Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA.

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.

Multiview confocal super-resolution microscopy.

Confocal microscopy1 remains a major workhorse in biomedical optical microscopy owing to its reliability and flexibility in imaging various samples, but suffers from substantial point spread function anisotropy, diffraction-limited resolution, depth-dependent degradation in scattering samples and volumetric bleaching2. Here we address these problems, enhancing confocal microscopy performance from the sub-micrometre to millimetre spatial scale and the millisecond to hour temporal scale, improving both lateral and axial resolution more than twofold while simultaneously reducing phototoxicity. We achieve these gains using an integrated, four-pronged approach: (1) developing compact line scanners that enable sensitive, rapid, diffraction-limited imaging over large areas; (2) combining line-scanning with multiview imaging, developing reconstruction algorithms that improve resolution isotropy and recover signal otherwise lost to scattering; (3) adapting techniques from structured illumination microscopy, achieving super-resolution imaging in densely labelled, thick samples; (4) synergizing deep learning with these advances, further improving imaging speed, resolution and duration. We demonstrate these capabilities on more than 20 distinct fixed and live samples, including protein distributions in single cells; nuclei and developing neurons in Caenorhabditis elegans embryos, larvae and adults; myoblasts in imaginal disks of Drosophila wings; and mouse renal, oesophageal, cardiac and brain tissues.

Bayesian networks identify determinants of outcomes following cardiac surgery in a UK population.

BACKGROUND: Traditional risk stratification tools do not describe the complex principle determinant relationships that exist amongst pre-operative and peri-operative factors and their influence on cardiac surgical outcomes. This paper reports on the use of Bayesian networks to investigate such outcomes. METHODS: Data were prospectively collected from 4776 adult patients undergoing cardiac surgery at a single UK institute between April 2012 and May 2019. Machine learning techniques were used to construct Bayesian networks for four key short-term outcomes including death, stroke and renal failure. RESULTS: Duration of operation was the most important determinant of death irrespective of EuroSCORE. Duration of cardiopulmonary bypass was the most important determinant of re-operation for bleeding. EuroSCORE was predictive of new renal replacement therapy but not mortality. CONCLUSIONS: Machine-learning algorithms have allowed us to analyse the significance of dynamic processes that occur between pre-operative and peri-operative elements. Length of procedure and duration of cardiopulmonary bypass predicted mortality and morbidity in patients undergoing cardiac surgery in the UK. Bayesian networks can be used to explore potential principle determinant mechanisms underlying outcomes and be used to help develop future risk models.

A highly predictive autoantibody-based biomarker panel for prognosis in early-stage NSCLC with potential therapeutic implications.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Surgical resection remains the definitive curative treatment for early-stage disease offering an overall 5-year survival rate of 62%. Despite careful case selection, a significant proportion of early-stage cancers relapse aggressively within the first year post-operatively. Identification of these patients is key to accurate prognostication and understanding the biology that drives early relapse might open up potential novel adjuvant therapies. METHODS: We performed an unsupervised interrogation of >1600 serum-based autoantibody biomarkers using an iterative machine-learning algorithm. RESULTS: We identified a 13 biomarker signature that was highly predictive for survivorship in post-operative early-stage lung cancer; this outperforms currently used autoantibody biomarkers in solid cancers. Our results demonstrate significantly poor survivorship in high expressers of this biomarker signature with an overall 5-year survival rate of 7.6%. CONCLUSIONS: We anticipate that the data will lead to the development of an off-the-shelf prognostic panel and further that the oncogenic relevance of the proteins recognised in the panel may be a starting point for a new adjuvant therapy.

Combining Panitumumab With Anti-PD-1 Antibody in Cutaneous Squamous Cell Carcinoma of the Head and Neck After Inadequate Response to Anti-PD-1 Antibody Alone.

