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Lower respiratory tract infections caused by Streptococcus pneumoniae ( Spn ) are a leading cause of death globally. Here we investigate the bronchial epithelial cellular response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD + salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD + . Knockdown of NAD + salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD + treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD + production increased NAD + levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD + treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD + . Thus, we identified the NAD + salvage pathway as an antibacterial pathway in Spn infections, predicting an antibacterial mechanism of NAD + . Streptococcus pneumoniae is a common cause of lower respiratory tract infection. Here, Klabunde et al. present a transcriptomic, metabolomic and proteomic characterisation of the bronchial epithelial cell response to infection and show that NAD + has a role in controlling bacterial replication.

Long noncoding RNAs (lncRNA) are crucial yet underexplored regulators of human immunity. Here we develop GRADR, a method integrating gradient profiling with RNA-binding proteome analysis, to map the protein interactomes of all expressed RNAs in a single experiment to study mechanisms of lncRNA-mediated regulation of human primary macrophages. Applying GRADR alongside CRISPR-multiomics, we reveal a network of NFκB-dependent lncRNAs, including LINC01215, AC022816.1 and ROCKI, which modulate distinct aspects of macrophage immunity, particularly through interactions with mRNA-processing factors, such as hnRNP proteins. We further uncover the function of ROCKI in repressing the messenger of the anti-inflammatory GATA2 transcription factor, thus promoting macrophage activation. Lastly, all data are consolidated in the SMyLR web interface, a searchable reference catalog for exploring lncRNA functions and pathway-dependencies in immune cells. Our results thus not only highlight the important functions of lncRNAs in immune regulation, but also provide a rich resource for lncRNA studies. Long non-coding RNAs (lncRNA) are known immune regulators, yet a systemic understanding of their regulatory crosstalk is still elusive. Here the authors establish a platform integrating RNA-binding proteome analyses and protein interactomes to map the lncRNA target network in human primary macrophages to build a searchable atlas of lncRNA.

Introduction Pulmonary segmentectomy, when combined with hilar and mediastinal lymphadenectomy, is currently considered the gold standard treatment for early-stage lung tumors (NSCLC) smaller than 2 cm in diameter. The preoperative planning for segmentectomies usually includes a contrast-enhanced CT with 2D reconstructions (axial, coronary, and sagittal). Recent technological advances allow 3D (volume rendering) reconstructions of preoperative CT scans, intended to improve the surgeon’s understanding of the segmental anatomy. The study aims to investigate the added value of 3D reconstruction in enhancing the surgeon’s understanding of anatomical structures, thus facilitating surgical planning and improving oncological outcomes. Methods and analysis This is a prospective, randomized, controlled study. Patients will be randomized into two groups: 1. Group 2D: the preoperative workup for these patients will consist of a contrast-enhanced chest CT with two-dimensional (2D) reconstructions (axial, coronary, and sagittal); 2. Group 3D: the preoperative workup for these patients will consist of a contrast-enhanced chest CT with two-dimensional (2D) reconstructions (axial, coronary, and sagittal) and a 3D reconstruction (volume rendering) of the same chest CT employing dedicated software. The primary endpoints will be negative margin (R0) resection rate, resection margin (staple line-to-tumor distance), and thoracotomy conversions. We will use Fisher’s exact test for binary outcomes and Mann–Whitney U test for continuous outcomes. For subgroup analyses, we will use regression. Multivariable analyses will be based on logistic regression for binary outcomes and linear regression for continuous outcomes. Ethics and dissemination The protocol and the model informed consent forms have been reviewed and approved by the ethics committee (N.: 1–2023) concerning scientific content and compliance with applicable research and human subject regulations. A Subcommittee on Publications was established to review all publications and report its recommendations to the steering committee. The anonymized participant-level dataset and statistical code for generating the results will not be publicly available. Trial registration The protocol was registered at ClinicalTrials.gov (ID: NCT05716815; Prospective rAndomized sTudy efficaCy tHree-dimensional rEconstructions Segmentectomy - Full-Text View - ClinicalTrials.gov). Jan 19, 2023.

