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Unter extrakorporaler Membranoxygenierung (ECMO) bzw. Extracorporeal life support (ECLS) versteht man den Einsatz einer miniaturisierten Herz-Lungen-Maschine, der bei respiratorischem (ECMO) bzw. kardialem (ECLS) Versagen erfolgt, wenn konservative therapeutische Masnahmen gescheitert sind. Die ECMO/ ECLS kann als Uberbruckung bis zur Erholung, bis zur Transplantation bzw. bis zur Implantation eines definitiven Unterstutzungssystems oder bis zu einer endgultigen therapeutischen Entscheidung (z. B. bei unklarer neurologischer Situation) eingesetzt werden. Die Maschine wird entweder venoarteriell (v.a.) oder venovenos (v.v.) angeschlossen. Venoarteriell besteht die Moglichkeit des zentralen Zugangs uber die Aorta ascendens und den rechten Vorhof oder peripher uber die Hals- bzw. Femoralgefase. Venovenos konnen entweder beide Vv. femorales, eine Femoralvene und die rechtsseitige V. jugularis oder nur die V. jugularis interna kanuliert werden. Indikationen, Kanulierungstechniken und intensivmedizinisches Management unterscheiden sich bei Kindern und Erwachsenen in einigen wichtigen Details. Bei angeborenen Herzfehlern konnen die venosen Konnexionen mit dem Herzen vor- oder auch nach kinderherzchirurgischen Operationen von der normalen Situation abweichen. Daher sollte die padiatrische ECMO-Therapie ausschlieslich von Kinder-Teams (Kinderherzchirurgen, Kinderkardiologen/Neonatologen und speziell geschulten Kardiotechnikern) durchgefuhrt werden. Im Folgenden werden die institutionelle Philosophie und die Techniken des ECMO-Programms der Autoren beispielhaft dargestellt. Die padiatrische ECMO-Therapie wird aufgrund der geringen Fallzahlen immer eine Therapie bleiben, die auf das jeweilige Kind masgeschneidert sein muss und sich von Zentrum zu Zentrum im Detail unterscheidet.

Flexibility regarding where and when work is completed is becoming increasingly available to employees, especially following the COVID-19 outbreak and subsequent shift in the nature of work. There is a plethora of research linking various flexible work arrangements (FWA) to a variety of positive outcomes across domains including reduced work–family conflict, better psychological health, and increased role satisfaction. While several studies have suggested that FWA are related to positive health, others have found no relationship between flexible work arrangements and health outcomes. To clarify these inconsistent findings, the current meta-analytic review (k = 33, n = 90,602) examines the relationship between flexible work arrangements available to employees and health behaviours and outcomes, specifically physical health, absenteeism, somatic symptoms, and physical activity. Results demonstrate that FWA are associated with better physical health, reduced absenteeism, and fewer somatic symptoms, suggesting that flexible work arrangements can facilitate employees in maintaining their health. There was no association between FWA and physical activity, though these results should be interpreted cautiously given the limited number of primary studies examining this relationship. These findings hold implications for future research and practice, including support for offering individualised flexible work arrangements as means of promoting employee health. [ABSTRACT FROM AUTHOR] Copyright of Work & Stress is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Our research examined the role of challenge and hindrance stressors, as well as the interactive effects of these stressors with positive and negative affect, in predicting work engagement and exhaustion using experience sampling methodology. In Study 1, university staff completed measures of challenge and hindrance stressors, positive and negative affect, work engagement, and exhaustion before the end of the workday over 5 working days. Results from multilevel regression indicated that challenge stressors were positively related to work engagement but not exhaustion, while hindrance stressors were unrelated to both work engagement and exhaustion. Additionally, positive affect moderated the association between challenge stressors and both work engagement and exhaustion. We partially replicated and extended these findings in our second sample of Amazon’s Mechanical Turk workers, who completed measures of affect in the mornings before starting work and stressors, work engagement, and exhaustion in the evenings before leaving work, over a period of 10 working days. Results suggested that challenge stressors were positively related to work engagement and exhaustion, while hindrance stressors were positively related to exhaustion and negatively related to work engagement. Similar to our results in Study 1, we found that positive affect interacted with challenge stressors in predicting each work outcome. Furthermore, positive affect moderated the hindrance stressor-work outcomes relationship. Lastly, negative affect moderated the association between challenge stressors and exhaustion. The findings of this study can be used to design interventions that enhance employee motivation and engagement in the presence of challenge and hindrance stressors.

