SEAN MONAGHAN, M.D.

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Blood RNA sequencing from sepsis patients was used to detect bacterial RNA and design rapid PCR tests targeting specific pathogens and their antibiotic-resistance genes. The new PCR tests successfully identified Pseudomonas aeruginosa and Staphylococcus aureus in patients with confirmed positive blood cultures. This approach could diagnose the cause of a septic infection hours faster than standard blood cultures, enabling earlier targeted treatment.

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When cells fail to recycle the RNA lariats left over after gene splicing, repetitive DNA sequences within those lariats fold into long double-stranded RNA structures that normally exist only in viruses. These structures overwhelm the cell's antiviral sensors PKR and RNase L, dulling their ability to detect a real viral infection. This explains why people with mutations in the lariat-recycling enzyme DBR1 are unusually susceptible to certain viruses.

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A computational pipeline was developed to track how abnormal splicing events in blood cells create premature stop codons that trigger nonsense-mediated mRNA decay, effectively silencing certain genes. In sepsis patients and those who died, this decay process was more active than in healthy controls or survivors, suggesting that widespread splicing disruption is a feature of critical illness. The pipeline also identified proteins with potential new roles in sepsis biology.

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A new computational pipeline was built to detect when abnormal RNA splicing in critically ill patients introduces early stop signals that trigger destruction of the resulting messenger RNA — a process called nonsense-mediated decay. Applying this pipeline to blood samples from ICU patients showed that this RNA destruction happens more in sepsis patients and in those who died. The findings point to new protein targets potentially involved in sepsis and show that measuring this RNA quality-control process can reveal disease severity.

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Some short DNA sequences in human genes can act as either end of a splice junction, functioning as both a 5' and 3' splice site. The polyubiquitin gene UBC uses a tandem array of these dual-specific sites to stochastically produce mRNAs encoding different numbers of ubiquitin units. This discovery expands our understanding of how splicing diversity is generated and suggests that dual-specific splice sites have driven the evolution of tandem-repeat genes.

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Using a mouse model of abdominal sepsis, this study found that a specialized immune cell population called invariant natural killer T cells shapes how peritoneal macrophages respond to infection. Without iNKT cells, macrophages showed altered surface markers and produced different amounts of anti-inflammatory cytokine IL-10 and reactive oxygen species. Because drugs targeting iNKT cell function are already in clinical trials, these findings could be relevant to treating patients with abdominal sepsis.

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More than a quarter of human introns contain paired repetitive elements that fold into double-stranded RNA when lariats are not properly recycled by the DBR1 enzyme. In cells lacking DBR1, these lariats escape to the cytoplasm and desensitize the key antiviral sensors MDA5, RIG-I, RNase L, and PKR. Several viruses including HSV-1 appear to exploit this mechanism by generating stable lariats that may help them evade immune detection during latency.

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Single-cell multiomics combining RNA sequencing and chromatin accessibility mapping was applied to lung tissue from mice subjected to hemorrhagic shock. After shock, the region of DNA controlling the receptor gene CALCRL became much less accessible in normal mice but remained open in mice lacking immune checkpoint genes PD-1, PD-L1, or VISTA. This suggests that these checkpoint proteins regulate the lung's response to shock by controlling access to genes tied to the peptide hormone adrenomedullin, which may contribute to the lung injury that follows trauma.

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Endothelial cells collected from balloon-tipped heart catheters in pulmonary hypertension patients were grown in the lab and subjected to RNA sequencing. Cells from patients with pulmonary arterial hypertension showed a distinct gene-expression pattern compared to controls, with upregulation of genes involved in sex steroid signaling and cancer-like growth, and these signatures tracked with disease progression over time. The approach offers a live cell biopsy from inside the pulmonary arteries that could help tailor treatment to individual patients.

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Deep RNA sequencing of blood from 15 critically ill COVID-19 patients detected viral RNA as well as RNA from other bacteria, archaea, and viruses in every patient. Immune-suppressing genes including PD-L1 and PD-L2 were more active in patients who died, and the degree of disorder in alternative RNA splicing predicted mortality. Standard nasal swab testing only confirms the virus is present; blood RNA sequencing provides a much richer picture of the immune response and disease trajectory.

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Deep RNA sequencing of blood from COVID-19 ICU patients was used to identify antibody sequences present in survivors versus non-survivors. Patients who survived had significantly higher levels of a class of neutralizing antibody called C135, which blocks the virus without directly covering the site where it normally grips human cells. Molecular simulations explained how C135 still prevents viral entry despite this indirect mechanism, suggesting it could be a targeted therapy for patients whose immune systems fail to produce it on their own.

