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This paper covers an experiment designed to investigate the relationship between the didactical setting and learning effects with animations. We investigated whether the cognitive load imposed by animations could be reduced when the students could control the flow of the animation. We did not find an effect due to the fact that the students did not actively use this feature to take more control of the presentation. Further, by applying differentiated knowledge measures, we investigated if the characteristics of the acquired knowledge were related to the characteristics of the multimedia presentation. We found that media do not influence knowledge acquisition homogeneously. The multimedia effects found in this study are in line with known principles of didactical multimedia design. This study sheds light on some theoretical aspects involved in the complex interaction between learning content, presentation, learning, and resulting knowledge. [ABSTRACT FROM AUTHOR]

Aim: Non-suicidal self-injury (NSSI) is a highly prevalent phenomenon during adolescence. Nonetheless, research on predictors of the clinical course of NSSI over time is still scarce. The present study aimed at investigating the impact of adverse childhood experiences (ACE) and hypothalamus-pituitary-adrenal (HPA) axis functioning on the longitudinal course of NSSI., Methods: In a sample of n = 51 help-seeking adolescents engaging in NSSI, diurnal cortisol secretion (CAR, cortisol awakening response; DSL, diurnal slope), hair cortisol concentrations and ACE were assessed at baseline. Clinical outcome was defined by change in the frequency of NSSI in the past 6 months measured 12 and 24 months after the baseline assessments. Mixed-effects linear regression models were used to test for effects of ACE and HPA axis functioning on the course of NSSI., Results: ACE and HPA axis functioning did not show main but interaction effects in the prediction of NSSI frequency over time: Adolescents with a low severity of ACE and either an increased CAR or a flattened DSL showed a steep decline of NSSI frequency in the first year followed by a subsequent increase of NSSI frequency in the second year., Conclusions: Our findings could be interpreted in the sense of high diurnal cortisol concentrations in the absence of ACE being favorable for clinical improvement on the short-term but bearing a risk of allostatic load and subsequent increase of NSSI frequency. In contrast, adolescents with severe ACE may benefit from elevated cortisol concentrations leading to slower but lasting decreases of NSSI frequency., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Borderline personality disorder (BPD) is an established diagnosis in adolescence with high comorbidity and psychosocial impairment. With the introduction of the alternative model for personality disorders in DSM-5 (AMPD), personality functioning is operationalized using the Level of Personality Functioning Scale (LPFS), which has been shown to be associated with severity of personality pathology. The present study aimed at examining differential psychopathological and psychosocial correlates of LPFS and BPD. A total of 526 adolescent in- and outpatients were interviewed with the STiP-5.1 (LPFS) and the SCID-II. Mixed linear regression was used to investigate the associations between the two interviews with measures of psychopathology and psychosocial impairment. 11.4% met the diagnostic threshold of both interviews, 16.1% only of the LPFS, and 64.1% were below the diagnostic threshold in both interviews (no PD). The BPD only group was larger than expected-8.4% of patients who met criteria for BPD did not fulfill criteria for significant impairment in the LPFS. The highest burden was found in individuals concurrently showing significant impairment in LPFS and fulfilling BPD diagnosis (LPFS + BPD). Differences between the LPFS only group and the BPD only group were found in risk behavior and traumatic experiences, with higher prevalence in the BPD group. Findings confirm the high psychopathological burden and psychosocial impairment associated with both BPD and LPFS. Those exceeding the diagnostic threshold of LPFS in combination with a BPD diagnosis are characterized by greatest disability. Not all adolescents fulfilling formal BPD diagnosis showed a clinically significant impairment in LPFS, which may refer to a distinct diagnostic group., (© 2024. The Author(s).)

Adenosine triphosphate (ATP)-producing modules energized by light-driven proton pumps are powerful tools for the bottom-up assembly of artificial cell-like systems. However, the maximum efficiency of such modules is prohibited by the random orientation of the proton pumps during the reconstitution process into lipid-surrounded nanocontainers. Here, we overcome this limitation using a versatile approach to uniformly orient the light-driven proton pump proteorhodopsin (pR) in liposomes. pR is post-translationally either covalently or noncovalently coupled to a membrane-impermeable protein domain guiding orientation during insertion into preformed liposomes. In the second scenario, we developed a novel bifunctional linker, tris NTA-SpyTag, that allows for the reversible connection of any SpyCatcher-containing protein and a HisTag-carrying protein. The desired protein orientations are verified by monitoring vectorial proton pumping and membrane potential generation. In conjunction with ATP synthase, highly efficient ATP production is energized by the inwardly pumping population. In comparison to other light-driven ATP-producing modules, the uniform orientation allows for maximal rates at economical protein concentrations. The presented technology is highly customizable and not limited to light-driven proton pumps but applicable to many membrane proteins and offers a general approach to overcome orientation mismatch during membrane reconstitution, requiring little to no genetic modification of the protein of interest.

