Explore the vast range of titles available.

PurposeSepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.MethodsRandomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters.ResultsTwelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.ConclusionsIn this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any ‘cytokine storm’. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted.Trial registration number (clinicaltrials.gov)NCT02960854.

Sarcoidosis is a disease involving abnormal collection of inflammatory cells forming nodules, called granulomas. Such granulomas occur in the lung and the mediastinal lymph nodes, in the heart, and in other vital and nonvital organs. The origin of the disease is unknown, and there are only limited clinical data on lung tissue of patients. No current model of sarcoidosis exists. In this paper we develop a mathematical model on the dynamics of the disease in the lung and use patients' lung tissue data to validate the model. The model is used to explore potential treatments.

Sarcoidosis is a lung disease of unknown cause characterized by noncaseating granulomas; the heart and nervous system may also be involved. It is often misdiagnosed; tissue biopsy is needed for a definitive diagnosis. Glucocorticoids are recommended as initial treatment, when needed, but not for long-term care.

Background The initial presentation of sepsis in the emergency department (ED) is difficult to distinguish from other acute illnesses based upon similar clinical presentations. A new blood parameter, a measurement of increased monocyte volume distribution width (MDW), may be used in combination with other clinical parameters to improve early sepsis detection. We sought to determine if MDW, when combined with other available clinical parameters at the time of ED presentation, improves the early detection of sepsis. Methods A retrospective analysis of prospectively collected clinical data available during the initial ED encounter of 2158 adult patients who were enrolled from emergency departments of three major academic centers, of which 385 fulfilled Sepsis-2 criteria, and 243 fulfilled Sepsis-3 criteria within 12 h of admission. Sepsis probabilities were determined based on MDW values, alone or in combination with components of systemic inflammatory response syndrome (SIRS) or quick sepsis-related organ failure assessment (qSOFA) score obtained during the initial patient presentation (i.e., within 2 h of ED admission). Results Abnormal MDW (> 20.0) consistently increased sepsis probability, and normal MDW consistently reduced sepsis probability when used in combination with SIRS criteria (tachycardia, tachypnea, abnormal white blood count, or body temperature) or qSOFA criteria (tachypnea, altered mental status, but not hypotension). Overall, and regardless of other SIRS or qSOFA variables, MDW > 20.0 (vs. MDW ≤ 20.0) at the time of the initial ED encounter was associated with an approximately 6-fold increase in the odds of Sepsis-2, and an approximately 4-fold increase in the odds of Sepsis-3. Conclusions MDW improves the early detection of sepsis during the initial ED encounter and is complementary to SIRS and qSOFA parameters that are currently used for this purpose. This study supports the incorporation of MDW with other readily available clinical parameters during the initial ED encounter for the early detection of sepsis. Trial registration ClinicalTrials.gov, NCT03145428 . First posted May 9, 2017. The first subjects were enrolled June 19, 2017, and the study completion date was January 26, 2018.

Cardiac sarcoidosis is difficult to diagnose, often requiring expensive and inconvenient advanced imaging techniques. Circulating exosomes contain genetic material, such as microRNA (miRNA), that are derived from diseased tissues and may serve as potential disease-specific biomarkers. We thus sought to determine whether circulating exosome-derived miRNA expression patterns would distinguish cardiac sarcoidosis (CS) from acute myocardial infarction (AMI). Plasma and serum samples conforming to CS, AMI or disease-free controls were procured from the Biologic Specimen and Data Repository Information Coordinating Center repository and National Jewish Health. Next generation sequencing (NGS) was performed on exosome-derived total RNA (n = 10 for each group), and miRNA expression levels were compared after normalization using housekeeping miRNA. Quality assurance measures excluded poor quality RNA samples. Differentially expressed (DE) miRNA patterns, based upon >2-fold change (p < 0.01), were established in CS compared to controls, and in CS compared to AMI. Relative expression of several DE-miRNA were validated by qRT-PCR. Despite the advanced age of the stored samples (~5-30 years), the quality of the exosome-derived miRNA was intact in ~88% of samples. Comparing plasma exosomal miRNA in CS versus controls, NGS yielded 18 DE transcripts (12 up-regulated, 6 down-regulated), including miRNA previously implicated in mechanisms of myocardial injury (miR-92, miR-21) and immune responses (miR-618, miR-27a). NGS further yielded 52 DE miRNA in serum exosomes from CS versus AMI: 5 up-regulated in CS; 47 up-regulated in AMI, including transcripts previously detected in AMI patients (miR-1-1, miR-133a, miR-208b, miR-423, miR-499). Five miRNAs with increased DE in CS included two isoforms of miR-624 and miR-144, previously reported as markers of cardiomyopathy. MiRNA patterns of exosomes derived from CS and AMI patients are distinct, suggesting that circulating exosomal miRNA patterns could serve as disease biomarkers. Further studies are required to establish their specificity relative to other cardiac disorders.