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A trauma center review found that 36% of patients who received the clot-preventing drug tranexamic acid (TXA) did not have documented evidence of active bleeding that would justify its use, and this rate rose to 52% among patients treated in the field by emergency medical services. Despite the high rate of unjustified use, no increase in dangerous blood clots was detected in that group, though the study was too small to rule one out. The findings call for tighter criteria before giving TXA, especially in prehospital settings.

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Blood RNA sequencing from 15 COVID-19 ICU patients detected the virus in every patient along with other microbes, and identified significant differences in immune gene expression between survivors and non-survivors. Genes encoding immune checkpoint proteins PD-L1 and PD-L2 were more highly expressed in patients who died, and the complexity of alternative RNA splicing patterns predicted mortality. This shows that deep blood RNA sequencing can simultaneously diagnose infection and forecast outcomes in the most severely ill patients.

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Sepsis kills through a dysregulated immune response that swings between dangerous overactivation and harmful immunosuppression, and no single treatment has reliably improved outcomes across patients. This review surveys experimental models and clinical trials to evaluate emerging therapeutic strategies including targeted immune modulation, microbiome optimization, and gene-based interventions. It concludes that real progress will require combining multiple approaches that address both the disease process and individual patient factors.

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A breathalyzer device called the Bubbler captures exhaled RNA from SARS-CoV-2 particles, converts it to barcoded DNA on the spot, and can test many patient samples in one pooled sequencing run. In 70 hospitalized patients, it detected virus more effectively than tongue swabs and better predicted lower respiratory tract involvement than existing tests. The same device was also used to sample viral particles suspended in room air, showing its potential for environmental infection surveillance.

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Trauma patients in the ICU showed markedly elevated expression of the coinhibitory receptor HVEM on their T lymphocytes compared to healthy controls. Patients who went on to develop a secondary infection during their hospital stay had lower HVEM expression at admission than those who stayed infection-free. This suggests HVEM signaling helps maintain immune defenses after injury, and that measuring HVEM levels could flag patients at highest risk for hospital-acquired infections.

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Checkpoint receptor proteins such as PD-1, CTLA-4, 2B4, and BTLA act as brakes on the immune system, and during sepsis they are strongly activated in ways that prevent the body from mounting an effective immune response to secondary infections. This review explains how these receptors and their ligands, when upregulated on both immune and non-immune cells during sepsis, contribute to a state of prolonged immune paralysis. Understanding these pathways points toward checkpoint-blocking therapies as potential treatments for sepsis-induced immunosuppression.

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A review of 31 patients aged 65 and older who required damage control laparotomy — emergency surgery to control bleeding with a planned return operation — found a 77% mortality rate. All seven survivors were discharged to rehabilitation facilities rather than home, and standard markers like blood pressure and lactate levels did not distinguish survivors from non-survivors. These findings indicate that damage control laparotomy carries an extremely high risk of death or permanent disability in elderly patients.

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Checkpoint proteins PD-1, CTLA-4, 2B4, and BTLA are expressed not just on T cells but also on innate immune cells like macrophages, monocytes, and neutrophils, and on non-immune cells, during sepsis and shock. Their upregulation tips the balance away from effective bacterial killing and toward immune-mediated tissue damage and eventual immune paralysis. Targeting these molecules pharmacologically offers a strategy to restore immune function in patients with life-threatening infections.

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A re-analysis of mutations in Lynch syndrome cancer genes showed that a much larger fraction than previously recognized — including many mutations inside exons, not just at the edges of introns — actually disrupt RNA splicing. Three of the main Lynch syndrome genes belong to a broader group of 86 disease genes that are unusually prone to splicing mutations. This means clinical genetic testing for hereditary cancer must look beyond obvious splice-site mutations to avoid missing a large number of disease-causing changes.

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Among nearly 90,000 elderly Medicare patients with traumatic brain injury admitted to nursing facilities, those who were oldest, male, cognitively impaired, or unable to communicate faced substantially higher risk of dying within 30 days and one year. Women had 37% lower mortality than men, and patients with poor cognitive or motor function at admission were about 2.5 times more likely to die. These findings give families and clinicians realistic data to set expectations when elderly brain injury patients transition to rehabilitation care.

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A soluble form of the immune checkpoint protein BTLA is released into the blood of critically ill patients through abnormal RNA splicing that cuts the protein short and removes its membrane anchor. Soluble BTLA levels in blood predicted a sepsis diagnosis on the day of hospital admission and, in lab experiments, promoted immune cell proliferation. This makes soluble BTLA both a potential early diagnostic marker for sepsis and a candidate immune modulator in critical illness.