Objectives: Although caring for dying patients and their family caregivers (FC) is integral to patient care, training in communication about approaching death is almost inexistent in medical and nursing curricula. Consequently, many health professionals have insufficient knowledge about conducting these conversations. In order to gain a broader insight into essential aspects of this communication from different perspectives, we conducted focus groups with key stakeholders., Methods: Medical specialists, nurses, medical students, bereaved FC and patient representatives participated in five focus groups ( n  = 30). Following a focus group schedule, we elicited relevant aspects of communication about approaching death, associated emotions, and appropriate communication frameworks. We analyzed data thematically., Results: Four main themes were central to conversations about approaching death: (1) embracing care within medical expertise, (2) preparing the conversation while remaining open to the unexpected, (3) recognizing and reflecting on own emotions and reactions, and (4) establishing a meaningful connection with others., Significance of Results: Communicating about approaching death with dying patients and their FC can be complex and challenging at a professional and personal level. With the recognition of the dying phase, a process is initiated for which health professionals need solid clinical knowledge about but also effective communication skills, constant self-reflection and self-care strategies. Comprehensive training and supervision while dealing with the challenges of communicating approaching death to dying patients and their FC are key, particularly for trainees, less experienced physicians and nurses. The essential components identified in this study can help health professionals to master these conversations.

Borderline personality disorder (BPD) has been associated with a reduced functional flexibility of the autonomic nervous system (ANS), indexed by decreased vagally mediated heart rate variability (vmHRV). Employing a comprehensive Section II-based assessment approach and a partial Section III-based assessment approach (including Criterion A of the alternative model of personality disorders [AMPD]), the present study investigates how different conceptualizations of personality disorders (PDs) according to the Diagnostic and Statistical Manual for Mental Disorders, 5th edition relate to ANS function. Using the BPD section of the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II, a Section II-based assessment approach) and the Semistructured Interview for Personality Functioning DSM-5 (STiP-5.1, a Section III-based assessment approach), we conducted linear regression analyses to examine how categorical (BPD diagnosis) and dimensional (severity and domain) measures of PD are associated with ANS activity among adolescent psychiatric patients ( N = 147, M age = 15.25 years). Replicating earlier findings, analyses revealed a statistically significant positive association between the SCID-II measures of BPD and heart rate (HR), b = 0.43, t (59) = 3.57, p = .001, f = .57, as well as a statistically significant negative association between the SCID-II measures of BPD and vmHRV, b = -0.34, t (59) = -2.74, p = .008, f = .47. Neither the STiP-5.1 total score nor the subscales of the Level of Personality Functioning Scale (LPFS) were associated with HR or vmHRV. The present findings indicate that the SCID-II may capture features of PD that are more informative of variance in physiological function than the STiP-5.1. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). In vitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL., Methods: In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3 + 3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458., Findings: Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67 > 30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively., Interpretation: The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features., Funding: SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen., Competing Interests: U.N. reports consulting fees and advisory board participation to/through the institution from and with Janssen-Cilag, Celgene (BMS), Takeda, AstraZeneca, Roche, Novartis, Incyte, Beigene, Kyowa Kirin, Gilead, Pierre Fabre and Miltenyi, payment of honoraria to the institution form Celgene (BMS), Novartis, Takeda, and Gilead, and meeting and/or travel support to the institution from Janssen, Roche, Gilead and Takeda. M.D. reports grants or contracts for research from Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, and Roche to the institution, payment of honoraria from AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis and Roche, meeting and/or travel support from Janssen and Roche, and Data Safety Monitoring Board or Advisory Boards with Abbvie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, and Roche. C.S. reports consulting fees from BMS and Janssen, payments of honoraria from BMS and AstraZeneca, and meeting and/or travel support from Kite Gilead. E.D. reports and research funding from ADC Therapeutics and Takeda, consulting fees from Roche, Beigene, Abbvie, AstraZeneca, and Takeda, payments or honoraria from Abbvie, Roche, Incyte and Beigene, support for meetings and/or travel from Abbvie and Beigene, a Data Safety Monitoring Board or Advisory Board role with Abbvie, Beigene, Takeda, and Roche, and the receipt of equipment, materials, drugs, medical writing, gifts or other services from ADC Therapeutics. T.Z. reports consulting fees from Beigene Switzerland GmbH. G.H. reports grants or contracts for research from Gilead/Kite, Incyte, Janssen, Morphosys, Pfizer, Roche, and Abbvie, consulting fees from Abbvie, ADC Therapeutics, AstraZeneca, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Miltenyi, Novartis, Roche, and Lilly, payments or honoraria from Abbvie, AstraZeneca, Beigene, BMS, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche, meeting and/or travel support from Janssen and Gilead/Kite, and Data Safety Monitoring Board or Advisory Boards with Miltenyi. U.M. reports meeting and/or travel support from Janssen-Cilag, an advisory board role with Janssen-Cilag, and participation in the committee of the German-Swiss-Austrian guidelines for mantle cell lymphoma. S.F. reports grants or contracts for research, consulting fees, honoraria, meeting and/or travel support, and advisory board activities from and with Janssen. S.B. reports grants or contracts for research from Janssen-Cilag Neuss and Miltenyi Bergisch Gladbach to the institution, honoraria from Roche, Abbvie, Janssen, AstraZeneca, and Sanofi, and a travel support from Janssen. E.Z. reports grants or contracts for research from AstraZeneca, Beigene, Celgene, Incyte, Janssen, and Roche, for research to the institution from Incyte, AstraZeneca, Beigene, Celgene/BMS, Merck/MSD, and Roche, honoraria for an educational event from Abbvie, an advisory board role with Abbvie, AstraZeneca, Beigene, Celgene/BMS, Celltrion Healthcare, Curis, Eli Lilly, Gilead/Kite, Incyte, Ipsen, Janssen, MeiPharma, Miltenyi Biomedicine, Merck/MSD, and Roche, Data Safety Monitoring Board activities with Merck/MSD, and meeting and/or travel support from Abbvie, Gilead/Kite, Janssen, and Roche, and an expert statement for Bristol Myers Squib. C.R. reports consulting fees to the institution from Abbvie, Celgene/BMS, and Roche, honoraria to the institution from Amgen, Janssen, Abbvie, Celgene/BMS, and Takeda, payment for expert testimonies to the institution from Gilead and Janssen, and meeting and/or travel support from Sanofi and Amgen. All other authors declare no competing interests., (© 2023 The Authors.)