Background The COVID-19 pandemic has had negative drawbacks on the healthcare system worldwide and on individuals other than those directly affected by the virus. Delays in cancer therapy and diagnosis have been reported in the literature. We hypothesized similar effects on patients with lung cancer at our center. Methods We retrospectively analyzed data of patients referred to our center with newly diagnosed lung cancer from 2018 to 2022. We considered distribution of UICC Stages and time from case presentation in our multidisciplinary tumor board or from therapeutic indication from treating physician to therapy initiation (surgery, systemic therapies and radiation) to define delays in diagnosis and treatment. Results 1020 patients with newly diagnosed lung cancer were referred to our center from 2018 to 2022, with a median of 206 cases yearly (range: 200–208). Cases with Stage IV in 2020–2022 were significantly higher than in 2018–2019 (57% vs. 46%, p  = 0,001). 228 operative resections took place between 2018 and 2022, 100 from January 2018 to February 2020 and 128 from March 2020 to December 2022. Median time from presentation in our tumor board to resection was also significantly longer after the beginning of the pandemic than before (22 days vs. 15,5 days, p  = 0,013). No significant delays were observed for administration of systemic treatment and initiation of radiation. Conclusions During the pandemic higher disease stages were reported for patients with lung cancer, yet there were no clinically relevant delays in treatment. In the context of the post-covid era new diagnostic strategies are necessary to facilitate early diagnosis of lung cancer. Despite the pandemic, for patients with suspicious symptoms prompt access to healthcare facilities is essential for early diagnosis.

Background Prolonged air leaks (PAL) are a common postoperative complication following lung surgery, associated with increased morbidity, extended hospital stays, and heightened healthcare costs. The incidence of air leaks ranges from 20 to 33%, with PAL occurring in 6%–26% of cases. Management strategies for PAL remain inconsistent, highlighting the need for standardized guidelines to address this issue. This study employed the GRADE approach to develop consensus-based recommendations for detecting and managing post-lung surgery PAL. Methods A task force of 18 thoracic surgeons, including a methodologist, conducted a systematic literature review focusing on 14 critical clinical questions. Recommendations were developed based on evidence from meta-analyses, randomized controlled trials, and observational studies, and graded according to the quality of evidence and the strength of the recommendation. Results Thirty-five studies were included in the final analysis. The consensus highlighted the lack of standardization in defining PAL and emphasized the need for personalized management based on clinical context. Key recommendations included the use of reinforced staples, parenchymal sutures, and sealants in high-risk patients, the preference for digital drainage systems, and the management of confirmed PALs with strategies such as chemical pleurodesis and surgical exploration. Conclusions The consensus underscores the importance of a multidisciplinary approach in managing PAL, the need for standardizing definitions, and the ongoing requirement for evidence-based guidelines to improve patient outcomes. Future research should focus on addressing the limitations identified in this study.

Paraneoplastic autoimmune multi-organ syndrome (PAMS) is a rare clinical condition characterized by variable and heterogeneous clinical phenotypes in the presence of neoplasias which largely depend on the activation of humoral and cellular immune responses. Clinically, these patients present with a spectrum of antibody-driven pemphigus-like lesions to graft-vs.-host-disease-like exanthemas with a lichenoid inflammatory infiltrate in the skin. PAMS is occasionally associated with thymoma, in which altered immune surveillance eventually leads to multiorgan autoimmunity which often includes variable cutaneous symptoms. This disorder is associated with a profound disturbance of peripheral immune tolerance against human autoantigens. We here present a patient with relapsing thymoma who developed PAMS with several cutaneous and extracutaneous autoimmune disorders. Peripheral blood mononuclear cells (PBMC), sera, and lesional skin biopsies were obtained at different clinical disease stages. Peripheral T cell subsets were characterized phenotypically and the cytokine profile of the peripheral blood T cellular response against distinct epidermal and dermal autoantigens of the skin was analyzed by ELISpot assay. Serological screening was performed by ELISA and immunoblot analysis. Skin biopsies were subjected to immunohistochemical analysis of distinct T cell subsets. Thymoma tissue was analyzed for the presence of T regulatory cells and compared with adult thymus and indolent thymoma. In the present case, thymoma was the cause of the observed multi-organ autoimmune syndromes as its recurrence and surgical removal was associated with the relapse and regression of the cutaneous symptoms, respectively. Initially, the patient presented with two autoimmune disorders with Th2/Th1 imbalance, myasthenia gravis (MG) and pemphigus foliaceus (PF), which regressed upon immunosuppressive treatment. Months later, the patient developed a lichenoid exanthema with a Th1-dominated skin infiltrate. Further clinical evaluation revealed the recurrence of the thymoma and the lichenoid exanthema gradually regressed upon thymectomy. Our contention that T cell recognition against distinct cutaneous autoantigens, such as desmoglein 1 (Dsg1), shifted from a Th2 to a Th1-dominated immune response could not be fully substantiated as the patient was on a stringent immunosuppressive treatment regimen. We could only observe a decrease of the initially present serum IgG autoantibodies against Dsg1. Phenotypic analysis of the associated thymoma showed a lower number of T regulatory cells compared to adult thymus and indolent thymoma, suggesting that impaired thymus-derived immune surveillance had a direct impact on the outcome of the observed cutaneous autoimmune disorders.

