Serologic Response to the Epstein-Barr Virus Peptidome and the Risk for Multiple Sclerosis.

Importance: It remains unclear why only a small proportion of individuals infected with the Epstein-Barr virus (EBV) develop multiple sclerosis (MS) and what the underlying mechanisms are. Objective: To assess the serologic response to all EBV peptides before the first symptoms of MS occur, determine whether the disease is associated with a distinct immune response to EBV, and evaluate whether specific EBV epitopes drive this response. Design, Setting, and Participants: In this prospective, nested case-control study, individuals were selected among US military personnel with serum samples stored in the US Department of Defense Serum Repository. Individuals with MS had serum collected at a median 1 year before onset (reported to the military in 2000-2011) and were matched to controls for age, sex, race and ethnicity, blood collection, and military branch. No individuals were excluded. The data were analyzed between September 1, 2022, and August 31, 2023. Exposure: Antibodies (enrichment z scores) to the human virome measured using VirScan (phage-displayed immunoprecipitation and sequencing). Main Outcome and Measure: Rate ratios (RRs) for MS for antibodies to 2263 EBV peptides (the EBV peptidome) were estimated using conditional logistic regression, adjusting for total anti-EBV nuclear antigen 1 (EBNA-1) antibodies, which have consistently been associated with a higher MS risk. The role of antibodies against other viral peptides was also explored. Results: A total of 30 individuals with MS were matched with 30 controls. Mean (SD) age at sample collection was 27.8 (6.5) years; 46 of 60 participants (76.7%) were male. The antibody response to the EBV peptidome was stronger in individuals with MS, but without a discernible pattern. The antibody responses to 66 EBV peptides, the majority mapping to EBNA antigens, were significantly higher in preonset sera from individuals with MS (RR of highest vs lowest tertile of antibody enrichment, 33.4; 95% CI, 2.5-448.4; P for trend = .008). Higher total anti-EBNA-1 antibodies were also associated with an elevated MS risk (top vs bottom tertile: RR, 27.6; 95% CI, 2.3-327.6; P for trend = .008). After adjusting for total anti-EBNA-1 antibodies, risk estimates from most EBV peptides analyses were attenuated, with 4 remaining significantly associated with MS, the strongest within EBNA-6/EBNA-3C, while the association between total anti-EBNA-1 antibodies and MS persisted. Conclusion and Relevance: These findings suggest that antibody response to EBNA-1 may be the strongest serologic risk factor for MS. No single EBV peptide stood out as being selectively targeted in individuals with MS but not controls. Larger investigations are needed to explore possible heterogeneity of anti-EBV humoral immunity in MS.

Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS during their period of service. Risk of MS increased 32-fold after infection with EBV but was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

TIPICO XI: report of the first series and podcast on infectious diseases and vaccines (aTIPICO).

TIPiCO is an annual expert meeting and workshop on infectious diseases and vaccination. The edition of 2020 changed its name and format to aTIPiCO, the first series and podcasts on infectious diseases and vaccines. A total of 13 prestigious experts from different countries participated in this edition launched on the 26 November 2020. The state of the art of coronavirus disease-2019 (COVID-19) and the responsible pathogen, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the options to tackle the pandemic situation were discussed in light of the knowledge in November 2020. Despite COVID-19, the status of other infectious diseases, including influenza infections, respiratory syncytial virus disease, human papillomavirus infection, measles, pertussis, tuberculosis, meningococcal disease, and pneumococcal disease, were also addressed. The essential lessons that can be learned from these diseases and their vaccines to use in the COVID-19 pandemic were also commented with the experts.

Predicting the need for massive transfusion: Prospective validation of a smartphone-based clinical decision support tool.