Background: Premature trial discontinuation and non-publication of trial results are still major issues negatively affecting reliable evidence generation., Objectives: To investigate trial completion and publication rate of cancer trials conducted within the Swiss Group for Clinical Cancer Research (SAKK)., Design: Cohort study of clinical trials., Setting: Cohort of interventional cancer trials conducted in Switzerland with accrual closure between 1986 and 2021 identified from the SAKK trial management system., Outcomes: Premature trial discontinuation and publication in peer-reviewed journal., Results: We included 261 trials; median number of recruited patients was 150.5 (range 1-8028). Most trials (67.0%) were randomised. Overall, 76 of 261 (29.1%) trials were prematurely closed for accrual. The three main reasons for premature closure were insufficient accrual in 28 trials, followed by stopping for futility in 17 or efficacy in 8 trials. We included 240 trials for the publication status (21 excluded, because 8 still in follow-up, for 10 the primary completion date was less than a year ago and for 3 the manuscript was submitted, but to accepted yet). 216 of 240 (90.0%) were published as a full article, 14 were published in other formats, leading to an overall publication rate of 95.8%. The rate of premature discontinuation declined over time, with 34.2%, 27.8% and 23.5% in trials activated before 2000, between 2000 and 2009, and since 2010, respectively. We observed an increasing publication rate in peer-reviewed journals over time: 79.2% (closed before 2000), 95.7% (closed between 2000 and 2009) and 93.2% (closed after 2010)., Conclusion: Insufficient patient recruitment is still the major reason for premature trial discontinuation. SAKK has continuously improved its quality management of trial conduct over time leading to increased successful trial completion and publication. However, there is still room for improvement to increase the number of trials reaching their target sample size., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There are only two Aphaenogaster species from the subterranea group in the western Mediterranean: A.ichnusa Santschi, 1925, from south-western Europe, and A.subterranea (Latreille, 1798), also occurring in central and eastern Europe. Historically, the two species have been widely misunderstood: A.ichnusa was long considered a Sardinian endemic subspecies of A.subterranea , while its continental populations were misidentified as A.subterranea s. str. Recently, A.ichnusa was elevated to species rank and its worker caste was redescribed with that of A.subterranea , allowing for their correct identification. Yet their distribution was documented in detail only for France and Sardinia. Furthermore, no morphological characters were described to distinguish the males and queens of the two species. By investigating private and museum collections, 276 new records of A.ichnusa are provided here and 154 of A.subterranea from the western Mediterranean. Additionally, qualitative and quantitative morphological characters were combined to identify their males and queens. We present the new southernmost, easternmost, and westernmost distribution limits for A.ichnusa . Based on our results, this species is widely distributed in Italy and Catalonia (Spain), also occurring on several Mediterranean islands, avoiding areas with continental climate and high altitudes. Sicily is the only island to host the less thermophilous A.subterranea , which otherwise extends westward to Galicia (Spain). Sympatric occurrence is not rare along the contact zone. Additional natural history observations are reported regarding foraging habits, associated myrmecophiles, habitat preferences, and colony structure in the two species., (Enrico Schifani, Antonio Alicata, Lech Borowiec, Fede García, Vincenzo Gentile, Kiko Gómez, Elia Nalini, Fabrizio Rigato, Sämi Schär, Antonio Scupola, Roger Vila, Mattia Menchetti.)