Anti-epidermal growth factor receptor (EGFR) antibodies and anti-programmed cell death 1 protein (PD-1) antibodies have been used separately to treat metastatic cutaneous squamous cell carcinoma (cSCC). While two anti-EGFR antibodies have similar clinical activity, cetuximab is administered weekly, whereas panitumumab is administered every two weeks. This report details findings using panitumumab in combination with anti-PD-1 antibody in patients with relapsed refractory cSCC. Three consecutive patients with poor performance status and rapidly progressive recurrent cutaneous squamous cell carcinoma (cSCC) of the face or scalp signed informed consent to receive an anti-PD-1 antibody with the option to add panitumumab were there inadequate response. After 2, 5, and 7 cycles of anti-PD-1 antibody treatment, respectively, panitumumab was added and the combination was continued for 27, 7, and 5 cycles, respectively. Fatigue, rash, and hypomagnesemia were reported, consistent with expectations for either agent alone. All three patients achieved durable complete response. The favorable clinical outcomes support further evaluation of the combination of anti-PD1 and anti-EGFR antibodies to control refractory cSCC of the face or scalp. J Drugs Dermatol. 2021;20(8):901-904. doi:10.36849/JDD.6175.

The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer.

Tumour-infiltrating immune cells have been widely implicated to play a significant role in carcinogenesis, through both pro- or anti-tumour effects. The multi-faceted effects of lung cancer associated T lymphocytes have been extensively studied, and yet, the role of B lymphocytes remains an area less studied. In this review, we will describe the current understanding of the role of tumour-infiltrating B lymphocytes in NSCLC, discuss their prognostic significance, their functionality within the tumour microenvironment and ultimately how we might harness B-cell biology to develop B-cell therapeutic strategies in cancer.

Higher ICU Capacity Strain Is Associated With Increased Acute Mortality in Closed ICUs.

OBJECTIVES: To determine whether patients admitted to an ICU during times of strain, when compared with its own norm (i.e. accommodating a greater number of patients, higher acuity of illness, or frequent turnover), is associated with a higher risk of death in ICUs with closed models of intensivist staffing. DESIGN: We conducted a large, multicenter, observational cohort study. Multilevel mixed effects logistic regression was used to examine relationships for three measures of ICU strain (bed census, severity-weighted bed census, and activity-weighted bed census) on the day of admission with risk-adjusted acute hospital mortality. SETTING: Pooled case mix and outcome database of adult general ICUs participating in the Intensive Care National Audit and Research Centre Case Mix Programme. MEASUREMENTS AND MAIN RESULTS: The analysis included 149,310 patients admitted to 215 adult general ICUs in 213 hospitals in United Kingdom, Wales, and Northern Ireland. A relative lower strain in ICU capacity as measured by bed census on the calendar day (daytime hours) of admission was associated with decreased risk-adjusted acute hospital mortality (odds ratio, 0.94; 95% CI, 0.90-0.99; p = 0.01), whereas a nonsignificant association was seen between higher strain and increased acute hospital mortality (odds ratio, 1.04; 95% CI, 1.00-1.10; p = 0.07). The relationship between periods of high ICU strain and acute hospital mortality was strongest when bed census was composed of higher acuity patients (odds ratio, 1.05; 95% CI, 1.01-1.10; p = 0.03). No relationship was seen between high strain and ICU mortality. CONCLUSIONS: In closed staffing models of care, variations in bed census within individual ICUs was associated with patient's predicted risk of acute hospital mortality, particularly when its standardized bed census consisted of sicker patients.

Effectiveness of Compressive External Bracing in Patients with Flexible Pectus Carinatum Deformity: A Review.

There has been a growing interest in the nonoperative treatment of chest wall deformities over the last few decades; with the advent of external compressive orthotics, similar outcomes have been reported compared with surgical intervention. There have been fewer major complications reported with dynamic compression bracing on the chest wall; however, the Achilles heel of this approach still lies with treatment tolerability and compliance. A Medline literature search was undertaken to evaluate the evidence concerning the techniques, modifications, and outcomes associated with external compressive bracing in the setting of pectus carinatum. Sixteen articles were integrated after literature review and data were collected on methods of assessing pectus carinatum (degree of severity as well as type), patient selection protocol (i.e., suitability for external compressive bracing), the bracing protocol itself, duration of treatment, metrics used to assess outcome, and success, compliance, and dropout rate, and length of long-term follow-up. Compressive external bracing appears to be a safe and well tolerated nonsurgical treatment option for young patients with flexible pectus carinatum deformities. However, there is still a need for robust level I randomized data from multiple centers with a clearly standardized bracing protocol, objective measurement of outcomes, and recording of results at the end of the bracing treatment program in sufficiently powered sample sizes over a significant follow-up period.

