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The incidence of empyema is increasing worldwide, which, coupled with the aging global population, makes the non-surgical management of pleural space infections increasingly important. Despite this, there remains no consensus for management of chronic empyema in those patients who are not surgical candidates and do not get adequate source control with chest tube and intra-pleural lytic therapy, particularly for patients with non-expandable lungs. We reviewed the literature regarding non-surgical management of chronic empyema and present two cases that support the use of pleuroscopy in conjunction with tunneled pleural catheters for management of chronic empyema in non-surgical candidates.

The MRGPRX family of receptors (MRGPRX1-4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2-5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

Abstract Background Random monoallelic expression contributes to phenotypic variation of cells and organisms. However, the epigenetic mechanisms by which individual alleles are randomly selected for expression are not known. Taking cues from chromatin signatures at imprinted gene loci such as the insulin-like growth factor 2 gene 2 (IGF2), we evaluated the contribution of CTCF, a zinc finger protein required for parent-of-origin-specific expression of the IGF2 gene, as well as a role for allele-specific association with DNA methylation, histone modification and RNA polymerase II. Results Using array-based chromatin immunoprecipitation, we identified 293 genomic loci that are associated with both CTCF and histone H3 trimethylated at lysine 9 (H3K9me3). A comparison of their genomic positions with those of previously published monoallelically expressed genes revealed no significant overlap between allele-specifically expressed genes and colocalized CTCF/H3K9me3. To analyze the contributions of CTCF and H3K9me3 to gene regulation in more detail, we focused on the monoallelically expressed IGF2BP1 gene. In vitro binding assays using the CTCF target motif at the IGF2BP1 gene, as well as allele-specific analysis of cytosine methylation and CTCF binding, revealed that CTCF does not regulate mono- or biallelic IGF2BP1 expression. Surprisingly, we found that RNA polymerase II is detected on both the maternal and paternal alleles in B lymphoblasts that express IGF2BP1 primarily from one allele. Thus, allele-specific control of RNA polymerase II elongation regulates the allelic bias of IGF2BP1 gene expression. Conclusions Colocalization of CTCF and H3K9me3 does not represent a reliable chromatin signature indicative of monoallelic expression. Moreover, association of individual alleles with both active (H3K4me3) and silent (H3K27me3) chromatin modifications (allelic bivalent chromatin) or with RNA polymerase II also fails to identify monoallelically expressed gene loci. The selection of individual alleles for expression occurs in part during transcription elongation.

Abstract Background Masculinity norms play a crucial role in men’s help-seeking behaviors, service-use, and coping strategies for depression. While previous studies provided evidence for the association between gender role orientations, work related attitudes, stigmatization of men with depression and depressive symptoms, it remains unclear to what extent gender role orientations change over time and whether psychiatric and psychotherapeutic treatment have an impact on these transformations. Additionally, the role of partners in supporting depressed men and the impact of dyadic coping on these processes have not been explored. The aim of this study is to investigate how masculinity orientations and work-related attitudes change over time in men treated for depression, and to examine the role of their partners and dyadic coping in these transformation processes. Methods TRANSMODE is a prospective longitudinal mixed-methods study investigating the transformation of masculinity orientations and work-related attitudes in men treated for depression between the ages of 18 and 65 from different settings in Germany. The study will recruit 350 men from various settings for quantitative analysis. By applying a latent transition analysis, the primary outcome are changes in masculine orientations and work-related attitudes over time, measured at four times (t0, t1, t2, t3) with intervals of 6 months. Qualitative interview with a subsample of depressed men selected using latent profile analysis, will be conducted between t0 and t1 (a1) with a follow-up of 12 months (a2). In addition, qualitative interviews with the partners of depressed men will be conducted between t2 and t3 (p1). Qualitative data will be analysed using qualitative structured content analysis. Discussion A comprehensive understanding of the transformation processes of masculinity orientations over time including the impact of psychiatric/psychotherapeutic treatment and the role of partners can lead to the development of gender-sensitive depression treatment tailored to the unique needs of men with depression. Thus, the study can promote more effective and successful treatment outcomes and further contribute to reducing the stigma surrounding mental health issues among men and encourage them for mental health service use. Trial registration This study is registered in the German Clinical Trail Register (DRKS) and the WHO International Clinical Trials Registry Platform (ICTRP) under registration number DRKS00031065 (Date of registration 06 February 2023).

Abstract Background Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half‐life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long‐acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)‐induced cachexia in mice. Methods Male C57BL/6J mice (5‐ to 7‐month‐old) were implanted with 1 × 106 heat‐killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or EXT418 daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK‐treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD‐treated mice were pair‐fed to the T + V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination. Results In tumour‐bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, P = 0.030; and vs. T + 418 EOD, P = 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour‐bearing mice was improved by EXT418 daily (P = 0.010) or EOD (P = 0.008) administration compared with vehicle‐treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P = 0.015), IIB (P = 0.037) and IIX (P = 0.050) fibre cross‐sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P = 0.005). In skeletal muscles, tumour‐induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P ≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P = 0.039). In addition, EXT418 treatments ameliorated the tumour‐induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il‐6 transcript levels in adipose tissue and circulating IL‐10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. Conclusions EXT418 mitigates LLC‐induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake.