Biosensors based on miniaturized, functional electrodes are of high potential for various biosensing applications, especially at the point-of-care setting among others. However, the sensor performance of such electrochemical devices is still strongly limited, especially due to surface fouling in complex sample fluids, such as blood serum. Electrode coatings based on conductive nanomaterials embedded in antifouling matrices offer a promising strategy to overcome this limitation. However, known composite coatings require long (typically >24 h) and complex fabrication processes, which pose a strong barrier for cost-effective mass manufacturing and successful commercialization. Here, we describe a novel polymer/carbon nanotube (CNT) composite coating that can be produced from an ink containing a photoreactive and antifouling copolymer as well as conductive CNTs using fast and highly scalable printing processes. Coatings were prepared on screen-printed electrodes and characterized using cyclic voltammetry (CV) and protein fouling experiments. The coatings offered an electroactive surface area (EASA) comparable to uncoated screen-printed electrodes and retained >90% of initial EASA after 1 h of exposure to concentrated bovine serum albumin solution, while uncoated electrodes decreased to <20% of initial EASA after the same treatment. Utilizing the universal crosslinking reaction of the polymer coating, antibodies against the inflammatory biomarker C-reactive protein (CRP) were photochemically immobilized on the electrodes. Functionalized electrodes were fabricated in <2 h and were successfully used to quantify nanogram-range concentrations of CRP spiked in undiluted human blood serum using a sandwich-immunoassay with electrochemical read-out, demonstrating the high potential of the platform for biosensing applications.

Introduction: The aim of the present study was (1) to validate the method of guilt-induction by means of a written auto-biographical essay and (2) to test whether experimental pain is apt to alleviate the mental burden of guilt, a concept receiving support from both empirical research and clinical observation., Methods: Three independent groups of healthy male participants were recruited. Group allocation was not randomized but within group pain/sham administration was counterbalanced over the two test-days. Groups were tested in the following consecutive order: Group A: guilt induction, heat-pain/sham, N = 59; Group B: guilt induction, cold-pressure-pain/sham, N = 43; Group C: emotionally neutral induction, heat-pain/sham, N = 39. Guilt was induced on both test-days in group A and B before pain/sham administration. Visual analog scale (VAS) guilt ratings immediately after pain/sham stimulation served as the primary outcome. In a control group C the identical heat-pain experiment was performed like in group A but a neutral emotional state was induced., Results: A consistently strong overall effect of guilt-induction (heat-pain: p < 0.001, effect size r = 0.71; CPT-pain p < 0.001, r = 0.67) was found when compared to the control-condition ( p = 0.25, r = 0.08). As expected, heat- and cold-pressure-stimuli were highly painful in all groups ( p < 0.0001, r = 0.89). However, previous research supporting the hypothesis that pain is apt to reduce guilt was not replicated., Conclusion: Although guilt-induction was highly effective on both test-days no impact of pain on behavioral guilt-ratings in healthy individuals could be identified. Guilt induction per se did not depend on the order of testing. The result questions previous experimental work on the impact of pain on moral emotions., 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 Schär, Vehlen, Ebneter, Schicktanz, de Quervain, Wittmann, Götzmann, grosse Holtforth, Protic, Wettstein, Egloff, Streitberger and Schwegler.)

