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Background: Ibrutinib, a first-in-class inhibitor of Bruton's tyrosine kinase, is approved for the treatment of various B-cell malignancies and chronic graft-versus-host disease. Based on encouraging preclinical data, safety and efficacy of ibrutinib combined with companion drugs for advanced renal cell carcinoma (RCC), gastric/gastroesophageal junctional adenocarcinoma (GC), and colorectal adenocarcinoma (CRC) were evaluated., Methods: Ibrutinib 560 mg or 840 mg once daily was administered with standard doses of everolimus for RCC, docetaxel for GC, and cetuximab for CRC. Endpoints included determination of the recommended phase 2 dose (RP2D) of ibrutinib in phase 1b and efficacy (overall response rate [ORR] for GC and CRC; progression-free survival [PFS] for CRC) in phase 2., Results: A total of 39 (RCC), 46 (GC), and 50 (RCC) patients were enrolled and received the RP2D. Safety profiles were consistent with the individual agents used in the study. Confirmed ORRs were 3% (RCC), 21% (GC), and 19% (CRC). Median (90% CI) PFS was 5.6 (3.9-7.5) months in RCC, 4.0 (2.7-4.2) months in GC, and 5.4 (4.1-5.8) months in CRC., Conclusions: Clinically meaningful increases in efficacy were not observed compared to historical controls; however, the data may warrant further evaluation of ibrutinib combinations in other solid tumours., Trial Registration: ClinicalTrials.gov, NCT02599324., (© 2023. The Author(s).)

Relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) is a genetically complex and heterogeneous disease with a poor prognosis and limited treatment options. Thus, there is an urgent need to develop therapeutic combinations to overcome drug resistance in AML. This open-label, multicenter, international, phase 1b study evaluated the safety, efficacy, and pharmacokinetics of venetoclax in combination with alvocidib in patients with R/R AML. Patients were treated with escalating doses of venetoclax (400, 600, and 800 mg QD, orally, days 1-28) and alvocidib (45 and 60 mg/m 2 , intravenously, days 1-3) in 28-day cycles. The combination was found to be safe and tolerable, with no maximum tolerated dose reached. Drug-related Grade ≥3 adverse events were reported in 23 (65.7%) for venetoclax and 24 (68.6%) for alvocidib. No drug-related AEs were fatal. Gastrointestinal toxicities, including diarrhea, nausea, and vomiting were notable and frequent; otherwise, the toxicities reported were consistent with the safety profile of both agents. The response rate was modest (complete remission [CR] + incomplete CR [CRi], 11.4%; CR + CRi + partial response rate + morphologic leukemia-free state, 20%). There was no change in alvocidib pharmacokinetics with increasing doses of venetoclax. However, when venetoclax was administered with alvocidib, AUC 24 and C max decreased by 18% and 19%, respectively. A recommended phase 2 dose was not established due to lack of meaningful increase in efficacy across all cohorts compared to what was previously observed with each agent alone. Future studies could consider the role of the sequence, dosing, and the use of a more selective MCL1 inhibitor for the R/R AML population., (© 2023 AbbVie Inc. Hematological Oncology published by John Wiley & Sons Ltd.)