Research priorities in single-ventricle heart conditions: a United Kingdom national study.

OBJECTIVE: To bring together stakeholders in the United Kingdom to establish national priorities for research in single-ventricle heart conditions. METHODS: This study comprised two surveys and a workshop. The initial public online survey asked respondents up to three questions they would like answered for research. Responses were classified as unanswered, already answered, or unable to be answered by scientific research. In the follow-up survey, unanswered questions were divided into categories and respondents were asked to rank categories and questions by priority. A stakeholder workshop attended by patients, parents, healthcare professionals, researchers, and charities was held to determine the final list of research priorities. RESULTS: A total of 128 respondents posed 344 research questions, of which 271 were classified as unanswered, and after removing duplicates, 204 questions remained, which were divided into 20 categories. In the second survey, 56 (49.1%) respondents successfully ranked categories and questions. A total of 39 participants attended the workshop, drawing up a list of 30 research priorities across nine priority categories. The nine priority categories are: Associated co-morbidities; Brain & neurodevelopment; Exercise; Fontan failure; Heart function; Living with a single ventricle heart condition; Management of the well-functioning Fontan circulation; Surgery & perioperative care; and Transplantation, mechanical support & novel therapies. CONCLUSIONS: Through a multi-stage process, we engaged a wide range of interested parties to establish a list of research priorities in single-ventricle heart conditions. This provides a platform for clinicians, researchers, and funders in the United Kingdom and elsewhere to address the most important questions and improve outcomes in these rare but high-impact CHDs.

Unique patterns of organization and migration of FGF-expressing cells during Drosophila morphogenesis.

Fibroblast growth factors (FGF) are essential signaling proteins that regulate diverse cellular functions in developmental and metabolic processes. In Drosophila, the FGF homolog, branchless (bnl) is expressed in a dynamic and spatiotemporally restricted pattern to induce branching morphogenesis of the trachea, which expresses the Bnl-receptor, breathless (btl). Here we have developed a new strategy to determine bnl- expressing cells and study their interactions with the btl-expressing cells in the range of tissue patterning during Drosophila development. To enable targeted gene expression specifically in the bnl expressing cells, a new LexA based bnl enhancer trap line was generated using CRISPR/Cas9 based genome editing. Analyses of the spatiotemporal expression of the reporter in various embryonic stages, larval or adult tissues and in metabolic hypoxia, confirmed its target specificity and versatility. With this tool, new bnl expressing cells, their unique organization and functional interactions with the btl-expressing cells were uncovered in a larval tracheoblast niche in the leg imaginal discs, in larval photoreceptors of the developing retina, and in the embryonic central nervous system. The targeted expression system also facilitated live imaging of simultaneously labeled Bnl sources and tracheal cells, which revealed a unique morphogenetic movement of the embryonic bnl- source. Migration of bnl- expressing cells may create a dynamic spatiotemporal pattern of the signal source necessary for the directional growth of the tracheal branch. The genetic tool and the comprehensive profile of expression, organization, and activity of various types of bnl-expressing cells described in this study provided us with an important foundation for future research investigating the mechanisms underlying Bnl signaling in tissue morphogenesis.

Population-based trends in outcomes in adenoid cystic carcinoma of the oral cavity.

PURPOSE: Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm of secretory glands of the upper aerodigestive tract. It accounts for 3-5% of head and neck malignancies and most commonly arises from the minor salivary glands of the oral cavity. The clinical behavior of ACC from specific anatomic subsites, including the oral cavity, is not well described in the literature. We aim to elucidate patient demographics, clinicopathologic features, incidence, and survival trends for oral cavity ACC (OCACC). METHODS: Retrospective population-based analysis of OCACC in the SEER database between 1973 and 2012. RESULTS: 1066 OCACC patients were identified, of which 57.7% were female (P<0.0001). Incidence was 0.049 per 100,000. Whites were most commonly affected (81.1%). The hard palate was the most commonly involved subsite (44.1%). Nodal involvement was seen in 8.4% of cases and distant metastasis was present in 6.2% of cases at the time of presentation. Disease-specific survival (DSS) rates at 1, 5, 10, 15, and 20years were 97.4%, 83.9%, 69.9%, 57.6%, and 46.2%, respectively. Females had a higher 5-year DSS (87.8%) than males (78.4%, P=0.0004). Cases treated with surgery had a favorable prognosis regardless of whether they received radiotherapy (P<0.0001). Nodal involvement reduced 5-year DSS by 51.6% (P<0.0001), while distant metastasis reduced 5-year DSS by 46.4% (P<0.0001). CONCLUSIONS: OCACC is a rare malignancy with females and whites being more commonly affected. At presentation, regional and distant metastases are uncommon. Poor prognostic indicators include male gender, nonsurgical therapy, nodal involvement, and distant metastasis.