This phase 1 study evaluated safety, tolerability, and preliminary efficacy of obinutuzumab in combination with venetoclax in patients with previously untreated grade 1-3a follicular lymphoma in need of systemic therapy. Two DLs of venetoclax were evaluated with an expansion cohort at the recommended phase 2 dose. Twenty-five patients were enrolled. The recommended phase 2 dose was venetoclax 800 mg OD continuously for 6 cycles starting on day 2 of cycle 1, with obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6, followed by obinutuzumab maintenance every 2 months for 2 years. Only 1 patient had a DLT consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Neutropenia was the most common adverse event of grade ≥3 at least possibly attributed to study treatment. Twenty-four patients were evaluable for response after cycle 6 by computed tomography (CT) and 19 by positron emission tomography/CT (PET/CT): overall and complete response rates were 87.5% (95% CI, 67.6% to 97.3%) and 25% (95% CI, 9.8% to 46.7%) in the CT-evaluated patients and 84.2% (95% CI, 60.4% to 96.6%) and 68.4% (95% CI, 43.4% to 87.4%), respectively, in the PET/CT-evaluated patients. One-year progression-free survival was 77.8% (95% CI, 54.6% to 90.1%) and 79% (95% CI, 47.9% to 92.7%) for CT and PET/CT-evaluable patients, respectively, whereas progression-free survival at 30 months was 73.2% (95% CI, 49.8%, 87.0%) as assessed by CT and 79.0% (95% CI, 47.9%, 92.7%) by PET/CT. Despite the activity observed, our results do not support further development of the combination in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02877550., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Alterations in hypothalamic-pituitary-adrenal (HPA) axis and its effector hormone cortisol have been proposed as one possible mechanism linking child maltreatment experiences to health disparities. In this series of meta-analyses, we aimed to quantify the existing evidence on the effect of child maltreatment on various measures of HPA axis activity. The systematic literature search yielded 1,858 records, of which 87 studies (k = 132) were included. Using random-effects models, we found evidence for blunted cortisol stress reactivity in individuals exposed to child maltreatment. In contrast, no overall differences were found in any of the other HPA axis activity measures (including measures of daily activity, cortisol assessed in the context of pharmacological challenges and cumulative measures of cortisol secretion). The impact of several moderators (e.g., sex, psychopathology, study quality), the role of methodological shortcomings of existing studies, as well as potential directions for future research are discussed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the results of the radiation therapy (RT) quality assurance (QA) program of the phase 3 randomized SAKK 09/10 trial in patients with biochemically recurrent prostate cancer after prostatectomy., Methods and Materials: Within the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 09/10 trial testing 64-Gy versus 70-Gy salvage RT, a central collection of treatment plans was performed and thoroughly reviewed by a dedicated medical physicist and radiation oncologist. Adherence to the treatment protocol and specifically to the European Organization for the Research and Treatment of Cancer (EORTC) guidelines for target volume definition (classified as deviation observed yes vs no) and its potential correlation with acute and late toxicity (Common Terminology Criteria for Adverse Events version 4.0) and freedom from biochemical progression (FFBP) were investigated., Results: The treatment plans for 344 patients treated between February 2011 and April 2014 depicted important deviations from the EORTC guidelines and the recommendations per trial protocol. For example, in up to half of the cases, the delineated structures deviated from the protocol (eg, prostate bed in 48.8%, rectal wall [RW] in 41%). In addition, variations in clinical target volume (CTV) and planning target volume (PTV) occurred frequently (eg, CTV and PTV deviations in up to 42.4% and 25.9%, respectively). The detected deviations showed a significant association with a lower risk of grade ≥2 gastrointestinal acute toxicity when the CTV did not overlap the RW versus when the CTV overlapped the RW (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.22-0.85; P = .014), and a higher rate of grade ≥2 late genitourinary (GU) toxicity when the CTV overlapped the RW (OR, 2.58; 95% CI, 1.17-5.72; P = .019). A marginally significant lower risk of grade ≥2 late GU toxicity was observed when the prostate bed did not overlap versus did overlap the RW (OR, 0.51; 95% CI, 0.25-1.03; P = .06). In addition, a marginally significant decrease in FFBP was observed in patients with PTV not including surgical clips as potential markers of the limits of the prostate bed (hazard ratio, 1.44; 95% CI, 0.96-2.17; P = .07)., Conclusions: Despite a thorough QA program, the central review of a phase 3 trial showed limited adherence to treatment protocol recommendations, which was associated with a higher risk of toxicity by means of acute or late gastrointestinal or GU toxicity and showed a trend toward worse FFBP. Data from this QA review might help to refine future QA programs and prostate bed delineation guidelines., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Biological invasions are a grave threat to ecosystems. The black garden ant (Lasius niger) is a pest species in Europe. Current literature states that L. niger occupies a disjunct native distribution in the Holarctic, however, based on recent work, we re-evaluate this distribution. The native range of L. niger is reconsidered based on phylogenetic relationships (nine mitochondrial and nuclear markers, 5670 bp), DNA-barcoding (98 Holarctic specimens), morphometry (88 Holarctic specimens, 19 different measurements) and subjective assessment of phenotype. The potential spread of this species is estimated using ecological niche modeling. Lasius niger is more closely related to other Palearctic species than to the Nearctic ants known under this name. The latter are described as a distinct species, L. ponderosae sp. nov. However, DNA-barcoding discovered established populations of L. niger in metropolitan areas in Canada (Vancouver and Halifax). We describe a morphometrical method to delineate L. ponderosae sp. nov. and L. niger. MtDNA diversity and divergence is high within L. ponderosae sp. nov., but low within L. niger. More than 1,000,000 km 2 are suitable as a habitat for L. niger in North America. This case emphasizes the critical role of integrative taxonomy to detect cryptic species and identify potential biological invasions in their nascent stages., (© 2022. The Author(s).)