Mitochondrial transcription factor A (TFAM) is normally bound to and remains associated with mitochondrial DNA (mtDNA) when released from damaged cells. We hypothesized that TFAM, bound to mtDNA (or equivalent CpG-enriched DNA), amplifies TNFα release from TLR9-expressing plasmacytoid dendritic cells (pDCs) by engaging RAGE. Murine Flt3 ligand-expanded splenocytes obtained from C57BL/6 mice were treated with recombinant human TFAM, alone or in combination with CpG-enriched DNA with subsequent TNFα release measured by ELISA. The role of RAGE was determined by pre-treatment with soluble RAGE or heparin or by employing matching RAGE (-/-) splenocytes. TLR9 signaling was evaluated using a specific TLR9-blocking oligonucleotide and by inhibiting endosomal processing, PI3K and NF-κB. Additional studies examined whether heparin sulfate moieties or endothelin converting enzyme-1 (ECE-1)-dependent recycling of endosomal receptors were required for TFAM and CpG DNA recognition. TFAM augmented splenocyte TNFα release in response to CpGA DNA, which was strongly dependent upon pDCs and regulated by RAGE and TLR9 receptors. Putative TLR9 signaling pathways, including endosomal acidification and signaling through PI3K and NF-κB, were essential for splenocyte TNFα release in response to TFAM+CpGA DNA. Interestingly, TNFα release depended upon endothelin converting enzyme (ECE)-1, which cleaves and presumably activates TLR9 within endosomes. Recognition of the TFAM-CpGA DNA complex was dependent upon heparin sulfate moieties, and recombinant TFAM Box 1 and Box 2 proteins were equivalent in terms of augmenting TNFα release. TFAM promoted TNFα release in a splenocyte culture model representing complex cell-cell interactions in vivo with pDCs playing a critical role. To our knowledge, this study is the first to incriminate ECE-1-dependent endosomal cleavage of TLR9 as a critical step in the signaling pathway leading to TNFα release. These findings, and others reported herein, significantly advance our understanding of sterile immune responses triggered by mitochondrial danger signals.

IntroductionTargeted oxygenation protocols in mechanically ventilated patients are critical in avoiding the deleterious effects of hypoxaemia and hyperoxaemia. Peripheral oxygen saturation (SpO2) is a practical metric that commonly drives oxygen titration protocols and guidelines but has inaccuracies attributable to patient variability that can lead to occult hypoxaemia. Conversely, arterial oxygen saturation (SaO2) offers accuracy but is costly and invasive. We aim to develop a novel approach to targeted oxygenation that collectively uses the accuracy of SaO2 and the feasibility of SpO2 to mitigate occult hypoxaemia and prevent hyperoxaemia.Methods and analysisThe Optimization of Inspired Oxygen during Mechanical Ventilation trial is a pragmatic stepped wedge, open label, cluster-randomised controlled trial of an algorithm-based SpO2-SaO2 electronic alert-based oxygen titration protocol. The intervention arm includes targeted oxygenation via an electronic SpO2-SaO2 driven alert protocol. The control group will be subjected to oxygen titration according to standard practice. Within the intervention arm, patients will be assigned to groups with different SpO2 targets based on the degree of SpO2-SaO2 difference. In the ‘Conserve O2’ group, where SpO2SaO2 by 1–2%, electronic alerts will be used to titrate FiO2 to a target SpO2 of 90–94%. In the ‘Boosted O2’ group, where SpO2>SaO2 by 3–5%, electronic alerts will be used to titrate FiO2 to a target SpO2 of 93–97%. Patients with an SpO2-SaO2 difference >5% in either direction will be monitored but not assigned to either group. The sample size to determine efficacy is 1620 subjects, randomised over 60 weeks. The primary outcome is the proportion of time during mechanical ventilation spent within the target range, SpO2 of 90–94% (Conserve O2) or SpO2 of 93–97% (Boosted O2) at any FiO2. Secondary outcomes include the proportion of time with SpO2 >94% or SpO2 >97% with FiO2 ≤0.4 within each respective algorithm, the proportion of time with SpO2 <90% or SpO2 <93% within each respective algorithm, length of intensive care unit and hospital stay, hospital mortality, ventilator and vasopressor free days, new onset of arrhythmia when SpO2 <90%, and change to comfort care status (DNRCC) and time to DNRCC after enrolment.Ethics and disseminationThe protocol was approved by The Ohio State University Institutional Review Board (Protocol # 2023H0016) and is registered at ClinicalTrials.gov (NCT 05923853). Progress and safety of the trial are monitored by an independent Data and Safety Monitoring Board. Study results will be published in peer-reviewed medical journals. This study is being carried out with a waiver of consent as participation in the study presents no more than minimal incremental risk compared with routine clinical care for mechanically ventilated critically ill adults outside of the study.Trial registration numberNCT05923853.

