and ankle joints of the outside and inside leg as well as the lumbar joint. During the turning maneuver the speed of the skier was about 14 m/s with a minimum turn radius of about 16 m. The highest joint moments were observed at the lumbar joint with a maximum of 1.88 Nm/kg for lumbar extension. At the outside leg, the highest joint moments corresponded to the hip extension moment with 1.27 Nm/kg, the knee extension moment with 1.02 Nm/kg and the ankle plantarflexion moment with 0.85 Nm/kg. Compared to the classical inverse dynamics analysis, the present framework has four major advantages. First, using a forward dynamic optimization framework the underlying kinematics of the skier as well as the corresponding ground reaction forces are dynamically consistent. Second, the present framework can cope with incomplete data (i.e., without ground reaction force data). Third, the computation of the joint moments is less sensitive to errors in the measurement data. Fourth, the computed joint moments are constrained to stay within the physiological limits defined by the musculoskeletal model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heinrich, Van den Bogert  and Nachbauer .)

Despite being unicellular organisms, bacteria undergo complex regulation mechanisms which coordinate different physiological traits. Among others, DegU, DegS, and Spo0A are the pleiotropic proteins which govern various cellular responses and behaviors. However, the functions and regulatory networks between these three proteins are rarely described in the highly interesting bacterium Paenibacillus polymyxa. In this study, we investigate the roles of DegU, DegS, and Spo0A by introduction of targeted point mutations facilitated by a CRISPR-Cas9-based system. In total, five different mutant strains were generated, the single mutants DegU Q218*, DegS L99F, and Spo0A A257V, the double mutant DegU Q218* DegS L99F, and the triple mutant DegU Q218* DegS L99F Spo0A A257V. Characterization of the wild-type and the engineered strains revealed differences in swarming behavior, conjugation efficiency, sporulation, and viscosity formation of the culture broth. In particular, the double mutant DegU Q218* DegS L99F showed a significant increase in conjugation efficiency as well as a stable exopolysaccharides formation. Furthermore, we highlight similarities and differences in the roles of DegU, DegS, and Spo0A between P. polymyxa and related species. Finally, this study provides novel insights into the complex regulatory system of P. polymyxa DSM 365. IMPORTANCE To date, only limited knowledge is available on how complex cellular behaviors are regulated in P. polymyxa. In this study, we investigate several regulatory proteins which play a role in governing different physiological traits. Precise targeted point mutations were introduced to their respective genes by employing a highly efficient CRISPR-Cas9-based system. Characterization of the strains revealed some similarities, but also differences, to the model bacterium Bacillus subtilis with regard to the regulation of cellular behaviors. Furthermore, we identified several strains which have superior performance over the wild-type. The applicability of the CRISPR-Cas9 system as a robust genome editing tool, in combination with the engineered strain with increased genetic accessibility, would boost further research in P. polymyxa and support its utilization for biotechnological applications. Overall, our study provides novel insights, which will be of importance in understanding how multiple cellular processes are regulated in Paenibacillus species.

Background: Matching treatment based on tumour molecular characteristics has revolutionized the treatment of some cancers and has given hope to many patients. Although personalized cancer care is an old concept, renewed attention has arisen due to recent advancements in cancer diagnostics including access to high-throughput sequencing of tumour tissue. Targeted therapies interfering with cancer specific pathways have been developed and approved for subgroups of patients. These drugs might just as well be efficient in other diagnostic subgroups, not investigated in pharma-led clinical studies, but their potential use on new indications is never explored due to limited number of patients., Methods: In this national, investigator-initiated, prospective, open-label, non-randomized combined basket- and umbrella-trial, patients are enrolled in multiple parallel cohorts. Each cohort is defined by the patient's tumour type, molecular profile of the tumour, and study drug. Treatment outcome in each cohort is monitored by using a Simon two-stage-like 'admissible' monitoring plan to identify evidence of clinical activity. All drugs available in IMPRESS-Norway have regulatory approval and are funded by pharmaceutical companies. Molecular diagnostics are funded by the public health care system., Discussion: Precision oncology means to stratify treatment based on specific patient characteristics and the molecular profile of the tumor. Use of targeted drugs is currently restricted to specific biomarker-defined subgroups of patients according to their market authorization. However, other cancer patients might also benefit of treatment with these drugs if the same biomarker is present. The emerging technologies in molecular diagnostics are now being implemented in Norway and it is publicly reimbursed, thus more cancer patients will have a more comprehensive genomic profiling of their tumour. Patients with actionable genomic alterations in their tumour may have the possibility to try precision cancer drugs through IMPRESS-Norway, if standard treatment is no longer an option, and the drugs are available in the study. This might benefit some patients. In addition, it is a good example of a public-private collaboration to establish a national infrastructure for precision oncology. Trial registrations EudraCT: 2020-004414-35, registered 02/19/2021; ClinicalTrial.gov: NCT04817956, registered 03/26/2021., (© 2022. The Author(s).)