Should We Routinely Investigate Incidental Head and Neck Findings on 18-Fluorodeoxyglucose Positron Emission Tomography in Patients Being Staged for Non-small Cell Lung Cancer? A Retrospective Analysis.

BACKGROUND: Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) is routinely performed for investigating suspected lung cancers. Despite the known potential for false-positive FDG uptake in the head and neck, most suspicious lesions on FDG-PET are investigated. METHODS: Between October 2002 and January 2010, FDG-PET/PET-computed tomography (CT) reports showing significant incidental uptake were retrospectively analyzed using controls to compare time to treatment for lung cancer and the rate of secondary malignancy in those with and without incidental head and neck FDG uptake. RESULTS: In this study, 48/1,846 PET/PET-CT scan reports reviewed, and demonstrated nonthyroidal head and neck abnormalities. A total of 30 patients had proven non-small cell lung cancer (1.6%); 3/30 (10%) went on to have biopsy proven malignancy. Furthermore, there was a significant increase in time to treatment in those patients with incidental head and neck findings (p = 0.002). CONCLUSION: These unexpected findings are mostly of no clinical significance and the patient should continue treatment without delay; however, aggressive work-up should be pursued if concerns for head and neck pathology are raised following clinical assessment.

Lymph node dissection in lung cancer surgery.

Lung cancer, a leading cause of cancer-related death, often requires surgical resection for early-stage cases, with recent data supporting less invasive resections for tumors smaller than 2 cm. Central to resection is lymph node assessment, an area of controversy worldwide, compounded by advances in minimally invasive techniques. The review aims to assess current standards for lymph node assessment, recent data from the surgical era, and the immunobiological basis of how lymph node metastases impact patient outcomes. The British Thoracic Society guidelines recommend systematic nodal dissection during lung cancer resection, without specifying node removal or sampling. Historical data on mediastinal lymph node dissection (MLND) survival benefits are inconclusive, although proponents argue for lower recurrence rates. Recent trials such as ACOSOG Z0030 found no survival difference between MLND and nodal sampling, reinforcing the need for robust staging. While lobe-specific dissection strategies have been proposed, they currently lack consensus. JCOG1413 aims to compare the clinical benefits of lobe-specific and systematic dissection. TNM-9 staging revisions emphasize the prognostic significance of single-station N2 involvement. Robotic surgery shows promise, with trials such as RAVAL, which reported comparable outcomes to video-assisted thoracic surgery (VATS) and improved lymph node sampling. Immunobiological insights suggest preserving key immunological sites during lymphadenectomy, especially for patients receiving adjuvant immunotherapy. In conclusion, the standard lymph node resection strategy remains unsettled. The debate between systematic and selective dissection continues, with implications for staging accuracy and patient outcomes. As minimally invasive techniques evolve, robotic surgery emerges as an effective and low-risk approach to delivering optimal lymph node assessment.

Small cell lung carcinoma presenting initially with recurrent pneumothoraces: a case report.

BACKGROUND: Pneumothorax is a non-physiological collection of air in the pleural space. Pneumothoraces can be broadly divided into Primary, Secondary, and Traumatic. Cancer of the lung is a known cause of secondary pneumothorax in both primary and metastatic lesions, however, pneumothorax as the presentation of lung cancer is exceedingly rare. Non-small cell lung carcinoma (NSCLC) has been reported in the literature to present with a pneumothorax, particularly in adeno/squamous cell carcinomas. It is almost completely unheard of for small cell lung carcinoma (SCLC) to present with a pneumothorax. CASE PRESENTATION: We present the case of a 62-year-old male patient, presenting twice in two months with spontaneous pneumothorax. The initial management involved admission and chest drain insertion. The patient has a past medical history of COPD and a significant smoking history. On the second admission, he underwent a video-assisted thoracoscopic (VATS) bullectomy and talc pleurodesis. The pathology report of the resected specimen confirmed SCLC with extensive infiltration. No gross evidence of metastatic spread was present on CT. Due to the R1 resection and significant risk of recurrence, the management plan included four cycles of adjuvant chemotherapy with carboplatin and etoposide, and radiotherapy as a consideration upon completion. CONCLUSIONS: Pneumothorax as the presentation of lung cancer imparts a very poor prognosis, however the reasons for this are largely unknown. Furthermore, the mechanisms underlying spontaneous pneumothorax in lung cancer are also not well understood.