The COVID-19 pandemic represents one of the greatest global crises in modern history. In addition to recession and high unemployment, agencies such as the Centers for Disease Control and Prevention warn that stressors associated with a pandemic can cause increased strains, including difficulty concentrating, anxiety, and decreased mental health (CDC, 2020). Two general frameworks that explain these stressor-strain relationships over time include stress-reaction and adaptation models. Stress-reaction models suggest that stressors, such as heightened job demands due to the pandemic, accumulate over time and thus prolonged exposure to these stressors results in both immediate and long-term strain; conversely, adaptation models suggest that people adapt to stressors over time, such that strains produced by ongoing stressors tend to dissipate. After controlling for county-level COVID-19 cases, we found that (a) workers in general exhibited decreasing cognitive weariness and psychological symptoms over time, providing support for the adaptation model; (b) on-site workers experienced increasing physical fatigue over time, supporting the stress-reaction model among those workers; and (c) engaging in recovery behaviors was associated with improvements in cognitive weariness and psychological symptoms for all workers. We also found that our Time 1 outcomes were significantly different than pre-pandemic norms, such that our participants displayed lower initial levels of job-related burnout and higher initial levels of psychological symptoms than pre-pandemic norms. Furthermore, supplemental qualitative data support our quantitative findings for recovery behaviors. These findings have important implications for understanding workers' responses to the pandemic and they can help inform organizational practice.

The aim of this study was to evaluate gender aspects and trends in urological clinics, research and private practice. The focus was on the objectification of gender-specific changes in the field of urology at the current time and in the future.A digital survey among urological physicians in Germany was conducted with the SurveyMonkey© portal, which was sent to all registered members via the email distribution lists of the German Society of Urology (DGU) and the Professional Association of German Urologists (BvDU). Baseline data were collected in the outpatient and inpatient sectors, as were gender-specific data related to job distribution, goals, satisfaction, and reasons for career decisions.The analysis of 398 responses revealed that urological colleagues in private practice were less likely to be female (23.6%) and significantly older (mean age 53 years) than in the inpatient sector (female proportion 47.2%, mean age 43 years). More men (49.4%) than women (29.9%) were in private practice and this was indicated as a career aspiration by more men than women (28.1% vs. 22.8%). The reasons for setting up a practice were more often family-related for women than for men (main reasons good opportunity or career aspiration). Women were more likely to work part-time (27.0% vs. 11.5%) and more likely to aspire to a career as a senior physician (29.1% of women, 9.4% of men). Correspondingly, the desire for a postdoctoral position or professorship was more common among women than among men (20.5% vs. 15%). Significantly more female urologists perceived inequality in career advancement opportunities (59.7% vs. 17.5%, p 0.001) and 73.3% (vs. 18.5% of men, p 0.001) perceived their gender as a cause of disadvantage. This resulted in significantly lower satisfaction of women with their professional status (p = 0.008) as well as a lower feeling of being valued (p 0.001).In order to prepare our specialty field for the future, it is essential to give even greater consideration to gender aspects. The path taken to offer the next generation of urologists a modern specialty in which all physicians, regardless of their gender, enjoy working, are valued and where equal opportunities prevail, should definitely be pursued and intensified in order to position urology well for the future.HINTERGRUND UND FRAGESTELLUNG: Ziel dieser wissenschaftlichen Arbeit war es, Genderaspekte und Trends in Klinik, Forschung und Niederlassung in der Urologie zu analysieren. Dabei lag der Fokus auf der Objektivierung des genderspezifischen Wandels im Fachgebiet „Urologie“ zum aktuellen Zeitpunkt und in der Zukunft.Es erfolgte eine digitale Umfrage bei urologischen Ärzt:innen in Deutschland über das Portal SurveyMonkey©, welche über den E‑Mail-Verteiler der Deutschen Gesellschaft für Urologie e. V. (DGU) und des Berufsverbands der Deutschen Urologen e. V. (BvDU) an alle eingetragenen Mitglieder verschickt wurde. Es wurden Basisdaten im ambulanten und stationären Sektor erhoben, sowie geschlechtsspezifische Daten in Bezug auf Arbeitsplatzverteilung, Ziele, Zufriedenheit und Gründe für berufliche Entscheidungen.Die Auswertung von 398 Antworten ergab, dass urologische Kolleg:innen in der Niederlassung seltener weiblich (23,6 %) und deutlich älter (mittleres Alter 53 Jahre) waren als im stationären Sektor (Frauenanteil 47,2 %, mittleres Alter 43 Jahre). Niedergelassene Vertragsärzt:innen waren mehr Männer (49,4 %) als Frauen (29,9 %) und die Niederlassung wurde von mehr Männern als Berufswunsch angegeben (28,1 % vs. 22,8 %). Die Gründe für die Niederlassung lagen bei Frauen häufiger im familiären Bereich als bei den Männern (Hauptgründe gute Gelegenheit oder Berufswunsch). Frauen arbeiteten häufiger Teilzeit (27,0 % vs. 11,5 %) und strebten häufiger eine Karriere als Oberärztin an (29,1 % der Frauen, 9,4 % der Männer). Entsprechend war der Wunsch nach einer Habilitation oder Professur bei den Frauen häufiger als bei den Männern (20,5 % vs. 15 %). Signifikant mehr Urologinnen sahen eine Ungleichheit bei den beruflichen Aufstiegschancen (59,7 % vs. 17,5 %, p 0,001) und 73,3 % (vs. 18,5 % der Männer, p 0,001) empfanden ihr Geschlecht als Ursache einer Benachteiligung. Dies führte zu einer signifikant geringeren Zufriedenheit von Frauen mit ihrem beruflichen Status (p = 0,008), sowie einem geringeren Gefühl der Wertschätzung (p 0,001).Um die Urologie zukunftsfähig zu machen ist es essenziell, Genderaspekte noch stärker zu berücksichtigen. Der eingeschlagene Weg, der nächsten Generation von Urolog:innen ein modernes Fachgebiet zu bieten, in dem alle Ärzt:innen unabhängig von ihrem Geschlecht gerne arbeiten, wertgeschätzt werden und Chancengleichheit herrscht, sollte unbedingt weiter verfolgt und intensiviert werden, um die Urologie für die Zukunft gut aufzustellen.

Electrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the molecular mechanisms of ESD formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for channel localization, electrical communication, neural network function, and behavior (Lasseigne et al., 2021). Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and -Gamma. We demonstrate that ZO1b-Beta is localized to electrical synapses where it is necessary and sufficient for robust channel localization. Additionally, ZO1b-Gamma is also localized to synapses, yet plays a minor role in channel localization. By contrast, ZO1b-Alpha plays no role at the developmental stage examined. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute multiple independent isoforms to the macromolecular complex at the synapse with each differentially contributing to structural formation. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes, and that such proteomic diversity has critical impacts on the structure, function, and plasticity of electrical transmission.

The education curriculum in urology is aimed at better integration of inpatient and outpatient medicine and high-quality specialist training in order to recruit well-trained young people for urology in the future. For this purpose, in a modular system, rotations of 6-12 months in outpatient offices as well as optionally in other disciplines or in other clinics with different priorities are planned. The training period includes 5 modular seminars and a webinar series including examinations, in which the entire learning content required in the specialty training regulations is presented in interactive lectures. Clinics and outpatient offices certified to participate in the curriculum undergo regular evaluation, which leads to continuous improvement of training centers.Das Weiterbildungscurriculum Urologie zielt auf eine bessere Verzahnung von stationärer und ambulanter Medizin sowie auf eine qualitativ hochwertige fachliche Weiterbildung, um auch zukünftig fachlich gut ausgebildeten Nachwuchs für die Urologie zu gewinnen. Hierzu sind in einem modularen System Rotationen von 6–12 Monaten in eine Praxis sowie optional in andere Fachdisziplinen oder in andere Kliniken mit unterschiedlichen Schwerpunkten vorgesehen. Die Weiterbildungszeit wird von 5 Modulseminaren und einer Webinarreihe inklusive Prüfungen begleitet, in denen der gesamte in der Musterweiterbildungsordnung geforderte Lerninhalt in interaktiven Referaten vorgestellt wird. Für die Teilnahme am Curriculum zertifizierte Kliniken und Praxen unterziehen sich einer regelmäßigen Evaluation, welche zu einer kontinuierlichen Verbesserung der Weiterbildungsstätten führen wird.