Abstract Objectives Decision aids (DAs) are promising tools to foster evidence‐based shared decision‐making between practitioners and service users. Nevertheless, it is still obscure how an evidence‐based DA for people with severe mental illness, especially psychosis, should look in an inpatient treatment setting to be useful and feasible. Therefore, we conducted focus groups with psychiatrists and service users to collect and assess their expectations and wishes regarding an evidence‐based DA. From these findings, we derived immediate recommendations for the future development of DAs. Methods We held two group interviews with service users (n = 8) and three group interviews with psychiatrists (n = 10). We used an open, large‐scale topic guide. First, we presented data from a current meta‐analysis on antipsychotics to the interviewees and, in a second step, asked for their expectations and wishes towards a DA that integrates these data. Results Our thematic analysis revealed six key themes addressed by the respondents: (1) general considerations on the importance and usefulness of such a DA, (2) critical comments on psychiatry and psychopharmacotherapy, (3) communicative prerequisites for the use of a DA, (4) form and content of the DA, (5) data input, data processing and output as well as (6) application of the DA and possible obstacles. Conclusions Participants identified several important features for the development of DAs for selecting antipsychotics in inpatient psychiatric treatment. The digital format was met with the greatest approval. Especially the adaptability to different needs, users and psychopathologies and the possibility to outsource information dissemination via app seemed to be a decisive convincing argument. Further research is required to test specific features of DAs to be developed in clinical settings.

ABSTRACT: Background: Diagnosing myocarditis relies on multimodal data, including cardiovascular magnetic resonance (CMR), clinical symptoms, and blood values. The correct interpretation and integration of CMR findings require radiological expertise and knowledge. We aimed to investigate the performance of Generative Pre-trained Transformer 4 (GPT-4), a large language model, for report-based medical decision-making in the context of cardiac MRI for suspected myocarditis. Methods: This retrospective study includes CMR reports from 396 patients with suspected myocarditis and eight centers, respectively. CMR reports and patient data including blood values, age, and further clinical information were provided to GPT-4 and radiologists with 1 (resident 1), 2 (resident 2), and 4 years (resident 3) of experience in CMR and knowledge of the 2018 Lake Louise Criteria. The final impression of the report regarding the radiological assessment of whether myocarditis is present or not was not provided. The performance of Generative pre-trained transformer 4 (GPT-4) and the human readers were compared to a consensus reading (two board-certified radiologists with 8 and 10 years of experience in CMR). Sensitivity, specificity, and accuracy were calculated. Results: GPT-4 yielded an accuracy of 83%, sensitivity of 90%, and specificity of 78%, which was comparable to the physician with 1 year of experience (R1: 86%, 90%, 84%, p = 0.14) and lower than that of more experienced physicians (R2: 89%, 86%, 91%, p = 0.007 and R3: 91%, 85%, 96%, p

BackgroundScience is beginning to establish the benefits of the use of virtual reality (VR) in health care. This therapeutic approach may be an appropriate complementary treatment for some mental illnesses. It could prevent high levels of morbidity and improve the physical health of patients. For many years, the literature has shown the health benefits of physical exercise. Physical exercise in a VR environment may improve the management of mild to moderate mental health conditions. In this context, we developed a virtual environment combined with an ergocycle (the augmented physical training for isolated and confined environments [APTICE] system). ObjectiveThis study aims to investigate the impact of physical exercise in a VR environment. MethodsA total of 14 healthy participants (11 men and 3 women; mean age 43.28, SD 10.60 years) undertook 15 minutes of immersive physical exercise using the system. Measures included mindfulness and immersion disposition, subjective perceptions of sensory information, user experience, and VR experience (ie, psychological state, flow, and presence). ResultsFirst, the APTICE system appears to be a useful tool because the user experience is positive (subscales in the AttrakDiff questionnaire: pragmatic quality=0.99; hedonic quality–stimulation=1.90; hedonic quality–identification=0.67; attractiveness=1.58). Second, the system can induce a positive psychological state (negative emotion, P=.06) and an experience of flow and presence (P values ranging from