Objectives: Scleroderma renal crisis (SRC) is a rare vascular complication of systemic sclerosis with substantial risks for end-stage renal disease and premature death. Activating autoantibodies (Abs) targeting the angiotensin II type 1 (AT1R) and the endothelin-1 type A receptor (ETAR) have been identified as predictors for SRC. Here, we sought to determine their pathogenic significance for acute renal vascular injury potentially triggering kidney failure and malignant hypertension., Methods: IgG from patients with SRC was studied for AT1R and ETAR dependent biologic effects on isolated rat renal interlobar arteries and vascular cells including contraction, signalling and mechanisms of receptor activation., Results: In myography experiments, patient IgG exerted vasoconstriction sensitive to inhibition of AT1R and ETAR. This relied on MEK-ERK signalling indicating functional relevance of anti-AT1R and anti-ETAR Abs. The contractile response to angiotensin II and endothelin-1 was amplified by patient IgG containing anti-AT1R and anti-ETAR Abs with substantial crosstalk between both receptors implicating autoimmune receptor hypersensitization. Co-immunoprecipitation experiments indicated heterodimerization between both receptor types which may enable the observed functional interrelation by direct structural interactions., Conclusion: We provide experimental evidence that agonistic Abs may contribute to SRC. This effect is presumably related to direct receptor stimulation and additional allosteric effects, at least in heterodimeric receptor constellations. Novel therapies targeted at autoimmune hyperactivation of AT1R and ETAR might improve outcomes in severe cases of SRC., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: CT reports honoraria and institutional research funding from BeiGene, Janssen, and AbbVie. JM reports consulting for Pharmacyclics/AbbVie, Bayer, Gilead/Kite Pharma, Pfizer, Janssen, Juno/Celgene, BMS, Kyowa, Alexion, Fosunkite, Innovent, Seattle Genetics, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, BeiGene, Servier, Novartis, and Morphosys/Incyte; research funding from Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium; honoraria from Targeted Oncology, OncView, Curio, Kyowa, Physicians’ Education Resource, and Seattle Genetics; and serving on speakers’ bureaus for Gilead/Kite Pharma, Kyowa, Bayer, Pharmacyclics/Janssen, Seattle Genetics, Acrotech/Aurobindo, BeiGene, Verastem, AstraZeneca, Celgene/BMS, and Genentech/Roche. GC reports research funding from BeiGene, AstraZeneca, and LOXO Oncology; and honoraria/travel support from Roche and Glycomimetics. SO has acted as a consultant/advisor for AbbVie, BeiGene, Janssen, Gilead, Roche, Mundipharma, Merck, and Bristol Myers Squibb; has received research funding from AbbVie, BeiGene, Janssen, Gilead, Roche, and Epizyme; and has received honoraria from AbbVie, BeiGene, Janssen, Gilead, Roche, Merck, and Bristol Myers Squibb. HA, XZ, JS, and JH, are employees of, and own stock in, BeiGene. KB is an employee of BeiGene. AT reports serving on advisory boards and speakers’ bureaus for AbbVie, Janssen Spa, AstraZeneca, and BeiGene.

Despite increased awareness of the essential role of neighborhood characteristics for residents' health and wellbeing, the development of neighborhood-level indicator systems has received relatively little attention to date. To address this gap, we describe the participatory development process of a small-area indicator system that includes information on local health needs in a pilot neighborhood in the German city of Mannheim. To identify relevant indicators, we partnered with representatives of the city's public health department and used an iterative approach that included multiple Plan-Do-Check-Act cycles with ongoing feedback from local key stakeholders. The described process resulted in a web-based indicator system with a total of 86 indicators. Additionally, 123 indicators were perceived as relevant by stakeholders but could not be included due to data unavailability. Overall, stakeholders evaluated the participatory approach as useful. Even though the onset of the COVID-19 pandemic and the lack of some data elements hindered instrument development, close collaboration with public health partners facilitated the process. To identify and target sub-national health inequalities, we encourage local public health stakeholders to develop meaningful and useful neighborhood-level indicator systems, building on our experiences from the applied development process and considering identified barriers and facilitators.

Distress is a widespread phenomenon in the general population, but also among university students, associated with poorer learning success and negative health consequences. A source of distress might be the experience of injustice. Theoretical and empirical work in the area of perceived fairness in the workplace ("organizational justice") has shown that perceived unfairness is related to various stress indicators and health outcomes. Preliminary evidence indicates that unfairness matters not only in the work context but also in the university context. However, an adapted and validated tool to assess perceived unfairness in the university context is hitherto missing. The goal of the proposed project is therefore to adapt the construct of organizational justice to the university context and to develop a corresponding questionnaire by means of established scientific procedures. An exploratory sequential mixed-methods design is applied in which qualitative and quantitative methods are combined. A valid and practicable measurement instrument ("UFair" University Fairness Questionnaire) will be developed and tested, and the relationship with various health outcomes will be examined. The UFair questionnaire will be made available free of charge to other researchers.