Background: Non-suicidal self-injury (NSSI), typically observed in the context of various mental disorders, represents a highly prevalent and serious problem among adolescents. Based on studies linking NSSI with stress, alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning have been suggested to contribute to the development and maintenance of this behavior. While research has mainly focused on cortisol - the main hormonal output of this system - to our knowledge, no study has examined pituitary gland volume (PGV) - an alternative approach of assessing HPA axis functionality that is less state-dependent - in adolescents engaging in NSSI., Methods: Magnetic Resonance Imaging (MRI) was performed among n = 35 adolescents (aged 12-17 years) fulfilling the diagnostic criteria for NSSI disorder according to DSM-5 and n = 31 age-matched healthy controls; PGV was obtained by manual tracing. To test for group differences - our primary aim - a hierarchical linear regression model was computed, controlling for several potential confounding variables. Since adolescence reflects a time period for significant brain development - including changes in PGV - we also tested for an age-dependent group effect. In a second step, we aimed to investigate whether differences in PGV are accounted for by the experience of childhood adversity or psychopathology. Finally, following an exploratory approach, the dimensional association between PGV and various clinical characteristics (e.g., frequency of NSSI) were explored., Results: No evidence was found for overall volumetric differences between healthy control participants and adolescents engaging in NSSI (p > 0.05) - recognizing that small effect size differences could not be detected in the present study - but group membership significantly interacted with age in predicting PGV (p = 0.02). Particularly, while PGV increased linearly with age in healthy controls (B = 61.39, SE = 14.94, p < 0.01), no corresponding association was found in NSSI patients (B = 16.83, SE = 12.20, p = 0.17). PGV was not related to adverse experiences during childhood and none of the clinical characteristics (e.g., frequency of NSSI) significantly correlated with PGV (p > 0.05)., Conclusion: These results provide preliminary evidence for alterations in pituitary maturation in adolescents engaging in NSSI, although replication in longitudinal studies with larger samples is warranted., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accurate estimation of the progression risk after first-line therapy represents an unmet clinical need in diffuse large B-cell lymphoma (DLBCL). Baseline (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) parameters, together with genetic analysis of lymphoma cells, could refine the prediction of treatment failure. We evaluated the combined impact of mutation profiling and baseline PET/CT functional parameters on the outcome of DLBCL patients treated with the R-CHOP14 regimen in the SAKK38/07 clinical trial (NCT00544219). The concomitant presence of mutated SOCS1 with wild-type CREBBP and EP300 defined a group of patients with a favorable prognosis and 2-year progression-free survival (PFS) of 100%. Using an unsupervised recursive partitioning approach, we generated a classification-tree algorithm that predicts treatment outcomes. Patients with elevated metabolic tumor volume (MTV) and high metabolic heterogeneity (MH) (15%) had the highest risk of relapse. Patients with low MTV and favorable mutational profile (9%) had the lowest risk, while the remaining patients constituted the intermediate-risk group (76%). The resulting model stratified patients among three groups with 2-year PFS of 100%, 82%, and 42%, respectively ( p < 0.001).

Functional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression-free (PFS), cause-specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET-derived radiomics may improve the prediction of outcome in DLBCL patients., (© 2022 John Wiley & Sons Ltd.)

The biogenic substance E-indigo can form supramolecular, hydrophobic structures using self-organization. These structures show a low coefficient of friction as a gliding layer against polar surfaces. The formation of primary particles with platelet morphology based on hydrogen-bonded E-indigo molecules is ideal to produce the gliding layer. Structures with excellent gliding properties can be achieved by means of directed friction and high pressure, as well as through tempering. The resulting hard, thin gliding layer of E-indigo does not easily absorb dirt and, thus, prevents a rapid increase in friction. Field tests on snow, with cross-country skis, have shown promising results in comparison to fluorinated and non-fluorinated waxes. Based on quantitative structure-activity relationship (QSAR) data for E-indigo, and its isomers and tautomers, it has been demonstrated that both the application and abrasion of the thin indigo layers are harmless to health, and are ecologically benign and, therefore, sustainable.

Producing electricity from renewable sources and reducing its consumption by buildings are necessary to meet energy and climate change challenges. Wood is an excellent "green" building material and, owing to its piezoelectric behavior, could enable direct conversion of mechanical energy into electricity. Although this phenomenon has been discovered decades ago, its exploitation as an energy source has been impaired by the ultralow piezoelectric output of native wood. Here, we demonstrate that, by enhancing the elastic compressibility of balsa wood through a facile, green, and sustainable fungal decay pretreatment, the piezoelectric output is increased over 55 times. A single cube (15 mm by 15 mm by 13.2 mm) of decayed wood is able to produce a maximum voltage of 0.87 V and a current of 13.3 nA under 45-kPa stress. This study is a fundamental step to develop next-generation self-powered green building materials for future energy supply and mitigation of climate change., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The relapse of follicular lymphoma (FL) within 24 months (POD24) of chemoimmunotherapy has been associated with poor survival. We analyzed a pooled dataset of three randomized trials including FL patients with advanced disease, conducted by the Swiss Group for Clinical Cancer Research (SAKK). Overall, POD24 was observed in 27% of 318 patients, but rate variance among studies suggested that the rituximab schedule might affect POD24 rate. POD24 was associated with lower 10-year overall survival rates than in the reference group (69% vs. 77%; hazard ratio, 3·12; 95% confidence interval, 1·73-5·65). POD24 retains its prognostic validity in patients treated without chemotherapy and may represent a useful end-point for future studies., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