BACKGROUND: Improper or delayed activation of a massive transfusion protocol may have consequences to individuals and institutions. We designed a complex predictive algorithm that was packaged within a smartphone application. We hypothesized it would accurately assess the need for massive transfusion protocol activation and assist clinicians in that decision. METHODS: We prospectively enrolled patients at an urban, level I trauma center. The application recorded the surgeon's initial opinion for activation and then prompted inputs for the model. The application provided a prediction and recorded the surgeon's final decision on activation. RESULTS: Three hundred and twenty-one patients were enrolled (83% male; 59% penetrating; median Injury Severity Score 9; mean base deficit -4.11). Of 36 massive transfusion protocol activations, 26 had an app prediction of "high" or "moderate" probability. Of these, 4 (15%) patients received <10 u blood as a result of early hemorrhage control. Two hundred and eighty-five patients did not have massive transfusion protocol activated by the surgeon with 27 (9%) patients having "moderate" or "high" likelihood predicted by the application. Twenty-four of these did not require massive transfusion, and all patients had acidosis that unrelated to hemorrhagic shock. For 13 (50%) of the patients with "high" probability, the surgeon correctly altered their initial decision based on this information. The algorithm demonstrated an adjusted accuracy of 0.96 (95% confidence interval [0.93-0.98); P ≤ .001]), sensitivity = 0.99, specificity 0.72, positive predictive value 0.96, negative predictive value 0.99, and area under the receiver operating curve = 0.86. CONCLUSION: A smartphone-based clinical decision tools can aid surgeons in the decision to active massive transfusion protocol in real time, although it does not completely replace clinician judgment.

Test sensitivity is secondary to frequency and turnaround time for COVID-19 screening.

The COVID-19 pandemic has created a public health crisis. Because SARS-CoV-2 can spread from individuals with presymptomatic, symptomatic, and asymptomatic infections, the reopening of societies and the control of virus spread will be facilitated by robust population screening, for which virus testing will often be central. After infection, individuals undergo a period of incubation during which viral titers are too low to detect, followed by exponential viral growth, leading to peak viral load and infectiousness and ending with declining titers and clearance. Given the pattern of viral load kinetics, we model the effectiveness of repeated population screening considering test sensitivities, frequency, and sample-to-answer reporting time. These results demonstrate that effective screening depends largely on frequency of testing and speed of reporting and is only marginally improved by high test sensitivity. We therefore conclude that screening should prioritize accessibility, frequency, and sample-to-answer time; analytical limits of detection should be secondary.

A Global lmmunological Observatory to meet a time of pandemics.

SARS-CoV-2 presents an unprecedented international challenge, but it will not be the last such threat. Here, we argue that the world needs to be much better prepared to rapidly detect, define and defeat future pandemics. We propose that a Global Immunological Observatory and associated developments in systems immunology, therapeutics and vaccine design should be at the heart of this enterprise.

Assessment of CD52 expression in "double-hit" and "double-expressor" lymphomas: Implications for clinical trial eligibility.

"Double-hit" and "double-expressor" lymphomas represent distinct but overlapping subsets of aggressive B-cell non-Hodgkin lymphoma. The high rates of bone marrow involvement by these lymphomas pose a major therapeutic challenge due to the chemotherapy-resistant nature of the bone marrow microenvironment and the limited utility of rituximab-based salvage regimens in patients with relapsed/refractory disease. Preclinical studies utilizing high-dose cyclophosphamide in combination with the anti-CD52 monoclonal antibody alemtuzumab have recently shown promise in the treatment of intramedullary disease, and a Phase I human trial is now underway. In support of such efforts, here we perform CD52 target validation on a series of double-hit (n = 40) and double-expressor (n = 58) lymphomas using immunohistochemistry. CD52 expression levels varied considerably across samples, however positive staining was observed in 75% of both double-hit and double-expressor lymphomas. Similarly, high levels of CD52 expression were seen in patients whose disease was associated with high-risk clinical features, including primary refractory status (73%), higher IPI score (76%), and bone marrow involvement (74%). CD52 expression was not significantly correlated with diagnostically relevant pathologic features such as morphology, cytogenetic findings or other immunophenotypic features, but was notably present in all cases lacking CD20 expression (n = 6). We propose that CD52 expression status be evaluated on a case-by-case basis to guide eligibility for clinical trial enrollment.