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In a mouse model of trauma-followed-by-sepsis lung injury, removing the immune checkpoint protein PD-L1 reduced lung fluid leakage, inflammation, and death, going beyond the benefits seen from removing PD-1 alone. PD-L1 deficiency specifically protected the lung's blood vessel lining by preserving a stabilizing signaling pathway involving Angiopoietin and its receptor Tie2, while PD-1 deficiency reduced the influx of damaging immune cells. This means PD-L1 on lung blood vessel cells plays its own independent role in driving acute respiratory distress syndrome, separate from its role in immune regulation.

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Sepsis strongly upregulates the immune checkpoint protein PD-L1 on intestinal lining cells in both mice and humans, and mice lacking PD-L1 had less gut leakiness, less tissue inflammation, and better preservation of the tight junction proteins that seal the gut barrier. Blocking PD-L1 with an antibody in human intestinal cells in culture reversed the barrier breakdown caused by inflammatory signals. This makes PD-L1 on gut epithelial cells a potential therapeutic target for preventing the intestinal dysfunction that worsens outcomes in sepsis.

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ICU patients with sepsis had higher levels of the adhesion molecule CD29 on their T cells compared to patients with non-infectious systemic inflammation (SIRS), and patients with abdominal sepsis had higher levels still. CD18 expression was near-uniform across all groups and was not informative. These differences in T-cell integrin expression point to distinct immune states in SIRS versus sepsis that could potentially be used to distinguish the two conditions at the bedside.

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Five percent of trauma patients at a Level I center presented more than 24 hours after their injury, and this group was older, more likely to have psychiatric conditions, and at higher risk for substance withdrawal during hospitalization. Toxicology screening was done at lower rates in delayed-presenting patients despite their higher withdrawal risk. These patients need automatic withdrawal monitoring protocols and early social work involvement given their distinct risk profile.

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Among more than 11,000 admitted trauma patients, those with a pre-existing psychiatric diagnosis were 30% more likely to develop an infection during their hospital stay, with urinary tract infections being the most common complication. This association held after adjusting for age, sex, injury severity, diabetes, and obesity. Psychiatric illness represents a previously overlooked independent risk factor for post-trauma infections, warranting closer attention to this patient group.

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Surgical residents' communication skills during patient handoffs improved significantly after structured education sessions about effective sign-out techniques, with scores in all three evaluated areas roughly doubling. These improvements were sustained in a follow-up blinded assessment, suggesting the training had a durable effect. Trauma morning report, with its mix of training levels and real patient cases, proved to be an effective venue for teaching and assessing this critical skill.

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In a mouse model of indirect ARDS triggered by hemorrhagic shock followed by sepsis, blocking the blood vessel-destabilizing growth factor Angiopoietin-2 immediately after the initial shock event — but not after the septic second hit — significantly reduced lung injury and improved ten-day survival. Angiopoietin-2 spiked in the lung immediately after hemorrhage and remained elevated through the septic phase, consistent with a key priming role. These findings identify a narrow therapeutic window right after traumatic injury when blocking Angiopoietin-2 could prevent subsequent lung failure.

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A soluble form of the immune checkpoint receptor PD-1 was found at elevated levels in the blood and lung fluid of ARDS patients, and high levels accurately predicted the diagnosis in both humans and a mouse model. In lab experiments, lung fluid containing soluble PD-1 suppressed production of the inflammatory molecule TNF-alpha by immune cells. Soluble PD-1 may serve as both a diagnostic biomarker for ARDS and a natural anti-inflammatory molecule that could be developed as a therapy.

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Sepsis patients with abdominal infections had higher numbers of circulating invariant natural killer T cells but lower activation of those cells compared to patients with non-abdominal infections such as pneumonia. In patients with non-abdominal infections, having more activated iNKT cells was associated with better survival. The distinct iNKT cell profiles in abdominal versus non-abdominal sepsis suggest the immune response to infection is fundamentally shaped by where in the body the infection originates.

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In ICU patients with sepsis, the invariant natural killer T cell population was expanded rather than depleted — unlike conventional T cells, which fell sharply. This expansion was most pronounced in elderly patients who died, and in those non-survivors the iNKT cells showed reduced activation markers, pointing to a dysfunctional rather than simply increased population. The combination of elevated but poorly activated iNKT cells may mark a particularly dangerous immune state in older septic patients.

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The immune checkpoint protein B7-H1 (PD-L1) was found to be broadly upregulated on immune cells during sepsis, and mice lacking B7-H1 survived sepsis at higher rates with less organ damage and lower inflammatory cytokine levels than normal mice. Higher percentages of B7-H1-positive neutrophils in blood correlated with elevated cytokines and death in septic patients. These findings establish B7-H1 on neutrophils as a potential biomarker of sepsis severity and a target distinct from PD-1 for therapeutic intervention.