Objectives: To synthesise the evidence on the role of compositional or contextual characteristics of schools in the association between students' socioeconomic position and their health in primary and secondary education in developed economies., Design: Scoping review. We included studies examining the role of at least one school or class characteristic on students' health inequalities and was published since 1 January 2000, in English or German. We searched PubMed/Medline, Web of Science and Education Resources Information Center. We provided a narrative synthesis and an overview of findings. School characteristics were grouped into five broad categories: school composition, school climate, school policies and organisation, food environment and facilities., Results: Of 8520 records identified, 26 studies were included. Twelve studies found a moderating and 3 a mediating effect. The strongest evidence came from studies examining the moderating effect of school composition, that is, the negative impact of a low individual socioeconomic position on mental health and well-being was aggravated by a low average socioeconomic position of schools. Evidence concerning the role of school climate, school stratification (eg, performance base tracking) and sponsorship, food environment and sport facilities and equipment was generally weak or very weak and mostly based on singular findings. Overall, favourable meso-level characteristics mitigated the negative impact of low individual socioeconomic position on health outcomes., Conclusions: School characteristics affect health inequalities in children and adolescents to some degree, but future research is necessary to strengthen the existing evidence and address under-represented aspects in school characteristics and health outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In Europe, there have been several addiction-expert rankings of harms related to the use of psychotropic substances in the last 15 years. Among them, only one expert ranking took into account the potential benefits of these drugs. Non-Opioidergic Analgesics (NOAs), such as gabapentinoids and NSAIDs, which have been increasingly the subject of abuse / misuse reports, have not been considered in such expert rankings. Likewise, there is currently no multi-substance comparison as to whether the valuation rank of the harmfulness of an illegal drug may change along with an imagined change in legal status in Germany., Objectives and Methods: Using a questionnaire, 101 experienced addiction physicians (first cohort) evaluated 33 psychoactive substances including analgesics with regard to their health and social harms as well as potential usefulness for the consumer and their environment / society ('others'). In addition, this cohort investigated whether the harmfulness assessment of an illegal substance changes if it would be legalized. In order to obtain the average overall harmfulness (overall risk) of a substance, the percentage contribution of each dimension to the overall harmfulness was determined in a second survey (second cohort, 36 experienced addiction medicine experts). Finally, the average benefit and overall risk ratings of each substance were related to each other., Results: Prescription psychoactive substances such as analgesics, NOAs (including gabapentinoids) and opioidergic maintenance medications to treat opiate dependence were judged to have a favorable benefit-harm profile. Cannabis and ketamine were placed in the midfield of both, the harm and benefit rankings. Together with most illicit narcotic drugs, alcohol and nicotine, have been ranked among the most harmful and least useful substances, whereby alcohol was judged on average to be more harmful but also more useful than nicotine. In the event of potential legalization, the overall harm of the traditional illegal drugs methamphetamine, heroin, cocaine and cannabis was estimated to be reduced. This was mainly due to a more favorable valuation of the harm to others under these virtual conditions., Conclusion: Prescription substances including opioidergic and non-opioidergic analgesics as well as opioid maintenance therapy medications (methadone and buprenorphine) were assigned a favorable benefit-harm profile. Alcohol, nicotine and traditional illicit drugs (with the exception of cannabis and ketamine) were determined to have an unfavorable profile. The overall harm of traditional illicit drugs was assessed to decrease along with legalization, mainly by decreasing the harm to others in this virtual event., Competing Interests: Prof. Dr. med. Scherbaum erhielt Honorare für verschiedene Aktivitäten (z. B. Mitgliedschaft im Beirat, Vorträge, Manuskripte) von AbbVie, Camurus, Hexal, Janssen-Cilag, MSD, Medice, Mundipharma, Reckitt-Benckiser/Indivior und Sanofi-Aventis. In den letzten drei Jahren hat er an klinischen Studien teilgenommen, die von der Pharmaindustrie finanziert wurden.Dr. med. Thomas Alberti erhielt Honorare (z. B. Mitgliedschaft im Beirat) und / oder Ausbildungsstipendien von Janssen-Cilag, Medice und Otsuka-Lundbeck.Prof. Dr. med. Norbert Wodarz erhielt Honorare für (nicht produktbezogene) Vorträge (Janssen-Cilag, Mundipharma und Reckitt-Benckiser/Indivior). Er erhielt öffentliche Mittel (BayStMGP) zur Bewertung von „Naloxon zum Mitnehmen“.Prof. Dr. med. Thomas Hillemacher hat Honorare für verschiedene Aktivitäten (z. B. Mitgliedschaft im Beirat, Vorträge) von Janssen-Cilag, Amomed, Shire, Takeda, Servier erhalten.Prof. Dr. med. Michael Soyka arbeitet seit drei Jahren als Berater oder hält Vorträge für Ammomed, Indivior, Camurus.Prof. Dr. med. Jens Reimer erhielt Honorare für die Teilnahme an Beiräten, Beratungen und Vorträgen von AbbVie, Amomed, Camurus, Gilead, Indivior und Sanofi-Aventis.Prof. Dr. med. Jens Kuhn erhielt Honorare von Bayer, Janssen, Lundbeck, Neuraxpharm, Otsuka Pharma, Schwabe und Servier für Vorträge auf Konferenzen und für die Reisen dorthin. Von der Medtronic GmbH hat er finanzielle Unterstützungen für Investigator-initiierte Studien erhalten. Die übrigen Autoren gaben an, keine Interessenskonflikte bezüglich dieser Studie zu haben., (Thieme. All rights reserved.)