Redox Pathogenesis in Rheumatic Diseases.

Despite being some of the most anecdotally well-known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end-organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

Lymph node dissection in lung cancer surgery: a comparison between robot-assisted vs. video-assisted thoracoscopic approach.

Background: TNM staging is the most important prognosticator for non-small cell lung cancer (NSCLC) patients. Staging has significant implications for the treatment modality for these patients. Lymph node dissection in robot-assisted thoracoscopic (RATS) surgery remains an area of ongoing evaluation. In this study, we aim to compare lymph node dissection in RATS and VATS approach for lung resection in NSCLC patients. Methods: We retrospectively compiled a database of 717 patients from July 31, 2015-July 7, 2022, who underwent either a wedge resection, segmentectomy or lobectomy. We analysed the database according to lymph node dissection. The database was divided into RATS (n = 375) and VATS (n = 342) procedures. Results: The mean number of lymph nodes harvested overall with RATS was 6.1 ± 1.5 nodes; with VATS approach, it was 5.53 ± 1.8 nodes. The mean number of N1 stations harvested was 2.66 ± 0.8 with RATS, 2.36 ± 0.9 with VATS. RATS approach showed statistically higher lymph node dissection rates compared to VATS (p = 0.002). Out of the 375 RATS procedures, 26 (6.4%) patients undergoing a RATS procedure were upstaged from N0/N1 staging to N2. N0/N1-N2 upstaging was reported in 28 of 342 (8.2%) patients undergoing a VATS procedure. The majority of upstaging was seen in N0-N2 disease: 19 of 375 (5%) for RATS and 23 of 342 (6.7%) for VATS. Conclusions: We conclude that in RATS procedures, there is a higher rate of lymph node dissection compared to VATS procedures. Upstaging was mostly seen in N0-N2 disease, this was observed at a higher rate with VATS procedures.

Salvage surgery for recurrent transdiaphragmatic thymoma in a patient not eligible for chemotherapy.

The recurrence rate following thymoma surgery has been reported to be as high as 29%. In cases of localized recurrence, complete resection can result in prolonged patient survival. However, surgery is rarely considered in cases of invasive recurrent thymomas with high disease burden. Here, we present the case of a woman with type B2 thymoma (Masaoka-Koga stage IVa) treated with surgery, chemotherapy, and radiotherapy. The disease recurred 6 years later, with invasion of the left lung and the 12th thoracic vertebra, as well as extension into the retroperitoneum. Due to the development of chemotherapy-associated toxicity, she underwent surgery with complete tumor resection and has remained free of disease at a 12-months follow-up. Radical surgery for recurrent invasive thymoma extending through the diaphragm is a feasible and safe therapeutic option in highly selected patients who are not eligible for systemic treatments.