Reassessing the cardiac box: A comprehensive evaluation of the relationship between thoracic gunshot wounds and cardiac injury.

BACKGROUND: High-energy missiles can cause cardiac injury regardless of entrance site. This study assesses the adequacy of the anatomic borders of the current "cardiac box" to predict cardiac injury. METHODS: Retrospective autopsy review was performed to identify patients with penetrating torso gunshot wounds (GSWs) 2011 to 2013. Using a circumferential grid system around the thorax, logistic regression analysis was performed to detect differences in rates of cardiac injury from entrance/exit wounds in the "cardiac box" versus the same for entrance/exit wounds outside the box. Analysis was repeated to identify regions to compare risk of cardiac injury between the current cardiac box and other regions of the thorax. RESULTS: Over the study period, 263 patients (89% men; mean age, 34 years; median injuries/person, 2) sustained 735 wounds (80% GSWs), and 239 patients with 620 GSWs were identified for study. Of these, 95 (34%) injured the heart. Of the 257 GSWs entering the cardiac box, 31% caused cardiac injury, whereas 21% GSWs outside the cardiac box (n = 67) penetrated the heart, suggesting that the current "cardiac box" is a poor predictor of cardiac injury relative to the thoracic non-"cardiac box" regions (relative risk [RR], 0.96; p = 0.82). The regions from the anterior to posterior midline of the left thorax provided the highest positive predictive value (41%) with high sensitivity (90%) while minimizing false-positives, making this region the most statistically significant discriminator of cardiac injury (RR, 2.9; p = 0.01). CONCLUSION: For GSWs, the current cardiac box is inadequate to discriminate whether a GSW will cause a cardiac injury. As expected, entrance wounds nearest to the heart are the most likely to result in cardiac injury, but, from a clinical standpoint, it is best to think outside the "box" for GSWs to the thorax. LEVEL OF EVIDENCE: Therapeutic/care management, level IV.

Factors affecting mortality after penetrating cardiac injuries: 10-year experience at urban level I trauma center.

BACKGROUND: Despite the lethality of injuries to the heart, optimizing factors that impact mortality for victims that do survive to reach the hospital is critical. METHODS: From 2003 to 2012, prehospital data, injury characteristics, and clinical patient factors were analyzed for victims with penetrating cardiac injuries (PCIs) at an urban, level I trauma center. RESULTS: Over the 10-year study, 80 PCI patients survived to reach the hospital. Of the 21 factors analyzed, prehospital cardiopulmonary resuscitation (odds ratio [OR] = 30), scene time greater than 10 minutes (OR = 58), resuscitative thoracotomy (OR = 19), and massive left hemothorax (OR = 15) had the greatest impact on mortality. Cardiac tamponade physiology demonstrated a "protective" effect for survivors to the hospital (OR = .08). CONCLUSIONS: Trauma surgeons can improve mortality after PCI by minimizing time to the operating room for early control of hemorrhage. In PCI patients, tamponade may provide a physiologic advantage (lower mortality) compared to exsanguination.

Penetrating cardiac injuries: A 36-year perspective at an urban, Level I trauma center.

BACKGROUND: This study evaluates patterns of injuries and outcomes from penetrating cardiac injuries (PCIs) at Grady Memorial Hospital, an urban, Level I trauma center in Atlanta, Georgia, over 36 years. METHODS: Patients sustaining PCIs were identified from the Trauma Registry of the American College of Surgeons and the Emory Department of Surgery database; data of patients who died prior to any therapy were excluded. Demographics and outcomes were compared over three time intervals: Period 1 (1975-1985; n = 113), Period 2 (1986-1996; n = 79), and Period 3 (2000-2010; n = 79). RESULTS: Two hundred seventy-one patients (86% were male; mean age, 33 years; initial base deficit = -11.3 mEq/L) sustained cardiac stab (SW, 60%) or gunshot wounds (GSW, 40%). Emergency department thoracotomy was performed in 67 (25%) of 271 patients. Overall mortality increased in the modern era (Period 1, 27%, vs. Period 2, 22%, vs. Period 3, 42%; p = 0.03) along with GSW mechanisms (Period 1, 32%, vs. Period 2, 33%, vs. Period 3, 57%; p = 0.001), GSW mortality (Period 1, 36%, vs. Period 2, 42%, vs. Period 3, 56%; p = 0.04), and multichamber injuries (Period 1, 12%, vs. Period 2, 10%, vs. Period 3, 34%; p< 0.001). In Period 3, GSWs (n = 45) resulted in multichamber injuries in 28 patients (62%) and multicavity injuries in 19 patients (42%). Surgeon-performed ultrasound accurately identified pericardial blood in 55 of 55 patients in Period 3. CONCLUSIONS: Increased frequency of GSWs in the past decade is associated with increased overall mortality, multichamber injuries, and multicavity injuries. Ultrasound is sensitive for detection of PCI. LEVEL OF EVIDENCE: Therapeutic study, level IV; epidemioligc study, level III.