The Swiss Group for Clinical Cancer Research (SAKK) conducted the SAKK 35/03 randomized trial (NCT00227695) to investigate different rituximab monotherapy schedules in patients with follicular lymphoma (FL). Here, we report their long-term treatment outcome. Two-hundred and seventy FL patients were treated with 4 weekly doses of rituximab monotherapy (375 mg/m2); 165 of them, achieving at least a partial response, were randomly assigned to maintenance rituximab (375 mg/m2 every 2 months) on a short-term (4 administrations; n = 82) or a long-term (up to a maximum of 5 years; n = 83) schedule. The primary end point was event-free survival (EFS). At a median follow-up period of 10 years, median EFS was 3.4 years (95% confidence interval [CI], 2.1-5.5) in the short-term arm and 5.3 years (95% CI, 3.5-7.5) in the long-term arm. Using the prespecified log-rank test, this difference is not statistically significant (P = .39). There also was not a statistically significant difference in progression-free survival or overall survival (OS). Median OS was 11.0 years (95% CI, 11.0-NA) in the short-term arm and was not reached in the long-term arm (P = .80). The incidence of second cancers was similar in the 2 arms (9 patients after short-term maintenance and 10 patients after long-term maintenance). No major late toxicities emerged. No significant benefit of prolonged maintenance became evident with longer follow-up. Notably, in symptomatic patients in need of immediate treatment, the 10-year OS rate was 83% (95% CI, 73-89%). These findings indicate that single-agent rituximab may be a valid first-line option for symptomatic patients with advanced FL., (© 2020 by The American Society of Hematology.)

Positron emission computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) enrolled in a prospective clinical trial were reviewed to test the impact of quantitative parameters from interim PET/CT scans on overall (OS) and progression-free (PFS) survival. We centrally reviewed baseline and interim PET/CT scans of 138 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone given every 14 days (R-CHOP14) in the SAKK38/07 trial (ClinicalTrial.gov identifier: NCT00544219). Cutoff values for maximum standardized uptake value (SUV max ), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic heterogeneity (MH) were defined by receiver operating characteristic analysis. Responses were scored using the Deauville scale (DS). Patients with DS 5 at interim PET/CT (defined by uptake >2 times higher than in normal liver) had worse PFS (P = 0.014) and OS (P < 0.0001). A SUV max reduction (Δ) greater than 66% was associated with longer PFS (P = 0.0027) and OS (P < 0.0001). Elevated SUV max , MTV, TLG, and MH at interim PET/CT also identified patients with poorer outcome. At multivariable analysis, ΔSUV max and baseline MTV appeared independent outcome predictors. A prognostic model integrating ΔSUV max and baseline MTV discriminated three risk groups with significantly (log-rank test for trend, P < 0.0001) different PFS and OS. Moreover, the integration of MH and clinical prognostic indices could further refine the prediction of OS. PET metrics-derived prognostic models perform better than the international indices alone. Integration of baseline and interim PET metrics identified poor-risk DLBCL patients who might benefit from alternative treatments., (© 2020 John Wiley & Sons Ltd.)

Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown., Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations., Design, Setting, and Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019., Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy., Main Outcomes and Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations., Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively., Conclusions and Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.

Myelodysplastic syndromes (MDSs) represent a heterogeneous group of hematological stem cell disorders with an increasing burden on health care systems. Evidence-based MDS guidelines and recommendations (G/Rs) are published but do not necessarily translate into better quality of care if adherence is not maintained in daily clinical practice. Guideline-based indicators (GBIs) are measurable elements for the standardized assessment of quality of care and, thus far, have not been developed for adult MDS patients. To this end, we screened relevant G/Rs published between 1999 and 2018 and aggregated all available information as candidate GBIs into a formalized handbook as the basis for the subsequent consensus rating procedure. An international multidisciplinary expert panel group (EPG) of acknowledged MDS experts (n = 17), health professionals (n = 7), and patient advocates (n = 5) was appointed. The EPG feedback rates for the first and second round were 82% (23 of 28) and 96% (26 of 27), respectively. A final set of 29 GBIs for the 3 domains of diagnosis (n = 14), therapy (n = 8), and provider/infrastructural characteristics (n = 7) achieved the predefined agreement score for selection (>70%). We identified shortcomings in standardization of patient-reported outcomes, toxicity, and geriatric assessments that need to be optimized in the future. Our GBIs represent the first comprehensive consensus on measurable elements addressing best practice performance, outcomes, and structural resources. They can be used as a standardized instrument with the goal of assessing, comparing, and fostering good quality of care within clinical development cycles in the daily care of adult MDS patients., (© 2020 by The American Society of Hematology.)