Endoscopic Versus Traditional Thoracic Discectomy: A Multicenter Retrospective Case Series and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Surgical treatment for symptomatic thoracic disc herniations (TDH) involves invasive open surgical approaches with relatively high complication rates and prolonged hospital stays. Although advantages of full endoscopic spine surgery (FESS) are well-established in lumbar disc herniations, data are limited for the endoscopic treatment of TDH despite potential benefits regarding surgical invasiveness. The aim of this study was to provide a comprehensive evaluation of potential benefits of FESS for the treatment of TDH. METHODS: PubMed, MEDLINE, EMBASE, and Scopus were systematically searched for the term "thoracic disc herniation" up to March 2023 and study quality appraised with a subsequent meta-analysis. Primary outcomes were perioperative complications, need for instrumentation, and reoperations. Simultaneously, we performed a multicenter retrospective evaluation of outcomes in patients undergoing full endoscopic thoracic discectomy. RESULTS: We identified 3190 patients from 108 studies for the traditional thoracic discectomy meta-analysis. Pooled incidence rates of complications were 25% (95% CI 0.22-0.29) for perioperative complications and 7% (95% CI 0.05-0.09) for reoperation. In this cohort, 37% (95% CI 0.26-0.49) of patients underwent instrumentation. The pooled mean for estimated blood loss for traditional approaches was 570 mL (95% CI 477.3-664.1) and 7.0 days (95% CI 5.91-8.14) for length of stay. For FESS, 41 patients from multiple institutions were retrospectively reviewed, perioperative complications were reported in 4 patients (9.7%), 4 (9.7%) required revision surgery, and 6 (14.6%) required instrumentation. Median blood loss was 5 mL (IQR 5-10), and length of stay was 0.43 days (IQR 0-1.23). CONCLUSION: The results suggest that full endoscopic thoracic discectomy is a safe and effective treatment option for patients with symptomatic TDH. When compared with open surgical approaches, FESS dramatically diminishes invasiveness, the rate of complications, and need for prolonged hospitalizations. Full endoscopic spine surgery has the capacity to alter the standard of care for TDH treatment toward an elective outpatient surgery.

Role of vitamin D supplementation in modifying outcomes after surgery: a systematic review of randomised controlled trials.

BACKGROUND: There is increasing evidence to suggest vitamin D plays a role in immune and vascular function; hence, it may be of biological and clinical relevance for patients undergoing major surgery. With a greater number of randomised studies being conducted evaluating the impact of vitamin D supplementation on surgical patients, it is an opportune time to conduct further analysis of the impact of vitamin D on surgical outcomes. METHODS: MEDLINE, EMBASE and the Cochrane Trials Register were interrogated up to December 2023 to identify randomised controlled trials of vitamin D supplementation in surgery. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias tool. A narrative synthesis was conducted for all studies. The primary outcome assessed was overall postoperative survival. RESULTS: We screened 4883 unique studies, assessed 236 full-text articles and included 14 articles in the qualitative synthesis, comprising 1982 patients. The included studies were highly heterogeneous with respect to patient conditions, ranging from open heart surgery to cancer operations to orthopaedic conditions, and also with respect to the timing and equivalent daily dose of vitamin D supplementation (range: 0.5-7500 mcg; 20-300 000 IU). No studies reported significant differences in overall survival or postoperative mortality with vitamin D supplementation. There was also no clear evidence of benefit with respect to overall or intensive care unit length of stay. DISCUSSION: Numerous studies have reported the benefits of vitamin D supplementation in different surgical settings without any consistency. However, this systematic review found no clear evidence of benefit, which warrants the supposition that a single biological effect of vitamin D supplementation does not exist. The observed improvement in outcomes in low vitamin D groups has not been convincingly proven beyond chance findings. TRIAL REGISTRATION NUMBER: CRD42021232067.

Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation.

Activation of the mechanistic target of rapamycin (mTOR) is a key metabolic checkpoint of pro-inflammatory T-cell development that contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), however, the underlying mechanisms remain poorly understood. Here, we identify a functional role for Rab4A-directed endosome traffic in CD98 receptor recycling, mTOR activation, and accumulation of mitochondria that connect metabolic pathways with immune cell lineage development and lupus pathogenesis. Based on integrated analyses of gene expression, receptor traffic, and stable isotope tracing of metabolic pathways, constitutively active Rab4AQ72L exerts cell type-specific control over metabolic networks, dominantly impacting CD98-dependent kynurenine production, mTOR activation, mitochondrial electron transport and flux through the tricarboxylic acid cycle and thus expands CD4+ and CD3+CD4-CD8- double-negative T cells over CD8+ T cells, enhancing B cell activation, plasma cell development, antinuclear and antiphospholipid autoantibody production, and glomerulonephritis in lupus-prone mice. Rab4A deletion in T cells and pharmacological mTOR blockade restrain CD98 expression, mitochondrial metabolism and lineage skewing and attenuate glomerulonephritis. This study identifies Rab4A-directed endosome traffic as a multilevel regulator of T cell lineage specification during lupus pathogenesis.