Background The SARS CoV-2 pandemic has resulted in more than 1.1 million deaths in the USA alone. Therapeutic options for critically ill patients with COVID-19 are limited. Prior studies showed that post-infection treatment of influenza A virus-infected mice with the liponucleotide CDP-choline, which is an essential precursor for de novo phosphatidylcholine synthesis, improved gas exchange and reduced pulmonary inflammation without altering viral replication. In unpublished studies, we found that treatment of SARS CoV-2-infected K18-hACE2-transgenic mice with CDP-choline prevented development of hypoxemia. We hypothesize that administration of citicoline (the pharmaceutical form of CDP-choline) will be safe in hospitalized SARS CoV-2-infected patients with hypoxemic acute respiratory failure (HARF) and that we will obtain preliminary evidence of clinical benefit to support a larger Phase 3 trial using one or more citicoline doses. Methods We will conduct a single-site, double-blinded, placebo-controlled, and randomized Phase 1/2 dose-ranging and safety study of Somazina® citicoline solution for injection in consented adults of any sex, gender, age, or ethnicity hospitalized for SARS CoV-2-associated HARF. The trial is named “SCARLET” (Supplemental Citicoline Administration to Reduce Lung injury Efficacy Trial). We hypothesize that SCARLET will show that i.v. citicoline is safe at one or more of three doses (0.5, 2.5, or 5 mg/kg, every 12 h for 5 days) in hospitalized SARS CoV-2-infected patients with HARF (20 per dose) and provide preliminary evidence that i.v. citicoline improves pulmonary outcomes in this population. The primary efficacy outcome will be the S p O 2 :F i O 2 ratio on study day 3. Exploratory outcomes include Sequential Organ Failure Assessment (SOFA) scores, dead space ventilation index, and lung compliance. Citicoline effects on a panel of COVID-relevant lung and blood biomarkers will also be determined. Discussion Citicoline has many characteristics that would be advantageous to any candidate COVID-19 therapeutic, including safety, low-cost, favorable chemical characteristics, and potentially pathogen-agnostic efficacy. Successful demonstration that citicoline is beneficial in severely ill patients with SARS CoV-2-induced HARF could transform management of severely ill COVID patients. Trial registration The trial was registered at www.clinicaltrials.gov on 5/31/2023 (NCT05881135). Trial status Currently enrolling.

Rationale Despite the availability of multi-“omics” strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures. Objective To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis). Methods Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways. Results Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers ( STAB1, HBEGF, and NOTCH4 ), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2 . Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level. Conclusion These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.

To aggregate literature on the diagnostic performance of monocyte distribution width (MDW) for sepsis detection among adults in the emergency department and inpatient settings. We searched the MEDLINE, EMBASE, SCOPUS, and Cochrane databases for studies evaluating MDW for sepsis diagnosis in adults in the hospital setting through October 19, 2024. Two authors (G.E. and Q.H.) independently performed eligibility assessment, data extraction, and risk of bias assessment. We evaluated performance for sepsis-2 and sepsis-3 separately and applied separate diagnostic thresholds depending on the anticoagulant used in blood collection. Data were pooled using a random-effects model. We performed multiple sensitivity analyses to evaluate the stability of our findings. Twenty-five observational studies comprising 39,041 patients were included. The area under the summary receiver operating curve (AUC) was 0.82 (95% CI, 0.78-0.85) for both sepsis-2 and sepsis-3. Sensitivity and specificity were 0.79 (95% CI, 0.74-0.83) and 0.7 (95% CI, 0.61-0.78) for sepsis-2 and 0.83 (95% CI, 0.78-0.88) and 0.64 (95% CI, 0.55-0.71) for sepsis-3. The threshold-independent weighted-average AUC was 0.76 (SD, 0.1) for sepsis-2 and 0.77 (SD, 0.07) for sepsis-3. The aggregate negative predictive value was 94% for sepsis-2 and 96% for sepsis-3. We observed similar performance across all sensitivity analyses. We assessed the overall quality of evidence to be low. MDW performs similarly to other biomarkers such as procalcitonin for the diagnosis of sepsis, with the unique advantage of rapid availability as part of routine testing.