High-dose (HD) cisplatin remains the standard of care with chemoradiation for locally advanced oropharyngeal cancer (OPC). Cooperative group trials mandate bolus-HD (100 mg/m2 × 1 day, every 3 weeks) cisplatin administration at the beginning of the week to optimize radiosensitization-a requirement which may be unnecessary. This analysis evaluates the impact of chemotherapy administration day of week (DOW) on outcomes. We also report our institutional experience with an alternate dosing schedule, split-HD (50 mg/m2 × 2 days, every 3 weeks). We retrospectively reviewed 435 definitive chemoradiation OPC patients from 10 December 2001 to 23 December 2014. Those receiving non-HD cisplatin regimens or induction chemotherapy were excluded. Data collected included DOW, dosing schedule (bolus-HD vs split-HD), smoking, total cumulative dose (TCD), stage, Karnofsky Performance Status, human papillomavirus status and creatinine (baseline, peak and posttreatment baseline). Local failure (LF), regional failure (RF), locoregional failure (LRF), distant metastasis (DM), any failure (AF, either LRF or DM) and overall survival (OS) were calculated from radiation therapy start. Median follow-up was 8.0 years (1.8 months-17.0 years). DOW, dosing schedule and TCD were not associated with any outcomes in univariable or multivariable regression models. There was no statistically significant difference in creatinine or association with TCD in split-HD vs bolus-HD. There was no statistically significant association between DOW and outcomes, suggesting that cisplatin could be administered any day. Split-HD had no observed differences in outcomes, renal toxicity or TCD compared to bolus-HD cisplatin. Our data suggest that there is some flexibility of when and how to give HD cisplatin compared to clinical trial mandates.

PURPOSE The objective response rate (ORR) for single-agent anti–programmed death receptor 1 (anti–PD-1) therapy is modest in patients with metastatic or recurrent head and neck squamous cell carcinoma (HNSCC). We aimed to test whether radiotherapy may act synergistically with anti–PD-1 therapy to improve response through the abscopal effect. PATIENTS AND METHODS We conducted a single-center, randomized, phase II trial of nivolumab (anti–PD-1 therapy) versus nivolumab plus stereotactic body radiotherapy (SBRT) in patients with metastatic HNSCC. Patients had at least two metastatic lesions: one that could be safely irradiated and one measurable by RECIST version 1.1. Patients were randomly assigned (1:1), stratified by human papillomavirus status, to nivolumab (3 mg/kg intravenously every 2 weeks) or nivolumab (same dose) plus SBRT (9 Gy × 3) to 1 lesion. The primary end point was ORR in nonirradiated lesions, which was assessed by RECIST in patients with at least one available set of on-treatment images; safety was assessed in a per-protocol population. RESULTS Between March 11, 2016, and June 22, 2018, 62 patients were randomly assigned to nivolumab (n = 30) or nivolumab plus SBRT (n = 32). There was no statistically significant ORR difference between arms (34.5% [95% CI, 19.9% to 52.7%] v 29.0% [95% CI, 16.1% to 46.6%]; P = .86). There was no significant difference in overall survival ( P = .75), progression-free survival ( P = .79), or response duration ( P = .26). Grade 3-5 toxicities were similar (13.3% v 9.7%; P = .70). CONCLUSION We found no improvement in response and no evidence of an abscopal effect with the addition of SBRT to nivolumab in unselected patients with metastatic HNSCC.

Workplace participatory ergonomics (PE) programs may foster the prevention of injuries and illnesses as well as promote healthier behaviors and productivity among employees. Facilitating leadership has been identified as a critical component to the implementation of PE programs. Several contemporary leadership styles and theories have been proposed in the Industrial and Organizational (I/O) Psychology literature. A bibliometric mapping analysis was performed to assess the extent to which contemporary leadership styles have been studied in relation to PE programs in the ergonomics and public, environmental, and occupational health literature categories of the Clarivate Analytics Web of Science (WoS). Results indicated that while production in the collective areas of PE programs and leadership has increased significantly in recent decades, the study of contemporary leadership styles and/or theories in PE programs has been limited. The results highlight an opportunity for additional interdisciplinary research that may lead to more effective PE program implementation.