Objectives: Early clinical trials showed promising outcomes with immune-checkpoint inhibitors (ICI) in a subset of patients with relapsed small-cell lung carcinoma (SCLC). The aim of this retrospective analysis was to assess the efficacy and safety of ICI for relapsed SCLC in a real-world patient population., Methods: Nine cancer centres in Switzerland contributed data to this cohort. Responses were assessed by the local investigators using standard RECIST v1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were analysed by the Kaplan-Meier method. Associations between potential predictive markers and survival endpoints were probed by Cox proportional hazards., Results: Forty-five patients were included in the analysis. Median age was 63 years, 73% were males and 18% had an ECOG performance status (PS) ≥ 2. ICIs were given as second-line treatment in 60%. Twenty-four patients (53%) received ipilimumab with nivolumab. Twenty-eight patients (62%) had undergone irradiation (RT) prior to or during ICI. Overall response rate (ORR) was 29% and median PFS and OS were 2.3 and 6.5 months, respectively. Median duration of response was 9 months (95% CI 2.8-NA). Five patients maintained their response for > 6 months, all of them receiving combination treatment. There were no new safety signals., Conclusion: This is the first report of "real-world" data on ICI in relapsed SCLC also including patients with poor PS. Promising durable responses were observed. No biological prognostic marker could be identified.

Climate change and invasive species threaten biodiversity, yet rigorous monitoring of their impact can be costly. Citizen science is increasingly used as a tool for monitoring exotic species, because citizens are geographically and temporally dispersed, whereas scientists tend to cluster in museums and at universities. Here we report on the establishment of the first exotic ant taxon ( Tetramorium immigrans ) in Denmark, which was discovered by children participating in The Ant Hunt. The Ant Hunt is a citizen science project for children that we ran in 2017 and 2018, with a pilot study in 2015. T. immigrans was discovered in the Botanical Garden of the Natural History Museum of Denmark in 2015 and confirmed as established in 2018. This finding extends the northern range boundary of T. immigrans by almost 460 km. Using climatic niche modelling, we compared the climatic niche of T. immigrans in Europe with that of T. caespitum based on confirmed observations from 2006 to 2019. T. immigrans and T. caespitum had a 13% niche overlap, with T. immigrans showing stronger occurrence in warmer and drier areas compared to T. caespitum . Mapping the environmental niches onto geographic space identified several, currently uninhabited, areas as climatically suitable for the establishment of T. immigrans . Tetramorium immigrans was sampled almost three times as often in areas with artificial surfaces compared to T. caespitum , suggesting that T. immigrans may not be native to all of Europe and is being accidentally introduced by humans. Overall, citizen scientists collected data on ants closer to cities and harbours than scientists did and had a stronger bias towards areas of human disturbance. This increased sampling effort in areas of likely introduction of exotic species naturally increases the likelihood of discovering species sooner, making citizen science an excellent tool for exotic species monitoring, as long as trained scientists are involved in the identification process., Competing Interests: The authors declare that they have no competing interests., (© 2020 Sheard et al.)

Several functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P = .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P = .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P = .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P < .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P = .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219., (© 2020 by The American Society of Hematology.)

The role of specialization in diversification can be explored along two geological axes in the butterfly family Lycaenidae. In addition to variation in host-plant specialization normally exhibited by butterflies, the caterpillars of most Lycaenidae have symbioses with ants ranging from no interactions through to obligate and specific associations, increasing niche dimensionality in ant-associated taxa. Based on mitochondrial sequences from 8282 specimens from 967 species and 249 genera, we show that the degree of ecological specialization of lycaenid species is positively correlated with genetic divergence, haplotype diversity and an increase in isolation by distance. Nucleotide substitution rate is higher in carnivorous than phytophagous lycaenids. The effects documented here for both micro- and macroevolutionary processes could result from increased spatial segregation as a consequence of reduced connectivity in specialists, niche-based divergence or a combination of both. They could also provide an explanation for the extraordinary diversity of the Lycaenidae and, more generally, for diversity in groups of organisms with similar multi-dimensional ecological specialization., (© 2018 The Author(s).)

Social insects such as ants have evolved collective rather than individual immune defence strategies against diseases and parasites at the level of their societies (colonies), known as social immunity. Ants frequently host other arthropods, so-called myrmecophiles, in their nests. Here, we tested the hypothesis that myrmecophily may partly arise from selection for exploiting the ants' social immunity. We used larvae of the wax moth Galleria mellonella as 'model myrmecophiles' (baits) to test this hypothesis. We found significantly reduced abundance of entomopathogens in ant nests compared with the surrounding environment. Specific entomopathogen groups (Isaria fumosorosea and nematodes) were also found to be significantly less abundant inside than outside ant nests, whereas one entomopathogen (Beauveria brongniartii) was significantly more abundant inside nests. We therefore hypothesize that immunological benefits of entering ant nests may provide us a new explanation of why natural selection acts in favour of such a life-history strategy.