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Elderly trauma patients who developed a secondary infection during their ICU stay had lower initial levels of the inflammatory cytokines IL-6 and IL-10 than those who did not, while elderly patients who died had cytokine levels as high as those seen in younger patients who survived. This means that a robust inflammatory response in an elderly patient signals danger rather than resilience. Clinicians need different reference ranges for interpreting inflammatory markers in older trauma patients.

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Trauma patients who initially tested negative for ventilator-associated pneumonia and received empiric antibiotics while awaiting culture results, but later developed pneumonia during the same hospitalization, showed a different bacterial profile than patients who had pneumonia from the start — with more Enterobacter and less Staphylococcus aureus. Despite this shift in bacterial species, the empiric antibiotic course did not increase rates of drug-resistant organisms, C. difficile infections, or length of stay. Early empiric antibiotic treatment appears safe but does alter which bacteria eventually cause pneumonia.

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During sepsis, invariant natural killer T cells migrate from the liver into the peritoneal cavity through a mechanism that requires the immune checkpoint protein PD-1. Once in the peritoneum, iNKT cells help macrophages effectively kill bacteria: mice lacking iNKT cells had impaired macrophage phagocytosis, but this dysfunction was reversed by adding normal iNKT cells back. This positions iNKT cells as active regulators of the innate immune response to abdominal infection.

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ICU patients with sepsis had higher levels of the immune checkpoint protein BTLA on their CD4+ T cells compared to non-septic critically ill patients. In non-septic patients, high BTLA expression predicted development of a hospital-acquired infection and longer hospital stays. In mice, BTLA drove apoptotic loss of immune cells in lymphoid organs during sepsis, and mice lacking BTLA had less of this cell death — suggesting BTLA suppresses immune defenses and its level on T cells could help identify patients at risk of infection.

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In severely injured trauma patients, failing to recover from low lymphocyte counts within the first four days of hospitalization was independently associated with a 64% higher risk of death, even after accounting for age, sex, and injury severity. Paradoxically, among survivors, persistent low lymphocyte counts were linked to shorter hospital stays. This is the first report identifying persistent lymphopenia as an independent mortality predictor after trauma, suggesting that tracking lymphocyte recovery could help identify high-risk patients early.

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In mouse sepsis, innate immune cells including macrophages, monocytes, dendritic cells, and neutrophils showed sharply increased expression of the checkpoint protein BTLA and its binding partner HVEM at the site of infection. Mice lacking BTLA cleared bacteria better, produced less of the immunosuppressive cytokine IL-10, had less organ damage, and survived at higher rates. Elevated BTLA and HVEM were also found on circulating monocytes and neutrophils of septic ICU patients, making these proteins potential diagnostic markers and therapeutic targets.

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Among critically ill surgical and trauma patients, those with the most severe physiological dysfunction had more immune cells expressing the checkpoint receptor PD-1, and PD-1 expression on monocytes correlated with levels of the anti-inflammatory cytokine IL-10. This suggests PD-1 is not just an immunological marker but tracks with the overall severity of illness. Measuring PD-1 expression could help gauge the degree of immune dysfunction in critically ill patients.

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When surgical residents were asked weekly to describe the most important thing they learned, and their responses were categorized by learning domain, the program identified that patient care and clinical knowledge were the dominant areas while self-directed learning was minimal. Structured communication training prompted by this feedback doubled scores on patient handoff quality assessments, and these gains persisted in a subsequent blinded evaluation phase. Regular reflective self-reporting by residents can identify curriculum gaps and drive targeted educational interventions.

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Among trauma ICU patients, developing a ventilator-associated pneumonia increased the risk of any cardiac injury by more than fivefold, and a urinary tract infection more than doubled that risk. While minor cardiac injury alone did not predict death, severe cardiac injury combined with UTI and advancing age was associated with higher mortality. Infections in trauma patients trigger inflammatory cascades that damage the heart, which may contribute to the increased mortality seen with infectious complications.

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Uninsured trauma patients were more likely to die than insured patients, but this gap disappeared when comparing only patients who had documented pre-existing medical conditions, suggesting the real driver is that uninsured patients have conditions that go undiagnosed and untreated. After adjusting for demographics, insured patients were about twice as likely to have a documented diagnosis of conditions like diabetes, hypertension, or heart disease. Undiagnosed comorbidities, a consequence of limited healthcare access, appear to be a major reason uninsured trauma patients fare worse.