Degree of reproductive synchronization in prey is hypothesized as a predator defense strategy reducing prey risk via predator satiation or predator avoidance. Species with precocial young, especially those exposed to specialist predators, should be highly synchronous to satiate predators (predator satiation hypothesis), while prey with nonprecocial (i.e. altricial) young, especially those exposed to generalist predators, should become relatively asynchronous to avoid predator detection (predator avoidance hypothesis). The white‐tailed deer Odocoileus virginianus in North America is an example of a nonprecocial ungulate that uses the hider strategy early in life; its primary predator (coyote; Canis latrans) is a generalist, making white‐tailed deer a good model species to test the predator avoidance hypothesis. We used birth dates and known fates of white‐tailed deer neonates (n = 1,032) across nine study sites varying in relative synchrony and predator assemblages to test the predator avoidance hypothesis. We predicted that relative birthing asynchrony of the population would increase relative survival at the population level; therefore, at the individual scale, neonate birth date nearer to mean birthing date in a respective population would not influence individual survival. Coyotes were responsible for the majority of predation events, and survival of those neonates increased the closer the individual was born to peak birthing season in each respective population. Also, at the population level, reproductive asynchronization negatively affected survival. Contrary to the predator avoidance hypothesis, our data indicate patterns in neonate survival for white‐tailed deer better support the predator satiation hypothesis at the individual and population level. Additionally, coyotes may present a selective force great enough to shift reproductive synchrony such that predator satiation may become a feasible defense strategy for neonates at local spatial scales. Our results indicate that synchronizing reproduction may still be the most effective strategy to reduce individual predation risk from generalist predators, particularly when the window of heightened resource availability to the prey is narrow. A free Plain Language Summary can be found within the Supporting Information of this article.

Despite strong evidence that individuals process stressor-strain relationships differently, little attention in work-family conflict research has been given to moderating effects of core self-evaluations (CSE). Integrating conservation of resources theory with work-family conflict and CSE research, we predicted that CSE has moderating effects between the relationships of work-to-family conflict (WFC) and voluntary turnover, job promotions, and physical health. We tested our predictions at two time points over a 14-month period with a sample of 731 working mothers in Japan. Results confirmed that CSE moderated the relationships between WFC and voluntary turnover, job promotions, and physical health, such that respondents with higher CSE had lower degrees of voluntary turnover, higher degrees of job promotions, and lower degrees of health problems. This study helps clarify the inconsistent effects of WFC on voluntary turnover in previous research, expands on the limited research examining WFC and job promotion, and provides consistent evidence that CSE act as a moderator between WFC and outcomes.

Habitat availability can affect important life-history traits such as survival; however, little information exists on how microhabitat characteristics found at parturition sites selected by dams and bed sites selected by their offspring differ from the surrounding area and from each other. Therefore, we assessed how vegetation affected maternal parturition and offspring bed site selection for white-tailed deer (Odocoileus virginianus) in the Northern Great Plains. Dams selected for sites with decreased vegetation height, potentially improving their visibility, which may increase their ability to escape approaching predators. Conversely, there was no variation between vegetative characteristics at neonate bed sites and their associated random sites, indicating grasslands provide adequate concealment for neonates. Dams possess the ability to flee from approaching predators, thus increasing the importance of visibility while giving birth. Conversely, neonates depend on fear bradycardia as their main antipredator defense, so concealment is more important. Our results suggest that vegetation structure is an important characteristic to white-tailed deer as habitat needs vary between adults and neonates.

Die Urologie ist aufgrund ihrer Vielseitigkeit und der Haufigkeit der urologischen Erkrankungen eine medizinische Schlusseldisziplin fur beide Geschlechter und Kinder, was grosen Teilen der Bevolkerung unbekannt ist. 2016 wurde als Initiative zur Gesundheitsforderung der Deutschen Gesellschaft fur Urologie (DGU) die „Triple F-Kampagne“ gegrundet mit dem Ziel, sowohl uber die Bedeutung des Faches als auch uber die Wichtigkeit rechtzeitiger urologischer Untersuchungen inklusive PSA-gestutzter (prostataspezifisches Antigen) Fruherkennung aufzuklaren. Mit den Roth-Brudern als Gesichter der Kampagne wurde eine Homepage erstellt mit Informationen uber die wichtigsten urologischen Erkrankungen, Flyer und Poster fur Arzte und Patienten an 3500 Arzte verschickt, ein Urologensuchportal fur Patienten mit bislang 2200 registrierten Kollegen eingerichtet etc. Geplant sind weitere Aktivitaten, u. a. mit dem Ziel einer immer weiter wachsenden Beteiligung der deutschen Urologen und ihrer Patienten.