Background. Lateral approaches to the spine have gained increased popularity due to enabling minimally invasive access to the spine, less blood loss, decreased operative time, and less postoperative pain. The objective of the study was to analyze the use of intraoperative computed tomography with navigation and the implementation of augmented reality in facilitating a lateral approach to the spine. Methods. We prospectively analyzed all patients who underwent surgery with a lateral approach to the spine from September 2016 to January 2021 using intraoperative CT applying a 32-slice movable CT scanner, which was used for automatic navigation registration. Sixteen patients, with a median age of 64.3 years, were operated on using a lateral approach to the thoracic and lumbar spine and using intraoperative CT with navigation. Indications included a herniated disc (six patients), tumors (seven), instability following the fracture of the thoracic or lumbar vertebra (two), and spondylodiscitis (one). Results. Automatic registration, applying intraoperative CT, resulted in high accuracy (target registration error: 0.84 ± 0.10 mm). The effective radiation dose of the registration CT scans was 6.16 ± 3.91 mSv. In seven patients, a control iCT scan was performed for resection and implant control, with an ED of 4.51 ± 2.48 mSv. Augmented reality (AR) was used to support surgery in 11 cases, by visualizing the tumor outline, pedicle screws, herniated discs, and surrounding structures. Of the 16 patients, corpectomy was performed in six patients with the implantation of an expandable cage, and one patient underwent discectomy using the XLIF technique. One patient experienced perioperative complications. One patient died in the early postoperative course due to severe cardiorespiratory failure. Ten patients had improved and five had unchanged neurological status at the 3-month follow up. Conclusions. Intraoperative computed tomography with navigation facilitates the application of lateral approaches to the spine for a variety of indications, including fusion procedures, tumor resection, and herniated disc surgery.

Background Double-lumen tube (DLT) intubation is necessary for thoracic surgery and other operations with the need for lung separation. However, DLT insertion is complex and might result in airway trauma. A new videolaryngoscopy (GVL) with a thin blade might improve the intubation time and reduce complexity as well as iatrogenic airway complications compared to conventional direct laryngoscopy (DL) for DLT intubation. Methods A randomised, controlled trial was conducted in 70 patients undergoing elective thoracic surgery using DLT for lung separation. Primary endpoint was time to successful intubation. The secondary endpoints of this study were number of intubation attempts, the assessment of difficulty, any complications during DLT intubation and the incidence of objective trauma of the oropharynx and supraglottic space and intubation-related subjective symptoms. Results 65 patients were included (DL group [ n   =  31], GVL group [ n   =  34]). Median intubation time (25th–75th percentiles) in GVL group was 93 s (63–160) versus 74 (58–94) in DL group [ p  = 0.044]. GVL resulted in significantly improved visualisation of the larynx (Cormack and Lehane grade of 1 in GVL group was 97% vs. 74% in DL Group [ p  = 0.008]). Endoscopic examinations revealed significant differences in GVL group compared to DL group showing less red-blooded vocal cord [ p  = 0.004], vocal cord haematoma [ p  = 0.022] and vocal cord haemorrhage [ p  = 0.002]. No significant differences regarding the postoperative subjective symptoms of airway were found. Conclusions Videolaryngoscopy using the GlideScope®-Titanium shortly prolongs DLT intubation duration compared to direct laryngoscopy but improves the view. Objective intubation trauma but not subjective complaints are reduced. Trial registration German Clinical Trial Register DRKS00020978 , retrospectively registered on 09. March 2020.

Typical and atypical carcinoid tumors belong to the neuroendocrine lung tumors. They have low recurrence and proliferation rate, lymph node, and distant metastases. Nevertheless, these tumors have shown a more aggressive behavior. In the last years, microRNAs were screened as new tumor markers for their potential diagnostic and therapeutic relevance. The expression of hsa-let-7b-5p, hsa-let-7f-5p, hsa-miR-222-3p, and their targets HMGA2 (high-mobility group A2) and CDKN1B (cyclin-dependent kynase inhibitor 1B, p27kip1) was evaluated in this rare small group of patients. We analyzed the clinical data of all typical and atypical carcinoid tumors of patients who underwent surgical operation at Marburg University Hospital (n = 18) from 2000. Quantitative reverse transcription polymerase chain reaction was performed in formalin-fixed paraffin-embedded tumor tissue versus four tumor-free lung tissue samples. HMGA2 was stable or downregulated; only one patient showed a significant overexpression. CDKN1B showed a significant overexpression or a stable level; it was downregulated in two samples only. Hsa-miR-222-3p resulted almost stable or overexpressed except for two samples (significantly downregulated). Hsa-let-7f-5p was stable or overexpressed in the majority of analyzed samples, whereas hsa-let-7b-5p was significantly downregulated. HMGA2 and CDKN1B are differently expressed between atypical and typical carcinoid tumors, thus representing valid biomarkers for the classification of the two tumor groups. Hsa-let-7f-5p and HMGA2 are inversely correlated. Hsa-miR-222-3p does not correlate with its predicted target CDKN1B.