Supramolecular materials provide unique opportunities to mimic both the structure and mechanics of the biopolymer networks that compose the extracellular matrix. However, strategies to modify their filamentous structures in space and time in 3D cell culture to study cell behavior as encountered in development and disease are lacking. We herein disclose a multicomponent squaramide-based supramolecular material whose mechanics and bioactivity can be controlled by light through co-assembly of a 1,2-dithiolane (DT) monomer that forms disulfide cross-links. Remarkably, increases in storage modulus from ∼200 Pa to >10 kPa after stepwise photo-cross-linking can be realized without an initiator while retaining colorlessness and clarity. Moreover, viscoelasticity and plasticity of the supramolecular networks decrease upon photo-irradiation, reducing cellular protrusion formation and motility when performed at the onset of cell culture. When applied during 3D cell culture, force-mediated manipulation is impeded and cells move primarily along earlier formed channels in the materials. Additionally, we show photopatterning of peptide cues in 3D using either a photomask or direct laser writing. We demonstrate that these squaramide-based filamentous materials can be applied to the development of synthetic and biomimetic 3D in vitro cell and disease models, where their secondary cross-linking enables mechanical heterogeneity and shaping at multiple length scales.

Background and Objectives: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM)., Methods: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections., Results: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected., Discussion: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Intracellular transport is pivotal for cell growth and survival. Malfunctions in this process have been associated with devastating neurodegenerative diseases, highlighting the need for a deeper understanding of the mechanisms involved. Here, we use an experimental methodology that leads neurites of differentiated PC12 cells into either one of two configurations: a one-dimensional configuration, where the neurites align along lines, or a two-dimensional configuration, where the neurites adopt a random orientation and shape on a flat substrate. We subsequently monitored the motion of functional organelles, the lysosomes, inside the neurites. Implementing a time-resolved analysis of the mean-squared displacement, we quantitatively characterized distinct motion modes of the lysosomes. Our results indicate that neurite alignment gives rise to faster diffusive and super-diffusive lysosomal motion than the situation in which the neurites are randomly oriented. After inducing lysosome swelling through an osmotic challenge by sucrose, we confirmed the predicted slowdown in diffusive mobility. Surprisingly, we found that the swelling-induced mobility change affected each of the (sub-/super-)diffusive motion modes differently and depended on the alignment configuration of the neurites. Our findings imply that intracellular transport is significantly and robustly dependent on cell morphology, which might in part be controlled by the extracellular matrix.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is continuing to spread globally. SARS-CoV-2 infections of feline and canine species have also been reported. However, it is not entirely clear to what extent natural SARS-CoV-2 infection of pet dogs and cats is in households. We have developed enzyme-linked immunosorbent assays (ELISAs) using recombinant SARS-CoV-2 nucleocapsid (N) protein and the receptor-binding-domain (RBD) of the spike protein, and the SARS-CoV-2 spike-pseudotyped vesicular stomatitis virus (VSV)-based neutralization assay to screen serum samples of 239 pet cats and 510 pet dogs in Minnesota in the early phase of the COVID-19 pandemic from mid-April to early June 2020 for evidence of SARS-CoV-2 exposures. A cutoff value was used to identify the seropositive samples in each experiment. The average seroprevalence of N- and RBD-specific antibodies in pet cats were 8% and 3%, respectively. Among nineteen (19) N-seropositive cat sera, fifteen (15) exhibited neutralizing activity and seven (7) were also RBD-seropositive. The N-based ELISA is also specific and does not cross react with antigens of common feline coronaviruses. In contrast, SARS-CoV-2 antibodies were detected at a very low percentage in pet dogs (~ 1%) and were limited to IgG antibodies against SARS-CoV-2 N protein with no neutralizing activities. Our results demonstrate that SARS-CoV-2 seropositive rates are higher in pet cats than in pet dogs in MN early in the pandemic and that SARS-CoV-2 N-specific IgG antibodies can detect SARS-CoV-2 infections in companion animals with higher levels of specificity and sensitivity than RBD-specific IgG antibodies in ELISA-based assays.

In this study, a novel approach to create arbitrarily shaped 3D hydrogel objects is presented, wherein freeform two-photon polymerization (2PP) is enabled by the combination of a photosensitive hydrogel and an intrinsic support matrix. This way, topologies without physical contact such as a highly porous 3D network of concatenated rings were realized, which are impossible to manufacture with most current 3D printing technologies. Micro-Raman and nanoindentation measurements show the possibility to control water uptake and hence tailor the Young's modulus of the structures via the light dosage, proving the versatility of the concept regarding many scaffold characteristics that makes it well suited for cell specific cell culture as demonstrated by cultivation of human induced pluripotent stem cell derived cardiomyocytes.

Towards the goal of obtaining non-invasive biomarkers reflecting the anterior cruciate ligament's (ACL) loading capacity, this project aimed to develop a magnetic resonance imaging (MRI)-based method facilitating the measurement of ACL elongations during the execution of knee stress tests. An MRI-compatible, computer-controlled, and pneumatically driven knee loading device was designed to perform Lachman-like tests and induce ACL strain. A human cadaveric leg was used for test purposes. During the execution of the stress tests, a triggered real-time cine MRI sequence with a temporal resolution of 10 Hz was acquired in a parasagittal plane to capture the resultant ACL elongations. To test the accuracy of these measurements, the results were compared to in situ data of ACL elongation that were acquired by measuring the length changes of a surgical wire directly sutured to the ACL's anteromedial bundle. The MRI-based ACL elongations ranged between 0.7 and 1.7 mm and agreed very well with in situ data (root mean square errors, RMSEs ≤ 0.25 mm), although peak elongation rates were underestimated by the MRI (RMSEs 0.19-0.36 mm/s). The high accuracy of elongation measurements underlines the potential of the technique to yield an imaging-based biomarker of the ACL's loading capacity.

[Figure: see text].