Objective The first available CFTR modulator combination for homozygous F508del patients, lumacaftor/ivacaftor, has not been tested in patients with percentage predicted (pp)FEV1 > 90 in the phase III trials. The objective of this study is to share real life experience about treatment results in this group. Methods In this retrospective observational study, patients aged 6 years or older starting on lumacaftor/ivacaftor in standard care were in strict follow up. For these patients, data were obtained about FEV1, BMI, CFQ-R and sweat chloride before start and after 6 months of treatment, and data about FEV1 and BMI were recorded every 3 months. Exacerbations were recorded continuously. Results We identified 40 patients with a ppFEV1 ≥ 90 at the start of lumacaftor/ivacaftor who had been in follow up for at least 12 months. After 12 months, ppFEV1 was unchanged, whereas mean absolute change in BMI was +0.88 (p = 0.001) with a mean change in SDS for BMI of +0.26 (p = 0.014). Mean CFQ-R overall score at 6 months improved by 2.6% (p = 0.004) and mean decrease in sweat chloride was -27.3 mEq/L (p = 0.000). Exacerbation rate declined from 1.03 to 0.53/person/year (p = 0.003). One patient discontinued treatment in the first 12 months because of progression of CFRLD, two paused treatment but resumed later. Conclusion Homozygous F508del patients starting lumacaftor/ivacaftor at ppFEV1 ≥ 90 improved significantly in nutritional status, sweat chloride levels and exacerbation rate, but did not respond in ppFEV1. Treatment is well tolerated in this patient group. These effects make it worth considering to treat this group of patients with lumacaftor/ivacaftor.

Background CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations. Methods Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function. Findings FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02–0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09–0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = −0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = −0.16, 95% CI -0.48–0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089). Interpretation FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

Purpose Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration–approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods and Materials This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. Results Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. Conclusions The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

Purpose To demonstrate temporal lobe necrosis (TLN) rate and clinical/dose-volume factors associated with TLN in radiation-naïve patients with head and neck cancer treated with proton therapy where the field of radiation involved the skull base. Materials and Methods Medical records and dosimetric data for radiation-naïve patients with head and neck cancer receiving proton therapy to the skull base were retrospectively reviewed. Patients with Results Between 2013 and 2019, 234 patients were included. The median follow-up time was 22.5 months (range = 3.2–69.3). Overall TLN rates of any grade, ≥ grade 2, and ≥ grade 3 were 5.6% (N = 13), 2.1%, and 0.9%, respectively. The estimated 2-year TLN rate was 4.6%, and the 2-year rate of any brain necrosis was 6.8%. The median time to TLN was 20.9 months from proton completion. Absolute volume receiving 40, 50, 60, and 70 GyRBE (absolute volume [aV]); mean and maximum dose received by the temporal lobe; and dose to the 0.5, 1, and 2 cm3 volume receiving the maximum dose (D0.5cm3, D1cm3, and D2cm3, respectively) of the temporal lobe were associated with greater TLN risk while clinical parameters showed no correlation. Among volume parameters, aV50 gave maximum AUC (0.921), and D2cm3 gave the highest AUC (0.935) among dose parameters. The 11-cm3 cutoff value for aV50 and 62 GyRBE for D2cm3 showed maximum specificity and sensitivity. Conclusion The estimated 2-year TLN rate was 4.6% with a low rate of toxicities ≥grade 3; aV50 ≤11 cm3, D2cm3 ≤62 GyRBE and other cutoff values are suggested as constraints in proton therapy planning to minimize the risk of any grade TLN. Patients whose temporal lobe(s) unavoidably receive higher doses than these thresholds should be carefully followed with MRI after proton therapy.

Background The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin’s lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. Methods Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. Results In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. Conclusions AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. Trial registration NCT02106091. Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911. Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.

Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown.We examined the alterations in histone modifications in patient-derived colorectal cancer organoids. Patient-derived colorectal cancer organoids and mouse intestinal organoids were genetically manipulated for functional studies in patient-derived xenograft and orthotopic transplantation. Gene expression profiling, micrococcal nuclease assay, and chromatin immunoprecipitation were performed to understand epigenetic regulation of chromatin states and gene expression in patient-derived and mouse intestinal organoids.We found that reduced H4K20me3 levels occurred predominantly in right-sided patient-derived colorectal cancer organoids, which were associated with increased chromatin accessibility. Re-compaction of chromatin by methylstat, a histone demethylase inhibitor, resulted in reduced growth selectively in subcutaneously grown tumors derived from right-sided cancers. Using mouse intestinal organoids, we confirmed that Suv4-20h2-mediated H4K20me3 is required for maintaining heterochromatin compaction and to prevent R-loop formation. Cross-species comparison of Suv4-20h2-depleted murine organoids with right-sided colorectal cancer organoids revealed a large overlap of gene signatures involved in chromatin silencing, DNA methylation, and stemness/Wnt signaling.Loss of Suv4-20h2-mediated H4K20me3 drives right-sided colorectal tumorigenesis through an epigenetically controlled mechanism of chromatin compaction. Our findings unravel a conceptually novel approach for subtype-specific therapy of this aggressive form of colorectal cancer.

Objective Patient‐centered care and shared decision making (SDM) are generally recognized as the gold standard for medical consultations, especially for preference‐sensitive decisions. However, little is known about psychological patient characteristics that influence patient‐reported preferences. We set out to explore the role of personality and anxiety for a preference‐sensitive decision in bladder cancer patients (choice of urinary diversion, UD) and to determine if anxiety predicts patients' participation preferences. Methods We recruited a sample of bladder cancer patients (N = 180, primarily male, retired) who awaited a medical consultation on radical cystectomy and their choice of UD. We asked patients to fill in a set of self‐report questionnaires before this consultation, including measures of treatment preference, personality (BFI‐10), anxiety (STAI), and participation preference (API and API‐Uro), as well as sociodemographic characteristics. Results Most patients (79%) indicated a clear preference for one of the treatment options (44% continent UD, 34% incontinent UD). Patients who reported more conscientiousness were more likely to prefer more complex methods (continent UD). The majority (62%) preferred to delegate decision making to healthcare professionals. A substantial number of patients reported elevated anxiety (32%), and more anxiety was predictive of higher participation preference, specifically for uro‐oncological decisions (β = 0.207, p < 0.01). Conclusions Our findings provide insight into the role of psychological patient characteristics for SDM. Aspects of personality such as conscientiousness influence treatment preferences. Anxiety contributes to patients' motivation to be involved in pertinent decisions. Thus, personality and negative affect should be considered to improve SDM., We set out to explore the role of personality and anxiety for a preference‐sensitive decision in a multicenter assessment of bladder cancer patients (N = 180; choice of urinary diversion, UD). Most patients indicated a clear preference for one of the treatment options (44% continent UD, 34% incontinent UD) and patients who reported more conscientiousness were more likely to prefer more complex treatment methods (continent UD). Moreover, anxiety was predictive of higher participation preference, specifically for uro‐oncological decisions. image, publishedVersion

PLOS ONE 17(8), 1-14 (2022). doi:10.1371/journal.pone.0272656, Published by PLOS, San Francisco, California, US

Estrogen deficiency is associated with left ventricular (LV) dysfunction in postmenopausal women and ovariectomized rats. Whether the relationship between estrogen deficiency and LV dysfunction is independent of cardiovascular disease (CVD) risk factors remains uncertain. This study assessed the effects of short-term and long-term estrogen deficiency on cardiac structure and function using conventional and speckle tracking echocardiography, independent of traditional CVD risk factors.Female Sprague-Dawley rats were divided into short-term (6 wks) ovariectomized (n = 9), short-term sham-operated (n = 10), long-term (6 mo) ovariectomized (n = 8), and long-term sham-operated (n = 9) groups. Cardiac geometry, systolic and diastolic function, and myocardial deformation and motion were measured using echocardiography.Ovariectomy had no effect on conventional echocardiography measures of cardiac structure or function. Compared with short-term, long-term groups had reduced LV internal diameter (false discovery rate [FDR] adjusted P = 0.05) and impaired relaxation (e'; FDR adjusted P = 0.0005) independent of body mass and blood pressure (BP). Global longitudinal strain was impaired in ovariectomized compared with sham-operated rats (FDR adjusted P = 0.05), but not after adjusting for body mass and BP (FDR adjusted P = 0.16). Global longitudinal strain (FDR adjusted P = 0.05), strain rate (FDR adjusted P = 0.002), and velocity (FDR adjusted P = 0.04) were impaired in long-term compared with short-term groups. Global longitudinal strain rate remained impaired after adjustments for body mass and BP (FDR adjusted P = 0.02).Estrogen deficiency does not independently cause cardiac remodeling, LV dysfunction, or impaired myocardial deformation. Traditional CVD risk factors accompanying estrogen deficiency may account for cardiac remodeling and dysfunction observed in postmenopausal women.