Objective: Thioesterase superfamily member 1 (Them1) is a long chain acyl-CoA thioesterase comprising two N-terminal HotDog fold enzymatic domains linked to a C-terminal lipid-sensing steroidogenic acute regulatory transfer-related (START) domain, which allosterically modulates enzymatic activity. Them1 is highly expressed in thermogenic adipose tissue, where it functions to suppress energy expenditure by limiting rates of fatty acid oxidation, and is induced markedly in liver in response to high fat feeding, where it suppresses fatty acid oxidation and promotes glucose production. Them1−/− mice are protected against non-alcoholic fatty liver disease (NAFLD), suggesting Them1 as a therapeutic target. Methods: A high-throughput small molecule screen was performed to identify promising inhibitors targeting the fatty acyl-CoA thioesterase activity of purified recombinant Them1.Counter screening was used to determine specificity for Them1 relative to other acyl-CoA thioesterase isoforms. Inhibitor binding and enzyme inhibition were quantified by biophysical and biochemical approaches, respectively. Following structure-based optimization, lead compounds were tested in cell culture. Results: Two lead allosteric inhibitors were identified that selectively inhibited Them1 by binding the START domain. In mouse brown adipocytes, these inhibitors promoted fatty acid oxidation, as evidenced by increased oxygen consumption rates. In mouse hepatocytes, they promoted fatty acid oxidation, but also reduced glucose production. Conclusion: Them1 inhibitors could prove attractive for the pharmacologic management of NAFLD.

The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment, but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ-modified mRNA (D1-modRNA), and D1-modRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an up-regulation of Stat1 and RnaseL, and increased systemic inflammation. This result correlated with significantly reduced antigen-specific antibody responses and reduced protection against influenza virus infection compared with D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material.

IntroductionLong-duration space missions will be a real challenge for maintaining astronauts' adaptability. Research on transcutaneous vagus nerve stimulation (taVNS) is expanding rapidly, and its modalities constitute a major research challenge. A growing number of reviews stress the need to validate biomarkers for monitoring effects to enhance our understanding of the processes by which taVNS acts. Heart rate variability (HRV) appears to be a relevant candidate that informs on the autonomic nervous system (ANS). This is a promising technique to minimize the pathogenic effects of such large-scale missions and thus might be a relevant countermeasure. This study aimed to investigate the impact of taVNS on cognitive, psychological, and physiological functioning, including ANS functioning, and the benefits of increasing the number of taVNS sessions.MethodA total of 44 healthy participants were randomly assigned to one of the two cross-over protocols: a single session protocol (one taVNS and one sham simulation) or a repeated session protocol (three taVNS and three sham simulations). Cognitive, psychological, and physiological measures were performed before (pre) and after (post) each intervention. Sleep monitoring was only recorded before the first and after the last intervention in each protocol. For the repeated session protocol only, participants were allocated to two groups according to their parasympathetic activation gain during the three interventions: high parasympathetic delta (HPd) and low parasympathetic delta (LPd).ResultsParticipants in the repeated session protocol increased their HRV, cognitive performance, and sleep efficiency. In particular, taVNS induced higher parasympathetic activation and cardiac flexibility compared to the sham simulation in the repeated session protocol. Nevertheless, the perception of stress may indicate a nocebo effect of the repeated session. The HPd profile had higher interoceptive awareness, HRV highlighted by non-linear measures, and cognitive performance, but presented a decrease in some indicators of sleep efficiency compared to the LPd profile.ConclusiontaVNS seems to induce positive health outcomes, especially when the stimulation is repeated three times per week. Our findings highlight the benefits of parasympathetic activation during taVNS on psychophysiological and cognitive functioning. Further research is needed to validate these results on a large sample, using longitudinal measures over several months. This intervention appears promising as a countermeasure to extreme missions and occupations.

Biased signaling in κ-opiod receptors (KOR) offer an attractive strategy for pain management. Here the authors identify determinants of KOR signaling bias using structural methods in combination with molecular dynamics simulations.

Abstract Background Rituximab has become a standard treatment for non‐Hodgkin lymphoma. Clinical studies have demonstrated the efficacy of rituximab in combination with standard chemotherapies in the treatment of follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) patients. This non‐interventional study aimed to evaluate the effectiveness and safety of subcutaneous (SC) rituximab in routine clinical practice. Methods Adult patients with previously untreated CD20 positive DLBCL or FL who received rituximab SC and chemotherapy as first‐line treatment were observed between 07/2014 and 07/2019 at 99 institutions in Germany. Primary endpoint was the (unconfirmed) complete remission (CR/CRu) rate. Primary outcome was analyzed inferentially; other variables were evaluated descriptively. Results Overall 583 patients (247 FL; 336 DLBCL) were evaluated. CR/CRu rates were 51.4% (95% CI: 45.2; 57.6) in the FL set and 48.5% (95% CI: 43.2; 53.8) in the DLBCL set. Regarding progression‐free survival in the FL group, the probability of being event‐free was 94.2% in the first year and 86.2% in the second year. An overall response was achieved in 85.8% (FL) and 85.4% patients (DLBCL). Patient satisfaction at the end of study with the time saving simplification of the SC vs. intravenous route was 98% for FL and 97% for DLBCL. 45.3% of FL and 47.0% of DLBCL patients experienced an adverse event of grade ≥3. Serious adverse events of grade ≥3 occurred in 27.9% FL and 32.4% DLBCL patients, with the highest incidences for leucopenia, anemia, nausea, and fatigue. No new safety signals were detected. Conclusions The results confirmed the effectiveness and safety of rituximab SC in both the FL and the DLBCL group. Satisfaction of patients and nurses with SC administration was high.