JAM-A associates with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and regulate epithelial barrier function.

Intestinal barrier function is regulated by epithelial tight junctions (TJs), structures that control paracellular permeability. Junctional adhesion molecule-A (JAM-A) is a TJ-associated protein that regulates barrier; however, mechanisms linking JAM-A to epithelial permeability are poorly understood. Here we report that JAM-A associates directly with ZO-2 and indirectly with afadin, and this complex, along with PDZ-GEF1, activates the small GTPase Rap2c. Supporting a functional link, small interfering RNA-mediated down-regulation of the foregoing regulatory proteins results in enhanced permeability similar to that observed after JAM-A loss. JAM-A-deficient mice and cultured epithelial cells demonstrate enhanced paracellular permeability to large molecules, revealing a potential role of JAM-A in controlling perijunctional actin cytoskeleton in addition to its previously reported role in regulating claudin proteins and small-molecule permeability. Further experiments suggest that JAM-A does not regulate actin turnover but modulates activity of RhoA and phosphorylation of nonmuscle myosin, both implicated in actomyosin contraction. These results suggest that JAM-A regulates epithelial permeability via association with ZO-2, afadin, and PDZ-GEF1 to activate Rap2c and control contraction of the apical cytoskeleton.

Base deficit as a marker of survival after traumatic injury: consistent across changing patient populations and resuscitation paradigms.

BACKGROUND: Damage control resuscitation (DCR) has improved outcomes in severely injured patients. In civilian centers, massive transfusion protocols (MTPs) represent the most formal application of DCR principles, ensuring early, accurate delivery of high fixed ratios of blood components. Recent data suggest that DCR may also help address early trauma-induced coagulopathy. Finally, base deficit (BD) is a long-recognized and simple early prognostic marker of survival after injury. METHODS: Outcomes of patients with admission BD data resuscitated during the DCR era (2007-2010) were compared with previously published data (1995-2003) of patients cared for before the DCR era (pre-DCR). Patients were considered to have no hypoperfusion (BD, >-6), mild (BD, -6 to -14.9), moderate (BD, -15 to -23.9), or severe hypoperfusion (BD, <-24). RESULTS: Of 6,767 patients, 4,561 were treated in the pre-DCR era and 2,206 in the DCR era. Of the latter, 218 (9.8%) represented activations of the MTP. DCR patients tended to be slightly older, more likely victims of penetrating trauma, and slightly more severely injured as measured by trauma scores and BD. Despite these differences, overall survival was unchanged in the two eras (86.4% vs. 85.7%, p = 0.67), and survival curves stratified by mechanism of injury were nearly identical. Patients with severe BD who were resuscitated using the MTP, however, experienced a substantial increase in survival compared with pre-DCR counterparts. CONCLUSION: Despite limited adoption of formal DCR, overall survival after injury, stratified by BD, is identical in the modern era. Patients with severely deranged physiology, however, experience better outcomes. BD remains a consistent predictor of mortality after traumatic injury. Predicted survival depends more on the energy level of the injury (stab wound vs. nonstab wound) than the mechanism of injury (blunt vs. penetrating).