ImportanceUse of proton therapy reirradiation (PT-ReRT) for head and neck cancer is increasing; however, reports are heterogenous and outcomes can be difficult to interpret.ObjectiveTo evaluate outcomes and toxic effects following PT-ReRT in a uniform and consecutive cohort of patients with head and neck squamous cell carcinoma.Design, Setting, and ParticipantsThis retrospective cohort study included patients with recurrent primary head and neck squamous cell carcinoma who were treated with PT-ReRT from January 1, 2013, to December 31, 2020, at a single institution. Patient, clinical, and treatment characteristics were obtained, and multidisciplinary review was performed to record and grade early and late toxic effects.ExposuresProton therapy reirradiation.Main Outcomes and MeasuresFollow-up was defined from the start of PT-ReRT. The Kaplan-Meier method was used for outcomes of interest, including local control (LC), locoregional control, distant metastatic control, progression-free survival, and overall survival (OS). Cox proportional hazards regression modeling was used to assess associations of covariates with OS.ResultsA total of 242 patients (median [range] age, 63 [21-96] years; 183 [75.6%] male) were included. Of these patients, 231 (95.9%) had a Karnofsky performance status score of 70 or higher, and 145 (59.9%) had at least a 10–pack-year smoking history. Median (range) follow-up was 12.0 (5.8-26.0) months for all patients and 24.5 (13.8-37.8) months for living patients. A total of 206 patients (85.1%) had recurrent disease vs second primary or residual disease. The median (range) interval between radiation courses was 22 (1-669) months. Median PT-ReRT dose was 70 cobalt gray equivalents (CGE) for the fractionated cohort and 44.4 CGE for the quad shot cohort. For the fractionated cohort, the 1-year LC was 71.8% (95% CI, 62.8%-79.0%) and the 1-year OS was 66.6% (95% CI, 58.1%-73.8%). For the quad shot cohort, the 1-year LC was 61.6% (95% CI, 46.4%-73.6%) and the 1-year OS was 28.5% (95% CI, 19.4%-38.3%). Higher Karnofsky performance status scores (hazard ratio [HR], 0.50; 95% CI, 0.25-0.99; P = .046) and receipt of salvage surgery prior to PT-ReRT (HR, 0.57; 95% CI, 0.39-0.84; P = .005) were associated with improved OS, whereas receipt of quad shot (HR, 1.97; 95% CI, 1.36-2.86; P Conclusions and RelevanceThe findings of this cohort study suggest that, compared with previous reports with photon-based reirradiation, patients are living longer with aggressive PT-ReRT; however, surviving patients remain at risk of early and late complications.

To compare two portable lactate devices, Lactate Scout and StatStrip Xpress, to a laboratory reference device by assessing the concordance of cord blood lactate values at birth.We conducted a single-center prospective validation study in a level 3 maternity hospital. For all cord samples taken at birth, we analyzed lactates on the reference device (GEM4000®) and on two portable devices Lactate Scout and StatStrip Xpress. We compared the lactate values from each of the two handheld devices to the reference device.A total of 101 samples were collected. Each was analyzed by all three machines. The average lactate value obtained by the different machines was 3.7mmol/L. The mean difference between the Lactate Scout and GEM4000® apparatus was 0.0mmol/L±0.8mmol/L. Between these two devices at lactate threshold of 4.8mmol/L, the negative predictive value was 96,2% (76/79) and the area under the curve was 0.98 (95% CI 0.96-1]. The mean difference between StatStrip Xpress and GEM4000® was 0.1mmol/L±0.7mmol/L. Between these two devices at the lactate threshold of 4.8mmol/L, the negative predictive value was 97,4% (76/78) and the area under the curve was 0.95 (95% CI 0.86-1).There is a good correlation between the lactates obtained by the reference device and the two portable devices Lactate Scout and StatStrip Xpress.